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Call for emergency action to limit global temperature increases, restore biodiversity and protect health: Wealthy nations must do much more, much faster†
Lukoye Atwoli, Abdullah H Baqui, Thomas Benfield, Raffaella Bosurgi, Fiona Godlee, Stephen Hancocks, Richard Horton, Laurie Laybourn-Langton, Carlos Augusto Monteiro, Ian Norman, Kirsten Patrick, Nigel Praities, Marcel G M Olde Rikkert, Eric J Rubin, Peush Sahni, Richard Smith, Nick Talley, Sue Turale, Damián Vázquez
doi : 10.1093/brain/awab296
Brain, Volume 144, Issue 10, October 2021, Pages 2897–2899
From a different angle: 50 years of cerebral computed tomography
Bart Lutters, Peter J Koehler
doi : 10.1093/brain/awab221
Brain, Volume 144, Issue 10, October 2021, Pages 2900–2903
An unexpected iron in the fire of speech production
Martin Sommer, Shahriar SheikhBahaei, Gerald A Maguire
doi : 10.1093/brain/awab348
Brain, Volume 144, Issue 10, October 2021, Pages 2904–2905
Cellular correlates of epileptic spikes with high-frequency oscillations in the human temporal lobe
Gilles Huberfeld, Michel Le Van Quyen
doi : 10.1093/brain/awab349
Brain, Volume 144, Issue 10, October 2021, Pages 2906–2908
The yin and yang of intracellular reactive oxygen species following T-cell activation
Hani S Mousa, Joanne L Jones
doi : 10.1093/brain/awab361
Brain, Volume 144, Issue 10, October 2021, Pages 2909–2911
Distal symmetric polyneuropathy in diabetes: a progressive disorder?
Troels S Jensen, Nanna B Finnerup
doi : 10.1093/brain/awab355
Brain, Volume 144, Issue 10, October 2021, Pages 2912–2914
Karyopherin abnormalities in neurodegenerative proteinopathies
Terouz Pasha, Anna Zatorska, Daulet Sharipov, Boris Rogelj, Tibor Hortobágyi, Frank Hirth
doi : 10.1093/brain/awab201
Brain, Volume 144, Issue 10, October 2021, Pages 2915–2932
Neurodegenerative proteinopathies are characterized by progressive cell loss that is preceded by the mislocalization and aberrant accumulation of proteins prone to aggregation. Despite their different physiological functions, disease-related proteins like tau, ?-synuclein, TAR DNA binding protein-43, fused in sarcoma and mutant huntingtin, all share low complexity regions that can mediate their liquid-liquid phase transitions. The proteins’ phase transitions can range from native monomers to soluble oligomers, liquid droplets and further to irreversible, often-mislocalized aggregates that characterize the stages and severity of neurodegenerative diseases.
Macrophage phagocytosis after spinal cord injury: when friends become foes
Jana Van Broeckhoven, Daniela Sommer, Dearbhaile Dooley, Sven Hendrix, Aimée J P M Franssen
doi : 10.1093/brain/awab250
Brain, Volume 144, Issue 10, October 2021, Pages 2933–2945
After spinal cord injury, macrophages can exert either beneficial or detrimental effects depending on their phenotype. Aside from their critical role in inflammatory responses, macrophages are also specialized in the recognition, engulfment, and degradation of pathogens, apoptotic cells, and tissue debris. They promote remyelination and axonal regeneration by removing inhibitory myelin components and cellular debris. However, excessive intracellular presence of lipids and dysregulated intracellular lipid homeostasis result in the formation of foamy macrophages. These develop a pro-inflammatory phenotype that may contribute to further neurological decline. Additionally, myelin-activated macrophages play a crucial role in axonal dieback and retraction.
Beyond the average patient: how neuroimaging models can address heterogeneity in dementia
Serena Verdi, Andre F Marquand, Jonathan M Schott, James H Cole
doi : 10.1093/brain/awab165
Brain, Volume 144, Issue 10, October 2021, Pages 2946–2953
Dementia is a highly heterogeneous condition, with pronounced individual differences in age of onset, clinical presentation, progression rates and neuropathological hallmarks, even within a specific diagnostic group. However, the most common statistical designs used in dementia research studies and clinical trials overlook this heterogeneity, instead relying on comparisons of group average differences (e.g. patient versus control or treatment versus placebo), implicitly assuming within-group homogeneity. This one-size-fits-all approach potentially limits our understanding of dementia aetiology, hindering the identification of effective treatments. Neuroimaging has enabled the characterization of the average neuroanatomical substrates of dementias; however, the increasing availability of large open neuroimaging datasets provides the opportunity to examine patterns of neuroanatomical variability in individual patients. In this update, we outline the causes and consequences of heterogeneity in dementia and discuss recent research that aims to tackle heterogeneity directly, rather than assuming that dementia affects everyone in the same way. We introduce spatial normative modelling as an emerging data-driven technique, which can be applied to dementia data to model neuroanatomical variation, capturing individualized neurobiological ‘fingerprints’. Such methods have the potential to detect clinically relevant subtypes, track an individual’s disease progression or evaluate treatment responses, with the goal of moving towards precision medicine for dementia.
The potential of serum neurofilament as biomarker for multiple sclerosis
Stefan Bittner, Jiwon Oh, Eva Kubala Havrdová, Mar Tintoré, Frauke Zipp
doi : 10.1093/brain/awab241
Brain, Volume 144, Issue 10, October 2021, Pages 2954–2963
Multiple sclerosis is a highly heterogeneous disease, and the detection of neuroaxonal damage as well as its quantification is a critical step for patients. Blood-based serum neurofilament light chain (sNfL) is currently under close investigation as an easily accessible biomarker of prognosis and treatment response in patients with multiple sclerosis. There is abundant evidence that sNfL levels reflect ongoing inflammatory-driven neuroaxonal damage (e.g. relapses or MRI disease activity) and that sNfL levels predict disease activity over the next few years. In contrast, the association of sNfL with long-term clinical outcomes or its ability to reflect slow, diffuse neurodegenerative damage in multiple sclerosis is less clear. However, early results from real-world cohorts and clinical trials using sNfL as a marker of treatment response in multiple sclerosis are encouraging. Importantly, clinical algorithms should now be developed that incorporate the routine use of sNfL to guide individualized clinical decision-making in people with multiple sclerosis, together with additional fluid biomarkers and clinical and MRI measures. Here, we propose specific clinical scenarios where implementing sNfL measures may be of utility, including, among others: initial diagnosis, first treatment choice, surveillance of subclinical disease activity and guidance of therapy selection.
Plasma amyloid-? ratios in autosomal dominant Alzheimer’s disease: the influence of genotype
Antoinette O'Connor, Josef Pannee, Teresa Poole, Charles Arber, Erik Portelius, Imogen J Swift, Amanda J Heslegrave, Emily Abel, Nanet Willumsen, Helen Rice, Philip S J Weston, Natalie S Ryan, James M Polke, Jennifer M Nicholas, Simon Mead, Selina Wray, Lucía Chávez-Gutiérrez, Chris Frost, Kaj Blennow, Henrik Zetterberg, Nick C Fox
doi : 10.1093/brain/awab166
Brain, Volume 144, Issue 10, October 2021, Pages 2964–2970
In vitro studies of autosomal dominant Alzheimer’s disease implicate longer amyloid-? peptides in disease pathogenesis; however, less is known about the behaviour of these mutations in vivo. In this cross-sectional cohort study, we used liquid chromatography-tandem mass spectrometry to analyse 66 plasma samples from individuals who were at risk of inheriting a mutation or were symptomatic. We tested for differences in amyloid-? (A?)42:38, A?42:40 and A?38:40 ratios between presenilin 1 (PSEN1) and amyloid precursor protein (APP) carriers. We examined the relationship between plasma and in vitro models of amyloid-? processing and tested for associations with parental age at onset. Thirty-nine participants were mutation carriers (28 PSEN1 and 11 APP). Age- and sex-adjusted models showed marked differences in plasma amyloid-? between genotypes: higher A?42:38 in PSEN1 versus APP (P?<?0.001) and non-carriers (P?<?0.001); higher A?38:40 in APP versus PSEN1 (P?<?0.001) and non-carriers (P?<?0.001); while A?42:40 was higher in both mutation groups compared to non-carriers (both P?<?0.001). Amyloid-? profiles were reasonably consistent in plasma and cell lines. Within the PSEN1 group, models demonstrated associations between A?42:38, A?42:40 and A?38:40 ratios and parental age at onset. In vivo differences in amyloid-? processing between PSEN1 and APP carriers provide insights into disease pathophysiology, which can inform therapy development.
PTEN somatic mutations contribute to spectrum of cerebral overgrowth
Daniel C Koboldt, Katherine E Miller, Anthony R Miller, Jocelyn M Bush, Sean McGrath, Kristen Leraas, Erin Crist, Summer Fair, Wesley Schwind, Saranga Wijeratne, James Fitch, Jeffrey Leonard, Ammar Shaikhouni, Mark E Hester, Vincent Magrini, Mai-Lan Ho, Christopher R Pierson, Richard K Wilson, Adam P Ostendorf, Elaine R Mardis, Tracy A Bedrosian
doi : 10.1093/brain/awab173
Brain, Volume 144, Issue 10, October 2021, Pages 2971–2978
Phosphatase and tensin homologue (PTEN) regulates cell growth and survival through inhibition of the mammalian target of rapamycin (MTOR) signalling pathway. Germline genetic variation of PTEN is associated with autism, macrocephaly and PTEN hamartoma tumour syndromes. The effect of developmental PTEN somatic mutations on nervous system phenotypes is not well understood, although brain somatic mosaicism of MTOR pathway genes is an emerging cause of cortical dysplasia and epilepsy in the paediatric population.
Elevated iron concentration in putamen and cortical speech motor network in developmental stuttering
Gabriel J Cler, Saloni Krishnan, Daniel Papp, Charlotte E E Wiltshire, Jennifer Chesters, Kate E Watkins
doi : 10.1093/brain/awab283
Brain, Volume 144, Issue 10, October 2021, Pages 2979–2984
Theoretical accounts of developmental stuttering implicate dysfunctional cortico-striatal-thalamo-cortical motor loops through the putamen. However, the analysis of conventional MRI brain scans in individuals who stutter has failed to yield strong support for this theory in terms of reliable differences in the structure or function of the basal ganglia.
Gys1 antisense therapy rescues neuropathological bases of murine Lafora disease
Saija Ahonen, Silvia Nitschke, Tamar R Grossman, Holly Kordasiewicz, Peixiang Wang, Xiaochu Zhao, Dikran R Guisso, Sahba Kasiri, Felix Nitschke, Berge A Minassian
doi : 10.1093/brain/awab194
Brain, Volume 144, Issue 10, October 2021, Pages 2985–2993
Lafora disease is a fatal progressive myoclonus epilepsy. At root, it is due to constant acquisition of branches that are too long in a subgroup of glycogen molecules, leading them to precipitate and accumulate into Lafora bodies, which drive a neuroinflammatory response and neurodegeneration. As a potential therapy, we aimed to downregulate glycogen synthase, the enzyme responsible for glycogen branch elongation, in mouse models of the disease. We synthesized an antisense oligonucleotide (Gys1-ASO) that targets the mRNA of the brain-expressed glycogen synthase 1 gene (Gys1). We administered Gys1-ASO by intracerebroventricular injection and analysed the pathological hallmarks of Lafora disease, namely glycogen accumulation, Lafora body formation, and neuroinflammation. Gys1-ASO prevented Lafora body formation in young mice that had not yet formed them. In older mice that already exhibited Lafora bodies, Gys1-ASO inhibited further accumulation, markedly preventing large Lafora bodies characteristic of advanced disease. Inhibition of Lafora body formation was associated with prevention of astrogliosis and strong trends towards correction of dysregulated expression of disease immune and neuroinflammatory markers. Lafora disease manifests gradually in previously healthy teenagers. Our work provides proof of principle that an antisense oligonucleotide targeting the GYS1 mRNA could prevent, and halt progression of, this catastrophic epilepsy.
Motor cortex stimulation for chronic neuropathic pain: results of a double-blind randomized study
Clement Hamani, Erich T Fonoff, Daniella C Parravano, Valquiria A Silva, Ricardo Galhardoni, Bernardo A Monaco, Jessie Navarro, Lin T Yeng, Manoel J Teixeira, Daniel Ciampi de Andrade
doi : 10.1093/brain/awab189
Brain, Volume 144, Issue 10, October 2021, Pages 2994–3004
Motor cortex stimulation via surgically implanted electrodes has been used as an off-label treatment for chronic neuropathic pain, but its efficacy has not been fully established. We aimed to objectively study the efficacy of motor cortex stimulation and characterize potential predictors of response.
Engineered microRNA-based regulatory element permits safe high-dose miniMECP2 gene therapy in Rett mice
Sarah E Sinnett, Emily Boyle, Christopher Lyons, Steven J Gray
doi : 10.1093/brain/awab182
Brain, Volume 144, Issue 10, October 2021, Pages 3005–3019
MECP2 gene transfer has been shown to extend the survival of Mecp2?/y knockout mice modelling Rett syndrome, an X-linked neurodevelopmental disorder. However, controlling deleterious overexpression of MECP2 remains the critical unmet obstacle towards a safe and effective gene therapy approach for Rett syndrome. A recently developed truncated miniMECP2 gene has also been shown to be therapeutic after AAV9-mediated gene transfer in knockout neonates.
Biallelic mutations in RNF220 cause laminopathies featuring leukodystrophy, ataxia and deafness
Leukodystrophies are a heterogeneous group of rare inherited disorders that mostly involve the white matter of the CNS. These conditions are characterized by primary glial cell and myelin sheath pathology of variable aetiology, which causes secondary axonal degeneration, generally emerging with disease progression.
doi : 10.1093/brain/awab185
Brain, Volume 144, Issue 10, October 2021, Pages 3020–3035
Leukodystrophies are a heterogeneous group of rare inherited disorders that mostly involve the white matter of the CNS. These conditions are characterized by primary glial cell and myelin sheath pathology of variable aetiology, which causes secondary axonal degeneration, generally emerging with disease progression.
Biallelic variants in VPS50 cause a neurodevelopmental disorder with neonatal cholestasis
Pauline E Schneeberger, Sheela Nampoothiri, Tess Holling, Dhanya Yesodharan, Malik Alawi, A S Knisely, Thomas Müller, Barbara Plecko, Andreas R Janecke, Kerstin Kutsche
doi : 10.1093/brain/awab206
Brain, Volume 144, Issue 10, October 2021, Pages 3036–3049
Golgi-associated retrograde protein (GARP) and endosome-associated recycling protein (EARP) complexes are membrane-tethering heterotetramers located at the trans-Golgi network and recycling endosomes, respectively. GARP and EARP share the three subunits VPS51, VPS52 and VPS53, while VPS50 is unique to EARP and VPS54 to GARP. Retrograde transport of endosomal cargos to the trans-Golgi network is mediated by GARP and endocytic recycling by EARP.
UNC13B variants associated with partial epilepsy with favourable outcome
Jie Wang, Jing-Da Qiao, Xiao-Rong Liu, De-Tian Liu, Yan-Hui Chen, Yi Wu, Yan Sun, Jing Yu, Rong-Na Ren, Zhen Mei, Yu-Xi Liu, Yi-Wu Shi, Mi Jiang, Si-Mei Lin, Na He, Bin Li, Wen-Jun Bian, Bing-Mei Li, Yong-Hong Yi, Tao Su, Han-Kui Liu, Wei-Yue Gu, Wei-Ping Liao for the China Epilepsy Gene 1.0 Project
doi : 10.1093/brain/awab164
Brain, Volume 144, Issue 10, October 2021, Pages 3050–3060
The unc-13 homolog B (UNC13B) gene encodes a presynaptic protein, mammalian uncoordinated 13-2 (Munc13-2), which is highly expressed in the brain—predominantly in the cerebral cortex—and plays an essential role in synaptic vesicle priming and fusion, potentially affecting neuronal excitability. However, the functional significance of the UNC13B mutation in human disease is not known.
Neuronal deletion of Wwox, associated with WOREE syndrome, causes epilepsy and myelin defects
Srinivasarao Repudi, Daniel J Steinberg, Nimrod Elazar, Vanessa L Breton, Mark S Aquilino, Afifa Saleem, Sara Abu-Swai, Anna Vainshtein, Yael Eshed-Eisenbach, Bharath Vijayaragavan, Oded Behar, Jacob J Hanna, Elior Peles, Peter L Carlen, Rami I Aqeilan
doi : 10.1093/brain/awab174
Brain, Volume 144, Issue 10, October 2021, Pages 3061–3077
WWOX-related epileptic encephalopathy (WOREE) syndrome caused by human germline bi-allelic mutations in WWOX is a neurodevelopmental disorder characterized by intractable epilepsy, severe developmental delay, ataxia and premature death at the age of 2–4?years. The underlying mechanisms of WWOX actions are poorly understood.
Interictal spikes with and without high-frequency oscillation have different single-neuron correlates
Tim A Guth, Lukas Kunz, Armin Brandt, Matthias Dümpelmann, Kerstin A Klotz, Peter C Reinacher, Andreas Schulze-Bonhage, Julia Jacobs, Jan Schönberger
doi : 10.1093/brain/awab288
Brain, Volume 144, Issue 10, October 2021, Pages 3078–3088
Interictal epileptiform discharges (IEDs) are a widely used biomarker in patients with epilepsy but lack specificity. It has been proposed that there are truly epileptogenic and less pathological or even protective IEDs. Recent studies suggest that highly pathological IEDs are characterized by high-frequency oscillations (HFOs). Here, we aimed to dissect these ‘HFO-IEDs’ at the single-neuron level, hypothesizing that the underlying mechanisms are distinct from ‘non-HFO-IEDs’. Analysing hybrid depth electrode recordings from patients with temporal lobe epilepsy, we found that single-unit firing rates were higher in HFO- than in non-HFO-IEDs. HFO-IEDs were characterized by a pronounced pre-peak increase in firing, which coincided with the preferential occurrence of HFOs, whereas in non-HFO-IEDs, there was only a mild pre-peak increase followed by a post-peak suppression. Comparing each unit’s firing during HFO-IEDs to its baseline activity, we found many neurons with a significant increase during the HFO component or ascending part, but almost none with a decrease. No such imbalance was observed during non-HFO-IEDs. Finally, comparing each unit’s firing directly between HFO- and non-HFO-IEDs, we found that most cells had higher rates during HFO-IEDs and, moreover, identified a distinct subset of neurons with a significant preference for this IED subtype. In summary, our study reveals that HFO- and non-HFO-IEDs have different single-unit correlates. In HFO-IEDs, many neurons are moderately activated, and some participate selectively, suggesting that both types of increased firing contribute to highly pathological IEDs.
Lesion location and lesion creation affect outcomes after focused ultrasound thalamotomy
David J Segar, Asad M Lak, Shane Lee, Maya Harary, Vamsidhar Chavakula, Peter Lauro, Nathan McDannold, Jason White, G Rees Cosgrove
doi : 10.1093/brain/awab176
Brain, Volume 144, Issue 10, October 2021, Pages 3089–3100
MRI-guided focused ultrasound thalamotomy has been shown to be an effective treatment for medication refractory essential tremor. Here, we report a clinical-radiological analysis of 123 cases of MRI-guided focused ultrasound thalamotomy, and explore the relationships between treatment parameters, lesion characteristics and outcomes.
Huntingtin silencing delays onset and slows progression of Huntington’s disease: a biomarker study
Hongshuai Liu, Chuangchuang Zhang, Jiadi Xu, Jing Jin, Liam Cheng, Xinyuan Miao, Qian Wu, Zhiliang Wei, Peiying Liu, Hanzhang Lu, Peter C M van Zijl, Christopher A Ross, Jun Hua, Wenzhen Duan
doi : 10.1093/brain/awab190
Brain, Volume 144, Issue 10, October 2021, Pages 3101–3113
Huntington’s disease is a dominantly inherited, fatal neurodegenerative disorder caused by a CAG expansion in the huntingtin (HTT) gene, coding for pathological mutant HTT protein (mHTT). Because of its gain-of-function mechanism and monogenic aetiology, strategies to lower HTT are being actively investigated as disease-modifying therapies. Most approaches are currently targeted at the manifest stage, where clinical outcomes are used to evaluate the effectiveness of therapy. However, as almost 50% of striatal volume has been lost at the time of onset of clinical manifest, it would be preferable to begin therapy in the premanifest period.
The spatiotemporal changes in dopamine, neuromelanin and iron characterizing Parkinson’s disease
Emma Biondetti, Mathieu D Santin, Romain Valabrègue, Graziella Mangone, Rahul Gaurav, Nadya Pyatigorskaya, Matthew Hutchison, Lydia Yahia-Cherif, Nicolas Villain, Marie-Odile Habert, Isabelle Arnulf, Smaranda Leu-Semenescu, Pauline Dodet, Miquel Vila, Jean-Christophe Corvol, Marie Vidailhet, Stéphane Lehéricy
doi : 10.1093/brain/awab191
Brain, Volume 144, Issue 10, October 2021, Pages 3114–3125
In Parkinson’s disease, there is a progressive reduction in striatal dopaminergic function, and loss of neuromelanin-containing dopaminergic neurons and increased iron deposition in the substantia nigra. We tested the hypothesis of a relationship between impairment of the dopaminergic system and changes in the iron metabolism. Based on imaging data of patients with prodromal and early clinical Parkinson’s disease, we assessed the spatiotemporal ordering of such changes and relationships in the sensorimotor, associative and limbic territories of the nigrostriatal system.
Dimethyl fumarate treatment restrains the antioxidative capacity of T cells to control autoimmunity
Marie Liebmann, Lisanne Korn, Claudia Janoschka, Stefanie Albrecht, Sarah Lauks, Alexander M Herrmann, Andreas Schulte-Mecklenbeck, Nicholas Schwab, Tilman Schneider-Hohendorf, Maria Eveslage, Brigitte Wildemann, Felix Luessi, Stephan Schmidt, Martin Diebold, Stefan Bittner, Catharina C Gross, Stjepana Kovac, Frauke Zipp, Tobias Derfuss, Tanja Kuhlmann, Simone König, Sven G Meuth, Heinz Wiendl, Luisa Klotz
doi : 10.1093/brain/awab307
Brain, Volume 144, Issue 10, October 2021, Pages 3126–3141
Dimethyl fumarate, an approved treatment for relapsing-remitting multiple sclerosis, exerts pleiotropic effects on immune cells as well as CNS resident cells.
Human platelet lysate biotherapy for traumatic brain injury: preclinical assessment
Ouada Nebie, Kevin Carvalho, Lassina Barro, Liling Delila, Emilie Faivre, Ting-Yi Renn, Ming-Li Chou, Yu-Wen Wu, Ariunjargal Nyam-Erdene, Szu-Yi Chou, Luc Buée, Chaur-Jong Hu, Chih-Wei Peng, David Devos, David Blum, Thierry Burnouf
doi : 10.1093/brain/awab205
Brain, Volume 144, Issue 10, October 2021, Pages 3142–3158
Traumatic brain injury (TBI) leads to major brain anatomopathological damages underlined by neuroinflammation, oxidative stress and progressive neurodegeneration, ultimately leading to motor and cognitive deterioration. The multiple pathological events resulting from TBI can be addressed not by a single therapeutic approach, but rather by a synergistic biotherapy capable of activating a complementary set of signalling pathways and providing synergistic neuroprotective, anti-inflammatory, antioxidative, and neurorestorative activities. Human platelet lysate might fulfil these requirements as it is composed of a plethora of biomolecules readily accessible as a TBI biotherapy.
Predicting neurological recovery after traumatic spinal cord injury by time-resolved analysis of monocyte subsets
Raban Arved Heller, Julian Seelig, Helena Lucia Crowell, Maximilian Pilz, Patrick Haubruck, Qian Sun, Lutz Schomburg, Volker Daniel, Arash Moghaddam, Bahram Biglari
doi : 10.1093/brain/awab203
Brain, Volume 144, Issue 10, October 2021, Pages 3159–3174
Monocytes and lymphocytes elicit crucial activities for the regenerative processes after various types of injury. The survival of neurons exposed to mechanical and oxidative stress after traumatic spinal cord injury depends on a multitude of factors. In this study, we sought to evaluate a correlation between remission after traumatic spinal cord injury and the dynamics of monocyte subsets in respect to the lymphocytes’ responsive potential, cytokine expression, patterns of trace element concentration and clinical covariates.
SREBP2 gene therapy targeting striatal astrocytes ameliorates Huntington’s disease phenotypes
Giulia Birolini, Gianluca Verlengia, Francesca Talpo, Claudia Maniezzi, Lorena Zentilin, Mauro Giacca, Paola Conforti, Chiara Cordiglieri, Claudio Caccia, Valerio Leoni, Franco Taroni, Gerardo Biella, Michele Simonato, Elena Cattaneo, Marta Valenza
doi : 10.1093/brain/awab186
Brain, Volume 144, Issue 10, October 2021, Pages 3175–3190
Brain cholesterol is produced mainly by astrocytes and is important for neuronal function. Its biosynthesis is severely reduced in mouse models of Huntington’s disease. One possible mechanism is a diminished nuclear translocation of the transcription factor sterol regulatory element-binding protein 2 (SREBP2) and, consequently, reduced activation of SREBP2-controlled genes in the cholesterol biosynthesis pathway.
Effects of statins on dopamine loss and prognosis in Parkinson’s disease
Seong Ho Jeong, Hye Sun Lee, Seok Jong Chung, Han Soo Yoo, Jin Ho Jung, Kyoungwon Baik, Yang Hyun Lee, Young H Sohn, Phil Hyu Lee
doi : 10.1093/brain/awab292
Brain, Volume 144, Issue 10, October 2021, Pages 3191–3200
Statins are more widely used not only for the primary and secondary prevention of cardiovascular disease by blocking cholesterol biosynthesis but also for the potential neuroprotective agents during neurological disorders due to their pleiotropic effects. In this study, we investigate whether the previous use of statins affect baseline nigrostriatal dopamine loss at the time of diagnosis and longitudinal motor and cognitive outcomes in patients with Parkinson’s disease.
Sex modifies APOE ?4 dose effect on brain tau deposition in cognitively impaired individuals
Shaozhen Yan, Chaojie Zheng, Manish D Paranjpe, Yanxiao Li, Weihua Li, Xiuying Wang, Tammie L S Benzinger, Jie Lu, Yun Zhou for the Alzheimer's Disease Neuroimaging Initiative
doi : 10.1093/brain/awab160
Brain, Volume 144, Issue 10, October 2021, Pages 3201–3211
Recent studies in cognitively unimpaired elderly individuals suggest that the APOE ?4 allele exerts a dosage-dependent effect on brain tau deposition. The aim of this study was to investigate sex differences in APOE ?4 gene dosage effects on brain tau deposition in cognitively impaired individuals using quantitative 18F-flortaucipir PET.
Dementia with Lewy bodies: association of Alzheimer pathology with functional connectivity networks
Julia Schumacher, Jeffrey L Gunter, Scott A Przybelski, David T Jones, Jonathan Graff-Radford, Rodolfo Savica, Christopher G Schwarz, Matthew L Senjem, Clifford R Jack, Jr, Val J Lowe, David S Knopman, Julie A Fields, Walter K Kremers, Ronald C Petersen, Neill R Graff-Radford, Tanis J Ferman, Bradley F Boeve, Alan J Thomas, John-Paul Taylor, Kejal Kantarci
doi : 10.1093/brain/awab218
Brain, Volume 144, Issue 10, October 2021, Pages 3212–3225
Dementia with Lewy bodies (DLB) is neuropathologically defined by the presence of ?-synuclein aggregates, but many DLB cases show concurrent Alzheimer’s disease pathology in the form of amyloid-? plaques and tau neurofibrillary tangles.
Pharmacological SARM1 inhibition protects axon structure and function in paclitaxel-induced peripheral neuropathy
Todd Bosanac, Robert O Hughes, Thomas Engber, Rajesh Devraj, Andrew Brearley, Kerstin Danker, Kenneth Young, Jens Kopatz, Melanie Hermann, Antoine Berthemy, Susan Boyce, Jonathan Bentley, Raul Krauss
doi : 10.1093/brain/awab184
Brain, Volume 144, Issue 10, October 2021, Pages 3226–3238
Axonal degeneration is an early and ongoing event that causes disability and disease progression in many neurodegenerative disorders of the peripheral and central nervous systems. Chemotherapy-induced peripheral neuropathy (CIPN) is a major cause of morbidity and the main cause of dose reductions and discontinuations in cancer treatment. Preclinical evidence indicates that activation of the Wallerian-like degeneration pathway driven by sterile alpha and TIR motif containing 1 (SARM1) is responsible for axonopathy in CIPN. SARM1 is the central driver of an evolutionarily conserved programme of axonal degeneration downstream of chemical, inflammatory, mechanical or metabolic insults to the axon. SARM1 contains an intrinsic NADase enzymatic activity essential for its pro-degenerative functions, making it a compelling therapeutic target to treat neurodegeneration characterized by axonopathies of the peripheral and central nervous systems. Small molecule SARM1 inhibitors have the potential to prevent axonal degeneration in peripheral and central axonopathies and to provide a transformational disease-modifying treatment for these disorders.
Giant axonal neuropathy: cross-sectional analysis of a large natural history cohort
Diana X Bharucha-Goebel, Gina Norato, Dimah Saade, Eduardo Paredes, Victoria Biancavilla, Sandra Donkervoort, Rupleen Kaur, Tanya Lehky, Margaret Fink, Diane Armao, Steven J Gray, Melissa Waite, Sarah Debs, Gilberto Averion, Ying Hu, Wadih M Zein, A Reghan Foley, Minal Jain, Carsten G Bönnemann
doi : 10.1093/brain/awab179
Brain, Volume 144, Issue 10, October 2021, Pages 3239–3250
Giant axonal neuropathy (GAN) is an ultra-rare autosomal recessive, progressive neurodegenerative disease with early childhood onset that presents as a prominent sensorimotor neuropathy and commonly progresses to affect both the PNS and CNS. The disease is caused by biallelic mutations in the GAN gene located on 16q23.2, leading to loss of functional gigaxonin, a substrate specific ubiquitin ligase adapter protein necessary for the regulation of intermediate filament turnover.
Progression and regression of nerve fibre pathology and dysfunction early in diabetes over 5 years
Dan Ziegler, Gidon J Bönhof, Alexander Strom, Klaus Straßburger, Yanislava Karusheva, Julia Szendroedi, Michael Roden for the GDS group
doi : 10.1093/brain/awab330
Brain, Volume 144, Issue 10, October 2021, Pages 3251–3263
It has traditionally been suggested that the early development of diabetic sensorimotor polyneuropathy (DSPN) is characterized by predominant and progressive injury to small nerve fibres followed by large fibre impairment. We alternatively hypothesized that small and large fibre damage due to DSPN in type 1 and type 2 diabetes could develop in parallel and may not only be progressive but also reversible.
Pathological laughter and crying: insights from lesion network-symptom-mapping
Julian Klingbeil, Max Wawrzyniak, Anika Stockert, Max-Lennart Brandt, Hans-Ralf Schneider, Moritz Metelmann, Dorothee Saur
doi : 10.1093/brain/awab224
Brain, Volume 144, Issue 10, October 2021, Pages 3264–3276
The study of pathological laughter and crying (PLC) allows insights into the neural basis of laughter and crying, two hallmarks of human nature. PLC is defined by brief, intense and frequent episodes of uncontrollable laughter or crying provoked by trivial stimuli. It occurs secondary to CNS disorders such as stroke, tumours or neurodegenerative diseases. Based on case studies reporting various lesions locations, PLC has been conceptualized as dysfunction in a cortico-limbic-subcortico-thalamo-ponto-cerebellar network.
Expanding the mutational landscape and clinical phenotype of the YIF1B related brain disorder
Eva Medico Salsench, Reza Maroofian, Ruizhi Deng, Kristina Lanko, Anita Nikoncuk, Belén Pérez, Obdulia Sánchez-Lijarcio, Salvador Ibáñez-Mico, Antonina Wojcik, Marcelo Vargas, Nouriya Abbas Al-Sannaa, Marian Y Girgis, Tainá Regina Damaceno Silveira, Peter Bauer, Audrey Schroeder, Chin-To Fong, Amber Begtrup, Meisam Babaei, Mehran Beiraghi Toosi, Farah Ashrafzadeh, Shima Imannezhad, Mohammad Doosti, Najmeh Ahangari, Paria Najarzadeh Torbati, Ehsan Ghayoor Karimiani, David Murphy, Elisa Cali, Ibrahim H Kaya, Mohammad AlMuhaizea, Dilek Colak, Kelly J Cardona-Londoño, Stefan T Arold, Henry Houlden, Aida Bertoli-Avella, Namik Kaya, Tahsin Stefan Barakat
doi : 10.1093/brain/awab297
Brain, Volume 144, Issue 10, October 2021, Page e85
Erratum to: Cardiovascular brain impulses in Alzheimer’s disease
doi : 10.1093/brain/awab298
Brain, Volume 144, Issue 10, October 2021, Page e86
