Brain

Peripheral neuropathy is one of the most common complications of both type 1 and type 2 diabetes. Up to half of patients with diabetes develop neuropathy during the course of their disease, which is accompanied by neuropathic pain in 30–40% of cases. Peripheral nerve injury in diabetes can manifest as progressive distal symmetric polyneuropathy, autonomic neuropathy, radiculo-plexopathies, and mononeuropathies. The most common diabetic neuropathy is distal symmetric polyneuropathy, which we will refer to as DN, with its characteristic glove and stocking like presentation of distal sensory or motor function loss. DN or its painful counterpart, painful DN, are associated with increased mortality and morbidity; thus, early recognition and preventive measures are essential. Nevertheless, it is not easy to diagnose DN or painful DN, particularly in patients with early and mild neuropathy, and there is currently no single established diagnostic gold standard. The most common diagnostic approach in research is a hierarchical system, which combines symptoms, signs, and a series of confirmatory tests. The general lack of long-term prospective studies has limited the evaluation of the sensitivity and specificity of new morphometric and neurophysiological techniques. Thus, the best paradigm for screening DN and painful DN both in research and in clinical practice remains uncertain. Herein, we review the diagnostic challenges from both clinical and research perspectives and their implications for managing patients with DN. There is no established DN treatment, apart from improved glycaemic control, which is more effective in type 1 than in type 2 diabetes, and only symptomatic management is available for painful DN. Currently, less than one-third of patients with painful DN derive sufficient pain relief with existing pharmacotherapies. A more precise and distinct sensory profile from patients with DN and painful DN may help identify responsive patients to one treatment versus another. Detailed sensory profiles will lead to tailored treatment for patient subgroups with painful DN by matching to novel or established DN pathomechanisms and also for improved clinical trials stratification. Large randomized clinical trials are needed to identify the interventions, i.e. pharmacological, physical, cognitive, educational, etc., which lead to the best therapeutic outcomes.

خرید پکیج و مشاهده آنلاین مقاله

Surface-in pathology in multiple sclerosis: a new view on pathogenesis?

Matteo Pardini, J William L Brown, Roberta Magliozzi, Richard Reynolds, Declan T Chard

doi : 10.1093/brain/awab025

Brain, Volume 144, Issue 6, June 2021, Pages 1646–1654

While multiple sclerosis can affect any part of the CNS, it does not do so evenly. In white matter it has long been recognized that lesions tend to occur around the ventricles, and grey matter lesions mainly accrue in the outermost (subpial) cortex. In cortical grey matter, neuronal loss is greater in the outermost layers. This cortical gradient has been replicated in vivo with magnetization transfer ratio and similar gradients in grey and white matter magnetization transfer ratio are seen around the ventricles, with the most severe abnormalities abutting the ventricular surface. The cause of these gradients remains uncertain, though soluble factors released from meningeal inflammation into the CSF has the most supporting evidence. In this Update, we review this ‘surface-in’ spatial distribution of multiple sclerosis abnormalities and consider the implications for understanding pathogenic mechanisms and treatments designed to slow or stop them.

خرید پکیج و مشاهده آنلاین مقاله

Prolonged disorders of consciousness: a critical evaluation of the new UK guidelines

Neil Scolding, Adrian M Owen, John Keown

doi : 10.1093/brain/awab063

Brain, Volume 144, Issue 6, June 2021, Pages 1655–1660

In March 2020, the Royal College of Physicians in the UK published national guidelines on the management of patients with prolonged disorders of consciousness, updating their 2013 guidance ‘particularly in relation to recent developments in assessment and management and … changes in the law governing … the withdrawal of clinically assisted nutrition and hydration’. The report’s primary focus is on patients who could live for many years with treatment and care. This update, by a neurologist, an imaging neuroscientist, and a lawyer-ethicist, questions the document’s rejection of any significant role for neuroimaging techniques including functional MRI and/or bedside EEG to detect covert consciousness in such patients. We find the reasons for this rejection unconvincing, given (i) the significant advances made in the use of this technology in recent years; and (ii) the wider scope for its use envisaged by the earlier (2018) guidelines issued by the American Academy of Neurology. We suggest that, since around one in five patients diagnosed with prolonged disorders of consciousness are in fact conscious enough to follow commands in a neuroimaging context (i.e. those who are ‘covertly conscious’ or those with ‘cognitive motor dissociation’), and given the clinical, ethical and legal importance of determining whether patients with prolonged disorders of consciousness are legally competent or at least able to express their views and feelings, the guidance from the Royal College of Physicians requires urgent review.

خرید پکیج و مشاهده آنلاین مقاله

CSP? reduces aggregates and rescues striatal dopamine release in ?-synuclein transgenic mice

Laura Cal?, Eric Hidari, Michal Wegrzynowicz, Jeffrey W Dalley, Bernard L Schneider ...

doi : 10.1093/brain/awab076

Brain, Volume 144, Issue 6, June 2021, Pages 1661–1669

?-Synuclein aggregation at the synapse is an early event in Parkinson’s disease and is associated with impaired striatal synaptic function and dopaminergic neuronal death. The cysteine string protein (CSP?) and ?-synuclein have partially overlapping roles in maintaining synaptic function and mutations in each cause neurodegenerative diseases. CSP? is a member of the DNAJ/HSP40 family of co-chaperones and like ?-synuclein, chaperones the SNARE complex assembly and controls neurotransmitter release. ?-Synuclein can rescue neurodegeneration in CSP?KO mice. However, whether ?-synuclein aggregation alters CSP? expression and function is unknown. Here we show that ?-synuclein aggregation at the synapse is associated with a decrease in synaptic CSP? and a reduction in the complexes that CSP? forms with HSC70 and STGa. We further show that viral delivery of CSP? rescues in vitro the impaired vesicle recycling in PC12 cells with ?-synuclein aggregates and in vivo reduces synaptic ?-synuclein aggregates increasing monomeric ?-synuclein and restoring normal dopamine release in 1-120h?Syn mice. These novel findings reveal a mechanism by which ?-synuclein aggregation alters CSP? at the synapse, and show that CSP? rescues ?-synuclein aggregation-related phenotype in 1-120h?Syn mice similar to the effect of ?-synuclein in CSP?KO mice. These results implicate CSP? as a potential therapeutic target for the treatment of early-stage Parkinson’s disease.

خرید پکیج و مشاهده آنلاین مقاله

The hedgehog pathway suppresses neuropathogenesis in CD4 T cell-driven inflammation

Nail Benallegue, Hania Kebir, Richa Kapoor, Alexis Crockett, Cen Li ...

doi : 10.1093/brain/awab083

Brain, Volume 144, Issue 6, June 2021, Pages 1670–1683

The concerted actions of the CNS and the immune system are essential to coordinating the outcome of neuroinflammatory responses. Yet, the precise mechanisms involved in this crosstalk and their contribution to the pathophysiology of neuroinflammatory diseases largely elude us. Here, we show that the CNS-endogenous hedgehog pathway, a signal triggered as part of the host response during the inflammatory phase of multiple sclerosis and experimental autoimmune encephalomyelitis, attenuates the pathogenicity of human and mouse effector CD4 T cells by regulating their production of inflammatory cytokines. Using a murine genetic model, in which the hedgehog signalling is compromised in CD4 T cells, we show that the hedgehog pathway acts on CD4 T cells to suppress the pathogenic hallmarks of autoimmune neuroinflammation, including demyelination and axonal damage, and thus mitigates the development of experimental autoimmune encephalomyelitis. Impairment of hedgehog signalling in CD4 T cells exacerbates brain-brainstem-cerebellum inflammation and leads to the development of atypical disease. Moreover, we present evidence that hedgehog signalling regulates the pathogenic profile of CD4 T cells by limiting their production of the inflammatory cytokines granulocyte-macrophage colony-stimulating factor and interferon-? and by antagonizing their inflammatory program at the transcriptome level. Likewise, hedgehog signalling attenuates the inflammatory phenotype of human CD4 memory T cells. From a therapeutic point of view, our study underlines the potential of harnessing the hedgehog pathway to counteract ongoing excessive CNS inflammation, as systemic administration of a hedgehog agonist after disease onset effectively halts disease progression and significantly reduces neuroinflammation and the underlying neuropathology. We thus unveil a previously unrecognized role for the hedgehog pathway in regulating pathogenic inflammation within the CNS and propose to exploit its ability to modulate this neuroimmune network as a strategy to limit the progression of ongoing neuroinflammation.

خرید پکیج و مشاهده آنلاین مقاله

Myelin and axon pathology in multiple sclerosis assessed by myelin water and multi-shell diffusion imaging

Reza Rahmanzadeh, Po-Jui Lu, Muhamed Barakovic, Matthias Weigel, Pietro Maggi

doi : 10.1093/brain/awab088

Brain, Volume 144, Issue 6, June 2021, Pages 1684–1696

Damage to the myelin sheath and the neuroaxonal unit is a cardinal feature of multiple sclerosis; however, a detailed characterization of the interaction between myelin and axon damage in vivo remains challenging. We applied myelin water and multi-shell diffusion imaging to quantify the relative damage to myelin and axons (i) among different lesion types; (ii) in normal-appearing tissue; and (iii) across multiple sclerosis clinical subtypes and healthy controls. We also assessed the relation of focal myelin/axon damage with disability and serum neurofilament light chain as a global biological measure of neuroaxonal damage. Ninety-one multiple sclerosis patients (62 relapsing-remitting, 29 progressive) and 72 healthy controls were enrolled in the study. Differences in myelin water fraction and neurite density index were substantial when lesions were compared to healthy control subjects and normal-appearing multiple sclerosis tissue: both white matter and cortical lesions exhibited a decreased myelin water fraction and neurite density index compared with healthy (P?<?0.0001) and peri-plaque white matter (P?<?0.0001). Periventricular lesions showed decreased myelin water fraction and neurite density index compared with lesions in the juxtacortical region (P?<?0.0001 and P?<?0.05). Similarly, lesions with paramagnetic rims showed decreased myelin water fraction and neurite density index relative to lesions without a rim (P?<?0.0001). Also, in 75% of white matter lesions, the reduction in neurite density index was higher than the reduction in the myelin water fraction. Besides, normal-appearing white and grey matter revealed diffuse reduction of myelin water fraction and neurite density index in multiple sclerosis compared to healthy controls (P?<?0.01). Further, a more extensive reduction in myelin water fraction and neurite density index in normal-appearing cortex was observed in progressive versus relapsing-remitting participants. Neurite density index in white matter lesions correlated with disability in patients with clinical deficits (P?<?0.01, beta = ?10.00); and neurite density index and myelin water fraction in white matter lesions were associated to serum neurofilament light chain in the entire patient cohort (P?<?0.01, beta = ?3.60 and P?<?0.01, beta?=?0.13, respectively). These findings suggest that (i) myelin and axon pathology in multiple sclerosis is extensive in both lesions and normal-appearing tissue; (ii) particular types of lesions exhibit more damage to myelin and axons than others; (iii) progressive patients differ from relapsing-remitting patients because of more extensive axon/myelin damage in the cortex; and (iv) myelin and axon pathology in lesions is related to disability in patients with clinical deficits and global measures of neuroaxonal damage.

خرید پکیج و مشاهده آنلاین مقاله

Formation and immunomodulatory function of meningeal B cell aggregates in progressive CNS autoimmunity

Meike Mitsdoerffer, Giovanni Di Liberto, Sarah D?tsch, Christopher Sie, Ingrid Wagner

doi : 10.1093/brain/awab093

Brain, Volume 144, Issue 6, June 2021, Pages 1697–1710

Meningeal B lymphocyte aggregates have been described in autopsy material of patients with chronic multiple sclerosis. The presence of meningeal B cell aggregates has been correlated with worse disease. However, the functional role of these meningeal B cell aggregates is not understood. Here, we use a mouse model of multiple sclerosis, the spontaneous opticospinal encephalomyelitis model, which is built on the double transgenic expression of myelin oligodendrocyte glycoprotein-specific T-cell and B-cell receptors, to show that the formation of meningeal B cell aggregates is dependent on the expression of ?4 integrins by antigen-specific T cells. T cell-conditional genetic ablation of ?4 integrins in opticospinal encephalomyelitis mice impaired the formation of meningeal B cell aggregates, and surprisingly, led to a higher disease incidence as compared to opticospinal encephalomyelitis mice with ?4 integrin-sufficient T cells. B cell-conditional ablation of ?4 integrins in opticospinal encephalomyelitis mice resulted in the entire abrogation of the formation of meningeal B cell aggregates, and opticospinal encephalomyelitis mice with ?4 integrin-deficient B cells suffered from a higher disease burden than regular opticospinal encephalomyelitis mice. While anti-CD20 antibody-mediated systemic depletion of B cells in opticospinal encephalomyelitis mice after onset of disease failed to efficiently decrease meningeal B cell aggregates without significantly modulating disease progression, treatment with anti-CD19 chimeric antigen receptor-T cells eliminated meningeal B cell aggregates and exacerbated clinical disease in opticospinal encephalomyelitis mice. Since about 20% of B cells in organized meningeal B cell aggregates produced either IL-10 or IL-35, we propose that meningeal B cell aggregates might also have an immunoregulatory function as to the immunopathology in adjacent spinal cord white matter. The immunoregulatory function of meningeal B cell aggregates needs to be considered when designing highly efficient therapies directed against meningeal B cell aggregates for clinical application in multiple sclerosis.

خرید پکیج و مشاهده آنلاین مقاله

Silent cold-sensing neurons contribute to cold allodynia in neuropathic pain

Donald Iain MacDonald, Ana P Luiz, Federico Iseppon, Queensta Millet, Edward C Emery ...

doi : 10.1093/brain/awab086

Brain, Volume 144, Issue 6, June 2021, Pages 1711–1726

Patients with neuropathic pain often experience innocuous cooling as excruciating pain. The cell and molecular basis of this cold allodynia is little understood. We used in vivo calcium imaging of sensory ganglia to investigate how the activity of peripheral cold-sensing neurons was altered in three mouse models of neuropathic pain: oxaliplatin-induced neuropathy, partial sciatic nerve ligation, and ciguatera poisoning. In control mice, cold-sensing neurons were few in number and small in size. In neuropathic animals with cold allodynia, a set of normally silent large diameter neurons became sensitive to cooling. Many of these silent cold-sensing neurons responded to noxious mechanical stimuli and expressed the nociceptor markers Nav1.8 and CGRP?. Ablating neurons expressing Nav1.8 resulted in diminished cold allodynia. The silent cold-sensing neurons could also be activated by cooling in control mice through blockade of Kv1 voltage-gated potassium channels. Thus, silent cold-sensing neurons are unmasked in diverse neuropathic pain states and cold allodynia results from peripheral sensitization caused by altered nociceptor excitability.

خرید پکیج و مشاهده آنلاین مقاله

Paclitaxel increases axonal localization and vesicular trafficking of Nav1.7

Elizabeth J Akin, Matthew Alsaloum, Grant P Higerd, Shujun Liu, Peng Zhao

doi : 10.1093/brain/awab113

Brain, Volume 144, Issue 6, June 2021, Pages 1727–1737

The microtubule-stabilizing chemotherapy drug paclitaxel (PTX) causes dose-limiting chemotherapy-induced peripheral neuropathy (CIPN), which is often accompanied by pain. Among the multifaceted effects of PTX is an increased expression of sodium channel Nav1.7 in rat and human sensory neurons, enhancing their excitability. However, the mechanisms underlying this increased Nav1.7 expression have not been explored, and the effects of PTX treatment on the dynamics of trafficking and localization of Nav1.7 channels in sensory axons have not been possible to investigate to date. In this study we used a recently developed live imaging approach that allows visualization of Nav1.7 surface channels and long-distance axonal vesicular transport in sensory neurons to fill this basic knowledge gap. We demonstrate concentration and time-dependent effects of PTX on vesicular trafficking and membrane localization of Nav1.7 in real-time in sensory axons. Low concentrations of PTX increase surface channel expression and vesicular flux (number of vesicles per axon). By contrast, treatment with a higher concentration of PTX decreases vesicular flux. Interestingly, vesicular velocity is increased for both concentrations of PTX. Treatment with PTX increased levels of endogenous Nav1.7 mRNA and current density in dorsal root ganglion neurons. However, the current produced by transfection of dorsal root ganglion neurons with Halo-tag Nav1.7 was not increased after exposure to PTX. Taken together, this suggests that the increased trafficking and surface localization of Halo-Nav1.7 that we observed by live imaging in transfected dorsal root ganglion neurons after treatment with PTX might be independent of an increased pool of Nav1.7 channels. After exposure to inflammatory mediators to mimic the inflammatory condition seen during chemotherapy, both Nav1.7 surface levels and vesicular transport are increased for both low and high concentrations of PTX. Overall, our results show that PTX treatment increases levels of functional endogenous Nav1.7 channels in dorsal root ganglion neurons and enhances trafficking and surface distribution of Nav1.7 in sensory axons, with outcomes that depend on the presence of an inflammatory milieu, providing a mechanistic explanation for increased excitability of primary afferents and pain in CIPN.

خرید پکیج و مشاهده آنلاین مقاله

Towards realizing the vision of precision medicine: AI based prediction of clinical drug response

Johann de Jong, Ioana Cutcutache, Matthew Page, Sami Elmoufti, Cynthia Dilley

doi : 10.1093/brain/awab108

Brain, Volume 144, Issue 6, June 2021, Pages 1738–1750

Accurate and individualized prediction of response to therapies is central to precision medicine. However, because of the generally complex and multifaceted nature of clinical drug response, realizing this vision is highly challenging, requiring integrating different data types from the same individual into one prediction model. We used the anti-epileptic drug brivaracetam as a case study and combine a hybrid data/knowledge-driven feature extraction with machine learning to systematically integrate clinical and genetic data from a clinical discovery dataset (n?=?235 patients). We constructed a model that successfully predicts clinical drug response [area under the curve (AUC)?=?0.76] and show that even with limited sample size, integrating high-dimensional genetics data with clinical data can inform drug response prediction. After further validation on data collected from an independently conducted clinical study (AUC?=?0.75), we extensively explore our model to gain insights into the determinants of drug response, and identify various clinical and genetic characteristics predisposing to poor response. Finally, we assess the potential impact of our model on clinical trial design and demonstrate that, by enriching for probable responders, significant reductions in clinical study sizes may be achieved. To our knowledge, our model represents the first retrospectively validated machine learning model linking drug mechanism of action and the genetic, clinical and demographic background in epilepsy patients to clinical drug response. Hence, it provides a blueprint for how machine learning-based multimodal data integration can act as a driver in achieving the goals of precision medicine in fields such as neurology.

خرید پکیج و مشاهده آنلاین مقاله

Travelling waves reveal a dynamic seizure source in human focal epilepsy

Joshua M Diamond, Benjamin E Diamond, Michael S Trotta, Kate Dembny, Sara K Inati

doi : 10.1093/brain/awab089

Brain, Volume 144, Issue 6, June 2021, Pages 1751–1763

Treatment of patients with drug-resistant focal epilepsy relies upon accurate seizure localization. Ictal activity captured by intracranial EEG has traditionally been interpreted to suggest that the underlying cortex is actively involved in seizures. Here, we hypothesize that such activity instead reflects propagated activity from a relatively focal seizure source, even during later time points when ictal activity is more widespread. We used the time differences observed between ictal discharges in adjacent electrodes to estimate the location of the hypothesized focal source and demonstrated that the seizure source, localized in this manner, closely matches the clinically and neurophysiologically determined brain region giving rise to seizures. Moreover, we determined this focal source to be a dynamic entity that moves and evolves over the time course of a seizure. Our results offer an interpretation of ictal activity observed by intracranial EEG that challenges the traditional conceptualization of the seizure source.

خرید پکیج و مشاهده آنلاین مقاله

A decision-neuroscientific intervention to improve cognitive recovery after stroke

Bettina Studer, Alicja Timm, Barbara J Sahakian, Tobias Kalenscher, Stefan Knecht

doi : 10.1093/brain/awab128

Brain, Volume 144, Issue 6, June 2021, Pages 1764–1773

Functional recovery after stroke is dose-dependent on the amount of rehabilitative training. However, rehabilitative training is subject to motivational hurdles. Decision neuroscience formalizes drivers and dampers of behaviour and provides strategies for tipping motivational trade-offs and behaviour change. Here, we used one such strategy, upfront voluntary choice restriction (‘precommitment’), and tested if it can increase the amount of self-directed rehabilitative training in severely impaired stroke patients. In this randomized controlled study, stroke patients with working memory deficits (n = 83) were prescribed daily self-directed gamified cognitive training as an add-on to standard therapy during post-acute inpatient neurorehabilitation. Patients allocated to the precommitment intervention could choose to restrict competing options to self-directed training, specifically the possibility to meet visitors. This upfront choice restriction was opted for by all patients in the intervention group and highly effective. Patients in the precommitment group performed the prescribed self-directed gamified cognitive training twice as often as control group patients who were not offered precommitment [on 50% versus 21% of days, Pcorr = 0.004, d = 0.87, 95% confidence interval (CI95%) = 0.31 to 1.42], and, as a consequence, reached a 3-fold higher total training dose (90.21 versus 33.60 min, Pcorr = 0.004, d = 0.83, CI95% = 0.27 to 1.38). Moreover, add-on self-directed cognitive training was associated with stronger improvements in visuospatial and verbal working memory performance (Pcorr = 0.002, d = 0.72 and Pcorr = 0.036, d = 0.62). Our neuroscientific decision add-on intervention strongly increased the amount of effective cognitive training performed by severely impaired stroke patients. These results warrant a full clinical trial to link decision-based neuroscientific interventions directly with clinical outcome.

خرید پکیج و مشاهده آنلاین مقاله

Comparative connectivity correlates of dystonic and essential tremor deep brain stimulation

Takashi Tsuboi, Joshua K Wong, Robert S Eisinger, Lela Okromelidze, Mathew R Burns

doi : 10.1093/brain/awab074

Brain, Volume 144, Issue 6, June 2021, Pages 1774–1786

The pathophysiology of dystonic tremor and essential tremor remains partially understood. In patients with medication-refractory dystonic tremor or essential tremor, deep brain stimulation (DBS) targeting the thalamus or posterior subthalamic area has evolved into a promising treatment option. However, the optimal DBS targets for these disorders remains unknown. This retrospective study explored the optimal targets for DBS in essential tremor and dystonic tremor using a combination of volumes of tissue activated estimation and functional and structural connectivity analyses. We included 20 patients with dystonic tremor who underwent unilateral thalamic DBS, along with a matched cohort of 20 patients with essential tremor DBS. Tremor severity was assessed preoperatively and approximately 6 months after DBS implantation using the Fahn-Tolosa-Marin Tremor Rating Scale. The tremor-suppressing effects of DBS were estimated using the percentage improvement in the unilateral tremor-rating scale score contralateral to the side of implantation. The optimal stimulation region, based on the cluster centre of gravity for peak contralateral motor score improvement, for essential tremor was located in the ventral intermediate nucleus region and for dystonic tremor in the ventralis oralis posterior nucleus region along the ventral intermediate nucleus/ventralis oralis posterior nucleus border (4 mm anterior and 3 mm superior to that for essential tremor). Both disorders showed similar functional connectivity patterns: a positive correlation between tremor improvement and involvement of the primary sensorimotor, secondary motor and associative prefrontal regions. Tremor improvement, however, was tightly correlated with the primary sensorimotor regions in essential tremor, whereas in dystonic tremor, the correlation was tighter with the premotor and prefrontal regions. The dentato-rubro-thalamic tract, comprising the decussating and non-decussating fibres, significantly correlated with tremor improvement in both dystonic and essential tremor. In contrast, the pallidothalamic tracts, which primarily project to the ventralis oralis posterior nucleus region, significantly correlated with tremor improvement only in dystonic tremor. Our findings support the hypothesis that the pathophysiology underpinning dystonic tremor involves both the cerebello-thalamo-cortical network and the basal ganglia-thalamo-cortical network. Further our data suggest that the pathophysiology of essential tremor is primarily attributable to the abnormalities within the cerebello-thalamo-cortical network. We conclude that the ventral intermediate nucleus/ventralis oralis posterior nucleus border and ventral intermediate nucleus region may be a reasonable DBS target for patients with medication-refractory dystonic tremor and essential tremor, respectively. Uncovering the pathophysiology of these disorders may in the future aid in further improving DBS outcomes.

خرید پکیج و مشاهده آنلاین مقاله

Regional brain iron and gene expression provide insights into neurodegeneration in Parkinson’s disease

George E C Thomas, Angeliki Zarkali, Mina Ryten, Karin Shmueli, Ana Luisa Gil-Martinez

doi : 10.1093/brain/awab084

Brain, Volume 144, Issue 6, June 2021, Pages 1787–1798

The mechanisms responsible for the selective vulnerability of specific neuronal populations in Parkinson’s disease are poorly understood. Oxidative stress secondary to brain iron accumulation is one postulated mechanism. We measured iron deposition in 180 cortical regions of 96 patients with Parkinson’s disease and 35 control subjects using quantitative susceptibility mapping. We estimated the expression of 15?745 genes in the same regions using transcriptomic data from the Allen Human Brain Atlas. Using partial least squares regression, we then identified the profile of gene transcription in the healthy brain that underlies increased cortical iron in patients with Parkinson’s disease relative to controls. Applying gene ontological tools, we investigated the biological processes and cell types associated with this transcriptomic profile and identified the sets of genes with spatial expression profiles in control brains that correlated significantly with the spatial pattern of cortical iron deposition in Parkinson’s disease. Gene ontological analyses revealed that these genes were enriched for biological processes relating to heavy metal detoxification, synaptic function and nervous system development and were predominantly expressed in astrocytes and glutamatergic neurons. Furthermore, we demonstrated that the genes differentially expressed in Parkinson’s disease are associated with the pattern of cortical expression identified in this study. Our findings provide mechanistic insights into regional selective vulnerabilities in Parkinson’s disease, particularly the processes involving iron accumulation.

خرید پکیج و مشاهده آنلاین مقاله

The computational neurology of movement under active inference

Thomas Parr, Jakub Limanowski, Vishal Rawji, Karl Friston

doi : 10.1093/brain/awab085

Brain, Volume 144, Issue 6, June 2021, Pages 1799–1818

We propose a computational neurology of movement based on the convergence of theoretical neurobiology and clinical neurology. A significant development in the former is the idea that we can frame brain function as a process of (active) inference, in which the nervous system makes predictions about its sensory data. These predictions depend upon an implicit predictive (generative) model used by the brain. This means neural dynamics can be framed as generating actions to ensure sensations are consistent with these predictions—and adjusting predictions when they are not. We illustrate the significance of this formulation for clinical neurology by simulating a clinical examination of the motor system using an upper limb coordination task. Specifically, we show how tendon reflexes emerge naturally under the right kind of generative model. Through simulated perturbations, pertaining to prior probabilities of this model’s variables, we illustrate the emergence of hyperreflexia and pendular reflexes, reminiscent of neurological lesions in the corticospinal tract and cerebellum. We then turn to the computational lesions causing hypokinesia and deficits of coordination. This in silico lesion-deficit analysis provides an opportunity to revisit classic neurological dichotomies (e.g. pyramidal versus extrapyramidal systems) from the perspective of modern approaches to theoretical neurobiology—and our understanding of the neurocomputational architecture of movement control based on first principles.

خرید پکیج و مشاهده آنلاین مقاله

The GGC repeat expansion in NOTCH2NLC is associated with oculopharyngodistal myopathy type 3

Jiaxi Yu, Jianwen Deng, Xueyu Guo, Jingli Shan, Xinghua Luan ...

doi : 10.1093/brain/awab077

Brain, Volume 144, Issue 6, June 2021, Pages 1819–1832

Oculopharyngodistal myopathy (OPDM) is an adult-onset neuromuscular disease characterized by progressive ocular, facial, pharyngeal and distal limb muscle involvement. Trinucleotide repeat expansions in LRP12 or GIPC1 were recently reported to be associated with OPDM. However, a significant portion of OPDM patients have unknown genetic causes. In this study, long-read whole-genome sequencing and repeat-primed PCR were performed and we identified GGC repeat expansions in the NOTCH2NLC gene in 16.7% (4/24) of a cohort of Chinese OPDM patients, designated as OPDM type 3 (OPDM3). Methylation analysis indicated that methylation levels of the NOTCH2NLC gene were unaltered in OPDM3 patients, but increased significantly in asymptomatic carriers. Quantitative real-time PCR analysis indicated that NOTCH2NLC mRNA levels were increased in muscle but not in blood of OPDM3 patients. Immunofluorescence on OPDM muscle samples and expressing mutant NOTCH2NLC with (GGC)69 repeat expansions in HEK293 cells indicated that mutant NOTCH2NLC-polyglycine protein might be a major component of intranuclear inclusions, and contribute to toxicity in cultured cells. In addition, two RNA-binding proteins, hnRNP A/B and MBNL1, were both co-localized with p62 in intranuclear inclusions in OPDM muscle samples. These results indicated that a toxic protein gain-of-function mechanism and RNA gain-of-function mechanism may both play a vital role in the pathogenic processes of OPDM3. This study extended the spectrum of NOTCH2NLC repeat expansion-related diseases to a predominant myopathy phenotype presenting as OPDM, and provided evidence for possible pathogenesis of these diseases.

خرید پکیج و مشاهده آنلاین مقاله

A delta-secretase-truncated APP fragment activates CEBPB, mediating Alzheimer’s disease pathologies

Yinan Yao, Seong Su Kang, Yiyuan Xia, Zhi-Hao Wang, Xia Liu

doi : 10.1093/brain/awab062

Brain, Volume 144, Issue 6, June 2021, Pages 1833–1852

Amyloid-? precursor protein (APP) is sequentially cleaved by secretases and generates amyloid-?, the major components in senile plaques in Alzheimer’s disease. APP is upregulated in human Alzheimer’s disease brains. However, the molecular mechanism of how APP contributes to Alzheimer’s disease pathogenesis remains incompletely understood. Here we show that truncated APP C586-695 fragment generated by ?-secretase directly binds to CCAAT/enhancer-binding protein beta (CEBPB), an inflammatory transcription factor, and enhances its transcriptional activity, escalating Alzheimer’s disease-related gene expression and pathogenesis. The APP C586-695 fragment, but not full-length APP, strongly associates with CEBPB and elicits its nuclear translocation and augments the transcriptional activities on APP itself, MAPT (microtubule-associated protein tau), ?-secretase and inflammatory cytokine mRNA expression, finally triggering Alzheimer’s disease pathology and cognitive disorder in a viral overexpression mouse model. Blockade of ?-secretase cleavage of APP by mutating the cleavage sites reduces its stimulatory effect on CEBPB, alleviating amyloid pathology and cognitive dysfunctions. Clearance of APP C586-695 from 5xFAD mice by antibody administration mitigates Alzheimer’s disease pathologies and restores cognitive functions. Thus, in addition to the sequestration of amyloid-?, APP implicates in Alzheimer’s disease pathology by activating CEBPB upon ?-secretase cleavage.

خرید پکیج و مشاهده آنلاین مقاله

Ageing promotes pathological alpha-synuclein propagation and autonomic dysfunction in wild-type rats

Nathalie Van Den Berge, Nelson Ferreira, Trine Werenberg Mikkelsen, Aage Kristian Olsen Alstrup, Gültekin Tamgüney

doi : 10.1093/brain/awab061

Brain, Volume 144, Issue 6, June 2021, Pages 1853–1868

Neuronal aggregates of misfolded alpha-synuclein protein are found in the brain and periphery of patients with Parkinson’s disease. Braak and colleagues have hypothesized that the initial formation of misfolded alpha-synuclein may start in the gut, and then spread to the brain via peripheral autonomic nerves hereby affecting several organs, including the heart and intestine. Age is considered the greatest risk factor for Parkinson’s disease, but the effect of age on the formation of pathology and its propagation has not been studied in detail. We aimed to investigate whether propagation of alpha-synuclein pathology from the gut to the brain is more efficient in old versus young wild-type rats, upon gastrointestinal injection of aggregated alpha-synuclein. Our results demonstrate a robust age-dependent gut-to-brain and brain-to-gut spread of alpha-synuclein pathology along the sympathetic and parasympathetic nerves, resulting in age-dependent dysfunction of the heart and stomach, as observed in patients with Parkinson’s disease. Moreover, alpha-synuclein pathology is more densely packed and resistant to enzymatic digestion in old rats, indicating an age-dependent maturation of alpha-synuclein aggregates. Our study is the first to provide a detailed investigation of alpha-synuclein pathology in several organs within one animal model, including the brain, skin, heart, intestine, spinal cord and autonomic ganglia. Taken together, our findings suggest that age is a crucial factor for alpha-synuclein aggregation and complete propagation to heart, stomach and skin, similar to patients. Given that age is the greatest risk factor for human Parkinson’s disease, it seems likely that older experimental animals will yield the most relevant and reliable findings. These results have important implications for future research to optimize diagnostics and therapeutics in Parkinson’s disease and other age-associated synucleinopathies. Increased emphasis should be placed on using aged animals in preclinical studies and to elucidate the nature of age-dependent interactions.

خرید پکیج و مشاهده آنلاین مقاله

Systemic infection exacerbates cerebrovascular dysfunction in Alzheimer’s disease

Daniel Asby, Delphine Boche, Stuart Allan, Seth Love, J Scott Miners

doi : 10.1093/brain/awab094

Brain, Volume 144, Issue 6, June 2021, Pages 1869–1883

We studied the effects of systemic infection on brain cytokine level and cerebral vascular function in Alzheimer’s disease and vascular dementia, in superior temporal cortex (Brodmann area 22) from Alzheimer’s disease patients (n?=?75), vascular dementia patients (n?=?22) and age-matched control subjects (n?=?46), stratified according to the presence or absence of terminal systemic infection. Brain cytokine levels were measured using Mesoscale Discovery Multiplex Assays and markers of cerebrovascular function were assessed by ELISA. Multiple brain cytokines were elevated in Alzheimer’s disease and vascular dementia: IL-15 and IL-17A were maximally elevated in end-stage Alzheimer’s disease (Braak tangle stage V–VI) whereas IL-2, IL-5, IL12p40 and IL-16 were highest in intermediate Braak tangle stage III–IV disease. Several cytokines (IL-1?, IL-6, TNF-?, IL-8 and IL-15) were further raised in Alzheimer’s disease with systemic infection. Cerebral hypoperfusion—indicated by decreased MAG:PLP1 and increased vascular endothelial growth factor-A (VEGF)—and blood–brain barrier leakiness, indicated by raised levels of fibrinogen, were exacerbated in Alzheimer’s disease and vascular dementia patients, and also in non-dementia controls, with systemic infection. Amyloid-?42 level did not vary with infection or in association with brain cytokine levels. In controls, cortical perfusion declined with increasing IFN-?, IL-2, IL-4, IL-6, IL-10, IL-12p70, IL-13 and tumour necrosis factor-? (TNF-?) but these relationships were lost with progression of Alzheimer’s disease, and with infection (even in Braak stage 0–II brains). Cortical platelet-derived growth factor receptor-? (PDGFR?), a pericyte marker, was reduced, and endothelin-1 (EDN1) level was increased in Alzheimer’s disease; these were related to amyloid-? level and disease progression and only modestly affected by systemic infection. Our findings indicate that systemic infection alters brain cytokine levels and exacerbates cerebral hypoperfusion and blood–brain barrier leakiness associated with Alzheimer’s disease and vascular dementia, independently of the level of insoluble amyloid-?, and highlight systemic infection as an important contributor to dementia, requiring early identification and treatment in the elderly population.

خرید پکیج و مشاهده آنلاین مقاله

Photo-oxygenation by a biocompatible catalyst reduces amyloid-? levels in Alzheimer’s disease mice

Shuta Ozawa, Yukiko Hori, Yusuke Shimizu, Atsuhiko Taniguchi, Takanobu Suzuki

doi : 10.1093/brain/awab058

Brain, Volume 144, Issue 6, June 2021, Pages 1884–1897

Amyloid formation and the deposition of the amyloid-? peptide are hallmarks of Alzheimer’s disease pathogenesis. Immunotherapies using anti-amyloid-? antibodies have been highlighted as a promising approach for the prevention and treatment of Alzheimer’s disease by enhancing microglial clearance of amyloid-? peptide. However, the efficiency of antibody delivery into the brain is limited, and therefore an alternative strategy to facilitate the clearance of brain amyloid is needed. We previously developed an artificial photo-oxygenation system using a low molecular weight catalytic compound. The photocatalyst specifically attached oxygen atoms to amyloids upon irradiation with light, and successfully reduced the neurotoxicity of aggregated amyloid-? via inhibition of amyloid formation. However, the therapeutic effect and mode of actions of the photo-oxygenation system in vivo remained unclear. In this study, we demonstrate that photo-oxygenation facilitates the clearance of aggregated amyloid-? from the brains of living Alzheimer’s disease model mice, and enhances the microglial degradation of amyloid-? peptide. These results suggest that photo-oxygenation may represent a novel anti-amyloid-? strategy in Alzheimer’s disease, which is compatible with immunotherapy.

خرید پکیج و مشاهده آنلاین مقاله

Failure to engage the temporoparietal junction/posterior superior temporal sulcus predicts impaired naturalistic social cognition in schizophrenia

Gaurav H Patel, Sophie C Arkin, Daniel R Ruiz-Betancourt, Fabiola I Plaza, Safia A Mirza

doi : 10.1093/brain/awab081

Brain, Volume 144, Issue 6, June 2021, Pages 1898–1910

Schizophrenia is associated with marked impairments in social cognition. However, the neural correlates of these deficits remain unclear. Here we use naturalistic stimuli to examine the role of the right temporoparietal junction/posterior superior temporal sulcus (TPJ-pSTS)—an integrative hub for the cortical networks pertinent to the understanding complex social situations—in social inference, a key component of social cognition, in schizophrenia. Twenty-seven schizophrenia participants and 21 healthy control subjects watched a clip of the film The Good, the Bad and the Ugly while high resolution multiband functional MRI images were collected. We used inter-subject correlation to measure the evoked activity, which we then compared to social cognition as measured by The Awareness of Social Inference Test (TASIT). We also compared between groups the TPJ-pSTS blood oxygen level-dependent activity (i) relationship with the motion content in the film; (ii) synchronization with other cortical areas involved in the viewing of the movie; and (iii) relationship with the frequency of saccades made during the movie. Activation deficits were greatest in middle TPJ (TPJm) and correlated significantly with impaired TASIT performance across groups. Follow-up analyses of the TPJ-pSTS revealed decreased synchronization with other cortical areas, decreased correlation with the motion content of the movie, and decreased correlation with the saccades made during the movie. The functional impairment of the TPJm, a hub area in the middle of the TPJ-pSTS, predicts deficits in social inference in schizophrenia participants by disrupting the integration of visual motion processing into the TPJ. This disrupted integration then affects the use of the TPJ to guide saccades during the visual scanning of the movie clip. These findings suggest that the TPJ may be a treatment target for improving deficits in a key component of social cognition in schizophrenia participants.

خرید پکیج و مشاهده آنلاین مقاله

A neurogenetic analysis of female autism

Allison Jack, Catherine A W Sullivan, Elizabeth Aylward, Susan Y Bookheimer, Mirella Dapretto ...

doi : 10.1093/brain/awab064

Brain, Volume 144, Issue 6, June 2021, Pages 1911–1926

Females versus males are less frequently diagnosed with autism spectrum disorder (ASD), and while understanding sex differences is critical to delineating the systems biology of the condition, female ASD is understudied. We integrated functional MRI and genetic data in a sex-balanced sample of ASD and typically developing youth (8–17 years old) to characterize female-specific pathways of ASD risk. Our primary objectives were to: (i) characterize female ASD (n?=?45) brain response to human motion, relative to matched typically developing female youth (n?=?45); and (ii) evaluate whether genetic data could provide further insight into the potential relevance of these brain functional differences. For our first objective we found that ASD females showed markedly reduced response versus typically developing females, particularly in sensorimotor, striatal, and frontal regions. This difference between ASD and typically developing females does not resemble differences between ASD (n?=?47) and typically developing males (n?=?47), even though neural response did not significantly differ between female and male ASD. For our second objective, we found that ASD females (n?=?61), versus males (n?=?66), showed larger median size of rare copy number variants containing gene(s) expressed in early life (10 postconceptual weeks to 2 years) in regions implicated by the typically developing female > female functional MRI contrast. Post hoc analyses suggested this difference was primarily driven by copy number variants containing gene(s) expressed in striatum. This striatal finding was reproducible among n?=?2075 probands (291 female) from an independent cohort. Together, our findings suggest that striatal impacts may contribute to pathways of risk in female ASD and advocate caution in drawing conclusions regarding female ASD based on male-predominant cohorts.

خرید پکیج و مشاهده آنلاین مقاله

UQCRC1 variants in Parkinson’s disease: a large cohort study in Chinese mainland population

Yu-wen Zhao, Hong-xu Pan, Chun-yu Wang, Qian Zeng, Yige Wang

doi : 10.1093/brain/awab137

Brain, Volume 144, Issue 6, June 2021, Page e54

خرید پکیج و مشاهده آنلاین مقاله

Reply: UQCRC1 variants in Parkinson’s disease: a large cohort study in Chinese mainland population

Chin-Hsien Lin, Matthew J Farrer, Ruey-Meei Wu

doi : 10.1093/brain/awab138

Brain, Volume 144, Issue 6, June 2021, Page e55

خرید پکیج و مشاهده آنلاین مقاله

Was this Thomas Willis’s greatest clinical success?

Andrew N Williams, Jeffrey K Aronson

doi : 10.1093/brain/awab143

Brain, Volume 144, Issue 6, June 2021, Page e56

خرید پکیج و مشاهده آنلاین مقاله

Erratum to: Time course of phosphorylated-tau181 in blood across the Alzheimer’s disease spectrum

doi : 10.1093/brain/awab075

Brain, Volume 144, Issue 6, June 2021, Page e57

خرید پکیج و مشاهده آنلاین مقاله

Erratum to: Glycation potentiates ?-synuclein-associated neurodegeneration in synucleinopathies

Hugo Vicente Miranda, ?va M Szeg?, Lu?s M A Oliveira, Carlo Breda, Ekrem Darendelioglu

doi : 10.1093/brain/awab175

Brain, Volume 144, Issue 6, June 2021, Page e58

خرید پکیج و مشاهده آنلاین مقاله