Influence of cerebrovascular disease on brain networks in prodromal and clinical Alzheimer’s disease Brain (IF 10.292) Pub Date : 2017-09-19 Joanna Su Xian Chong, Siwei Liu, Yng Miin Loke, Saima Hilal, Mohammad Kamran Ikram, Xin Xu, Boon Yeow Tan, Narayanaswamy Venketasubramanian, Christopher Li-Hsian Chen, Juan Zhou
Network-sensitive neuroimaging methods have been used to characterize large-scale brain network degeneration in Alzheimer’s disease and its prodrome. However, few studies have investigated the combined effect of Alzheimer’s disease and cerebrovascular disease on brain network degeneration. Our study sought to examine the intrinsic functional connectivity and structural covariance network changes in 235 prodromal and clinical Alzheimer’s disease patients with and without cerebrovascular disease. We focused particularly on two higher-order cognitive networks—the default mode network and the executive control network. We found divergent functional connectivity and structural covariance patterns in Alzheimer’s disease patients with and without cerebrovascular disease. Alzheimer’s disease patients without cerebrovascular disease, but not Alzheimer’s disease patients with cerebrovascular disease, showed reductions in posterior default mode network functional connectivity. By comparison, while both groups exhibited parietal reductions in executive control network functional connectivity, only Alzheimer’s disease patients with cerebrovascular disease showed increases in frontal executive control network connectivity. Importantly, these distinct executive control network changes were recapitulated in prodromal Alzheimer’s disease patients with and without cerebrovascular disease. Across Alzheimer’s disease patients with and without cerebrovascular disease, higher default mode network functional connectivity z-scores correlated with greater hippocampal volumes while higher executive control network functional connectivity z-scores correlated with greater white matter changes. In parallel, only Alzheimer’s disease patients without cerebrovascular disease showed increased default mode network structural covariance, while only Alzheimer’s disease patients with cerebrovascular disease showed increased executive control network structural covariance compared to controls. Our findings demonstrate the differential neural network structural and functional changes in Alzheimer’s disease with and without cerebrovascular disease, suggesting that the underlying pathology of Alzheimer’s disease patients with cerebrovascular disease might differ from those without cerebrovascular disease and reflect a combination of more severe cerebrovascular disease and less severe Alzheimer’s disease network degeneration phenotype.
Reconnecting with Joseph and Augusta Dejerine: 100 hundred years on Brain (IF 10.292) Pub Date : 2017-09-15 Claude J. Bajada, Briony Banks, Matthew A. Lambon Ralph, Lauren L. Cloutman
Joseph Dejerine passed away on 28 February 1917 in the midst of a world at war. One hundred years later we celebrate the legacy of this pioneer in neuroscience. In 1895, Joseph Jules Dejerine published the first volume of the seminal work, Anatomie des centres nerveux; volume 2 was published in 1901. In a major section of this tome (vol. 1 pp. 749–80), Joseph Dejerine and his wife and long-term collaborator, Augusta Dejerine-Klumpke, produced a treatise on the white matter pathways of the brain, composed of anatomical descriptions of meticulous detail and beautiful illustration (drawn by H. Gillet) that reflected a combination of the most advanced methodologies of the day and a review of leading neuroscientific research. We have selected and focused this specific output (which is provided for the first time as an English translation in the Supplementary material) from the many that the Dejerines published because its ideas and findings continue to be of relevance to modern neuroscience researchers today; especially those with an interest in connectional anatomy.
WDR81 mutations cause extreme microcephaly and impair mitotic progression in human fibroblasts and Drosophila neural stem cells Brain (IF 10.292) Pub Date : 2017-09-13 Mara Cavallin, Maria A. Rujano, Nathalie Bednarek, Daniel Medina-Cano, Antoinette Bernabe Gelot, Severine Drunat, Camille Maillard, Meriem Garfa-Traore, Christine Bole, Patrick Nitschké, Claire Beneteau, Thomas Besnard, Benjamin Cogné, Marion Eveillard, Alice Kuster, Karine Poirier, Alain Verloes, Jelena Martinovic, Laurent Bidat, Marlene Rio, Stanislas Lyonnet, M. Louise Reilly, Nathalie Boddaert, Melanie Jenneson-Liver, Jacques Motte, Martine Doco-Fenzy, Jamel Chelly, Tania Attie-Bitach, Matias Simons, Vincent Cantagrel, Sandrine Passemard, Alexandre Baffet, Sophie Thomas, Nadia Bahi-Buisson
Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.
Biallelic MCM3AP mutations cause Charcot-Marie-Tooth neuropathy with variable clinical presentation Brain (IF 10.292) Pub Date : 2017-09-13 Mert Karakaya, Neda Mazaheri, Ipek Polat, Diana Bharucha-Goebel, Sandra Donkervoort, Reza Maroofian, Gholamreza Shariati, Irmgard Hoelker, Kristin Monaghan, Sara Winchester, Robert Zori, Hamid Galehdari, Carsten G. Bönnemann, Uluc Yis, Brunhilde Wirth
Cross-cueing cannot explain unified control in split-brain patients Brain (IF 10.292) Pub Date : 2017-09-13 Yair Pinto, Victor A. F. Lamme, Edward H. F. de Haan
Genetic variants influencing elevated myeloperoxidase levels increase risk of stroke Brain (IF 10.292) Pub Date : 2017-09-12 Chia-Ling Phuah, Tushar Dave, Rainer Malik, Miriam R. Raffeld, Alison M. Ayres, Joshua N. Goldstein, Anand Viswanathan, Steven M. Greenberg, Jeremiasz M. Jagiella, Björn M. Hansen, Bo Norrving, Jordi Jimenez-Conde, Jaume Roquer, Alexander Pichler, Christian Enzinger, Joan Montaner, Israel Fernandez-Cadenas, Arne Lindgren, Agnieszka Slowik, Reinhold Schmidt, Alessandro Biffi, Natalia Rost, Carl D. Langefeld, Hugh S. Markus, Braxton D. Mitchell, Brad B. Worrall, Steven J. Kittner, Daniel Woo, Martin Dichgans, Jonathan Rosand, Christopher D. Anderson
Primary intracerebral haemorrhage and lacunar ischaemic stroke are acute manifestations of progressive cerebral microvascular disease. Current paradigms suggest atherosclerosis is a chronic, dynamic, inflammatory condition precipitated in response to endothelial injury from various environmental challenges. Myeloperoxidase plays a central role in initiation and progression of vascular inflammation, but prior studies linking myeloperoxidase with stroke risk have been inconclusive. We hypothesized that genetic determinants of myeloperoxidase levels influence the development of vascular instability, leading to increased primary intracerebral haemorrhage and lacunar stroke risk. We used a discovery cohort of 1409 primary intracerebral haemorrhage cases and 1624 controls from three studies, an extension cohort of 12 577 ischaemic stroke cases and 25 643 controls from NINDS-SiGN, and a validation cohort of 10 307 ischaemic stroke cases and 29 326 controls from METASTROKE Consortium with genome-wide genotyping to test this hypothesis. A genetic risk score reflecting elevated myeloperoxidase levels was constructed from 15 common single nucleotide polymorphisms identified from prior genome-wide studies of circulating myeloperoxidase levels (P < 5 × 10−6). This genetic risk score was used as the independent variable in multivariable regression models for association with primary intracerebral haemorrhage and ischaemic stroke subtypes. We used fixed effects meta-analyses to pool estimates across studies. We also used Cox regression models in a prospective cohort of 174 primary intracerebral haemorrhage survivors for association with intracerebral haemorrhage recurrence. We present effects of myeloperoxidase elevating single nucleotide polymorphisms on stroke risk per risk allele, corresponding to a one allele increase in the myeloperoxidase increasing genetic risk score. Genetic determinants of elevated circulating myeloperoxidase levels were associated with both primary intracerebral haemorrhage risk (odds ratio, 1.07, P = 0.04) and recurrent intracerebral haemorrhage risk (hazards ratio, 1.45, P = 0.006). In analysis of ischaemic stroke subtypes, the myeloperoxidase increasing genetic risk score was strongly associated with lacunar subtype only (odds ratio, 1.05, P = 0.0012). These results, demonstrating that common genetic variants that increase myeloperoxidase levels increase risk of primary intracerebral haemorrhage and lacunar stroke, directly implicate the myeloperoxidase pathway in the pathogenesis of cerebral small vessel disease. Because genetic variants are not influenced by environmental exposures, these results provide new support for a causal rather than bystander role for myeloperoxidase in the progression of cerebrovascular disease. Furthermore, these results support a rationale for chronic inflammation as a potential modifiable stroke risk mechanism, and suggest that immune-targeted therapies could be useful for treatment and prevention of cerebrovascular disease.
Mutations of AKT3 are associated with a wide spectrum of developmental disorders including extreme megalencephaly Brain (IF 10.292) Pub Date : 2017-09-07 Diana Alcantara, Andrew E. Timms, Karen Gripp, Laura Baker, Kaylee Park, Sarah Collins, Chi Cheng, Fiona Stewart, Sarju G. Mehta, Anand Saggar, László Sztriha, Melinda Zombor, Oana Caluseriu, Ronit Mesterman, Margot I. Van Allen, Adeline Jacquinet, Sofia Ygberg, Jonathan A. Bernstein, Aaron M. Wenger, Harendra Guturu, Gill Bejerano, Natalia Gomez-Ospina, Anna Lehman, Enrico Alfei, Chiara Pantaleoni, Valerio Conti, Renzo Guerrini, Ute Moog, John M. Graham Jr., Robert Hevner, William B. Dobyns, Mark O’Driscoll, Ghayda M. Mirzaa
Mutations of genes within the phosphatidylinositol-3-kinase (PI3K)-AKT-MTOR pathway are well known causes of brain overgrowth (megalencephaly) as well as segmental cortical dysplasia (such as hemimegalencephaly, focal cortical dysplasia and polymicrogyria). Mutations of the AKT3 gene have been reported in a few individuals with brain malformations, to date. Therefore, our understanding regarding the clinical and molecular spectrum associated with mutations of this critical gene is limited, with no clear genotype–phenotype correlations. We sought to further delineate this spectrum, study levels of mosaicism and identify genotype–phenotype correlations of AKT3-related disorders. We performed targeted sequencing of AKT3 on individuals with these phenotypes by molecular inversion probes and/or Sanger sequencing to determine the type and level of mosaicism of mutations. We analysed all clinical and brain imaging data of mutation-positive individuals including neuropathological analysis in one instance. We performed ex vivo kinase assays on AKT3 engineered with the patient mutations and examined the phospholipid binding profile of pleckstrin homology domain localizing mutations. We identified 14 new individuals with AKT3 mutations with several phenotypes dependent on the type of mutation and level of mosaicism. Our comprehensive clinical characterization, and review of all previously published patients, broadly segregates individuals with AKT3 mutations into two groups: patients with highly asymmetric cortical dysplasia caused by the common p.E17K mutation, and patients with constitutional AKT3 mutations exhibiting more variable phenotypes including bilateral cortical malformations, polymicrogyria, periventricular nodular heterotopia and diffuse megalencephaly without cortical dysplasia. All mutations increased kinase activity, and pleckstrin homology domain mutants exhibited enhanced phospholipid binding. Overall, our study shows that activating mutations of the critical AKT3 gene are associated with a wide spectrum of brain involvement ranging from focal or segmental brain malformations (such as hemimegalencephaly and polymicrogyria) predominantly due to mosaic AKT3 mutations, to diffuse bilateral cortical malformations, megalencephaly and heterotopia due to constitutional AKT3 mutations. We also provide the first detailed neuropathological examination of a child with extreme megalencephaly due to a constitutional AKT3 mutation. This child has one of the largest documented paediatric brain sizes, to our knowledge. Finally, our data show that constitutional AKT3 mutations are associated with megalencephaly, with or without autism, similar to PTEN-related disorders. Recognition of this broad clinical and molecular spectrum of AKT3 mutations is important for providing early diagnosis and appropriate management of affected individuals, and will facilitate targeted design of future human clinical trials using PI3K-AKT pathway inhibitors.
Subarachnoid blood acutely induces spreading depolarizations and early cortical infarction Brain (IF 10.292) Pub Date : 2017-09-06 Jed A. Hartings, Jonathan York, Christopher P. Carroll, Jason M. Hinzman, Eric Mahoney, Bryan Krueger, Maren K. L. Winkler, Sebastian Major, Viktor Horst, Paul Jahnke, Johannes Woitzik, Vasilis Kola, Yifeng Du, Matthew Hagen, Jianxiong Jiang, Jens P. Dreier
Early cortical infarcts are common in poor-grade patients after aneurysmal subarachnoid haemorrhage. There are no animal models of these lesions and mechanisms are unknown, although mass cortical spreading depolarizations are hypothesized as a requisite mechanism and clinical marker of infarct development. Here we studied acute sequelae of subarachnoid haemorrhage in the gyrencephalic brain of propofol-anaesthetized juvenile swine using subdural electrode strips (electrocorticography) and intraparenchymal neuromonitoring probes. Subarachnoid infusion of 1–2 ml of fresh blood at 200 µl/min over cortical sulci caused clusters of spreading depolarizations (count range: 12–34) in 7/17 animals in the ipsilateral but not contralateral hemisphere in 6 h of monitoring, without meaningful changes in other variables. Spreading depolarization clusters were associated with formation of sulcal clots (P < 0.01), a high likelihood of adjacent cortical infarcts (5/7 versus 2/10, P < 0.06), and upregulation of cyclooxygenase-2 in ipsilateral cortex remote from clots/infarcts. In a second cohort, infusion of 1 ml of clotted blood into a sulcus caused spreading depolarizations in 5/6 animals (count range: 4–20 in 6 h) and persistent thick clots with patchy or extensive infarction of circumscribed cortex in all animals. Infarcts were significantly larger after blood clot infusion compared to mass effect controls using fibrin clots of equal volume. Haematoxylin and eosin staining of infarcts showed well demarcated zones of oedema and hypoxic-ischaemic neuronal injury, consistent with acute infarction. The association of spreading depolarizations with early brain injury was then investigated in 23 patients [14 female; age (median, quartiles): 57 years (47, 63)] after repair of ruptured anterior communicating artery aneurysms by clip ligation (n = 14) or coiling (n = 9). Frontal electrocorticography [duration: 54 h (34, 66)] from subdural electrode strips was analysed over Days 0–3 after initial haemorrhage and magnetic resonance imaging studies were performed at ∼ 24–48 h after aneurysm treatment. Patients with frontal infarcts only and those with frontal infarcts and/or intracerebral haemorrhage were both significantly more likely to have spreading depolarizations (6/7 and 10/12, respectively) than those without frontal brain lesions (1/11, P’s < 0.05). These results suggest that subarachnoid clots in sulci/fissures are sufficient to induce spreading depolarizations and acute infarction in adjacent cortex. We hypothesize that the cellular toxicity and vasoconstrictive effects of depolarizations act in synergy with direct ischaemic effects of haemorrhage as mechanisms of infarct development. Results further validate spreading depolarizations as a clinical marker of early brain injury and establish a clinically relevant model to investigate causal pathologic sequences and potential therapeutic interventions.
The L444P Gba1 mutation enhances alpha-synuclein induced loss of nigral dopaminergic neurons in mice Brain (IF 10.292) Pub Date : 2017-09-06 Anna Migdalska-Richards, Michal Wegrzynowicz, Raffaella Rusconi, Giulio Deangeli, Donato A. Di Monte, Maria G. Spillantini, Anthony H. V. Schapira
Mutations in glucocerebrosidase 1 (GBA1) represent the most prevalent risk factor for Parkinson’s disease. The molecular mechanisms underlying the link between GBA1 mutations and Parkinson’s disease are incompletely understood. We analysed two aged (24-month-old) Gba1 mouse models, one carrying a knock-out mutation and the other a L444P knock-in mutation. A significant reduction of glucocerebrosidase activity was associated with increased total alpha-synuclein accumulation in both these models. Gba1 mutations alone did not alter the number of nigral dopaminergic neurons nor striatal dopamine levels. We then investigated the effect of overexpression of human alpha-synuclein in the substantia nigra of aged (18 to 21-month-old) L444P Gba1 mice. Following intraparenchymal injections of human alpha-synuclein carrying viral vectors, pathological accumulation of phosphorylated alpha-synuclein occurred within the transduced neurons. Stereological counts of nigral dopaminergic neurons revealed a significantly greater cell loss in Gba1-mutant than wild-type mice. These results indicate that Gba1 deficiency enhances neuronal vulnerability to neurodegenerative processes triggered by increased alpha-synuclein expression.
A ventral glomerular deficit in Parkinson’s disease revealed by whole olfactory bulb reconstruction Brain (IF 10.292) Pub Date : 2017-09-03 Bolek Zapiec, Birger V. Dieriks, Sheryl Tan, Richard L. M. Faull, Peter Mombaerts, Maurice A. Curtis
Olfactory dysfunction is common in Parkinson’s disease and is an early symptom, but its pathogenesis remains poorly understood. Hindering progress in our mechanistic understanding of olfactory dysfunction in Parkinson’s disease is the paucity of literature about the human olfactory bulb, both from normal and Parkinson’s disease cases. Qualitatively it is well established that the neat arrangement of the glomerular array seen in the mouse olfactory bulb is missing in humans. But rigorous quantitative approaches to describe and compare the thousands of glomeruli in the human olfactory bulb are not available. Here we report a quantitative approach to describe the glomerular component of the human olfactory bulb, and its application to draw statistical comparisons between olfactory bulbs from normal and Parkinson’s disease cases. We subjected horizontal 10 µm sections of olfactory bulbs from six normal and five Parkinson’s disease cases to fluorescence immunohistochemistry with antibodies against vesicular glutamate transporter-2 and neural cell adhesion molecule. We scanned the immunostained sections with a fluorescence slide scanner, segmented the glomeruli, and generated 3D reconstructions of whole olfactory bulbs. We document the occurrence of atypical glomerular morphologies and glomerular-like structures deep in the olfactory bulb, both in normal and Parkinson’s disease cases. We define a novel and objective parameter: the global glomerular voxel volume, which is the total volume of all voxels that are classified immunohistochemically as glomerular. We find that the global glomerular voxel volume in Parkinson’s disease cases is half that of normal cases. The distribution of glomerular voxels along the dorsal-ventral dimension of the olfactory bulb in these series of horizontal sections is significantly altered in Parkinson’s disease cases: whereas most glomerular voxels reside within the ventral half of olfactory bulbs from normal cases, glomerular voxels are more evenly spread among the ventral and dorsal halves of olfactory bulbs from Parkinson’s disease cases. These quantitative whole-olfactory bulb analyses indicate a predominantly ventral deficit in the glomerular component in Parkinson’s disease, consistent with the olfactory vector hypothesis for the pathogenesis of this neurodegenerative disease. The distribution of serine 129-phosphorylated α-synuclein immunoreactive voxels correlates with that of glomerular voxels. The higher the serine 129-phosphorylated α-synuclein load of an olfactory bulb from a Parkinson’s disease case, the lower the global glomerular voxel volume. Our rigorous quantitative approach to the whole olfactory bulb will help understand the anatomy and histology of the normal human olfactory bulb and its pathological alterations in Parkinson’s disease.
Chronic non-freezing cold injury results in neuropathic pain due to a sensory neuropathy Brain (IF 10.292) Pub Date : 2017-08-31 Tom A. Vale, Mkael Symmonds, Michael Polydefkis, Kelly Byrnes, Andrew S. C. Rice, Andreas C. Themistocleous, David L. H. Bennett
Non-freezing cold injury develops after sustained exposure to cold temperatures, resulting in tissue cooling but not freezing. This can result in persistent sensory disturbance of the hands and feet including numbness, paraesthesia and chronic pain. Both vascular and neurological aetiologies of this pain have been suggested but remain unproven. We prospectively approached patients referred for clinical assessment of chronic pain following non-freezing cold injury between 12 February 2014 and 30 November 2016. Of 47 patients approached, 42 consented to undergo detailed neurological evaluations including: questionnaires to detail pain location and characteristics, structured neurological examination, quantitative sensory testing, nerve conduction studies and skin biopsy for intraepidermal nerve fibre assessment. Of the 42 study participants, all had experienced non-freezing cold injury while serving in the UK armed services and the majority were of African descent (76.2%) and male (95.2%). Many participants reported multiple exposures to cold. The median time between initial injury and referral was 3.72 years. Pain was principally localized to the hands and the feet, neuropathic in nature and in all study participants associated with cold hypersensitivity. Clinical examination and quantitative sensory testing were consistent with a sensory neuropathy. In all cases, large fibre nerve conduction studies were normal. The intraepidermal nerve fibre density was markedly reduced with 90.5% of participants having a count at or below the 0.05 centile of published normative controls. Using the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain grading for neuropathic pain, 100% had probable and 95.2% definite neuropathic pain. Chronic non-freezing cold injury is a disabling neuropathic pain disorder due to a sensory neuropathy. Why some individuals develop an acute painful sensory neuropathy on sustained cold exposure is not yet known, but individuals of African descent appear vulnerable. Screening tools, such as the DN4 questionnaire, and treatment algorithms for neuropathic pain should now be used in the management of these patients.
Distinct spatiotemporal patterns of neuronal functional connectivity in primary progressive aphasia variants Brain (IF 10.292) Pub Date : 2017-08-31 Kamalini G. Ranasinghe, Leighton B. Hinkley, Alexander J. Beagle, Danielle Mizuiri, Susanne M. Honma, Ariane E. Welch, Isabel Hubbard, Maria Luisa Mandelli, Zachary A. Miller, Coleman Garrett, Alice La, Adam L. Boxer, John F. Houde, Bruce L. Miller, Keith A. Vossel, Maria Luisa Gorno-Tempini, Srikantan S. Nagarajan
Primary progressive aphasia is a syndrome characterized by progressive loss of language abilities with three main phenotypic clinical presentations, including logopenic, non-fluent/agrammatic, and semantic variants. Previous imaging studies have shown unique anatomic impacts within language networks in each variant. However, direct measures of spontaneous neuronal activity and functional integrity of these impacted neural networks in primary progressive aphasia are lacking. The aim of this study was to characterize the spatial and temporal patterns of resting state neuronal synchronizations in primary progressive aphasia syndromes. We hypothesized that resting state brain oscillations will show unique deficits within language network in each variant of primary progressive aphasia. We examined 39 patients with primary progressive aphasia including logopenic variant (n = 14, age = 61 ± 9 years), non-fluent/agrammatic variant (n = 12, age = 71 ± 8 years) and semantic variant (n = 13, age = 65 ± 7 years) using magnetoencephalographic imaging, compared to a control group that was matched in age and gender to each primary progressive aphasia subgroup (n = 20, age = 65 ± 5 years). Each patient underwent a complete clinical evaluation including a comprehensive battery of language tests. We examined the whole-brain resting state functional connectivity as measured by imaginary coherence in each patient group compared to the control cohort, in three frequency oscillation bands—delta-theta (2–8 Hz); alpha (8–12 Hz); beta (12–30 Hz). Each variant showed a distinct spatiotemporal pattern of altered functional connectivity compared to age-matched controls. Specifically, we found significant hyposynchrony of alpha and beta frequency within the left posterior temporal and occipital cortices in patients with the logopenic variant, within the left inferior frontal cortex in patients with the non-fluent/agrammatic variant, and within the left temporo-parietal junction in patients with the semantic variant. Patients with logopenic variant primary progressive aphasia also showed significant hypersynchrony of delta-theta frequency within bilateral medial frontal and posterior parietal cortices. Furthermore, region of interest-based analyses comparing the spatiotemporal patterns of variant-specific regions of interest identified in comparison to age-matched controls showed significant differences between primary progressive aphasia variants themselves. We also found distinct patterns of regional spectral power changes in each primary progressive aphasia variant, compared to age-matched controls. Our results demonstrate neurophysiological signatures of network-specific neuronal dysfunction in primary progressive aphasia variants. The unique spatiotemporal patterns of neuronal synchrony signify diverse neurophysiological disruptions and pathological underpinnings of the language network in each variant.
A singular person with multiple interests Brain (IF 10.292) Pub Date : 2017-08-29 Christopher Gardner-Thorpe
Parkinson’s disease, sadly such a common diagnosis, derives its name from the London doctor, James Parkinson (1755–1824), about whom much more has become known in the past 30 years. Parkinson’s name was given to the disorder by Jean-Martin Charcot (1825–1893) who spoke of ‘la maladie de Parkinson’ and who owned a copy of Parkinson’s famous Essay on the Shaking Palsy (Fig. 1). A new biography is always fascinating and Cherry Lewis has, in The Enlightened Mr Parkinson, provided a fresh look supplemented by references, all of which is engaging and to be enjoyed.
On assessing neurofeedback effects: should double-blind replace neurophysiological mechanisms? Brain (IF 10.292) Pub Date : 2017-08-24 Thomas Fovet, Jean-Arthur Micoulaud-Franchi, François-Benoît Vialatte, Fabien Lotte, Christophe Daudet, Jean-Marie Batail, Jérémie Mattout, Guilherme Wood, Renaud Jardri, Stefanie Enriquez-Geppert, Tomas Ros
Reply: On assessing neurofeedback effects: should double-blind replace neurophysiological mechanisms? Brain (IF 10.292) Pub Date : 2017-08-24 Manuel Schabus
PRUNE1: a disease-causing gene for secondary microcephaly Brain (IF 10.292) Pub Date : 2017-08-23 Mert Karakaya, Sanem Yilmaz, Markus Storbeck, Irmgard Hoelker, Raoul Heller, Gül Serdaroglu, Sarenur Gökben, Uluc Yis, Brunhilde Wirth
Reply: PRUNE1: a disease-causing gene for secondary microcephaly Brain (IF 10.292) Pub Date : 2017-08-23 Emma L. Baple, Henry Houlden, Massimo Zollo, Andrew H. Crosby
Tourette syndrome: a disorder of the social decision-making network Brain (IF 10.292) Pub Date : 2017-08-22 Roger L. Albin
Tourette syndrome is a common neurodevelopmental disorder defined by characteristic involuntary movements, tics, with both motor and phonic components. Tourette syndrome is usually conceptualized as a basal ganglia disorder, with an emphasis on striatal dysfunction. While considerable evidence is consistent with these concepts, imaging data suggest diffuse functional and structural abnormalities in Tourette syndrome brain. Tourette syndrome exhibits features that are difficult to explain solely based on basal ganglia circuit dysfunctions. These features include the natural history of tic expression, with typical onset of tics around ages 5 to 7 years and exacerbation during the peri-pubertal years, marked sex disparity with higher male prevalence, and the characteristic distribution of tics. The latter are usually repetitive, somewhat stereotyped involuntary eye, facial and head movements, and phonations. A major functional role of eye, face, and head movements is social signalling. Prior work in social neuroscience identified a phylogenetically conserved network of sexually dimorphic subcortical nuclei, the Social Behaviour Network, mediating many social behaviours. Social behaviour network function is modulated developmentally by gonadal steroids and social behaviour network outputs are stereotyped sex and species specific behaviours. In 2011 O’Connell and Hofmann proposed that the social behaviour network interdigitates with the basal ganglia to form a greater network, the social decision-making network. The social decision-making network may have two functionally complementary limbs: the basal ganglia component responsible for evaluation of socially relevant stimuli and actions with the social behaviour network component responsible for the performance of social acts. Social decision-making network dysfunction can explain major features of the neurobiology of Tourette syndrome. Tourette syndrome may be a disorder of social communication resulting from developmental abnormalities at several levels of the social decision-making network. The social decision-making network dysfunction hypothesis suggests new avenues for research in Tourette syndrome and new potential therapeutic targets.
Using an engineered glutamate-gated chloride channel to silence sensory neurons and treat neuropathic pain at the source Brain (IF 10.292) Pub Date : 2017-08-19 Greg A. Weir, Steven J. Middleton, Alex J. Clark, Tarun Daniel, Nikita Khovanov, Stephen B. McMahon, David L. Bennett
Peripheral neuropathic pain arises as a consequence of injury to sensory neurons; the development of ectopic activity in these neurons is thought to be critical for the induction and maintenance of such pain. Local anaesthetics and anti-epileptic drugs can suppress hyperexcitability; however, these drugs are complicated by unwanted effects on motor, central nervous system and cardiac function, and alternative more selective treatments to suppress hyperexcitability are therefore required. Here we show that a glutamate-gated chloride channel modified to be activated by low doses of ivermectin (but not glutamate) is highly effective in silencing sensory neurons and reversing neuropathic pain-related hypersensitivity. Activation of the glutamate-gated chloride channel expressed in either rodent or human induced pluripotent stem cell-derived sensory neurons in vitro potently inhibited their response to both electrical and algogenic stimuli. We have shown that silencing is achieved both at nerve terminals and the soma and is independent of membrane hyperpolarization and instead likely mediated by lowering of the membrane resistance. Using intrathecal adeno-associated virus serotype 9-based delivery, the glutamate-gated chloride channel was successfully targeted to mouse sensory neurons in vivo, resulting in high level and long-lasting expression of the channel selectively in sensory neurons. This enabled reproducible and reversible modulation of thermal and mechanical pain thresholds in vivo; analgesia was observed for 3 days after a single systemic dose of ivermectin. We did not observe any motor or proprioceptive deficits and noted no reduction in cutaneous afferent innervation or upregulation of the injury marker ATF3 following prolonged glutamate-gated chloride channel expression. Established mechanical and cold pain-related hypersensitivity generated by the spared nerve injury model of neuropathic pain was reversed by ivermectin treatment. The efficacy of ivermectin in ameliorating behavioural hypersensitivity was mirrored at the cellular level by a cessation of ectopic activity in sensory neurons. These findings demonstrate the importance of aberrant afferent input in the maintenance of neuropathic pain and the potential for targeted chemogenetic silencing as a new treatment modality in neuropathic pain.
Glymphatic MRI in idiopathic normal pressure hydrocephalus Brain (IF 10.292) Pub Date : 2017-08-18 Geir Ringstad, Svein Are Sirirud Vatnehol, Per Kristian Eide
The glymphatic system has in previous studies been shown as fundamental to clearance of waste metabolites from the brain interstitial space, and is proposed to be instrumental in normal ageing and brain pathology such as Alzheimer’s disease and brain trauma. Assessment of glymphatic function using magnetic resonance imaging with intrathecal contrast agent as a cerebrospinal fluid tracer has so far been limited to rodents. We aimed to image cerebrospinal fluid flow characteristics and glymphatic function in humans, and applied the methodology in a prospective study of 15 idiopathic normal pressure hydrocephalus patients (mean age 71.3 ± 8.1 years, three female and 12 male) and eight reference subjects (mean age 41.1 + 13.0 years, six female and two male) with suspected cerebrospinal fluid leakage (seven) and intracranial cyst (one). The imaging protocol included T1-weighted magnetic resonance imaging with equal sequence parameters before and at multiple time points through 24 h after intrathecal injection of the contrast agent gadobutrol at the lumbar level. All study subjects were kept in the supine position between examinations during the first day. Gadobutrol enhancement was measured at all imaging time points from regions of interest placed at predefined locations in brain parenchyma, the subarachnoid and intraventricular space, and inside the sagittal sinus. Parameters demonstrating gadobutrol enhancement and clearance in different locations were compared between idiopathic normal pressure hydrocephalus and reference subjects. A characteristic flow pattern in idiopathic normal hydrocephalus was ventricular reflux of gadobutrol from the subarachnoid space followed by transependymal gadobutrol migration. At the brain surfaces, gadobutrol propagated antegradely along large leptomeningeal arteries in all study subjects, and preceded glymphatic enhancement in adjacent brain tissue, indicating a pivotal role of intracranial pulsations for glymphatic function. In idiopathic normal pressure hydrocephalus, we found delayed enhancement (P < 0.05) and decreased clearance of gadobutrol (P < 0.05) at the Sylvian fissure. Parenchymal (glymphatic) enhancement peaked overnight in both study groups, possibly indicating a crucial role of sleep, and was larger in normal pressure hydrocephalus patients (P < 0.05 at inferior frontal gyrus). We interpret decreased gadobutrol clearance from the subarachnoid space, along with persisting enhancement in brain parenchyma, as signs of reduced glymphatic clearance in idiopathic normal hydrocephalus, and hypothesize that reduced glymphatic function is instrumental for dementia in this disease. The study shows promise for glymphatic magnetic resonance imaging as a method to assess human brain metabolic function and renders a potential for contrast enhanced brain extravascular space imaging.
Progranulin: a new avenue towards the understanding and treatment of neurodegenerative disease Brain (IF 10.292) Pub Date : 2017-08-18 Babykumari P. Chitramuthu, Hugh P. J. Bennett, Andrew Bateman
Progranulin, a secreted glycoprotein, is encoded in humans by the single GRN gene. Progranulin consists of seven and a half, tandemly repeated, non-identical copies of the 12 cysteine granulin motif. Many cellular processes and diseases are associated with this unique pleiotropic factor that include, but are not limited to, embryogenesis, tumorigenesis, inflammation, wound repair, neurodegeneration and lysosome function. Haploinsufficiency caused by autosomal dominant mutations within the GRN gene leads to frontotemporal lobar degeneration, a progressive neuronal atrophy that presents in patients as frontotemporal dementia. Frontotemporal dementia is an early onset form of dementia, distinct from Alzheimer’s disease. The GRN-related form of frontotemporal lobar dementia is a proteinopathy characterized by the appearance of neuronal inclusions containing ubiquitinated and fragmented TDP-43 (encoded by TARDBP). The neurotrophic and neuro-immunomodulatory properties of progranulin have recently been reported but are still not well understood. Gene delivery of GRN in experimental models of Alzheimer’s- and Parkinson’s-like diseases inhibits phenotype progression. Here we review what is currently known concerning the molecular function and mechanism of action of progranulin in normal physiological and pathophysiological conditions in both in vitro and in vivo models. The potential therapeutic applications of progranulin in treating neurodegenerative diseases are highlighted.
Biallelic mutations in the homeodomain of NKX6-2 underlie a severe hypomyelinating leukodystrophy Brain (IF 10.292) Pub Date : 2017-08-18 Imen Dorboz, Chiara Aiello, Cas Simons, Robert Thompson Stone, Marcello Niceta, Monique Elmaleh, Mohammad Abuawad, Diane Doummar, Alessandro Bruselles, Nicole I. Wolf, Lorena Travaglini, Odile Boespflug-Tanguy, Marco Tartaglia, Adeline Vanderver, Diana Rodriguez, Enrico Bertini
Hypomyelinating leukodystrophies are genetically heterogeneous disorders with overlapping clinical and neuroimaging features reflecting variable abnormalities in myelin formation. We report on the identification of biallelic inactivating mutations in NKX6-2, a gene encoding a transcription factor regulating multiple developmental processes with a main role in oligodendrocyte differentiation and regulation of myelin-specific gene expression, as the cause underlying a previously unrecognized severe variant of hypomyelinating leukodystrophy. Five affected subjects (three unrelated families) were documented to share biallelic inactivating mutations affecting the NKX6-2 homeobox domain. A trio-based whole exome sequencing analysis in the first family detected a homozygous frameshift change [c.606delinsTA; p.(Lys202Asnfs*?)]. In the second family, homozygosity mapping coupled to whole exome sequencing identified a homozygous nucleotide substitution (c.565G>T) introducing a premature stop codon (p.Glu189*). In the third family, whole exome sequencing established compound heterozygosity for a non-conservative missense change affecting a key residue participating in DNA binding (c.599G>A; p.Arg200Gln) and a nonsense substitution (c.589C>T; p.Gln197*), in both affected siblings. The clinical presentation was homogeneous, with four subjects having severe motor delays, nystagmus and absent head control, and one individual showing gross motor delay at the age of 6 months. All exhibited neuroimaging that was consistent with hypomyelination. These findings define a novel, severe form of leukodystrophy caused by impaired NKX6-2 function.
Novel insights in the disease biology of mutant small heat shock proteins in neuromuscular diseases Brain (IF 10.292) Pub Date : 2017-08-14 Elias Adriaenssens, Thomas Geuens, Jonathan Baets, Andoni Echaniz-Laguna, Vincent Timmerman
Small heat shock proteins are molecular chaperones that exert diverse cellular functions. To date, mutations in the coding regions of HSPB1 (Hsp27) and HSPB8 (Hsp22) were reported to cause distal hereditary motor neuropathy and Charcot-Marie-Tooth disease. Recently, the clinical spectrum of HSPB1 and HSPB8 mutations was expanded to also include myopathies. Here we provide an update on the molecular genetics and biology of small heat shock protein mutations in neuromuscular diseases.
Mammalian target of rapamycin complex 1 activation sensitizes human glioma cells to hypoxia-induced cell death Brain (IF 10.292) Pub Date : 2017-08-11 Anna-Luisa Thiepold, Nadja I. Lorenz, Martha Foltyn, Anna L. Engel, Iris Divé, Hans Urban, Sonja Heller, Ines Bruns, Ute Hofmann, Stefan Dröse, Patrick N. Harter, Michel Mittelbronn, Joachim P. Steinbach, Michael W. Ronellenfitsch
Glioblastomas are characterized by fast uncontrolled growth leading to hypoxic areas and necrosis. Signalling from EGFR via mammalian target of rapamycin complex 1 (mTORC1) is a major driver of cell growth and proliferation and one of the most commonly altered signalling pathways in glioblastomas. Therefore, epidermal growth factor receptor and mTORC1 signalling are plausible therapeutic targets and clinical trials with inhibitors are in progress. However, we have previously shown that epidermal growth factor receptor and mTORC1 inhibition triggers metabolic changes leading to adverse effects under the conditions of the tumour microenvironment by protecting from hypoxia-induced cell death. We hypothesized that conversely mTORC1 activation sensitizes glioma cells to hypoxia-induced cell death. As a model for mTORC1 activation we used gene suppression of its physiological inhibitor TSC2 (TSC2sh). TSC2sh glioma cells showed increased sensitivity to hypoxia-induced cell death that was accompanied by an earlier ATP depletion and an increase in reactive oxygen species. There was no difference in extracellular glucose consumption but an altered intracellular metabolic profile with an increase of intermediates of the pentose phosphate pathway. Mechanistically, mTORC1 upregulated the first and rate limiting enzyme of the pentose phosphate pathway, G6PD. Furthermore, an increase in oxygen consumption in TSC2sh cells was detected. This appeared to be due to higher transcription rates of genes involved in mitochondrial respiratory function including PPARGC1A and PPARGC1B (also known as PGC-1α and -β). The finding that mTORC1 activation causes an increase in oxygen consumption and renders malignant glioma cells susceptible to hypoxia and nutrient deprivation could help identify glioblastoma patient cohorts more likely to benefit from hypoxia-inducing therapies such as the VEGFA-targeting antibody bevacizumab in future clinical evaluations.
Monitoring clinical progression with mitochondrial disease biomarkers Brain (IF 10.292) Pub Date : 2017-08-03 Hannah E. Steele, Rita Horvath, Jon J. Lyon, Patrick F. Chinnery
Mitochondrial disorders are genetically determined metabolic diseases due to a biochemical deficiency of the respiratory chain. Given that multi-system involvement and disease progression are common features of mitochondrial disorders they carry substantial morbidity and mortality. Despite this, no disease-modifying treatments exist with clear clinical benefits, and the current best management of mitochondrial disease is supportive. Several therapeutic strategies for mitochondrial disorders are now at a mature preclinical stage. Some are making the transition into early-phase patient trials, but the lack of validated biomarkers of disease progression presents a challenge when developing new therapies for patients. This update discusses current biomarkers of mitochondrial disease progression including metabolomics, circulating serum markers, exercise physiology, and both structural and functional imaging. We discuss the advantages and disadvantages of each approach, and consider emerging techniques with a potential role in trials of new therapies.
Anatomic consistencies across epilepsies: a stereotactic-EEG informed high-resolution structural connectivity study Brain (IF 10.292) Pub Date : 2017-08-02 Pierre Besson, S. Kathleen Bandt, Timothée Proix, Stanislas Lagarde, Viktor K. Jirsa, Jean-Philippe Ranjeva, Fabrice Bartolomei, Maxime Guye
Drug-resistant localization-related epilepsies are now recognized as network diseases. However, the exact relationship between the organization of the epileptogenic network and brain anatomy overall remains incompletely understood. To better understand this relationship, we studied structural connectivity obtained from diffusion weighted imaging in patients with epilepsy using both stereo-electroencephalography (SEEG)-determined epileptic brain regions and whole-brain analysis. High resolution structural connectivity analysis was applied in 15 patients with drug-resistant localization-related epilepsies and 36 healthy control subjects to study structural connectivity changes in epilepsy. Two different methods of structural connectivity analysis were carried out using diffusion weighted imaging, one focusing on the relationship between epileptic regions determined by SEEG investigations and one blinded to epileptic regions looking at whole-brain connectivity. First, we performed zone-based analysis comparing structural connectivity findings in patients and controls within and between SEEG-defined zones of interest. Next, we performed whole-brain structural connectivity analysis in all subjects and compared findings to the same SEEG-defined zones of interest. Finally, structural connectivity findings were correlated against clinical features. Zone-based analysis revealed no significant decreased structural connectivity within nodes of the epilepsy network at the group level, but did demonstrate significant structural connectivity differences between nodes of the epileptogenic network (regions involved in seizures generation and propagation) and the remaining of the brain in patients compared to controls. Whole-brain analyses showed a total of 133 clusters of significantly decreased structural connectivity across all patients. One cluster of significantly increased structural connectivity was identified in a single patient. Clusters of decreased structural connectivity showed topographical preference for both the salience and default mode networks despite clinical heterogeneity within our patient sample. Correlation analysis did not reveal any significant findings regarding either the effect of age at disease onset, disease duration or post-surgical outcome on structural connectivity. Taken together, this work demonstrates that structural connectivity disintegration targets distributed functional networks while sparing the epilepsy network.
The cerebellum in Alzheimer’s disease: evaluating its role in cognitive decline Brain (IF 10.292) Pub Date : 2017-07-28 Heidi I. L. Jacobs, David A. Hopkins, Helen C. Mayrhofer, Emiliano Bruner, Fred W. van Leeuwen, Wijnand Raaijmakers, Jeremy D. Schmahmann
The cerebellum has long been regarded as essential only for the coordination of voluntary motor activity and motor learning. Anatomical, clinical and neuroimaging studies have led to a paradigm shift in the understanding of the cerebellar role in nervous system function, demonstrating that the cerebellum appears integral also to the modulation of cognition and emotion. The search to understand the cerebellar contribution to cognitive processing has increased interest in exploring the role of the cerebellum in neurodegenerative and neuropsychiatric disorders. Principal among these is Alzheimer’s disease. Here we review an already sizeable existing literature on the neuropathological, structural and functional neuroimaging studies of the cerebellum in Alzheimer’s disease. We consider these observations in the light of the cognitive deficits that characterize Alzheimer’s disease and in so doing we introduce a new perspective on its pathophysiology and manifestations. We propose an integrative hypothesis that there is a cerebellar contribution to the cognitive and neuropsychiatric deficits in Alzheimer’s disease. We draw on the dysmetria of thought theory to suggest that this cerebellar component manifests as deficits in modulation of the neurobehavioural deficits. We provide suggestions for future studies to investigate this hypothesis and, ultimately, to establish a comprehensive, causal clinicopathological disease model.
Cell-based therapeutic strategies for multiple sclerosis Brain (IF 10.292) Pub Date : 2017-07-21 Neil J. Scolding, Marcelo Pasquini, Stephen C. Reingold, Jeffrey A. Cohen, Harold Atkins, Brenda Banwell, Amit Bar-Or, Bruce Bebo, James Bowen, Richard Burt, Peter Calabresi, Jeffrey Cohen, Giancarlo Comi, Peter Connick, Anne Cross, Gary Cutter, Tobias Derfuss, Charles Ffrench-Constant, Mark Freedman, Jacques Galipeau, Myla Goldman, Steven Goldman, Andrew Goodman, Ari Green, Linda Griffith, Hans-Peter Hartung, Bernhard Hemmer, Insoo Hyun, Ellen Iacobaeus, Matilde Inglese, Burk Jubelt, Dimitrios Karussis, Patrick Küry, Douglas Landsman, Cornelia Laule, Roland Liblau, Giovanni Mancardi, Ruth Ann Marrie, Aaron Miller, Robert Miller, David Miller, Ellen Mowry, Paolo Muraro, Richard Nash, Daniel Ontaneda, Marcelo Pasquini, Daniel Pelletier, Luca Peruzzotti-Jametti, Stefano Pluchino, Michael Racke, Stephen Reingold, Claire Rice, Olle Ringdén, Alex Rovira, Riccardo Saccardi, Saud Sadiq, Stefanie Sarantopoulos, Sean Savitz, Neil Scolding, Per Soelberg Sorensen, Maria Pia Sormani, Olaf Stuve, Paul Tesar, Alan Thompson, Maria Trojano, Antonio Uccelli, Bernard Uitdehaag, Ursula Utz, Sandra Vukusic, Emmanuelle Waubant, Alastair Wilkins
The availability of multiple disease-modifying medications with regulatory approval to treat multiple sclerosis illustrates the substantial progress made in therapy of the disease. However, all are only partially effective in preventing inflammatory tissue damage in the central nervous system and none directly promotes repair. Cell-based therapies, including immunoablation followed by autologous haematopoietic stem cell transplantation, mesenchymal and related stem cell transplantation, pharmacologic manipulation of endogenous stem cells to enhance their reparative capabilities, and transplantation of oligodendrocyte progenitor cells, have generated substantial interest as novel therapeutic strategies for immune modulation, neuroprotection, or repair of the damaged central nervous system in multiple sclerosis. Each approach has potential advantages but also safety concerns and unresolved questions. Moreover, clinical trials of cell-based therapies present several unique methodological and ethical issues. We summarize here the status of cell-based therapies to treat multiple sclerosis and make consensus recommendations for future research and clinical trials.
Corrigendum Brain (IF 10.292) Pub Date : 2017-03-18
Yoshitsugu Aoki, Raquel Manzano, Yi Lee, Ruxandra Dafinca, Misako Aoki, Andrew G. L. Douglas, Miguel A. Varela, Chaitra Sathyaprakash, Jakub Scaber, Paola Barbagallo, Pieter Vader, Imre Mäger, Kariem Ezzat, Martin R. Turner, Naoki Ito, Samanta Gasco, Norihiko Ohbayashi, Samir El Andaloussi, Shin’ichi Takeda, Mitsunori Fukuda, Kevin Talbot and Matthew J. A. Wood. C9orf72 and RAB7L1 regulate vesicle trafficking in amyotrophic lateral sclerosis and frontotemporal dementia. BRAIN 2017; 140: doi:10.1093/brain/awx024.
Editorial Brain (IF 10.292) Pub Date : 2017-08-24 Dimitri M. Kullmann
The cover of this issue relates to an article by Neil Harrison and colleagues who examine 53 cases of psychogenic amnesia, finding that they fall into four groups: fugue state; fugue-to-focal retrograde amnesia; psychogenic focal retrograde amnesia following a minor neurological episode; and patients with gaps in their memories. Agatha Christie, the crime thriller writer, was on the front pages of newspapers throughout the English-speaking world in late 1926 when she disappeared from Styles, her home in Berkshire, and turned up in Harrogate 11 days later, having checked into the Swan Hydropathic Hotel as Mrs T. Neele. She was unable to account for her whereabouts during her absence, and apparently unaware that she had a daughter when met by her husband, Colonel Archibald Christie. She made...
Lost in space: do somatic symptoms affect the perception of extra-somatic stimuli? Brain (IF 10.292) Pub Date : 2017-08-24 Valéry Legrain
This scientific commentary refers to ‘Space-based bias of covert visual attention in complex regional pain syndrome’, by Bultitude et al. (doi:10.1093/brain/awx152).
Stereotypical activation of hippocampal ensembles during seizures Brain (IF 10.292) Pub Date : 2017-08-24 Pierre-Pascal Lenck-Santini
This scientific commentary refers to ‘Involvement of fast-spiking cells in ictal sequences during spontaneous seizures in rats with chronic temporal lobe epilepsy’, by Neumann et al. (doi:10.1093/brain/awx179).
Uncovering hidden integrative cerebral function in the intensive care unit Brain (IF 10.292) Pub Date : 2017-08-24 Nicholas D. Schiff
This scientific commentary refers to ‘Early detection of consciousness in patients with acute severe traumatic brain injury’, by Edlow et al. (doi:10.1093/brain/awx176).
Brain monoamine oxidases in human parkinsonian disorders Brain (IF 10.292) Pub Date : 2017-08-24 Kurt A. Jellinger
This scientific commentary refers to ‘Brain monoamine oxidase B and A in human parkinsonian dopamine deficiency disorders’ by Junchao Tong et al. (doi:10.1093/brain/awx172).
The synaptic function of parkin Brain (IF 10.292) Pub Date : 2017-02-23 Jenny Sassone, GiuliaMaia Serratto, Flavia Valtorta, Vincenzo Silani, Maria Passafaro, Andrea Ciammola
Loss of function mutations in the gene PARK2, which encodes the protein parkin, cause autosomal recessive juvenile parkinsonism, a neurodegenerative disease characterized by degeneration of the dopaminergic neurons localized in the substantia nigra pars compacta. No therapy is effective in slowing disease progression mostly because the pathogenesis of the disease is yet to be understood. From accruing evidence suggesting that the protein parkin directly regulates synapses it can be hypothesized that PARK2 gene mutations lead to early synaptic damage that results in dopaminergic neuron loss over time. We review evidence that supports the role of parkin in modulating excitatory and dopaminergic synapse functions. We also discuss how these findings underpin the concept that autosomal recessive juvenile parkinsonism can be primarily a synaptopathy. Investigation into the molecular interactions between parkin and synaptic proteins may yield novel targets for pharmacologic interventions.
Inflammasomes in neurological diseases: emerging pathogenic and therapeutic concepts Brain (IF 10.292) Pub Date : 2017-07-06 Manmeet K. Mamik, Christopher Power
Inflammasome activation in the central nervous system occurs in both health and disease. Inflammasomes are cytosolic protein complexes that sense specific infectious or host stimuli and initiate inflammatory responses through caspase activation. Assembly of inflammasomes results in caspase-1-mediated proteolytic cleavage and release of the pro-inflammatory cytokines, interleukin-1β and interleukin-18, with initiation of pyroptosis, an inflammatory programmed cell death. Recent developments in the inflammasome field have uncovered novel molecular mechanisms that contribute to a broad range of neurological disorders including those associated with specific mutations in inflammasome genes as well as diseases modulated by inflammasome activation. This update focuses on recent developments in the field of inflammasome biology highlighting different inflammasome activators and pathways discovered in the nervous system. We also discuss targeted therapies that regulate inflammasomes and improve neurological outcomes.
Distinct 18F-AV-1451 tau PET retention patterns in early- and late-onset Alzheimer’s disease Brain (IF 10.292) Pub Date : 2017-07-16 Michael Schöll, Rik Ossenkoppele, Olof Strandberg, Sebastian Palmqvist, Jonas Jögi, Tomas Ohlsson, Ruben Smith, Oskar Hansson
Patients with Alzheimer’s disease can present with different clinical phenotypes. Individuals with late-onset Alzheimer’s disease (>65 years) typically present with medial temporal lobe neurodegeneration and predominantly amnestic symptomatology, while patients with early-onset Alzheimer’s disease (<65 years) exhibit greater neocortical involvement associated with a clinical presentation including dyspraxia, executive dysfunction, or visuospatial impairment. We recruited 20 patients with early-onset Alzheimer’s disease, 21 with late-onset Alzheimer’s disease, three with prodromal early-onset Alzheimer’s disease and 13 with prodromal late-onset Alzheimer’s disease, as well as 30 cognitively healthy elderly controls, that had undergone 18F-AV-1451 tau positron emission tomography and structural magnetic resonance imaging to explore whether early- and late-onset Alzheimer’s disease exhibit differential regional tau pathology and atrophy patterns. Strong associations of lower age at symptom onset with higher 18F-AV-1451 uptake were observed in several neocortical regions, while higher age did not yield positive associations in neither patient group. Comparing patients with early-onset Alzheimer’s disease with controls resulted in significantly higher 18F-AV-1451 retention throughout the neocortex, while comparing healthy controls with late-onset Alzheimer’s disease patients yielded a distinct pattern of higher 18F-AV-1451 retention, predominantly confined to temporal lobe regions. When compared against each other, the early-onset Alzheimer’s disease group exhibited greater uptake than the late-onset group in prefrontal and premotor, as well as in inferior parietal cortex. These preliminary findings indicate that age may constitute an important contributor to Alzheimer’s disease heterogeneity highlighting the potential of tau positron emission tomography to capture phenotypic variation across patients with Alzheimer’s disease.
The antimyotonic effect of lamotrigine in non-dystrophic myotonias: a double-blind randomized study Brain (IF 10.292) Pub Date : 2017-08-24 Grete Andersen, Gitte Hedermann, Nanna Witting, Morten Duno, Henning Andersen, John Vissing
Mexiletine is the only drug with proven effect for treatment of non-dystrophic myotonia, but mexiletine is expensive, has limited availability and several side effects. There is therefore a need to identify other pharmacological compounds that can alleviate myotonia in non-dystrophic myotonias. Like mexiletine, lamotrigine is a sodium channel blocker, but unlike mexiletine, lamotrigine is available, inexpensive, and well tolerated. We investigated the potential of using lamotrigine for treatment of myotonia in patients with non-dystrophic myotonias. In this, randomized double-blind, placebo-controlled, two-period cross-over study, we included adult outpatients recruited from all of Denmark with clinical myotonia and genetically confirmed myotonia congenita and paramyotonia congenita for investigation at the Copenhagen Neuromuscular Center. A pharmacy produced the medication and placebo, and randomized patients in blocks of 10. Participants and investigators were all blinded to treatment until the end of the trial. In two 8-week periods, oral lamotrigine or placebo capsules were provided once daily, with increasing doses (from 25 mg, 50 mg, 150 mg to 300 mg) every second week. The primary outcome was a severity score of myotonia, the Myotonic Behaviour Scale ranging from asymptomatic (score 1) to invalidating myotonia (score 6), reported by the participants during Weeks 0 and 8 in each treatment period. Clinical myotonia was also measured and side effects were monitored. The study was registered at ClinicalTrials.gov (NCT02159963) and EudraCT (2013-003309-24). We included 26 patients (10 females, 16 males, age: 19–74 years) from 13 November 2013 to 6 July 2015. Twenty-two completed the entire study. One patient withdrew due to an allergic reaction to lamotrigine. Three patients withdrew for reasons not related to the trial intervention. The Myotonic Behaviour Scale at baseline was 3.2 ± 1.1, which changed after treatment with lamotrigine by 1.3 ± 0.2 scores (P < 0.001), but not with placebo (0.2 ± 0.1 scores, P = 0.4). The estimated effect size was 1.0 ± 0.2 (95% confidence interval = 0.5–1.5, P < 0.001, n = 22). The standardized effect size of lamotrigine was 1.5 (confidence interval: 1.2–1.8). Number needed to treat was 2.6 (P = 0.006, n = 26). No adverse or unsuspected event occurred. Common side effects occurred in both treatment groups; number needed to harm was 5.2 (P = 0.11, n = 26). Lamotrigine effectively reduced myotonia, emphasized by consistency between effects on patient-related outcomes and objective outcomes. The frequency of side effects was acceptable. Considering this and the high availability and low cost of the drug, we suggest that lamotrigine should be used as the first line of treatment for myotonia in treatment-naive patients with non-dystrophic myotonias.
Space-based bias of covert visual attention in complex regional pain syndrome Brain (IF 10.292) Pub Date : 2017-07-09 Janet H. Bultitude, Ian Walker, Charles Spence
See Legrain (doi:10.1093/awx188) for a scientific commentary on this article.
Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy Brain (IF 10.292) Pub Date : 2017-08-24 Steffen Syrbe, Frederike L. Harms, Elena Parrini, Martino Montomoli, Ulrike Mütze, Katherine L. Helbig, Tilman Polster, Beate Albrecht, Ulrich Bernbeck, Ellen van Binsbergen, Saskia Biskup, Lydie Burglen, Jonas Denecke, Bénédicte Heron, Henrike O. Heyne, Georg F. Hoffmann, Frauke Hornemann, Takeshi Matsushige, Ryuki Matsuura, Mitsuhiro Kato, G. Christoph Korenke, Alma Kuechler, Constanze Lämmer, Andreas Merkenschlager, Cyril Mignot, Susanne Ruf, Mitsuko Nakashima, Hirotomo Saitsu, Hannah Stamberger, Tiziana Pisano, Jun Tohyama, Sarah Weckhuysen, Wendy Werckx, Julia Wickert, Francesco Mari, Nienke E. Verbeek, Rikke S. Møller, Bobby Koeleman, Naomichi Matsumoto, William B. Dobyns, Domenica Battaglia, Johannes R. Lemke, Kerstin Kutsche, Renzo Guerrini
De novo in-frame deletions and duplications in the SPTAN1 gene, encoding the non-erythrocyte αII spectrin, have been associated with severe West syndrome with hypomyelination and pontocerebellar atrophy. We aimed at comprehensively delineating the phenotypic spectrum associated with SPTAN1 mutations. Using different molecular genetic techniques, we identified 20 patients with a pathogenic or likely pathogenic SPTAN1 variant and reviewed their clinical, genetic and imaging data. SPTAN1 de novo alterations included seven unique missense variants and nine in-frame deletions/duplications of which 12 were novel. The recurrent three-amino acid duplication p.(Asp2303_Leu2305dup) occurred in five patients. Our patient cohort exhibited a broad spectrum of neurodevelopmental phenotypes, comprising six patients with mild to moderate intellectual disability, with or without epilepsy and behavioural disorders, and 14 patients with infantile epileptic encephalopathy, of which 13 had severe neurodevelopmental impairment and four died in early childhood. Imaging studies suggested that the severity of neurological impairment and epilepsy correlates with that of structural abnormalities as well as the mutation type and location. Out of seven patients harbouring mutations outside the α/β spectrin heterodimerization domain, four had normal brain imaging and three exhibited moderately progressive brain and/or cerebellar atrophy. Twelve of 13 patients with mutations located within the spectrin heterodimer contact site exhibited severe and progressive brain, brainstem and cerebellar atrophy, with hypomyelination in most. We used fibroblasts from five patients to study spectrin aggregate formation by Triton-X extraction and immunocytochemistry followed by fluorescence microscopy. αII/βII aggregates and αII spectrin in the insoluble protein fraction were observed in fibroblasts derived from patients with the mutations p.(Glu2207del), p.(Asp2303_Leu2305dup) and p.(Arg2308_Met2309dup), all falling in the nucleation site of the α/β spectrin heterodimer region. Molecular modelling of the seven SPTAN1 amino acid changes provided preliminary evidence for structural alterations of the A-, B- and/or C-helices within each of the mutated spectrin repeats. We conclude that SPTAN1-related disorders comprise a wide spectrum of neurodevelopmental phenotypes ranging from mild to severe and progressive. Spectrin aggregate formation in fibroblasts with mutations in the α/β heterodimerization domain seems to be associated with a severe neurodegenerative course and suggests that the amino acid stretch from Asp2303 to Met2309 in the α20 repeat is important for α/β spectrin heterodimer formation and/or αII spectrin function.
Clinical spectrum and genotype–phenotype associations of KCNA2-related encephalopathies Brain (IF 10.292) Pub Date : 2017-08-24 Silvia Masnada, Ulrike B. S. Hedrich, Elena Gardella, Julian Schubert, Charu Kaiwar, Eric W. Klee, Brendan C. Lanpher, Ralitza H. Gavrilova, Matthis Synofzik, Thomas Bast, Kathleen Gorman, Mary D. King, Nicholas M. Allen, Judith Conroy, Bruria Ben Zeev, Michal Tzadok, Christian Korff, Fanny Dubois, Keri Ramsey, Vinodh Narayanan, Jose M. Serratosa, Beatriz G. Giraldez, Ingo Helbig, Eric Marsh, Margaret O’Brien, Christina A. Bergqvist, Adrian Binelli, Brenda Porter, Eduardo Zaeyen, Dafne D. Horovitz, Markus Wolff, Dragan Marjanovic, Hande S. Caglayan, Mutluay Arslan, Sergio D. J. Pena, Sanjay M. Sisodiya, Simona Balestrini, Steffen Syrbe, Pierangelo Veggiotti, Johannes R. Lemke, Rikke S. Møller, Holger Lerche, Guido Rubboli
Recently, de novo mutations in the gene KCNA2, causing either a dominant-negative loss-of-function or a gain-of-function of the voltage-gated K+ channel Kv1.2, were described to cause a new molecular entity within the epileptic encephalopathies. Here, we report a cohort of 23 patients (eight previously described) with epileptic encephalopathy carrying either novel or known KCNA2 mutations, with the aim to detail the clinical phenotype associated with each of them, to characterize the functional effects of the newly identified mutations, and to assess genotype–phenotype associations. We identified five novel and confirmed six known mutations, three of which recurred in three, five and seven patients, respectively. Ten mutations were missense and one was a truncation mutation; de novo occurrence could be shown in 20 patients. Functional studies using a Xenopus oocyte two-microelectrode voltage clamp system revealed mutations with only loss-of-function effects (mostly dominant-negative current amplitude reduction) in eight patients or only gain-of-function effects (hyperpolarizing shift of voltage-dependent activation, increased amplitude) in nine patients. In six patients, the gain-of-function was diminished by an additional loss-of-function (gain-and loss-of-function) due to a hyperpolarizing shift of voltage-dependent activation combined with either decreased amplitudes or an additional hyperpolarizing shift of the inactivation curve. These electrophysiological findings correlated with distinct phenotypic features. The main differences were (i) predominant focal (loss-of-function) versus generalized (gain-of-function) seizures and corresponding epileptic discharges with prominent sleep activation in most cases with loss-of-function mutations; (ii) more severe epilepsy, developmental problems and ataxia, and atrophy of the cerebellum or even the whole brain in about half of the patients with gain-of-function mutations; and (iii) most severe early-onset phenotypes, occasionally with neonatal onset epilepsy and developmental impairment, as well as generalized and focal seizures and EEG abnormalities for patients with gain- and loss-of-function mutations. Our study thus indicates well represented genotype–phenotype associations between three subgroups of patients with KCNA2 encephalopathy according to the electrophysiological features of the mutations.
Involvement of fast-spiking cells in ictal sequences during spontaneous seizures in rats with chronic temporal lobe epilepsy Brain (IF 10.292) Pub Date : 2017-08-04 Adam R. Neumann, Robrecht Raedt, Hendrik W. Steenland, Mathieu Sprengers, Katarzyna Bzymek, Zaneta Navratilova, Lilia Mesina, Jeanne Xie, Valerie Lapointe, Fabian Kloosterman, Kristl Vonck, Paul A. J. M. Boon, Ivan Soltesz, Bruce L. McNaughton, Artur Luczak
See Lenck-Santini (doi:10.1093/awx205) for a scientific commentary on this article.
Temporal lobe networks supporting the comprehension of spoken words Brain (IF 10.292) Pub Date : 2017-08-03 Leonardo Bonilha, Argye E. Hillis, Gregory Hickok, Dirk B. den Ouden, Chris Rorden, Julius Fridriksson
Auditory word comprehension is a cognitive process that involves the transformation of auditory signals into abstract concepts. Traditional lesion-based studies of stroke survivors with aphasia have suggested that neocortical regions adjacent to auditory cortex are primarily responsible for word comprehension. However, recent primary progressive aphasia and normal neurophysiological studies have challenged this concept, suggesting that the left temporal pole is crucial for word comprehension. Due to its vasculature, the temporal pole is not commonly completely lesioned in stroke survivors and this heterogeneity may have prevented its identification in lesion-based studies of auditory comprehension. We aimed to resolve this controversy using a combined voxel-based—and structural connectome—lesion symptom mapping approach, since cortical dysfunction after stroke can arise from cortical damage or from white matter disconnection. Magnetic resonance imaging (T1-weighted and diffusion tensor imaging-based structural connectome), auditory word comprehension and object recognition tests were obtained from 67 chronic left hemisphere stroke survivors. We observed that damage to the inferior temporal gyrus, to the fusiform gyrus and to a white matter network including the left posterior temporal region and its connections to the middle temporal gyrus, inferior temporal gyrus, and cingulate cortex, was associated with word comprehension difficulties after factoring out object recognition. These results suggest that the posterior lateral and inferior temporal regions are crucial for word comprehension, serving as a hub to integrate auditory and conceptual processing. Early processing linking auditory words to concepts is situated in posterior lateral temporal regions, whereas additional and deeper levels of semantic processing likely require more anterior temporal regions.
Cortical neurons and networks are dormant but fully responsive during isoelectric brain state Brain (IF 10.292) Pub Date : 2017-08-24 Tristan Altwegg-Boussac, Adrien E. Schramm, Jimena Ballestero, Fanny Grosselin, Mario Chavez, Sarah Lecas, Michel Baulac, Lionel Naccache, Sophie Demeret, Vincent Navarro, Séverine Mahon, Stéphane Charpier
A continuous isoelectric electroencephalogram reflects an interruption of endogenously-generated activity in cortical networks and systematically results in a complete dissolution of conscious processes. This electro-cerebral inactivity occurs during various brain disorders, including hypothermia, drug intoxication, long-lasting anoxia and brain trauma. It can also be induced in a therapeutic context, following the administration of high doses of barbiturate-derived compounds, to interrupt a hyper-refractory status epilepticus. Although altered sensory responses can be occasionally observed on an isoelectric electroencephalogram, the electrical membrane properties and synaptic responses of individual neurons during this cerebral state remain largely unknown. The aim of the present study was to characterize the intracellular correlates of a barbiturate-induced isoelectric electroencephalogram and to analyse the sensory-evoked synaptic responses that can emerge from a brain deprived of spontaneous electrical activity. We first examined the sensory responsiveness from patients suffering from intractable status epilepticus and treated by administration of thiopental. Multimodal sensory responses could be evoked on the flat electroencephalogram, including visually-evoked potentials that were significantly amplified and delayed, with a high trial-to-trial reproducibility compared to awake healthy subjects. Using an analogous pharmacological procedure to induce prolonged electro-cerebral inactivity in the rat, we could describe its cortical and subcortical intracellular counterparts. Neocortical, hippocampal and thalamo-cortical neurons were all silent during the isoelectric state and displayed a flat membrane potential significantly hyperpolarized compared with spontaneously active control states. Nonetheless, all recorded neurons could fire action potentials in response to intracellularly injected depolarizing current pulses and their specific intrinsic electrophysiological features were preserved. Manipulations of the membrane potential and intracellular injection of chloride in neocortical neurons failed to reveal an augmented synaptic inhibition during the isoelectric condition. Consistent with the sensory responses recorded from comatose patients, large and highly reproducible somatosensory-evoked potentials could be generated on the inactive electrocorticogram in rats. Intracellular recordings revealed that the underlying neocortical pyramidal cells responded to sensory stimuli by complex synaptic potentials able to trigger action potentials. As in patients, sensory responses in the isoelectric state were delayed compared to control responses and exhibited an elevated reliability during repeated stimuli. Our findings demonstrate that during prolonged isoelectric brain state neurons and synaptic networks are dormant rather than excessively inhibited, conserving their intrinsic properties and their ability to integrate and propagate environmental stimuli.
Early detection of consciousness in patients with acute severe traumatic brain injury Brain (IF 10.292) Pub Date : 2017-07-20 Brian L. Edlow, Camille Chatelle, Camille A. Spencer, Catherine J. Chu, Yelena G. Bodien, Kathryn L. O’Connor, Ronald E. Hirschberg, Leigh R. Hochberg, Joseph T. Giacino, Eric S. Rosenthal, Ona Wu
See Schiff (doi:10.1093/awx209) for a scientific commentary on this article.
Diagnostic criteria for chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) Brain (IF 10.292) Pub Date : 2017-08-24 W. Oliver Tobin, Yong Guo, Karl N. Krecke, Joseph E. Parisi, Claudia F. Lucchinetti, Sean J. Pittock, Jay Mandrekar, Divyanshu Dubey, Jan Debruyne, B. Mark Keegan
Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a central nervous system inflammatory syndrome predominantly affecting the brainstem, cerebellum, and spinal cord. Following its initial description, the salient features of CLIPPERS have been confirmed and expanded upon, but the lack of formalized diagnostic criteria has led to reports of patients with dissimilar features purported to have CLIPPERS. We evaluated clinical, radiological and pathological features of patients referred for suspected CLIPPERS and propose diagnostic criteria to discriminate CLIPPERS from non-CLIPPERS aetiologies. Thirty-five patients were evaluated for suspected CLIPPERS. Clinical and neuroimaging data were reviewed by three neurologists to confirm CLIPPERS by consensus agreement. Neuroimaging and neuropathology were reviewed by experienced neuroradiologists and neuropathologists, respectively, both of whom were blinded to the clinical data. CLIPPERS was diagnosed in 23 patients (18 male and five female) and 12 patients had a non-CLIPPERS diagnosis. CLIPPERS patients’ median age of onset was 58 years (interquartile range, 24–72) and were followed a median of 44 months (interquartile range 38–63). Non-CLIPPERS patients’ median age of onset was 52 years (interquartile range, 39–59) and were followed a median of 27 months (interquartile range, 14–47). Clinical symptoms of gait ataxia, diplopia, cognitive impairment, and facial paraesthesia did not discriminate CLIPPERS from non-CLIPPERS. Marked clinical and radiological corticosteroid responsiveness was observed in CLIPPERS (23/23), and clinical worsening occurred in all 12 CLIPPERS cases when corticosteroids were discontinued. Corticosteroid responsiveness was common but not universal in non-CLIPPERS [clinical improvement (8/12); radiological improvement (2/12); clinical worsening on discontinuation (3/8)]. CLIPPERS patients had brainstem predominant perivascular gadolinium enhancing lesions on magnetic resonance imaging that were discriminated from non-CLIPPERS by: homogenous gadolinium enhancing nodules <3 mm in diameter without ring-enhancement or mass effect, and homogenous T2 signal abnormality not significantly exceeding the T1 enhancement. Brain neuropathology on 14 CLIPPERS cases demonstrated marked CD3-positive T-lymphocyte, mild B-lymphocyte and moderate macrophage infiltrates, with perivascular predominance as well as diffuse parenchymal infiltration (14/14), present in meninges, white and grey matter, associated with variable tissue destruction, astrogliosis and secondary myelin loss. Clinical, radiological and pathological feature define CLIPPERS syndrome and are differentiated from non-CLIPPERS aetiologies by neuroradiological and neuropathological findings.
Towards personalized therapy for multiple sclerosis: prediction of individual treatment response Brain (IF 10.292) Pub Date : 2017-08-03 Tomas Kalincik, Ali Manouchehrinia, Lukas Sobisek, Vilija Jokubaitis, Tim Spelman, Dana Horakova, Eva Havrdova, Maria Trojano, Guillermo Izquierdo, Alessandra Lugaresi, Marc Girard, Alexandre Prat, Pierre Duquette, Pierre Grammond, Patrizia Sola, Raymond Hupperts, Francois Grand'Maison, Eugenio Pucci, Cavit Boz, Raed Alroughani, Vincent Van Pesch, Jeannette Lechner-Scott, Murat Terzi, Roberto Bergamaschi, Gerardo Iuliano, Franco Granella, Daniele Spitaleri, Vahid Shaygannejad, Celia Oreja-Guevara, Mark Slee, Radek Ampapa, Freek Verheul, Pamela McCombe, Javier Olascoaga, Maria Pia Amato, Steve Vucic, Suzanne Hodgkinson, Cristina Ramo-Tello, Shlomo Flechter, Edgardo Cristiano, Csilla Rozsa, Fraser Moore, Jose Luis Sanchez-Menoyo, Maria Laura Saladino, Michael Barnett, Jan Hillert, Helmut Butzkueven
Timely initiation of effective therapy is crucial for preventing disability in multiple sclerosis; however, treatment response varies greatly among patients. Comprehensive predictive models of individual treatment response are lacking. Our aims were: (i) to develop predictive algorithms for individual treatment response using demographic, clinical and paraclinical predictors in patients with multiple sclerosis; and (ii) to evaluate accuracy, and internal and external validity of these algorithms. This study evaluated 27 demographic, clinical and paraclinical predictors of individual response to seven disease-modifying therapies in MSBase, a large global cohort study. Treatment response was analysed separately for disability progression, disability regression, relapse frequency, conversion to secondary progressive disease, change in the cumulative disease burden, and the probability of treatment discontinuation. Multivariable survival and generalized linear models were used, together with the principal component analysis to reduce model dimensionality and prevent overparameterization. Accuracy of the individual prediction was tested and its internal validity was evaluated in a separate, non-overlapping cohort. External validity was evaluated in a geographically distinct cohort, the Swedish Multiple Sclerosis Registry. In the training cohort (n = 8513), the most prominent modifiers of treatment response comprised age, disease duration, disease course, previous relapse activity, disability, predominant relapse phenotype and previous therapy. Importantly, the magnitude and direction of the associations varied among therapies and disease outcomes. Higher probability of disability progression during treatment with injectable therapies was predominantly associated with a greater disability at treatment start and the previous therapy. For fingolimod, natalizumab or mitoxantrone, it was mainly associated with lower pretreatment relapse activity. The probability of disability regression was predominantly associated with pre-baseline disability, therapy and relapse activity. Relapse incidence was associated with pretreatment relapse activity, age and relapsing disease course, with the strength of these associations varying among therapies. Accuracy and internal validity (n = 1196) of the resulting predictive models was high (>80%) for relapse incidence during the first year and for disability outcomes, moderate for relapse incidence in Years 2–4 and for the change in the cumulative disease burden, and low for conversion to secondary progressive disease and treatment discontinuation. External validation showed similar results, demonstrating high external validity for disability and relapse outcomes, moderate external validity for cumulative disease burden and low external validity for conversion to secondary progressive disease and treatment discontinuation. We conclude that demographic, clinical and paraclinical information helps predict individual response to disease-modifying therapies at the time of their commencement.
Metformin reverses TRAP1 mutation-associated alterations in mitochondrial function in Parkinson’s disease Brain (IF 10.292) Pub Date : 2017-08-24 Julia C. Fitzgerald, Alexander Zimprich, Daniel A. Carvajal Berrio, Kevin M. Schindler, Brigitte Maurer, Claudia Schulte, Christine Bus, Anne-Kathrin Hauser, Manuela Kübler, Rahel Lewin, Dheeraj Reddy Bobbili, Lisa M. Schwarz, Evangelia Vartholomaiou, Kathrin Brockmann, Richard Wüst, Johannes Madlung, Alfred Nordheim, Olaf Riess, L. Miguel Martins, Enrico Glaab, Patrick May, Katja Schenke-Layland, Didier Picard, Manu Sharma, Thomas Gasser, Rejko Krüger
The mitochondrial proteins TRAP1 and HTRA2 have previously been shown to be phosphorylated in the presence of the Parkinson’s disease kinase PINK1 but the downstream signalling is unknown. HTRA2 and PINK1 loss of function causes parkinsonism in humans and animals. Here, we identified TRAP1 as an interactor of HTRA2 using an unbiased mass spectrometry approach. In our human cell models, TRAP1 overexpression is protective, rescuing HTRA2 and PINK1-associated mitochondrial dysfunction and suggesting that TRAP1 acts downstream of HTRA2 and PINK1. HTRA2 regulates TRAP1 protein levels, but TRAP1 is not a direct target of HTRA2 protease activity. Following genetic screening of Parkinson’s disease patients and healthy controls, we also report the first TRAP1 mutation leading to complete loss of functional protein in a patient with late onset Parkinson’s disease. Analysis of fibroblasts derived from the patient reveal that oxygen consumption, ATP output and reactive oxygen species are increased compared to healthy individuals. This is coupled with an increased pool of free NADH, increased mitochondrial biogenesis, triggering of the mitochondrial unfolded protein response, loss of mitochondrial membrane potential and sensitivity to mitochondrial removal and apoptosis. These data highlight the role of TRAP1 in the regulation of energy metabolism and mitochondrial quality control. Interestingly, the diabetes drug metformin reverses mutation-associated alterations on energy metabolism, mitochondrial biogenesis and restores mitochondrial membrane potential. In summary, our data show that TRAP1 acts downstream of PINK1 and HTRA2 for mitochondrial fine tuning, whereas TRAP1 loss of function leads to reduced control of energy metabolism, ultimately impacting mitochondrial membrane potential. These findings offer new insight into mitochondrial pathologies in Parkinson’s disease and provide new prospects for targeted therapies.
Brain monoamine oxidase B and A in human parkinsonian dopamine deficiency disorders Brain (IF 10.292) Pub Date : 2017-07-27 Junchao Tong, Gausiha Rathitharan, Jeffrey H. Meyer, Yoshiaki Furukawa, Lee-Cyn Ang, Isabelle Boileau, Mark Guttman, Oleh Hornykiewicz, Stephen J. Kish
See Jellinger (doi:10.1093/awx190) for a scientific commentary on this article.
Distinct processing of ambiguous speech in people with non-clinical auditory verbal hallucinations Brain (IF 10.292) Pub Date : 2017-08-20 Ben Alderson-Day, César F. Lima, Samuel Evans, Saloni Krishnan, Pradheep Shanmugalingam, Charles Fernyhough, Sophie K. Scott
Auditory verbal hallucinations (hearing voices) are typically associated with psychosis, but a minority of the general population also experience them frequently and without distress. Such ‘non-clinical’ experiences offer a rare and unique opportunity to study hallucinations apart from confounding clinical factors, thus allowing for the identification of symptom-specific mechanisms. Recent theories propose that hallucinations result from an imbalance of prior expectation and sensory information, but whether such an imbalance also influences auditory-perceptual processes remains unknown. We examine for the first time the cortical processing of ambiguous speech in people without psychosis who regularly hear voices. Twelve non-clinical voice-hearers and 17 matched controls completed a functional magnetic resonance imaging scan while passively listening to degraded speech (‘sine-wave’ speech), that was either potentially intelligible or unintelligible. Voice-hearers reported recognizing the presence of speech in the stimuli before controls, and before being explicitly informed of its intelligibility. Across both groups, intelligible sine-wave speech engaged a typical left-lateralized speech processing network. Notably, however, voice-hearers showed stronger intelligibility responses than controls in the dorsal anterior cingulate cortex and in the superior frontal gyrus. This suggests an enhanced involvement of attention and sensorimotor processes, selectively when speech was potentially intelligible. Altogether, these behavioural and neural findings indicate that people with hallucinatory experiences show distinct responses to meaningful auditory stimuli. A greater weighting towards prior knowledge and expectation might cause non-veridical auditory sensations in these individuals, but it might also spontaneously facilitate perceptual processing where such knowledge is required. This has implications for the understanding of hallucinations in clinical and non-clinical populations, and is consistent with current ‘predictive processing’ theories of psychosis.
Stimulating thought: a functional MRI study of transcranial direct current stimulation in schizophrenia Brain (IF 10.292) Pub Date : 2017-07-24 Natasza D. Orlov, Owen O’Daly, Derek K. Tracy, Yusuf Daniju, John Hodsoll, Lorena Valdearenas, John Rothwell, Sukhi S. Shergill
Individuals with schizophrenia typically suffer a range of cognitive deficits, including prominent deficits in working memory and executive function. These difficulties are strongly predictive of functional outcomes, but there is a paucity of effective therapeutic interventions targeting these deficits. Transcranial direct current stimulation is a novel neuromodulatory technique with emerging evidence of potential pro-cognitive effects; however, there is limited understanding of its mechanism. This was a double-blind randomized sham controlled pilot study of transcranial direct current stimulation on a working memory (n-back) and executive function (Stroop) task in 28 individuals with schizophrenia using functional magnetic resonance imaging. Study participants received 30 min of real or sham transcranial direct current stimulation applied to the left frontal cortex. The ‘real’ and ‘sham’ groups did not differ in online working memory task performance, but the transcranial direct current stimulation group demonstrated significant improvement in performance at 24 h post-transcranial direct current stimulation. Transcranial direct current stimulation was associated with increased activation in the medial frontal cortex beneath the anode; showing a positive correlation with consolidated working memory performance 24 h post-stimulation. There was reduced activation in the left cerebellum in the transcranial direct current stimulation group, with no change in the middle frontal gyrus or parietal cortices. Improved performance on the executive function task was associated with reduced activity in the anterior cingulate cortex. Transcranial direct current stimulation modulated functional activation in local task-related regions, and in more distal nodes in the network. Transcranial direct current stimulation offers a potential novel approach to altering frontal cortical activity and exerting pro-cognitive effects in schizophrenia.
Psychogenic amnesia: syndromes, outcome, and patterns of retrograde amnesia Brain (IF 10.292) Pub Date : 2017-08-24 Neil A. Harrison, Kate Johnston, Federica Corno, Sarah J. Casey, Kimberley Friedner, Kate Humphreys, Eli J. Jaldow, Mervi Pitkanen, Michael D. Kopelman
There are very few case series of patients with acute psychogenic memory loss (also known as dissociative/functional amnesia), and still fewer studies of outcome, or comparisons with neurological memory-disordered patients. Consequently, the literature on psychogenic amnesia is somewhat fragmented and offers little prognostic value for individual patients. In the present study, we reviewed the case records and neuropsychological findings in 53 psychogenic amnesia cases (ratio of 3:1, males:females), in comparison with 21 consecutively recruited neurological memory-disordered patients and 14 healthy control subjects. In particular, we examined the pattern of retrograde amnesia on an assessment of autobiographical memory (the Autobiographical Memory Interview). We found that our patients with psychogenic memory loss fell into four distinct groups, which we categorized as: (i) fugue state; (ii) fugue-to-focal retrograde amnesia; (iii) psychogenic focal retrograde amnesia following a minor neurological episode; and (iv) patients with gaps in their memories. While neurological cases were characterized by relevant neurological symptoms, a history of a past head injury was actually more common in our psychogenic cases (P = 0.012), perhaps reflecting a ‘learning episode’ predisposing to later psychological amnesia. As anticipated, loss of the sense of personal identity was confined to the psychogenic group. However, clinical depression, family/relationship problems, financial/employment problems, and failure to recognize the family were also statistically more common in that group. The pattern of autobiographical memory loss differed between the psychogenic groups: fugue cases showed a severe and uniform loss of memories for both facts and events across all time periods, whereas the two focal retrograde amnesia groups showed a ‘reversed’ temporal gradient with relative sparing of recent memories. After 3–6 months, the fugue patients had improved to normal scores for facts and near-normal scores for events. By contrast, the two focal retrograde amnesia groups showed less improvement and continued to show a reversed temporal gradient. In conclusion, the outcome in psychogenic amnesia, particularly those characterized by fugue, is better than generally supposed. Findings are interpreted in terms of Markowitsch’s and Kopelman’s models of psychogenic amnesia, and with respect to Anderson’s neuroimaging findings in memory inhibition.
The evolution of consciousness. Together with a diagram illustrating certain homologies in the nervous system. By W.H.B. Stoddart MD MRCP. Brain 1903; 26: 432–439. With The structure of consciousness by Michael Polanyi. Brain 1965; 88: 799–810 Brain (IF 10.292) Pub Date : 2017-08-24 Alastair Compston
Apart from occasional brief encounters, neurology has been content to leave ideas on the nature of consciousness to those who study the philosophy of mind and experts in the psychology of perception and behaviour. Neurologists know when their patients are unconscious and when they are not. They are aware that there are dualists and materialists and periodically themselves express opinion on one side or the other of the debate. Perhaps the majority are most comfortable with the middle position of consciousness as an emergent property that requires a material base; sleep as a busy process that differs from unconsciousness; and anaesthesia with absence of on-going experience or awareness of lapsed time as a state without consciousness during which physiological functions are sustained or artificially supported. The...
Patients with Huntington’s disease pioneered human stereotactic neurosurgery 70 years ago Brain (IF 10.292) Pub Date : 2017-08-01 Marwan Hariz, Sarah Tabrizi
It is well known that stereotactic functional neurosurgery, using ablative procedures or deep brain stimulation (DBS) is used mainly in the surgical treatment of Parkinson’s disease, essential tremor and dystonia. These are also the only established indications for functional stereotactic neurosurgery. What is less well known is that the first ever stereotactic operation was performed 70 years ago, and was for treatment of Huntington’s disease. This historical account will review the birth of human stereotactic surgery, and it’s very first applications.
Oscillatory coupling of the subthalamic nucleus in obsessive compulsive disorder Brain (IF 10.292) Pub Date : 2017-07-03 Lars Wojtecki, Jan Hirschmann, Saskia Elben, Matthias Boschheidgen, Carlos Trenado, Jan Vesper, Alfons Schnitzler
Reply: Oscillatory coupling of the subthalamic nucleus in obsessive compulsive disorder Brain (IF 10.292) Pub Date : 2017-07-03 Ettore A. Accolla, Andreas Horn, Maria Herrojo-Ruiz, Wolf-Julian Neumann, Andrea A. Kühn
Pope Francis champions Huntington’s disease Brain (IF 10.292) Pub Date : 2017-07-25 Laura Spinney
Yosbely Soto Soto shares a corrugated iron hut with her two sons on the shores of Venezuela’s Lake Maracaibo. The heat inside has been unbearable since her husband left her a few years ago, taking the air conditioner with him. The 32-year-old has to beg for food to feed herself and her children, something made all the harder because she is shunned by her community. So too are her brother and sister, who like Yosbely have Huntington’s disease.
Erratum Brain (IF 10.292) Pub Date : 2017-07-04
Moskowitz MA. Holes in the leaky migraine blood–brain barrier hypothesis? Brain 2017; 140: 1537-1539; 10.1093/brain/awx099.
Corrigendum Brain (IF 10.292) Pub Date : 2017-06-14
Lazzaro di Biase, John-Stuart Brittain, Syed Ahmar Shah, David J. Pedrosa, Hayriye Cagnan, Alexandre Mathy, Chiung Chu Chen, Juan Francisco, Martín-Rodríguez, Pablo Mir, Lars Timmerman, Petra Schwingenschuh, Kailash Bhatia, Vincenzo Di Lazzaro, Peter Brown. Tremor stability index: a new tool for differential diagnosis in tremor syndromes. Brain 2017; 140: 1977–1986; 10.1093/brain/awx104.
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