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  • Synaptic phosphorylated α-synuclein in dementia with Lewy bodies
    Brain (IF 10.292) Pub Date : 2017-11-21
    Martí Colom-Cadena, Jordi Pegueroles, Abigail G Herrmann, Christopher M Henstridge, Laia Muñoz, Marta Querol-Vilaseca, Carla San Martín-Paniello, Joan Luque-Cabecerans, Jordi Clarimon, Olivia Belbin, Raúl Núñez-Llaves, Rafael Blesa, Colin Smith, Chris-Anne McKenzie, Matthew P Frosch, Allyson Roe, Juan Fortea, Jordi Andilla, Pablo Loza-Alvarez, Ellen Gelpi, Bradley T Hyman, Tara L Spires-Jones, Alberto Lleó

    Dementia with Lewy bodies is characterized by the accumulation of Lewy bodies and Lewy neurites in the CNS, both of which are composed mainly of aggregated α-synuclein phosphorylated at Ser129. Although phosphorylated α-synuclein is believed to exert toxic effects at the synapse in dementia with Lewy bodies and other α-synucleinopathies, direct evidence for the precise synaptic localization has been difficult to achieve due to the lack of adequate optical microscopic resolution to study human synapses. In the present study we applied array tomography, a microscopy technique that combines ultrathin sectioning of tissue with immunofluorescence allowing precise identification of small structures, to quantitatively investigate the synaptic phosphorylated α-synuclein pathology in dementia with Lewy bodies. We performed array tomography on human brain samples from five patients with dementia with Lewy bodies, five patients with Alzheimer’s disease and five healthy control subjects to analyse the presence of phosphorylated α-synuclein immunoreactivity at the synapse and their relationship with synapse size. Main analyses were performed in blocks from cingulate cortex and confirmed in blocks from the striatum of cases with dementia with Lewy bodies. A total of 1 318 700 single pre- or postsynaptic terminals were analysed. We found that phosphorylated α-synuclein is present exclusively in dementia with Lewy bodies cases, where it can be identified in the form of Lewy bodies, Lewy neurites and small aggregates (<0.16 µm3). Between 19% and 25% of phosphorylated α-synuclein deposits were found in presynaptic terminals mainly in the form of small aggregates. Synaptic terminals that co-localized with small aggregates of phosphorylated α-synuclein were significantly larger than those that did not. Finally, a gradient of phosphorylated α-synuclein aggregation in synapses (pre > pre + post > postsynaptic) was observed. These results indicate that phosphorylated α-synuclein is found at the presynaptic terminals of dementia with Lewy bodies cases mainly in the form of small phosphorylated α-synuclein aggregates that are associated with changes in synaptic morphology. Overall, our data support the notion that pathological phosphorylated α-synuclein may disrupt the structure and function of the synapse in dementia with Lewy bodies.

    更新日期:2017-11-21
  • Reply: CLIPPERS, a possible symptomatic lymphohistiocytic immune reaction
    Brain (IF 10.292) Pub Date : 2017-11-17
    W Oliver Tobin, Yong Guo, B Mark Keegan

    Sir,

    更新日期:2017-11-17
  • CLIPPERS, a possible symptomatic lymphohistiocytic immune reaction
    Brain (IF 10.292) Pub Date : 2017-11-17
    Guillaume Taieb, Pierre Labauge

    Sir,

    更新日期:2017-11-17
  • Distinct spatiotemporal accumulation of N-truncated and full-length amyloid-β42 in Alzheimer’s disease
    Brain (IF 10.292) Pub Date : 2017-11-17
    Mitsuru Shinohara, Shunsuke Koga, Takuya Konno, Jeremy Nix, Motoko Shinohara, Naoya Aoki, Pritam Das, Joseph E Parisi, Ronald C Petersen, Terrone L Rosenberry, Dennis W Dickson, Guojun Bu

    Accumulation of amyloid-β peptides is a dominant feature in the pathogenesis of Alzheimer’s disease; however, it is not clear how individual amyloid-β species accumulate and affect other neuropathological and clinical features in the disease. Thus, we compared the accumulation of N-terminally truncated amyloid-β and full-length amyloid-β, depending on disease stage as well as brain area, and determined how these amyloid-β species respectively correlate with clinicopathological features of Alzheimer’s disease. To this end, the amounts of amyloid-β species and other proteins related to amyloid-β metabolism or Alzheimer’s disease were quantified by enzyme-linked immunosorbent assays (ELISA) or theoretically calculated in 12 brain regions, including neocortical, limbic and subcortical areas from Alzheimer’s disease cases (n = 19), neurologically normal elderly without amyloid-β accumulation (normal ageing, n = 13), and neurologically normal elderly with cortical amyloid-β accumulation (pathological ageing, n = 15). We observed that N-terminally truncated amyloid-β42 and full-length amyloid-β42 accumulations distributed differently across disease stages and brain areas, while N-terminally truncated amyloid-β40 and full-length amyloid-β40 accumulation showed an almost identical distribution pattern. Cortical N-terminally truncated amyloid-β42 accumulation was increased in Alzheimer’s disease compared to pathological ageing, whereas cortical full-length amyloid-β42 accumulation was comparable between Alzheimer’s disease and pathological ageing. Moreover, N-terminally truncated amyloid-β42 were more likely to accumulate more in specific brain areas, especially some limbic areas, while full-length amyloid-β42 tended to accumulate more in several neocortical areas, including frontal cortices. Immunoprecipitation followed by mass spectrometry analysis showed that several N-terminally truncated amyloid-β42 species, represented by pyroglutamylated amyloid-β11-42, were enriched in these areas, consistent with ELISA results. N-terminally truncated amyloid-β42 accumulation showed significant regional association with BACE1 and neprilysin, but not PSD95 that regionally associated with full-length amyloid-β42 accumulation. Interestingly, accumulations of tau and to a greater extent apolipoprotein E (apoE, encoded by APOE) were more strongly correlated with N-terminally truncated amyloid-β42 accumulation than those of other amyloid-β species across brain areas and disease stages. Consistently, immunohistochemical staining and in vitro binding assays showed that apoE co-localized and bound more strongly with pyroglutamylated amyloid-β11-x fibrils than full-length amyloid-β fibrils. Retrospective review of clinical records showed that accumulation of N-terminally truncated amyloid-β42 in cortical areas was associated with disease onset, duration and cognitive scores. Collectively, N-terminally truncated amyloid-β42 species have spatiotemporal accumulation patterns distinct from full-length amyloid-β42, likely due to different mechanisms governing their accumulations in the brain. These truncated amyloid-β species could play critical roles in the disease by linking other clinicopathological features of Alzheimer’s disease.

    更新日期:2017-11-17
  • Induced cortical responses require developmental sensory experience
    Brain (IF 10.292) Pub Date : 2017-11-16
    Prasandhya Astagiri Yusuf, Peter Hubka, Jochen Tillein, Andrej Kral

    Sensory areas of the cerebral cortex integrate the sensory inputs with the ongoing activity. We studied how complete absence of auditory experience affects this process in a higher mammal model of complete sensory deprivation, the congenitally deaf cat. Cortical responses were elicited by intracochlear electric stimulation using cochlear implants in adult hearing controls and deaf cats. Additionally, in hearing controls, acoustic stimuli were used to assess the effect of stimulus mode (electric versus acoustic) on the cortical responses. We evaluated time-frequency representations of local field potential recorded simultaneously in the primary auditory cortex and a higher-order area, the posterior auditory field, known to be differentially involved in cross-modal (visual) reorganization in deaf cats. The results showed the appearance of evoked (phase-locked) responses at early latencies (<100 ms post-stimulus) and more abundant induced (non-phase-locked) responses at later latencies (>150 ms post-stimulus). In deaf cats, substantially reduced induced responses were observed in overall power as well as duration in both investigated fields. Additionally, a reduction of ongoing alpha band activity was found in the posterior auditory field (but not in primary auditory cortex) of deaf cats. The present study demonstrates that induced activity requires developmental experience and suggests that higher-order areas involved in the cross-modal reorganization show more auditory deficits than primary areas.

    更新日期:2017-11-17
  • Epigenetic editing of the Dlg4/PSD95 gene improves cognition in aged and Alzheimer’s disease mice
    Brain (IF 10.292) Pub Date : 2017-11-16
    Fernando J Bustos, Estibaliz Ampuero, Nur Jury, Rodrigo Aguilar, Fahimeh Falahi, Jorge Toledo, Juan Ahumada, Jaclyn Lata, Paula Cubillos, Berta Henríquez, Miguel V Guerra, Jimmy Stehberg, Rachael L Neve, Nibaldo C Inestrosa, Ursula Wyneken, Marco Fuenzalida, Steffen Härtel, Miguel Sena-Esteves, Lorena Varela-Nallar, Marianne G Rots, Martin Montecino, Brigitte van Zundert

    The Dlg4 gene encodes for post-synaptic density protein 95 (PSD95), a major synaptic protein that clusters glutamate receptors and is critical for plasticity. PSD95 levels are diminished in ageing and neurodegenerative disorders, including Alzheimer’s disease and Huntington’s disease. The epigenetic mechanisms that (dys)regulate transcription of Dlg4/PSD95, or other plasticity genes, are largely unknown, limiting the development of targeted epigenome therapy. We analysed the Dlg4/PSD95 epigenetic landscape in hippocampal tissue and designed a Dlg4/PSD95 gene-targeting strategy: a Dlg4/PSD95 zinc finger DNA-binding domain was engineered and fused to effector domains to either repress (G9a, Suvdel76, SKD) or activate (VP64) transcription, generating artificial transcription factors or epigenetic editors (methylating H3K9). These epi-editors altered critical histone marks and subsequently Dlg4/PSD95 expression, which, importantly, impacted several hippocampal neuron plasticity processes. Intriguingly, transduction of the artificial transcription factor PSD95-VP64 rescued memory deficits in aged and Alzheimer’s disease mice. Conclusively, this work validates PSD95 as a key player in memory and establishes epigenetic editing as a potential therapy to treat human neurological disorders.

    更新日期:2017-11-17
  • Mutations affecting glycinergic neurotransmission in hyperekplexia increase pain sensitivity
    Brain (IF 10.292) Pub Date : 2017-11-15
    Pascal Henri Vuilleumier, Raphael Fritsche, Jürg Schliessbach, Bernhard Schmitt, Lars Arendt-Nielsen, Hanns Ulrich Zeilhofer, Michele Curatolo

    Inhibitory interneurons in the spinal cord use glycine and GABA for fast inhibitory neurotransmission. While there is abundant research on these inhibitory pain pathways in animal models, their relevance in humans remains unclear, largely due to the limited possibility to manipulate selectively these pathways in humans. Hyperekplexia is a rare human disease that is caused by loss-of-function mutations in genes encoding for glycine receptors and glycine transporters. In the present study, we tested whether hyperekplexia patients display altered pain perception or central pain modulation compared with healthy subjects. Seven patients with genetically and clinically confirmed hyperekplexia were compared to 14 healthy age- and sex-matched controls. The following quantitative sensory tests were performed: pressure pain detection threshold (primary outcome), ice water tolerance, single and repeated electrical pain detection thresholds, nociceptive withdrawal reflex threshold, and conditioned pain modulation. Statistical analysis was performed using linear mixed models. Hyperekplexia patients displayed lower pain thresholds than healthy controls for all of the quantitative sensory tests [mean (standard deviation)]: pressure pain detection threshold [273 (170) versus 475 (115) kPa, P = 0.003], ice water tolerance [49.2 (36.5) versus 85.7 (35.0) s, P = 0.015], electrical single pain detection threshold [5.42 (2.64) versus 7.47 (2.62) mA, P = 0.012], electrical repeated pain detection threshold [3.76 (1.41) versus 5.8 (1.73) mA, P = 0.003], and nociceptive withdrawal reflex [7.42 (3.63) versus 14.1 (6.9) mA, P = 0.015]. Conditioned pain modulation was significantly reduced in hyperekplexia [increase to baseline: 53.2 (63.7) versus 105 (57) kPa, P = 0.030]. Our data demonstrate increased pain sensitivity and impaired central pain modulation in hyperekplexia patients, supporting the importance of glycinergic neurotransmission for central pain modulation in humans.

    更新日期:2017-11-17
  • High-dimensional therapeutic inference in the focally damaged human brain
    Brain (IF 10.292) Pub Date : 2017-11-15
    Tianbo Xu, Hans Rolf Jäger, Masud Husain, Geraint Rees, Parashkev Nachev

    Though consistency across the population renders the extraordinarily complex functional anatomy of the human brain surveyable, the inverse inference—from common functional maps to individual behaviour—is constrained by marked individual deviation from the population mean. Such inference is fundamental to the evaluation of therapeutic interventions in focal brain injury, where the impact of an induced structural change in the brain is quantified by its behavioural consequences, inevitably refracted through the lens of lesion-outcome relations. Current therapeutic evaluations do not incorporate inferences to the individual outcome derived from a detailed specification of the lesion anatomy, relying only on reductive parameters such as lesion volume and crudely discretised location. Examining 1172 patients with anatomically registered focal brain lesions, here we show that such low-dimensional models are highly insensitive to therapeutic effects. In contrast, high-dimensional models supported by machine learning dramatically improve sensitivity by leveraging complex individuating patterns in the functional architecture of the brain. The failure to replicate in humans positive interventional effects in experimental animals is thus revealed to have a remediable inferential cause, forcing a radical re-evaluation of therapeutic inference in the human brain.

    更新日期:2017-11-17
  • The secret dream laboratory
    Brain (IF 10.292) Pub Date : 2017-11-14
    Matt ffytche, Dominic ffytche

    What does an eminent neuroanatomist dream of at night? The panic of being an auxiliary professor and receiving last minute instructions from the Dean to lecture on osteology? ‘Anxiety, distress … upon reviewing the bones in my memory. I list those of the hand: scaphoids, capitate, and I did not know any more’; or perhaps of secretly cutting slices of medulla for staining in a boarding house at night, or (a recurrent nightmare) that ‘they remove my skull and only skin covers the brain’—the dreamer is ‘alarmed and I awaken when I see that my brain is falling out’?

    更新日期:2017-11-17
  • Dr W. H. R. Rivers: Siegfried Sassoon and Robert Graves’ ‘fathering friend’
    Brain (IF 10.292) Pub Date : 2017-11-14
    Jean Moorcroft Wilson

    Dr William Halse Rivers Rivers (1864–1922) was a pioneer in many of the emerging fields of science between 1880 and 1920. Yet he is known today, if at all, less for his outstanding scientific achievements than for his friendship with two of the greatest names among the First World War poets, Siegfried Sassoon and Robert Graves, whom he met at Craiglockhart Military Hospital in 1917. Rivers’s mistake, according to Graves, who studied his work closely, ‘lay in being genuinely first class in too many subjects and exciting jealousy by relating together too brilliantly the result of his researches in medicine, physiology, morbid psychology, social psychology, ethnology, magic, religion and other over-specialised departments of human knowledge’. Graves’s words were written in response to two books by one...

    更新日期:2017-11-17
  • Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease
    Brain (IF 10.292) Pub Date : 2017-11-13
    Laurie A Robak, Iris E Jansen, Jeroen van Rooij, André G Uitterlinden, Robert Kraaij, Joseph Jankovic, Peter Heutink, Joshua M Shulman, Mike A Nalls, Vincent Plagnol, Dena G Hernandez, Manu Sharma, Una-Marie Sheerin, Mohamad Saad, Javier Simón-Sánchez, Claudia Schulte, Suzanne Lesage, Sigurlaug Sveinbjörnsdóttir, Sampath Arepalli, Roger Barker, Yoav Ben-, Henk W Berendse, Daniela Berg, Kailash Bhatia, Rob M A de Bie, Alessandro Biffi, Bas Bloem, Zoltan Bochdanovits, Michael Bonin, Jose M Bras, Kathrin Brockmann, Janet Brooks, David J Burn, Elisa Majounie, Gavin Charlesworth, Codrin Lungu, Honglei Chen, Patrick F Chinnery, Sean Chong, Carl E Clarke, Mark R Cookson, J Mark Cooper, Jean Christophe Corvol, Carl Counsell, Philippe Damier, Jean-François Dartigues, Panos Deloukas, Günther Deuschl, David T Dexter, Karin D van Dijk, Allissa Dillman, Frank Durif, Alexandra Dürr, Sarah Edkins, Jonathan R Evans, Thomas Foltynie, Jing Dong, Michelle Gardner, J Raphael Gibbs, Alison Goate, Emma Gray, Rita Guerreiro, Clare Harris, Jacobus J van Hilten, Albert Hofman, Albert Hollenbeck, Janice Holton, Michele Hu, Xuemei Huang, Isabel Wurster, Walter Mätzler, Gavin Hudson, Sarah E Hunt, Johanna Huttenlocher, Thomas Illig, Pálmi V Jónsson, Jean-Charles Lambert, Cordelia Langford, Andrew Lees, Peter Lichtner, Patricia Limousin, Grisel Lopez, Delia Lorenz, Codrin Lungu, Alisdair McNeill, Catriona Moorby, Matthew Moore, Huw R Morris, Karen E Morrison, Valentina Escott-Price, Ese Mudanohwo, Sean S O’Sullivan, Justin Pearson, Joel S Perlmutter, Hjörvar Pétursson, Pierre Pollak, Bart Post, Simon Potter, Bernard Ravina, Tamas Revesz, Olaf Riess, Fernando Rivadeneira, Patrizia Rizzu, Mina Ryten, Stephen Sawcer, Anthony Schapira, Hans Scheffer, Karen Shaw, Ira Shoulson, Joshua Shulman, Ellen Sidransky, Colin Smith, Chris C A Spencer, Hreinn Stefánsson, Francesco Bettella, Joanna D Stockton, Amy Strange, Kevin Talbot, Carlie M Tanner, Avazeh Tashakkori-Ghanbaria, François Tison, Daniah Trabzuni, Bryan J Traynor, André G Uitterlinden, Daan Velseboer, Marie Vidailhet, Robert Walker, Bart van de Warrenburg, Mirdhu Wickremaratchi, Nigel Williams, Caroline H Williams-Gray, Sophie Winder-Rhodes, Kári Stefánsson, Maria Martinez, Nicholas W Wood, John Hardy, Peter Heutink, Alexis Brice, Thomas Gasser, Andrew B Singleton

    Mutations in the glucocerebrosidase gene (GBA), which cause Gaucher disease, are also potent risk factors for Parkinson’s disease. We examined whether a genetic burden of variants in other lysosomal storage disorder genes is more broadly associated with Parkinson’s disease susceptibility. The sequence kernel association test was used to interrogate variant burden among 54 lysosomal storage disorder genes, leveraging whole exome sequencing data from 1156 Parkinson’s disease cases and 1679 control subjects. We discovered a significant burden of rare, likely damaging lysosomal storage disorder gene variants in association with Parkinson’s disease risk. The association signal was robust to the exclusion of GBA, and consistent results were obtained in two independent replication cohorts, including 436 cases and 169 controls with whole exome sequencing and an additional 6713 cases and 5964 controls with exome-wide genotyping. In secondary analyses designed to highlight the specific genes driving the aggregate signal, we confirmed associations at the GBA and SMPD1 loci and newly implicate CTSD, SLC17A5, and ASAH1 as candidate Parkinson’s disease susceptibility genes. In our discovery cohort, the majority of Parkinson’s disease cases (56%) have at least one putative damaging variant in a lysosomal storage disorder gene, and 21% carry multiple alleles. Our results highlight several promising new susceptibility loci and reinforce the importance of lysosomal mechanisms in Parkinson’s disease pathogenesis. We suggest that multiple genetic hits may act in combination to degrade lysosomal function, enhancing Parkinson’s disease susceptibility.

    更新日期:2017-11-17
  • Corrigendum
    Brain (IF 10.292) Pub Date : 2017-11-10

    Tobias Granberg, Qiuyun Fan, Constantina Andrada Treaba,Russell Ouellette, Elena Herranz, Gabriel Mangeat, Céline Louapre, Julien Cohen-Adad, Eric C. Klawiter, Jacob A. Sloane and Caterina Mainero. In vivo characterization of cortical and white matter neuroaxonal pathology in early multiple sclerosis. Brain 2017; 140: 2912-2926; doi:10.1093/brain/awx247

    更新日期:2017-11-17
  • Clinical presentation and prognosis in MOG-antibody disease: a UK study
    Brain (IF 10.292) Pub Date : 2017-11-09
    Maciej Jurynczyk, Silvia Messina, Mark R Woodhall, Naheed Raza, Rosie Everett, Adriana Roca-Fernandez, George Tackley, Shahd Hamid, Angela Sheard, Gavin Reynolds, Saleel Chandratre, Cheryl Hemingway, Anu Jacob, Angela Vincent, M Isabel Leite, Patrick Waters, Jacqueline Palace

    A condition associated with an autoantibody against MOG has been recently recognized as a new inflammatory disease of the central nervous system, but the disease course and disability outcomes are largely unknown. In this study we investigated clinical characteristics of MOG-antibody disease on a large cohort of patients from the UK. We obtained demographic and clinical data on 252 UK patients positive for serum immunoglobulin G1 MOG antibodies as tested by the Autoimmune Neurology Group in Oxford. Disability outcomes and disease course were analysed in more detail in a cohort followed in the Neuromyelitis Optica Oxford Service (n = 75), and this included an incident cohort who were diagnosed at disease onset (n = 44). MOG-antibody disease affects females (57%) slightly more often than males, shows no ethnic bias and typically presents with isolated optic neuritis (55%, bilateral in almost half), transverse myelitis (18%) or acute disseminated encephalomyelitis-like presentations (18%). In the total Oxford cohort after a median disease duration of 28 months, 47% of patients were left with permanent disability in at least one of the following: 16% patients had visual acuity ≤6/36 in at least one eye, mobility was limited in 7% (i.e. Expanded Disability Status Scale ≥ 4.0), 5% had Expanded Disability Status Scale ≥ 6.0, 28% had permanent bladder issues, 20% had bowel dysfunction, and 21% of males had erectile dysfunction. Transverse myelitis at onset was a significant predictor of long-term disability. In the incident cohort 36% relapsed after median disease duration of 16 months. The annualized relapse rate was 0.2. Immunosuppression longer than 3 months following the onset attack was associated with a lower risk of a second relapse. MOG-antibody disease has a moderate relapse risk, which might be mitigated by medium term immunosuppression at onset. Permanent disability occurs in about half of patients and more often involves sphincter and erectile functions than vision or mobility.

    更新日期:2017-11-17
  • ABCD1 dysfunction alters white matter microvascular perfusion
    Brain (IF 10.292) Pub Date : 2017-11-09
    Arne Lauer, Xiao Da, Mikkel Bo Hansen, Gregoire Boulouis, Yangming Ou, Xuezhu Cai, Afonso Liberato Celso Pedrotti, Jayashree Kalpathy-Cramer, Paul Caruso, Douglas L Hayden, Natalia Rost, Kim Mouridsen, Florian S Eichler, Bruce Rosen, Patricia L Musolino

    Cerebral X-linked adrenoleukodystrophy is a devastating neurodegenerative disorder caused by mutations in the ABCD1 gene, which lead to a rapidly progressive cerebral inflammatory demyelination in up to 60% of affected males. Selective brain endothelial dysfunction and increased permeability of the blood–brain barrier suggest that white matter microvascular dysfunction contributes to the conversion to cerebral disease. Applying a vascular model to conventional dynamic susceptibility contrast magnetic resonance perfusion imaging, we demonstrate that lack of ABCD1 function causes increased capillary flow heterogeneity in asymptomatic hemizygotes predominantly in the white matter regions and developmental stages with the highest probability for conversion to cerebral disease. In subjects with ongoing inflammatory demyelination we observed a sequence of increased capillary flow heterogeneity followed by blood–brain barrier permeability changes in the perilesional white matter, which predicts lesion progression. These white matter microvascular alterations normalize within 1 year after treatment with haematopoietic stem cell transplantation. For the first time in vivo, our studies unveil a model to assess how ABCD1 alters white matter microvascular function and explores its potential as an earlier biomarker for monitoring disease progression and response to treatment.

    更新日期:2017-11-17
  • Hereditary spastic paraplegia type 5: natural history, biomarkers and a randomized controlled trial
    Brain (IF 10.292) Pub Date : 2017-11-06
    Ludger Schöls, Tim W Rattay, Peter Martus, Christoph Meisner, Jonathan Baets, Imma Fischer, Christine Jägle, Matthew J Fraidakis, Andrea Martinuzzi, Jonas Alex Saute, Marina Scarlato, Antonella Antenora, Claudia Stendel, Philip Höflinger, Charles Marques Lourenco, Lisa Abreu, Katrien Smets, Martin Paucar, Tine Deconinck, Dana M Bis, Sarah Wiethoff, Peter Bauer, Alessia Arnoldi, Wilson Marques, Laura Bannach Jardim, Stefan Hauser, Chiara Criscuolo, Alessandro Filla, Stephan Züchner, Maria Teresa Bassi, Thomas Klopstock, Peter De Jonghe, Ingemar Björkhem, Rebecca Schüle

    Spastic paraplegia type 5 (SPG5) is a rare subtype of hereditary spastic paraplegia, a highly heterogeneous group of neurodegenerative disorders defined by progressive neurodegeneration of the corticospinal tract motor neurons. SPG5 is caused by recessive mutations in the gene CYP7B1 encoding oxysterol-7α-hydroxylase. This enzyme is involved in the degradation of cholesterol into primary bile acids. CYP7B1 deficiency has been shown to lead to accumulation of neurotoxic oxysterols. In this multicentre study, we have performed detailed clinical and biochemical analysis in 34 genetically confirmed SPG5 cases from 28 families, studied dose-dependent neurotoxicity of oxysterols in human cortical neurons and performed a randomized placebo-controlled double blind interventional trial targeting oxysterol accumulation in serum of SPG5 patients. Clinically, SPG5 manifested in childhood or adolescence (median 13 years). Gait ataxia was a common feature. SPG5 patients lost the ability to walk independently after a median disease duration of 23 years and became wheelchair dependent after a median 33 years. The overall cross-sectional progression rate of 0.56 points on the Spastic Paraplegia Rating Scale per year was slightly lower than the longitudinal progression rate of 0.80 points per year. Biochemically, marked accumulation of CYP7B1 substrates including 27-hydroxycholesterol was confirmed in serum (n = 19) and cerebrospinal fluid (n = 17) of SPG5 patients. Moreover, 27-hydroxycholesterol levels in serum correlated with disease severity and disease duration. Oxysterols were found to impair metabolic activity and viability of human cortical neurons at concentrations found in SPG5 patients, indicating that elevated levels of oxysterols might be key pathogenic factors in SPG5. We thus performed a randomized placebo-controlled trial (EudraCT 2015-000978-35) with atorvastatin 40 mg/day for 9 weeks in 14 SPG5 patients with 27-hydroxycholesterol levels in serum as the primary outcome measure. Atorvastatin, but not placebo, reduced serum 27-hydroxycholesterol from 853 ng/ml [interquartile range (IQR) 683–1113] to 641 (IQR 507–694) (−31.5%, P = 0.001, Mann-Whitney U-test). Similarly, 25-hydroxycholesterol levels in serum were reduced. In cerebrospinal fluid 27-hydroxycholesterol was reduced by 8.4% but this did not significantly differ from placebo. As expected, no effects were seen on clinical outcome parameters in this short-term trial. In this study, we define the mutational and phenotypic spectrum of SPG5, examine the correlation of disease severity and progression with oxysterol concentrations, and demonstrate in a randomized controlled trial that atorvastatin treatment can effectively lower 27-hydroxycholesterol levels in serum of SPG5 patients. We thus demonstrate the first causal treatment strategy in hereditary spastic paraplegia.

    更新日期:2017-11-17
  • 更新日期:2017-11-17
  • Complicated hereditary spastic paraplegia due to ATP13A2 mutations: what’s in a name?
    Brain (IF 10.292) Pub Date : 2017-11-03
    Susanne de Bot, Erik-Jan Kamsteeg, Bart P C van deWarrenburg

    Sir,

    更新日期:2017-11-17
  • Reply: Defining a functional network homeostasis after stroke: EEG-based approach is complementary to functional MRI
    Brain (IF 10.292) Pub Date : 2017-11-03
    Mohit H Adhikari, Gustavo Deco, Maurizio Corbetta

    Sir,

    更新日期:2017-11-17
  • Defining a functional network homeostasis after stroke: EEG-based approach is complementary to functional MRI
    Brain (IF 10.292) Pub Date : 2017-11-03
    Pietro Caliandro, Giuseppe Reale, Fabrizio Vecchio, Chiara Iacovelli, Francesca Miraglia, Gianvito Masi, Paolo Maria Rossini

    Sir,

    更新日期:2017-11-17
  • A lesion model of envy and Schadenfreude: legal, deservingness and moral dimensions as revealed by neurodegeneration
    Brain (IF 10.292) Pub Date : 2017-11-02
    Hernando Santamaría-García, Sandra Baez, Pablo Reyes, José A Santamaría-García, José M Santacruz-Escudero, Diana Matallana, Analía Arévalo, Mariano Sigman, Adolfo M García, Agustín Ibáñez

    The study of moral emotions (i.e. Schadenfreude and envy) is critical to understand the ecological complexity of everyday interactions between cognitive, affective, and social cognition processes. Most previous studies in this area have used correlational imaging techniques and framed Schadenfreude and envy as unified and monolithic emotional domains. Here, we profit from a relevant neurodegeneration model to disentangle the brain regions engaged in three dimensions of Schadenfreude and envy: deservingness, morality, and legality. We tested a group of patients with behavioural variant frontotemporal dementia (bvFTD), patients with Alzheimer’s disease, as a contrastive neurodegeneration model, and healthy controls on a novel task highlighting each of these dimensions in scenarios eliciting Schadenfreude and envy. Compared with the Alzheimer’s disease and control groups, patients with bvFTD obtained significantly higher scores on all dimensions for both emotions. Correlational analyses revealed an association between envy and Schadenfreude scores and greater deficits in social cognition, inhibitory control, and behaviour disturbances in bvFTD patients. Brain anatomy findings (restricted to bvFTD and controls) confirmed the partially dissociable nature of the moral emotions’ experiences and highlighted the importance of socio-moral brain areas in processing those emotions. In all subjects, an association emerged between Schadenfreude and the ventral striatum, and between envy and the anterior cingulate cortex. In addition, the results supported an association between scores for moral and legal transgression and the morphology of areas implicated in emotional appraisal, including the amygdala and the parahippocampus. By contrast, bvFTD patients exhibited a negative association between increased Schadenfreude and envy across dimensions and critical regions supporting social-value rewards and social-moral processes (dorsolateral prefrontal cortex, angular gyrus and precuneus). Together, this study provides lesion-based evidence for the multidimensional nature of the emotional experiences of envy and Schadenfreude. Our results offer new insights into the mechanisms subsuming complex emotions and moral cognition in neurodegeneration. Moreover, this study presents the exacerbation of envy and Schadenfreude as a new potential hallmark of bvFTD that could impact in diagnosis and progression.

    更新日期:2017-11-17
  • Elevated progranulin contributes to synaptic and learning deficit due to loss of fragile X mental retardation protein
    Brain (IF 10.292) Pub Date : 2017-10-31
    Kun Zhang, Yu-jiao Li, Yanyan Guo, Kai-yin Zheng, Qi Yang, Le Yang, Xin-shang Wang, Qian Song, Tao Chen, Min Zhuo, Ming-gao Zhao

    Fragile X syndrome is an inheritable form of intellectual disability caused by loss of fragile X mental retardation protein (FMRP, encoded by the FMR1 gene). Absence of FMRP caused overexpression of progranulin (PGRN, encoded by GRN), a putative tumour necrosis factor receptor ligand. In the present study, we found that progranulin mRNA and protein were upregulated in the medial prefrontal cortex of Fmr1 knock-out mice. In Fmr1 knock-out mice, elevated progranulin caused insufficient dendritic spine pruning and late-phase long-term potentiation in the medial prefrontal cortex of Fmr1 knock-out mice. Partial progranulin knock-down restored spine morphology and reversed behavioural deficits, including impaired fear memory, hyperactivity, and motor inflexibility in Fmr1 knock-out mice. Progranulin increased levels of phosphorylated glutamate ionotropic receptor GluA1 and nuclear factor kappa B in cultured wild-type neurons. Tumour necrosis factor receptor 2 antibody perfusion blocked the effects of progranulin on GluA1 phosphorylation; this result indicates that tumour necrosis factor receptor 2 is required for progranulin-mediated GluA1 phosphorylation and late-phase long-term potentiation expression. However, high basal level of progranulin in Fmr1 knock-out mice prevented further facilitation of synaptic plasticity by exogenous progranulin. Partial downregulation of progranulin or tumour necrosis factor receptor 2/nuclear factor kappa B signalling restored synaptic plasticity and memory deficits in Fmr1 knock-out mice. These findings suggest that elevated PGRN is linked to cognitive deficits of fragile X syndrome, and the progranulin/tumour necrosis factor receptor 2 signalling pathway may be a putative therapeutic target for improving cognitive deficits in fragile X syndrome.

    更新日期:2017-11-17
  • Preservation of hand movement representation in the sensorimotor areas of amputees
    Brain (IF 10.292) Pub Date : 2017-10-27
    Mark L C M Bruurmijn, Isabelle P L Pereboom, Mariska J Vansteensel, Mathijs A H Raemaekers, Nick F Ramsey

    Denervation due to amputation is known to induce cortical reorganization in the sensorimotor cortex. Although there is evidence that reorganization does not lead to a complete loss of the representation of the phantom limb, it is unclear to what extent detailed, finger-specific activation patterns are preserved in motor cortex, an issue that is also relevant for development of brain–computer interface solutions for paralysed people. We applied machine learning to obtain a quantitative measure for the functional organization within the motor and adjacent cortices in amputees, using high resolution functional MRI and attempted hand gestures. Subjects with above-elbow arm amputation (n = 8) and non-amputated controls (n = 9) made several gestures with either their right or left hand. Amputees attempted to make gestures with their amputated hand. Images were acquired using 7 T functional MRI. The sensorimotor cortex was divided into four regions, and activity patterns were classified in individual subjects using a support vector machine. Classification scores were significantly above chance for all subjects and all hands, and were highly similar between amputees and controls in most regions. Decodability of phantom movements from primary motor cortex reached the levels of right hand movements in controls. Attempted movements were successfully decoded from primary sensory cortex in amputees, albeit lower than in controls but well above chance level despite absence of somatosensory feedback. There was no significant correlation between decodability and years since amputation, or age. The ability to decode attempted gestures demonstrates that the detailed hand representation is preserved in motor cortex and adjacent regions after denervation. This encourages targeting sensorimotor activity patterns for development of brain–computer interfaces.

    更新日期:2017-11-17
  • The direct basal ganglia pathway is hyperfunctional in focal dystonia
    Brain (IF 10.292) Pub Date : 2017-10-26
    Kristina Simonyan, Hyun Cho, Azadeh Hamzehei Sichani, Estee Rubien-Thomas, Mark Hallett

    Focal dystonias are the most common type of isolated dystonia. Although their causative pathophysiology remains unclear, it is thought to involve abnormal functioning of the basal ganglia-thalamo-cortical circuitry. We used high-resolution research tomography with the radioligand 11C-NNC-112 to examine striatal dopamine D1 receptor function in two independent groups of patients, writer’s cramp and laryngeal dystonia, compared to healthy controls. We found that availability of dopamine D1 receptors was significantly increased in bilateral putamen by 19.6–22.5% in writer’s cramp and in right putamen and caudate nucleus by 24.6–26.8% in laryngeal dystonia (all P ≤ 0.009). This suggests hyperactivity of the direct basal ganglia pathway in focal dystonia. Our findings paralleled abnormally decreased dopaminergic function via the indirect basal ganglia pathway and decreased symptom-induced phasic striatal dopamine release in writer’s cramp and laryngeal dystonia. When examining topological distribution of dopamine D1 and D2 receptor abnormalities in these forms of dystonia, we found abnormal separation of direct and indirect pathways within the striatum, with negligible, if any, overlap between the two pathways and with the regions of phasic dopamine release. However, despite topological disorganization of dopaminergic function, alterations of dopamine D1 and D2 receptors were somatotopically localized within the striatal hand and larynx representations in writer’s cramp and laryngeal dystonia, respectively. This finding points to their direct relevance to disorder-characteristic clinical features. Increased D1 receptor availability showed significant negative correlations with dystonia duration but not its severity, likely representing a developmental endophenotype of this disorder. In conclusion, a comprehensive pathophysiological mechanism of abnormal basal ganglia function in focal dystonia is built upon upregulated dopamine D1 receptors that abnormally increase excitation of the direct pathway, downregulated dopamine D2 receptors that abnormally decrease inhibition within the indirect pathway, and weakened nigro-striatal phasic dopamine release during symptomatic task performance. Collectively, these aberrations of striatal dopaminergic function underlie imbalance between direct and indirect basal ganglia pathways and lead to abnormal thalamo-motor-cortical hyperexcitability in dystonia.

    更新日期:2017-11-17
  • Sleep apnoeas may represent a reversible risk factor for amyloid-β pathology
    Brain (IF 10.292) Pub Date : 2017-10-25
    Claudio Liguori, Agostino Chiaravalloti, Francesca Izzi, Marzia Nuccetelli, Sergio Bernardini, Orazio Schillaci, Nicola Biagio Mercuri, Fabio Placidi

    Sir,

    更新日期:2017-11-17
  • PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer’s disease
    Brain (IF 10.292) Pub Date : 2017-10-25
    Fang Du, Qing Yu, Shijun Yan, Gang Hu, Lih-Fen Lue, Douglas G Walker, Long Wu, Shi Fang Yan, Kim Tieu, Shirley ShiDu Yan

    Mitochondrial dysfunction and synaptic damage are early pathological features of the Alzheimer’s disease-affected brain. Memory impairment in Alzheimer’s disease is a manifestation of brain pathologies such as accumulation of amyloid-β peptide and mitochondrial damage. The underlying pathogenic mechanisms and effective disease-modifying therapies for Alzheimer’s disease remain elusive. Here, we demonstrate for the first time that decreased PTEN-induced putative kinase 1 (PINK1) expression is associated with Alzheimer’s disease pathology. Restoring neuronal PINK1 function strikingly reduces amyloid-β levels, amyloid-associated pathology, oxidative stress, as well as mitochondrial and synaptic dysfunction. In contrast, PINK1-deficient mAPP mice augmented cerebral amyloid-β accumulation, mitochondrial abnormalities, impairments in learning and memory, as well as synaptic plasticity at an earlier age than mAPP mice. Notably, gene therapy-mediated PINK1 overexpression promotes the clearance of damaged mitochondria by augmenting autophagy signalling via activation of autophagy receptors (OPTN and NDP52), thereby alleviating amyloid-β-induced loss of synapses and cognitive decline in Alzheimer’s disease mice. Loss of PINK1 activity or blockade of PINK1-mediated signalling (OPTN or NDP52) fails to reverse amyloid-β-induced detrimental effects. Our findings highlight a novel mechanism by which PINK1-dependent signalling promotes the rescue of amyloid pathology and amyloid-β-mediated mitochondrial and synaptic dysfunctions in a manner requiring activation of autophagy receptor OPTN or NDP52. Thus, activation of PINK1 may represent a new therapeutic avenue for combating Alzheimer’s disease.

    更新日期:2017-11-17
  • 更新日期:2017-11-17
  • Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons
    Brain (IF 10.292) Pub Date : 2017-10-13
    Patricia Rodriguez-Rodriguez, Anna Sandebring-Matton, Paula Merino-Serrais, Cristina Parrado-Fernandez, Alberto Rabano, Bengt Winblad, Jesús Ávila, Isidre Ferrer, Angel Cedazo-Minguez

    Insulin signalling deficiencies and insulin resistance have been directly linked to the progression of neurodegenerative disorders like Alzheimer’s disease. However, to date little is known about the underlying molecular mechanisms or insulin state and distribution in the brain under pathological conditions. Here, we report that insulin is accumulated and retained as oligomers in hyperphosphorylated tau-bearing neurons in Alzheimer’s disease and in several of the most prevalent human tauopathies. The intraneuronal accumulation of insulin is directly dependent on tau hyperphosphorylation, and follows the tauopathy progression. Furthermore, cells accumulating insulin show signs of insulin resistance and decreased insulin receptor levels. These results suggest that insulin retention in hyperphosphorylated tau-bearing neurons is a causative factor for the insulin resistance observed in tauopathies, and describe a novel neuropathological concept with important therapeutic implications.

    更新日期:2017-11-17
  • Corrigendum
    Brain (IF 10.292) Pub Date : 2017-10-11

    Heidi I. L. Jacobs, David A. Hopkins, Helen C. Mayrhofer, Emiliano Bruner, Fred W. van Leeuwen, Wijnand Raaijmakers and Jeremy D. Schmahmann. The cerebellum in Alzheimer’s disease: evaluating its role in cognitive decline. Brain 2017; 10.1093/brain/awx194.

    更新日期:2017-11-17
  • Corrigendum
    Brain (IF 10.292) Pub Date : 2017-10-11

    Claude J. Bajada, Briony Banks, Matthew A. Lambon Ralph, Lauren L. Cloutman. Reconnecting with Joseph and Augusta Dejerine: 100 years on. Brain 2017; 140: 2752-2759. 10.1093/brain/awx225.

    更新日期:2017-11-17
  • Reward deficits in behavioural variant frontotemporal dementia include insensitivity to negative stimuli
    Brain (IF 10.292) Pub Date : 2017-10-07
    David C Perry, Samir Datta, Virginia E Sturm, Kristie A Wood, Jessica Zakrzewski, William W Seeley, Bruce L Miller, Joel H Kramer, Howard J Rosen

    During reward processing individuals weigh positive and negative features of a stimulus to determine whether they will pursue or avoid it. Though patients with behavioural variant frontotemporal dementia display changes in their pursuit of rewards, such as food, alcohol, money, and sex, the basis for these shifts is not clearly established. In particular, it is unknown whether patients’ behaviour results from excessive focus on rewards, insensitivity to punishment, or to dysfunction in a particular stage of reward processing, such as anticipation, consumption, or action selection. Our goal was to determine the nature of the reward deficit in behavioural variant frontotemporal dementia and its underlying anatomy. We devised a series of tasks involving pleasant, unpleasant, and neutral olfactory stimuli, designed to separate distinct phases of reward processing. In a group of 25 patients with behavioural variant frontotemporal dementia and 21 control subjects, diagnosis by valence interactions revealed that patients with behavioural variant frontotemporal dementia rated unpleasant odours as less aversive than did controls and displayed lower skin conductance responses when anticipating an upcoming aversive odour. Subjective pleasantness ratings and skin conductance responses did not differ between behavioural variant frontotemporal dementia and controls for pleasant or neutral smells. In a task designed to measure the effort subjects would expend to smell or avoid smelling a stimulus, patients with behavioural variant frontotemporal dementia were less motivated, and therefore less successful than control subjects, at avoiding what they preferred not to smell, but had equivalent success at obtaining stimuli they found rewarding. Voxel-based morphometry of patients with behavioural variant frontotemporal dementia revealed that the inability to subjectively differentiate the valence of pleasant and unpleasant odours correlated with atrophy in right ventral mid-insula and right amygdala. High pleasantness ratings of unpleasant stimuli correlated with left dorsal anterior insula and frontal pole atrophy. These findings indicate that insensitivity to negative information may be a key component of the reward-seeking behaviours in behavioural variant frontotemporal dementia, and may relate to degeneration of structures that are involved in representing the emotional salience of sensory information.

    更新日期:2017-11-17
  • Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease
    Brain (IF 10.292) Pub Date : 2017-10-07
    Alexandre Bejanin, Daniel R Schonhaut, Renaud La Joie, Joel H Kramer, Suzanne L Baker, Natasha Sosa, Nagehan Ayakta, Averill Cantwell, Mustafa Janabi, Mariella Lauriola, James P O’Neil, Maria L Gorno-Tempini, Zachary A Miller, Howard J Rosen, Bruce L Miller, William J Jagust, Gil D Rabinovici

    Neuropathological and in vivo studies have revealed a tight relationship between tau pathology and cognitive impairment across the Alzheimer’s disease spectrum. However, tau pathology is also intimately associated with neurodegeneration and amyloid pathology. The aim of the present study was therefore to assess whether grey matter atrophy and amyloid pathology contribute to the relationship between tau pathology, as measured with 18F-AV-1451-PET imaging, and cognitive deficits in Alzheimer’s disease. We included 40 amyloid-positive patients meeting criteria for mild cognitive impairment due to Alzheimer’s disease (n = 5) or probable Alzheimer’s disease dementia (n = 35). Twelve patients additionally fulfilled the diagnostic criteria for posterior cortical atrophy and eight for logopenic variant primary progressive aphasia. All participants underwent 3 T magnetic resonance imaging, amyloid (11C-PiB) positron emission tomography and tau (18F-AV-1451) positron emission tomography, and episodic and semantic memory, language, executive and visuospatial functions assessment. Raw cognitive scores were converted to age-adjusted Z-scores (W-scores) and averaged to compute composite scores for each cognitive domain. Independent regressions were performed between 18F-AV-1451 binding and each cognitive domain, and we used the Biological Parametric Mapping toolbox to further control for local grey matter volumes, 11C-PiB uptake, or both. Partial correlations and causal mediation analyses (mediation R package) were then performed in brain regions showing an association between cognition and both 18F-AV-1451 uptake and grey matter volume. Our results showed that decreased cognitive performance in each domain was related to increased 18F-AV-1451 binding in specific brain regions conforming to established brain-behaviour relationships (i.e. episodic memory: medial temporal lobe and angular gyrus; semantic memory: left anterior temporal regions; language: left posterior superior temporal lobe and supramarginal gyrus; executive functions: bilateral frontoparietal regions; visuospatial functions: right more than left occipitotemporal regions). This pattern of regional associations remained essentially unchanged—although less spatially extended—when grey matter volume or 11C-PiB uptake maps were added as covariates. Mediation analyses revealed both direct and grey matter-mediated effects of 18F-AV-1451 uptake on cognitive performance. Together, these results show that tau pathology is related in a region-specific manner to cognitive impairment in Alzheimer’s disease. These regional relationships are weakly related to amyloid burden, but are in part mediated by grey matter volumes. This suggests that tau pathology may lead to cognitive deficits through a variety of mechanisms, including, but not restricted to, grey matter loss. These results might have implications for future therapeutic trials targeting tau pathology.

    更新日期:2017-11-17
  • Clinicopathological correlations in behavioural variant frontotemporal dementia
    Brain (IF 10.292) Pub Date : 2017-10-06
    David C Perry, Jesse A Brown, Katherine L Possin, Samir Datta, Andrew Trujillo, Anneliese Radke, Anna Karydas, John Kornak, Ana C Sias, Gil D Rabinovici, Maria Luisa Gorno-Tempini, Adam L Boxer, Mary De May, Katherine P Rankin, Virginia E Sturm, Suzee E Lee, Brandy R Matthews, Aimee W Kao, Keith A Vossel, Maria Carmela Tartaglia, Zachary A Miller, Sang Won Seo, Manu Sidhu, Stephanie E Gaus, Alissa L Nana, Jose Norberto S Vargas, Ji-Hye L Hwang, Rik Ossenkoppele, Alainna B Brown, Eric J Huang, Giovanni Coppola, Howard J Rosen, Daniel Geschwind, John Q Trojanowski, Lea T Grinberg, Joel H Kramer, Bruce L Miller, William W Seeley

    Accurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer’s disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick’s disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer’s disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least ‘possible’ bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual patients share atrophy in anterior cingulate, frontoinsula, striatum, and amygdala, indicating that degeneration of these regions is intimately linked to the behavioural syndrome produced by these diverse aetiologies. In addition to these unifying features, symptom profiles also differed among pathological subtypes, suggesting distinct anatomical vulnerabilities and informing a clinician’s prediction of pathological diagnosis. Data-driven classification into one of the 10 most common pathological diagnoses was most accurate (up to 60.2%) when using a combination of known predictive factors (genetic mutations, motor features, or striking atrophy patterns) and the results of a discriminant function analysis that incorporated clinical, neuroimaging, and neuropsychological data.

    更新日期:2017-11-17
  • Movement disorders with neuronal antibodies: syndromic approach, genetic parallels and pathophysiology
    Brain (IF 10.292) Pub Date : 2017-09-25
    Bettina Balint, Angela Vincent, Hans-Michael Meinck, Sarosh R. Irani, Kailash P. Bhatia

    Movement disorders are a prominent and common feature in many autoantibody-associated neurological diseases, a group of potentially treatable conditions that can mimic infectious, metabolic or neurodegenerative disease. Certain movement disorders are likely to associate with certain autoantibodies; for example, the characteristic dyskinesias, chorea and dystonia associated with NMDAR antibodies, stiff person spectrum disorders with GAD, glycine receptor, amphiphysin or DPPX antibodies, specific paroxysmal dystonias with LGI1 antibodies, and cerebellar ataxia with various anti-neuronal antibodies. There are also less-recognized movement disorder presentations of antibody-related disease, and a considerable overlap between the clinical phenotypes and the associated antibody spectra. In this review, we first describe the antibodies associated with each syndrome, highlight distinctive clinical or radiological ‘red flags’, and suggest a syndromic approach based on the predominant movement disorder presentation, age, and associated features. We then examine the underlying immunopathophysiology, which may guide treatment decisions in these neuroimmunological disorders, and highlight the exceptional interface between neuronal antibodies and neurodegeneration, such as the tauopathy associated with IgLON5 antibodies. Moreover, we elaborate the emerging pathophysiological parallels between genetic movement disorders and immunological conditions, with proteins being either affected by mutations or targeted by autoantibodies. Hereditary hyperekplexia, for example, is caused by mutations of the alpha subunit of the glycine receptor leading to an infantile-onset disorder with exaggerated startle and stiffness, whereas antibodies targeting glycine receptors can induce acquired hyperekplexia. The spectrum of such immunological and genetic analogies also includes cerebellar ataxias and some encephalopathies. Lastly, we discuss how these pathophysiological considerations could reflect on possible future directions regarding antigen-specific immunotherapies or targeting the pathophysiological cascades downstream of the antibody effects.

    更新日期:2017-11-17
  • 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.

    更新日期:2017-11-17
  • 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.

    更新日期:2017-11-17
  • 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.

    更新日期:2017-11-17
  • 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.

    更新日期:2017-11-17
  • Editorial
    Brain (IF 10.292) Pub Date : 2017-10-27
    Dimitri M Kullmann

    One of the more enjoyable roles of the editor is to choose a cover for each issue of Brain. Cover images are mostly, although not invariably, drawn from suggestions submitted by authors of papers appearing in the same issue. They often go through several iterations before being sent for production. Some covers are composed in the Editorial Office drawing on original artwork, or archives held by libraries and museums. For authors contemplating cover suggestions in the future, here are some guidelines. The image should be striking and invite the casual viewer to open the journal or to click on the link that describes it. It should, ideally, tell a story, or at least have some conceptual link to the message of the paper to which...

    更新日期:2017-11-17
  • The multiple faces of TOR1A: different inheritance, different phenotype
    Brain (IF 10.292) Pub Date : 2017-10-27
    Monia Ginevrino, Enza Maria Valente

    This scientific commentary refers to ‘TOR1A variants cause a severe arthrogryposis with developmental delay, strabismus and tremor’, by Kariminejad et al. (doi:10.1093/brain/awx230).

    更新日期:2017-11-17
  • Entangled cerebral networks in Parkinson’s disease
    Brain (IF 10.292) Pub Date : 2017-10-27
    Freek Nieuwhof, Rick C Helmich

    This scientific commentary refers to ‘Abnormal intrinsic brain functional network dynamics in Parkinson’s disease’, by Kim et al. (doi:10.1093/brain/awx233).

    更新日期:2017-11-17
  • Light at the beginning of the tunnel? Investigating early mechanistic changes in Alzheimer’s disease
    Brain (IF 10.292) Pub Date : 2017-10-27
    Lea Tenenholz Grinberg, Helmut Heinsen

    This scientific commentary refers to ‘Chemogenetic locus coeruleus activation restores reversal learning in a rat model of Alzheimer’s disease’, by Rorabaugh et al. (doi:10.1093/brain/awx232).

    更新日期:2017-11-17
  • Reduced neural ‘effort’ after naming treatment in anomia
    Brain (IF 10.292) Pub Date : 2017-10-27
    Hannah E Thompson, Anna M Woollams

    This scientific commentary refers to ‘Less is more: neural mechanisms underlying anomia treatment in chronic aphasic patients’, by Nardo et al. (doi:10.1093/brain/awx234).

    更新日期:2017-11-17
  • 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.

    更新日期:2017-11-17
  • Humanized mutant FUS drives progressive motor neuron degeneration without aggregation in ‘FUSDelta14’ knockin mice
    Brain (IF 10.292) Pub Date : 2017-10-07
    Anny Devoy, Bernadett Kalmar, Michelle Stewart, Heesoon Park, Beverley Burke, Suzanna J Noy, Yushi Redhead, Jack Humphrey, Kitty Lo, Julian Jaeger, Alan Mejia Maza, Prasanth Sivakumar, Cinzia Bertolin, Gianni Soraru, Vincent Plagnol, Linda Greensmith, Abraham Acevedo Arozena, Adrian M Isaacs, Benjamin Davies, Pietro Fratta, Elizabeth M C Fisher

    Mutations in FUS are causative for amyotrophic lateral sclerosis with a dominant mode of inheritance. In trying to model FUS-amyotrophic lateral sclerosis (ALS) in mouse it is clear that FUS is dosage-sensitive and effects arise from overexpression per se in transgenic strains. Novel models are required that maintain physiological levels of FUS expression and that recapitulate the human disease—with progressive loss of motor neurons in heterozygous animals. Here, we describe a new humanized FUS-ALS mouse with a frameshift mutation, which fulfils both criteria: the FUS Delta14 mouse. Heterozygous animals express mutant humanized FUS protein at physiological levels and have adult onset progressive motor neuron loss and denervation of neuromuscular junctions. Additionally, we generated a novel antibody to the unique human frameshift peptide epitope, allowing specific identification of mutant FUS only. Using our new FUSDelta14 ALS mouse-antibody system we show that neurodegeneration occurs in the absence of FUS protein aggregation. FUS mislocalization increases as disease progresses, and mutant FUS accumulates at the rough endoplasmic reticulum. Further, transcriptomic analyses show progressive changes in ribosomal protein levels and mitochondrial function as early disease stages are initiated. Thus, our new physiological mouse model has provided novel insight into the early pathogenesis of FUS-ALS.

    更新日期:2017-11-17
  • A null mutation in MICU2 causes abnormal mitochondrial calcium homeostasis and a severe neurodevelopmental disorder
    Brain (IF 10.292) Pub Date : 2017-09-25
    Hanan E Shamseldin, Ali Alasmari, Mohammed A Salih, Manar M Samman, Shahid A Mian, Tarfa Alshidi, Niema Ibrahim, Mais Hashem, Eissa Faqeih, Futwan Al-Mohanna, Fowzan S Alkuraya

    Mitochondrial calcium homeostasis is a tightly controlled process that is required for a variety of cellular functions. The mitochondrial calcium uniporter complex plays a critical role in this process. MICU2 is a major component of the mitochondrial calcium uniporter complex and its deficiency has been shown to impair mitochondrial calcium [Ca2+]m homeostasis although the exact mechanism remains unclear. We used exome sequencing, positional mapping, and functional characterization of MICU2 deficiency to investigate the role of MICU2 in calcium homeostasis. Using combined autozygome/exome analysis, a homozygous truncating mutation in MICU2 was found to fully segregate with a neurodevelopmental disorder in the form of severe cognitive impairment, spasticity, and white matter involvement in a multiplex consanguineous family. Patient-derived MICU2-deficient cells displayed impaired [Ca2+]m homeostasis, with associated increase in mitochondrial sensitivity to oxidative stress, and abnormal regulation of inner mitochondrial membrane potential. This is the first demonstration of MICU2 deficiency in humans, which we suggest causes a distinct neurodevelopmental phenotype secondary to impaired mitochondrial calcium uniporter-mediated regulation of intracellular calcium homeostasis.

    更新日期:2017-11-17
  • Long-term disability progression in primary progressive multiple sclerosis: a 15-year study
    Brain (IF 10.292) Pub Date : 2017-09-27
    Maria A Rocca, Maria Pia Sormani, Marco Rovaris, Domenico Caputo, Angelo Ghezzi, Enrico Montanari, Antonio Bertolotto, Alice Laroni, Roberto Bergamaschi, Vittorio Martinelli, Giancarlo Comi, Massimo Filippi

    Prognostic markers of primary progressive multiple sclerosis evolution are needed. We investigated the added value of magnetic resonance imaging measures of brain and cervical cord damage in predicting long-term clinical worsening of primary progressive multiple sclerosis compared to simple clinical assessment. In 54 patients, conventional and diffusion tensor brain scans and cervical cord T1-weighted scans were acquired at baseline and after 15 months. Clinical evaluation was performed after 5 and 15 years in 49 patients. Lesion load, brain and cord atrophy, mean diffusivity and fractional anisotropy values from the brain normal-appearing white matter and grey matter were obtained. Using linear regression models, we screened the clinical and imaging variables as independent predictors of 15-year disability change (measured on the expanded disability status scale). At 15 years, 90% of the patients had disability progression. Integrating clinical and imaging variables at 15 months predicted disability changes at 15 years better than clinical factors at 5 years (R2 = 61% versus R2 = 57%). The model predicted long-term disability change with a precision within one point in 38 of 49 patients (77.6%). Integration of clinical and imaging measures allows identification of primary progressive multiple sclerosis patients at risk of long-term disease progression 4 years earlier than when using clinical assessment alone.

    更新日期:2017-11-17
  • Clinical, pathological and functional characterization of riboflavin-responsive neuropathy
    Brain (IF 10.292) Pub Date : 2017-09-26
    Andreea Manole, Zane Jaunmuktane, Iain Hargreaves, Marthe H R Ludtmann, Vincenzo Salpietro, Oscar D Bello, Simon Pope, Amelie Pandraud, Alejandro Horga, Renata S Scalco, Abi Li, Balasubramaniem Ashokkumar, Charles M Lourenço, Simon Heales, Rita Horvath, Patrick F Chinnery, Camilo Toro, Andrew B Singleton, Thomas S Jacques, Andrey Y Abramov, Francesco Muntoni, Michael G Hanna, Mary M Reilly, Tamas Revesz, Dimitri M Kullmann, James E C Jepson, Henry Houlden

    Brown-Vialetto-Van Laere syndrome represents a phenotypic spectrum of motor, sensory, and cranial nerve neuropathy, often with ataxia, optic atrophy and respiratory problems leading to ventilator-dependence. Loss-of-function mutations in two riboflavin transporter genes, SLC52A2 and SLC52A3, have recently been linked to Brown-Vialetto-Van Laere syndrome. However, the genetic frequency, neuropathology and downstream consequences of riboflavin transporter mutations are unclear. By screening a large cohort of 132 patients with early-onset severe sensory, motor and cranial nerve neuropathy we confirmed the strong genetic link between riboflavin transporter mutations and Brown-Vialetto-Van Laere syndrome, identifying 22 pathogenic mutations in SLC52A2 and SLC52A3, 14 of which were novel. Brain and spinal cord neuropathological examination of two cases with SLC52A3 mutations showed classical symmetrical brainstem lesions resembling pathology seen in mitochondrial disease, including severe neuronal loss in the lower cranial nerve nuclei, anterior horns and corresponding nerves, atrophy of the spinothalamic and spinocerebellar tracts and posterior column–medial lemniscus pathways. Mitochondrial dysfunction has previously been implicated in an array of neurodegenerative disorders. Since riboflavin metabolites are critical components of the mitochondrial electron transport chain, we hypothesized that reduced riboflavin transport would result in impaired mitochondrial activity, and confirmed this using in vitro and in vivo models. Electron transport chain complex I and complex II activity were decreased in SLC52A2 patient fibroblasts, while global knockdown of the single Drosophila melanogaster riboflavin transporter homologue revealed reduced levels of riboflavin, downstream metabolites, and electron transport chain complex I activity. This in turn led to abnormal mitochondrial membrane potential, respiratory chain activity and morphology. Riboflavin transporter knockdown in Drosophila also resulted in severely impaired locomotor activity and reduced lifespan, mirroring patient pathology, and these phenotypes could be partially rescued using a novel esterified derivative of riboflavin. Our findings expand the genetic, clinical and neuropathological features of Brown-Vialetto-Van Laere syndrome, implicate mitochondrial dysfunction as a downstream consequence of riboflavin transporter gene defects, and validate riboflavin esters as a potential therapeutic strategy.

    更新日期:2017-11-17
  • Choline transporter mutations in severe congenital myasthenic syndrome disrupt transporter localization
    Brain (IF 10.292) Pub Date : 2017-10-27
    Haicui Wang, Claire G Salter, Osama Refai, Holly Hardy, Katy E S Barwick, Ugur Akpulat, Malin Kvarnung, Barry A Chioza, Gaurav Harlalka, Fulya Taylan, Thomas Sejersen, Jane Wright, Holly H Zimmerman, Mert Karakaya, Burkhardt Stüve, Joachim Weis, Ulrike Schara, Mark A Russell, Omar A Abdul-Rahman, John Chilton, Randy D Blakely, Emma L Baple, Sebahattin Cirak, Andrew H Crosby

    The presynaptic, high-affinity choline transporter is a critical determinant of signalling by the neurotransmitter acetylcholine at both central and peripheral cholinergic synapses, including the neuromuscular junction. Here we describe an autosomal recessive presynaptic congenital myasthenic syndrome presenting with a broad clinical phenotype due to homozygous choline transporter missense mutations. The clinical phenotype ranges from the classical presentation of a congenital myasthenic syndrome in one patient (p.Pro210Leu), to severe neurodevelopmental delay with brain atrophy (p.Ser94Arg) and extend the clinical outcomes to a more severe spectrum with infantile lethality (p.Val112Glu). Cells transfected with mutant transporter construct revealed a virtually complete loss of transport activity that was paralleled by a reduction in transporter cell surface expression. Consistent with these findings, studies to determine the impact of gene mutations on the trafficking of the Caenorhabditis elegans choline transporter orthologue revealed deficits in transporter export to axons and nerve terminals. These findings contrast with our previous findings in autosomal dominant distal hereditary motor neuropathy of a dominant-negative frameshift mutation at the C-terminus of choline transporter that was associated with significantly reduced, but not completely abrogated choline transporter function. Together our findings define divergent neuropathological outcomes arising from different classes of choline transporter mutation with distinct disease processes and modes of inheritance. These findings underscore the essential role played by the choline transporter in sustaining acetylcholine neurotransmission at both central and neuromuscular synapses, with important implications for treatment and drug selection.

    更新日期:2017-11-17
  • TOR1A variants cause a severe arthrogryposis with developmental delay, strabismus and tremor
    Brain (IF 10.292) Pub Date : 2017-09-23
    Ariana Kariminejad, Martin Dahl-Halvarsson, Gianina Ravenscroft, Fariba Afroozan, Elham Keshavarz, Hayley Goullée, Mark R Davis, Mehrshid Faraji Zonooz, Hossein Najmabadi, Nigel G Laing, Homa Tajsharghi

    See Ginevrino and Valente (doi:10.1093/brain/awx260) for a scientific commentary on this article.

    更新日期:2017-11-17
  • Exome sequencing and network analysis identifies shared mechanisms underlying spinocerebellar ataxia
    Brain (IF 10.292) Pub Date : 2017-10-06
    Esther A R Nibbeling, Anna Duarri, Corien C Verschuuren-Bemelmans, Michiel R Fokkens, Juha M Karjalainen, Cleo J L M Smeets, Jelkje J de Boer-Bergsma, Gerben van der Vries, Dennis Dooijes, Giovana B Bampi, Cleo van Diemen, Ewout Brunt, Elly Ippel, Berry Kremer, Monique Vlak, Noam Adir, Cisca Wijmenga, Bart P C van de Warrenburg, Lude Franke, Richard J Sinke, Dineke S Verbeek

    The autosomal dominant cerebellar ataxias, referred to as spinocerebellar ataxias in genetic nomenclature, are a rare group of progressive neurodegenerative disorders characterized by loss of balance and coordination. Despite the identification of numerous disease genes, a substantial number of cases still remain without a genetic diagnosis. Here, we report five novel spinocerebellar ataxia genes, FAT2, PLD3, KIF26B, EP300, and FAT1, identified through a combination of exome sequencing in genetically undiagnosed families and targeted resequencing of exome candidates in a cohort of singletons. We validated almost all genes genetically, assessed damaging effects of the gene variants in cell models and further consolidated a role for several of these genes in the aetiology of spinocerebellar ataxia through network analysis. Our work links spinocerebellar ataxia to alterations in synaptic transmission and transcription regulation, and identifies these as the main shared mechanisms underlying the genetically diverse spinocerebellar ataxia types.

    更新日期:2017-11-17
  • Rare GABRA3 variants are associated with epileptic seizures, encephalopathy and dysmorphic features
    Brain (IF 10.292) Pub Date : 2017-10-07
    Cristina Elena Niturad, Dorit Lev, Vera M Kalscheuer, Agnieszka Charzewska, Julian Schubert, Tally Lerman-Sagie, Hester Y Kroes, Renske Oegema, Monica Traverso, Nicola Specchio, Maria Lassota, Jamel Chelly, Odeya Bennett-Back, Nirit Carmi, Tal Koffler-Brill, Michele Iacomino, Marina Trivisano, Giuseppe Capovilla, Pasquale Striano, Magdalena Nawara, Sylwia Rzońca, Ute Fischer, Melanie Bienek, Corinna Jensen, Hao Hu, Holger Thiele, Janine Altmüller, Roland Krause, Patrick May, Felicitas Becker, Rudi Balling, Saskia Biskup, Stefan A Haas, Peter Nürnberg, Koen L I van Gassen, Holger Lerche, Federico Zara, Snezana Maljevic, Esther Leshinsky-Silver

    Genetic epilepsies are caused by mutations in a range of different genes, many of them encoding ion channels, receptors or transporters. While the number of detected variants and genes increased dramatically in the recent years, pleiotropic effects have also been recognized, revealing that clinical syndromes with various degrees of severity arise from a single gene, a single mutation, or from different mutations showing similar functional defects. Accordingly, several genes coding for GABAA receptor subunits have been linked to a spectrum of benign to severe epileptic disorders and it was shown that a loss of function presents the major correlated pathomechanism. Here, we identified six variants in GABRA3 encoding the α3-subunit of the GABAA receptor. This gene is located on chromosome Xq28 and has not been previously associated with human disease. Five missense variants and one microduplication were detected in four families and two sporadic cases presenting with a range of epileptic seizure types, a varying degree of intellectual disability and developmental delay, sometimes with dysmorphic features or nystagmus. The variants co-segregated mostly but not completely with the phenotype in the families, indicating in some cases incomplete penetrance, involvement of other genes, or presence of phenocopies. Overall, males were more severely affected and there were three asymptomatic female mutation carriers compared to only one male without a clinical phenotype. X-chromosome inactivation studies could not explain the phenotypic variability in females. Three detected missense variants are localized in the extracellular GABA-binding NH2-terminus, one in the M2-M3 linker and one in the M4 transmembrane segment of the α3-subunit. Functional studies in Xenopus laevis oocytes revealed a variable but significant reduction of GABA-evoked anion currents for all mutants compared to wild-type receptors. The degree of current reduction correlated partially with the phenotype. The microduplication disrupted GABRA3 expression in fibroblasts of the affected patient. In summary, our results reveal that rare loss-of-function variants in GABRA3 increase the risk for a varying combination of epilepsy, intellectual disability/developmental delay and dysmorphic features, presenting in some pedigrees with an X-linked inheritance pattern.

    更新日期:2017-11-17
  • Seizure onset zone localization using postictal hypoperfusion detected by arterial spin labelling MRI
    Brain (IF 10.292) Pub Date : 2017-09-28
    Ismael Gaxiola-Valdez, Shaily Singh, Tefani Perera, Sherry Sandy, Emmy Li, Paolo Federico

    Neurological dysfunction following epileptic seizures is a well-recognized phenomenon. Several potential mechanisms have been suggested to explain postictal dysfunction, with alteration in cerebral blood flow being one possibility. These vascular disturbances may be long lasting and localized to brain areas involved in seizure generation and propagation, as supported by both animal and human studies. Therefore, measuring perfusion changes in the postictal period may help localize the seizure onset zone. Arterial spin labelling is a non-invasive, rapid and reproducible magnetic resonance imaging technique that measures cerebral perfusion. To this end, we measured postictal perfusion in patients with drug resistant focal epilepsy who were admitted to our seizure-monitoring unit for presurgical evaluation. Twenty-one patients were prospectively recruited and underwent arterial spin labelling scanning within 90 min of a habitual seizure. Patients also underwent a similar scan in the interictal period, after they were seizure-free for at least 24 h. The acquired scans were subtracted to identify the areas of significant postictal hypoperfusion. The location of the maximal hypoperfusion was compared to the presumed seizure onset zone to assess for concordance. Also, the localizing value of this technique was compared to other structural and functional imaging modalities. Postictal perfusion reductions of >15 units (ml/100 g/l) were seen in 15/21 patients (71.4%). In 12/15 (80%) of these patients, the location of the hypoperfusion was partially or fully concordant with the location of the presumed seizure onset zone. This technique compared favourably to other neuroimaging modalities, being similar or superior to structural magnetic resonance imaging in 52% of cases, ictal single-photon emission computed tomography in 60% of cases and interictal positron emission tomography in 71% of cases. Better arterial spin labelling results were obtained in patients in whom the seizure onset zone was discernible based on non-invasive data. Thus, this technique is a safe, non-invasive and relatively inexpensive tool to detect postictal hypoperfusion that may provide useful data to localize the seizure onset zone. This technique may be incorporated into the battery of conventional investigations for presurgical evaluation of patients with drug resistant focal epilepsy.

    更新日期:2017-11-17
  • In vivo characterization of cortical and white matter neuroaxonal pathology in early multiple sclerosis
    Brain (IF 10.292) Pub Date : 2017-10-10
    Tobias Granberg, Qiuyun Fan, Constantina Andrada Treaba, Russell Ouellette, Elena Herranz, Gabriel Mangeat, Céline Louapre, Julien Cohen-Adad, Eric C Klawiter, Jacob A Sloane, Caterina Mainero

    Neuroaxonal pathology is a main determinant of disease progression in multiple sclerosis; however, its underlying pathophysiological mechanisms, including its link to inflammatory demyelination and temporal occurrence in the disease course are still unknown. We used ultra-high field (7 T), ultra-high gradient strength diffusion and T1/T2-weighted myelin-sensitive magnetic resonance imaging to characterize microstructural changes in myelin and neuroaxonal integrity in the cortex and white matter in early stage multiple sclerosis, their distribution in lesional and normal-appearing tissue, and their correlations with neurological disability. Twenty-six early stage multiple sclerosis subjects (disease duration ≤5 years) and 24 age-matched healthy controls underwent 7 T T2*-weighted imaging for cortical lesion segmentation and 3 T T1/T2-weighted myelin-sensitive imaging and neurite orientation dispersion and density imaging for assessing microstructural myelin, axonal and dendrite integrity in lesional and normal-appearing tissue of the cortex and the white matter. Conventional mean diffusivity and fractional anisotropy metrics were also assessed for comparison. Cortical lesions were identified in 92% of early multiple sclerosis subjects and they were characterized by lower intracellular volume fraction (P = 0.015 by paired t-test), lower myelin-sensitive contrast (P = 0.030 by related-samples Wilcoxon signed-rank test) and higher mean diffusivity (P = 0.022 by related-samples Wilcoxon signed-rank test) relative to the contralateral normal-appearing cortex. Similar findings were observed in white matter lesions relative to normal-appearing white matter (all P < 0.001), accompanied by an increased orientation dispersion (P < 0.001 by paired t-test) and lower fractional anisotropy (P < 0.001 by related-samples Wilcoxon signed-rank test) suggestive of less coherent underlying fibre orientation. Additionally, the normal-appearing white matter in multiple sclerosis subjects had diffusely lower intracellular volume fractions than the white matter in controls (P = 0.029 by unpaired t-test). Cortical thickness did not differ significantly between multiple sclerosis subjects and controls. Higher orientation dispersion in the left primary motor-somatosensory cortex was associated with increased Expanded Disability Status Scale scores in surface-based general linear modelling (P < 0.05). Microstructural pathology was frequent in early multiple sclerosis, and present mainly focally in cortical lesions, whereas more diffusely in white matter. These results suggest early demyelination with loss of cells and/or cell volumes in cortical and white matter lesions, with additional axonal dispersion in white matter lesions. In the cortex, focal lesion changes might precede diffuse atrophy with cortical thinning. Findings in the normal-appearing white matter reveal early axonal pathology outside inflammatory demyelinating lesions.

    更新日期:2017-11-17
  • Neuroinflammation and its relationship to changes in brain volume and white matter lesions in multiple sclerosis
    Brain (IF 10.292) Pub Date : 2017-09-23
    Gourab Datta, Alessandro Colasanti, Eugenii A Rabiner, Roger N Gunn, Omar Malik, Olga Ciccarelli, Richard Nicholas, Eline Van Vlierberghe, Wim Van Hecke, Graham Searle, Andre Santos-Ribeiro, Paul M Matthews

    Brain magnetic resonance imaging is an important tool in the diagnosis and monitoring of multiple sclerosis patients. However, magnetic resonance imaging alone provides limited information for predicting an individual patient’s disability progression. In part, this is because magnetic resonance imaging lacks sensitivity and specificity for detecting chronic diffuse and multi-focal inflammation mediated by activated microglia/macrophages. The aim of this study was to test for an association between 18 kDa translocator protein brain positron emission tomography signal, which arises largely from microglial activation, and measures of subsequent disease progression in multiple sclerosis patients. Twenty-one patients with multiple sclerosis (seven with secondary progressive disease and 14 with a relapsing remitting disease course) underwent T1- and T2-weighted and magnetization transfer magnetic resonance imaging at baseline and after 1 year. Positron emission tomography scanning with the translocator protein radioligand 11C-PBR28 was performed at baseline. Brain tissue and lesion volumes were segmented from the T1- and T2-weighted magnetic resonance imaging and relative 11C-PBR28 uptake in the normal-appearing white matter was estimated as a distribution volume ratio with respect to a caudate pseudo-reference region. Normal-appearing white matter distribution volume ratio at baseline was correlated with enlarging T2-hyperintense lesion volumes over the subsequent year (ρ = 0.59, P = 0.01). A post hoc analysis showed that this association reflected behaviour in the subgroup of relapsing remitting patients (ρ = 0.74, P = 0.008). By contrast, in the subgroup of secondary progressive patients, microglial activation at baseline was correlated with later progression of brain atrophy (ρ = 0.86, P = 0.04). A regression model including the baseline normal-appearing white matter distribution volume ratio, T2 lesion volume and normal-appearing white matter magnetization transfer ratio for all of the patients combined explained over 90% of the variance in enlarging lesion volume over the subsequent 1 year. Glial activation in white matter assessed by translocator protein PET significantly improves predictions of white matter lesion enlargement in relapsing remitting patients and is associated with greater brain atrophy in secondary progressive disease over a period of short term follow-up.

    更新日期:2017-11-17
  • Pharmacological targeting of apelin impairs glioblastoma growth
    Brain (IF 10.292) Pub Date : 2017-10-03
    Elizabeth Harford-Wright, Gwennan Andre-Gregoire, Kathryn A Jacobs, Lucas Treps, Sophie Le Gonidec, Heloise M Leclair, Sara Gonzalez-Diest, Quentin Roux, François Guillonneau, Delphine Loussouarn, Lisa Oliver, François M Vallette, Fabienne Foufelle, Philippe Valet, Anthony P Davenport, Robert C Glen, Nicolas Bidere, Julie Gavard

    Glioblastoma are highly aggressive brain tumours that are associated with an extremely poor prognosis. Within these tumours exists a subpopulation of highly plastic self-renewing cancer cells that retain the ability to expand ex vivo as tumourspheres, induce tumour growth in mice, and have been implicated in radio- and chemo-resistance. Although their identity and fate are regulated by external cues emanating from endothelial cells, the nature of such signals remains unknown. Here, we used a mass spectrometry proteomic approach to characterize the factors released by brain endothelial cells. We report the identification of the vasoactive peptide apelin as a central regulator for endothelial-mediated maintenance of glioblastoma patient-derived cells with stem-like properties. Genetic and pharmacological targeting of apelin cognate receptor abrogates apelin- and endothelial-mediated expansion of glioblastoma patient-derived cells with stem-like properties in vitro and suppresses tumour growth in vivo. Functionally, selective competitive antagonists of apelin receptor were shown to be safe and effective in reducing tumour expansion and lengthening the survival of intracranially xenografted mice. Therefore, the apelin/apelin receptor signalling nexus may operate as a paracrine signal that sustains tumour cell expansion and progression, suggesting that apelin is a druggable factor in glioblastoma.

    更新日期:2017-11-17
  • Abnormal intrinsic brain functional network dynamics in Parkinson’s disease
    Brain (IF 10.292) Pub Date : 2017-10-05
    Jinhee Kim, Marion Criaud, Sang Soo Cho, María Díez-Cirarda, Alexander Mihaescu, Sarah Coakeley, Christine Ghadery, Mikaeel Valli, Mark F Jacobs, Sylvain Houle, Antonio P Strafella

    See Nieuwhof and Helmich (doi:10.1093/brain/awx267) for a scientific commentary on this article.

    更新日期:2017-11-17
  • Beta burst dynamics in Parkinson’s disease OFF and ON dopaminergic medication
    Brain (IF 10.292) Pub Date : 2017-10-10
    Gerd Tinkhauser, Alek Pogosyan, Huiling Tan, Damian M Herz, Andrea A Kühn, Peter Brown

    Exaggerated basal ganglia beta activity (13–35 Hz) is commonly found in patients with Parkinson’s disease and can be suppressed by dopaminergic medication, with the degree of suppression being correlated with the improvement in motor symptoms. Importantly, beta activity is not continuously elevated, but fluctuates to give beta bursts. The percentage number of longer beta bursts in a given interval is positively correlated with clinical impairment in Parkinson’s disease patients. Here we determine whether the characteristics of beta bursts are dependent on dopaminergic state. Local field potentials were recorded from the subthalamic nucleus of eight Parkinson’s disease patients during temporary lead externalization during surgery for deep brain stimulation. The recordings took place with the patient quietly seated following overnight withdrawal of levodopa and after administration of levodopa. Beta bursts were defined by applying a common amplitude threshold and burst characteristics were compared between the two drug conditions. The amplitude of beta bursts, indicative of the degree of local neural synchronization, progressively increased with burst duration. Treatment with levodopa limited this evolution leading to a relative increase of shorter, lower amplitude bursts. Synchronization, however, was not limited to local neural populations during bursts, but also, when such bursts were cotemporaneous across the hemispheres, was evidenced by bilateral phase synchronization. The probability of beta bursts and the proportion of cotemporaneous bursts were reduced by levodopa. The percentage number of longer beta bursts in a given interval was positively related to motor impairment, while the opposite was true for the percentage number of short duration beta bursts. Importantly, the decrease in burst duration was also correlated with the motor improvement. In conclusion, we demonstrate that long duration beta bursts are associated with an increase in local and interhemispheric synchronization. This may compromise information coding capacity and thereby motor processing. Dopaminergic activity limits this uncontrolled beta synchronization by terminating long duration beta bursts, with positive consequences on network state and motor symptoms.

    更新日期:2017-11-17
  • Presence of tau pathology within foetal neural allografts in patients with Huntington’s and Parkinson’s disease
    Brain (IF 10.292) Pub Date : 2017-10-27
    Giulia Cisbani, Alexander Maxan, Jeffrey H Kordower, Emmanuel Planel, Thomas B Freeman, Francesca Cicchetti

    Cell replacement has been explored as a therapeutic strategy to repair the brain in patients with Huntington’s and Parkinson’s disease. Post-mortem evaluations of healthy grafted tissue in such cases have revealed the development of Huntington- or Parkinson-like pathology including mutant huntingtin aggregates and Lewy bodies. An outstanding question remains if tau pathology can also be seen in patients with Huntington’s and Parkinson’s disease who had received foetal neural allografts. This was addressed by immunohistochemical/immunofluorescent stainings performed on grafted tissue of two Huntington’s disease patients, who came to autopsy 9 and 12 years post-transplantation, and two patients with Parkinson’s disease who came to autopsy 18 months and 16 years post-transplantation. We show that grafts also contain tau pathology in both types of transplanted patients. In two patients with Huntington’s disease, the grafted tissue showed the presence of hyperphosphorylated tau [both AT8 (phospho-tau Ser202 and Thr205) and CP13 (pSer202) immunohistochemical stainings] pathological inclusions, neurofibrillary tangles and neuropil threads. In patients with Parkinson’s disease, the grafted tissue was characterized by hyperphosphorylated tau (AT8; immunofluorescent staining) pathological inclusions, neurofibrillary tangles and neuropil threads but only in the patient who came to autopsy 16 years post-transplantation. Abundant tau-related pathology was observed in the cortex and striatum of all cases studied. While the striatum of the grafted Huntington’s disease patient revealed an equal amount of 3-repeat and 4-repeat isoforms of tau, the grafted tissue showed elevated 4-repeat isoforms by western blot. This suggests that transplants may have acquired tau pathology from the host brain, although another possibility is that this was due to acceleration of ageing. This finding not only adds to the recent reports that tau pathology is a feature of these neurodegenerative diseases, but also that tau pathology can manifest in healthy neural tissue transplanted into the brains of patients with two distinct neurodegenerative disorders.

    更新日期:2017-11-17
  • Upper limb cortical maps in amputees with targeted muscle and sensory reinnervation
    Brain (IF 10.292) Pub Date : 2017-10-27
    Andrea Serino, Michel Akselrod, Roy Salomon, Roberto Martuzzi, Maria Laura Blefari, Elisa Canzoneri, Giulio Rognini, Wietske van der Zwaag, Maria Iakova, François Luthi, Amedeo Amoresano, Todd Kuiken, Olaf Blanke

    Neuroprosthetics research in amputee patients aims at developing new prostheses that move and feel like real limbs. Targeted muscle and sensory reinnervation (TMSR) is such an approach and consists of rerouting motor and sensory nerves from the residual limb towards intact muscles and skin regions. Movement of the myoelectric prosthesis is enabled via decoded electromyography activity from reinnervated muscles and touch sensation on the missing limb is enabled by stimulation of the reinnervated skin areas. Here we ask whether and how motor control and redirected somatosensory stimulation provided via TMSR affected the maps of the upper limb in primary motor (M1) and primary somatosensory (S1) cortex, as well as their functional connections. To this aim, we tested three TMSR patients and investigated the extent, strength, and topographical organization of the missing limb and several control body regions in M1 and S1 at ultra high-field (7 T) functional magnetic resonance imaging. Additionally, we analysed the functional connectivity between M1 and S1 and of both these regions with fronto-parietal regions, known to be important for multisensory upper limb processing. These data were compared with those of control amputee patients (n = 6) and healthy controls (n = 12). We found that M1 maps of the amputated limb in TMSR patients were similar in terms of extent, strength, and topography to healthy controls and different from non-TMSR patients. S1 maps of TMSR patients were also more similar to normal conditions in terms of topographical organization and extent, as compared to non-targeted muscle and sensory reinnervation patients, but weaker in activation strength compared to healthy controls. Functional connectivity in TMSR patients between upper limb maps in M1 and S1 was comparable with healthy controls, while being reduced in non-TMSR patients. However, connectivity was reduced between S1 and fronto-parietal regions, in both the TMSR and non-TMSR patients with respect to healthy controls. This was associated with the absence of a well-established multisensory effect (visual enhancement of touch) in TMSR patients. Collectively, these results show how M1 and S1 process signals related to movement and touch are enabled by targeted muscle and sensory reinnervation. Moreover, they suggest that TMSR may counteract maladaptive cortical plasticity typically found after limb loss, in M1, partially in S1, and in their mutual connectivity. The lack of multisensory interaction in the present data suggests that further engineering advances are necessary (e.g. the integration of somatosensory feedback into current prostheses) to enable prostheses that move and feel as real limbs.

    更新日期:2017-11-17
  • 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.

    更新日期:2017-11-17
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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