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Proceedings of the 116th Meeting
of the
British Neuropathological Society
Institute of Child Health,
London, UK, 4–6 March 2015
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nan_41_s1_title_ps 03-02-2015 20:01 Page 1
President: S. Love
J. L. Holton
UCL Institute of Neurology, University
College London, UK
J. S. Lowe
University of Nottingham, UK
S. B. Wharton
University of Sheeld, UK
W. Bruck
Göttingen, Germany
S. Gentleman
London, UK
G. Halliday
Sydney, Australia
T. Jacques
London, UK
G. Reifenberger
Düsseldorf, Germany
C. Sewry
London, UK
C. Smith
Edinburgh, UK
R. O. Weller
Southhampton, UK
A. Li
London, UK
S. B. Wharton: 2007–2013
J. S. Lowe: 2000–2006
R. O. Weller: 1989–1999
J. B. Cavanagh: 1975–1988
J. Attems,
Newcastle, UK
D. Boche,
Southampton, UK
R. De Silva,
London, UK
E. Gelpi,
Barcelona, Spain
A. Gerhard,
Manchester, UK
R. Highley,
Sheeld, UK
P.G. Ince,
Sheeld, UK
P. H. Jensen,
Aarhus, Denmark
K. Josephs,
Rochester, Minnesota
R.N. Kalaria,
Newcastle, UK
J. Kirby,
Sheeld, UK
G. Kovacs,
Vienna, Austria
S. Marino, London, UK
J.P. Martinez-Barbera,
London, UK
R. McLendon,
Durham, North
R. Melki,
Paris, France
J. Nicoll,
Southampton, UK
S. Paine,
London, UK
A. Rozemuller,
The Netherlands
W. Stenzel,
Berlin, Germany
M. Thom,
London, UK
P. Wesseling,
Amsterdam, The
A. Shivane,
Plymouth, UK,
Secretary of the Society,
ex ocio
A. Aguzzi, Zurich, Switzerland
R. Castellani, Baltimore,
L. Chimelli, Rio de Janeiro,
V. Collins, Cambridge, UK
M. Dalakas, Athens, Greece
D. Dickson, Rochester,
J. Fazakerley, Edinburgh, UK
R. Franklin, Cambridge, UK
P. Gambetti, Cleveland, Ohio
B. Ghetti, Indianapolis, Indiana
H. Goebel, Berlin, Germany
F. Gray, Paris, France
J. Hardy, London, UK
J. Ironside, Edinburgh, UK
H. Lassmann, Vienna, Austria
N. Leigh, London, UK
S. Love, Bristol, UK
I. Mackenzie, Vancouver,
C. Masters, Melbourne,
H. K. Ng, Hong Kong
A. Oldfors, Gothenburg, Sweden
H. Perry, Southampton, UK
T. Revesz, London, UK
N. Rizzuto, Verona, Italy
U. Rueb, Frankfurt, Germany
K. Smith, London, UK
M. G. Spillantini, Cambridge, UK
H. Vinters, Los Angeles,
O. Wiestler, Bonn, Germany
W. Zhang, Beijing, China
Tara Noonan
Jeannie P. Ting
101-nan-v41-i2-editoria.indd 1 1/23/2015 4:28:12 PM
1 Programme for the 116th Meeting of the British Neuropathological Society
8 Oral Presentations
30 Poster Presentations
59 Author Index
Volume 41
Supplement 1
March 2015
Neuropathology & Applied Neurobiology
116th Meeting of the British Neuropathological Society
Institute of Child Health, London
Symposium Programme: Recent Advances in Muscle Disease
Chairs: Professor Caroline Sewry and Professor Janice Holton
UCL Institute of Child Health and UCL Institute of Neurology
13:00 Registration
14:00 Welcome and introduction – Caroline Sewry, UCL Institute of Child Health, London, UK
14:15 Advances in the treatment of muscle diseases
Professor Francesco Muntoni, UCL Institute of Child Health, London, UK
14:45 Protein aggregate myopathies: An update
Professor Rolf Schroder, University Hospital Erlangen, Erlangen, Germany
15:15 Autoantibodies in juvenile myositis: Associations, predictions and subphenotypes
Professor Lucy Wedderburn, UCL Institute of Child Health, London, UK
15.45 Coffee Break
16:15 Neurodevelopmental, neurodegenerative and neuromuscular disorders due to defects in
membrane traffi cking and autophagy
Dr Heinz Jungbluth, Guy’s and St Thomas’ NHS Foundation Trust, and King’s College, London, UK
16:45 Stem cell research in muscle disease
Professor Jenny Morgan, UCL Institute of Child Health, London, UK
17:15 Coffee break
17:30 Alfred Meyer Memorial Lecture
Professor Doug Turnbull, Newcastle University, Newcastle upon Tyne, UK
Advances in mitochondrial disease and new therapies
08:00 Registration
08:50 Opening of meeting Seth Love, BNS President
09:00 – 10:45 FIRST SCIENTIFIC SESSION – Neuropathology of Neurodegeneration
Chairs : Paul G. Ince and Johannes Attems
9:00 The effect of hypertension and anti-hypertensive treatment on A
plaque load and on
- and
-secretase activity in the frontal cor tex O01
E.L. Ashby, J.S. Miners, E. Dale, S. Love, P.G. Kehoe
9:15 The role of tau in the pathological process and clinical expression of
Huntington’s disease O02
R. Vuono, S. Winder-Rhodes, R. de Silva, G. Cisbani, J. Drouin-Ouellet, M.G. Spillantini, F. Cicchetti,
R.A. Barker
9:30 A cell-based biosensor for pathological tau uptake and aggregation O03
B. Hapuarachchi , M. Roberts, J. Staddon, T. Warner, R. de Silva
9:45 The presence of heterogeneous nuclear ribonucleoproteins in frontotemporal dementia
with FUS positive inclusions O04
T. L ash le y, P. Gami, R. Bandopadhyay, T. Revesz
10: 0 0 Accumulation of
-synuclein in dementia with Lewy bodies is associated with decline
in the
-synuclein-degrading enzymes kallikrein-6, calpain-1 and endothelin-converting
enzyme-1 and -2 O05
J.S. Miners , S. Love
10:15 Mitochondrial dysfunction in Parkinson’s disease: Is it the earliest feature? O06
C.E. Murray , S.N. Pressey, W.E. Heywood, I.P. Hargreaves, V. Neergheen, S. Wauters,
M. Palkovits, E. Gelpi, C. Troakes, S.M. Gentleman, K. Mills, J.L. Holton, T. Revesz, S. Gandhi
10 :30 Sub-regional nuc leus basalis of Meynert pathology in Lewy body disorders 007
A.K.L. Liu , R.C.C. Chang, R.K.B. Pearce, S.M. Gentleman
10:45 – 11:15 Coffee break
11:15 – 12:45 SECOND SCIENTIFIC SESSION – Tumours of the Central Nervous System
Chair: Silvia Marino and David W. Ellison
11:15 Infant posterior fossa ependymoma comprises two molecular subgroups O08
D.W. Ellison , K.W. Pajtler, T. Lin, S.M. P ster, T. Merchant, A. Korshunov
11:3 0 Establishing a diagnostic pipeline for methylome analysis of paediatric and
adult brain tumours in the UK using the Heidelberg classifi er O09
S. Brandner , Z. Jaunmuktane, T. J. Stone, J. Chalker, M. Hubank, T. S. Ja cque s
11: 45 c-Myc is expressed in a proportion of human choroid plexus tumours and
its overexpression in the developing mouse CNS induces choroid plexus tumorigenesis O10
A. Merve , X. Zhang, S. Acquati, S. Marino
12: 00 Glioneuronal tumours: Classifi cation, outcome and molecular genetics O11
T.J. S tone , A. Keeley, A. Virasami, W. Harkness, M. Tisdall, D. Hargrave, M. Hubank, J.H. Cross,
J. Ham, T.S. acques
12:15 Prognostic and therapeutic markers in chordomas: A study of 287 tumors O12
A. Tauziede-Espariat , M. Polivka, F. Labrousse, E . Aronica, S. Bouazza, H. Salle, A. Laquerriere,
S. Froelich, H. Adle-Biassette
12:30 The biological behaviour and prognosis of anaplastic oligodendroglioma
with necrosis O13
R. C. Laxton, M. Aizpurua , L. Doey, I. Bodi, A. King, R. Bhangoo, R. Beaney, L. Brazil,
K. Ashkan, S. Al-Sarraj
12:45 – 14:00 Lunch and Poster Discussion
Chair: Seth Love
Development of molecular markers for brain tumour classi cation
David Capper - University of Heidelberg
15:00 – 16:00 THIRD SCIENTIFIC SESSION – Neuropathology of Epilepsy
Chair: Thomas Jacques and Maria Thom
15: 0 0 A review of primary and secondary neuropathological changes in autopsy epileptic brains O14
O. Adegbaju , I. Bodi, M. Honavar, S. Al-Sarraj
15:15 Identifying novel cell types in focal cortical dysplasia by gene net work analysis O15
F. Scerif , S.R. Picker, S.A. Yasin, A. Virasami, A. Alahdal, W. Harkness, M. Tisdall, F. Guillemot,
S.M.L. Paine, J.H. Cross, T.S. Jacques
15: 30 Distribution of nestin and doublecortin expressing cells in temporal lobe epilepsy with
hippocampal sclerosis O16
M. Thom , J. Liu, C. Reeves, M. Matarin, S. Sisodiya
15: 45 Combined ex-vivo 9.4Tesla MRI and quantitative histopathological study in normal and
pathological surgical resec tions in focal epilepsy O17
C. Reeves , M. Tachrount, D. Thomas, Z. Michalak, J. Liu, M. E llis, S. Eriksson, T. Yousry, M. Thom
16:00 – 16:30 Coffee Break
16:30 – 17:30 BUSINESS MEETING
Southeast corner of Lincoln’s Inn Fields, junction with Serle Street, WC2A 3TL
9:00 – 10:30 FOURTH SCIENTIFIC SESSION – Pathology of Skeletal Muscle and Nerves
Chairs: Caroline A. Sewry and Janice L. Holton
9:00 Nuclear actin aggregation is a hallmark of anti-synthetase syndrome-induced
dysimmune myopathy 018
W. S t e n zel , C. Preuße, Y. Allenbach, D. Pehl, R. Junckerstorff, E. Aronica, E. Rushing,
O. Benveniste, J. Weis, H-H. Goebel
9:15 Sub-phenotyping of juvenile dermatomyositis O19
C.T. Deakin , S.A. Yasin, K. Arnold, S.L. Tansley, Z.E. Betteridge, N.J. McHugh,
J.L. Holton, T.S. Jacques, C. Pilkington, M. De Iorio, L.R. Wedderburn
9:30 Congenital myopathy with Lamin A/C mutation O20
J.L. Rinnenthal, A. Hucko, M. Schuelke, H.H. Goebel, W. Stenzel
9:45 Unique brick-red auto-fl uorescence of reducing bodies and protein aggregates is a
useful diagnostic biopsy marker for FHL1-associated myopathies O21
R. Phadke , D. Chambers, J. Hudson, L. Feng, C. T imson, D. Johnson, A. Man zur, F. Muntoni, C.A. Sewry
10: 0 0 Fasciitis frequently accompanies myopathy in acute critical illness muscle wasting:
Evidence from qualitative ultrasound and muscle biopsy analysis O22
R. Phadke , Z.A. Puthucheary, J. Rawal, M.J.W. McPhail, P.S. Sidhu, A. Rowlerson,
J. Moxham, S. Harridge, N. Hart, H.E. Montgomery
10:15 The role of simultaneous proximal and distal skin biopsies in the diagnosis of small
bre neuropathy O23
I. Bodi , R. Hadden, P. Bannister, A. Radunovic
10:30 – 11:00 Coffee break
11:00 – 12:00 FIFTH SCIENTIFIC SESSION – Neurodegeneration - Beyond Misfolded Proteins
Chairs: Isidro Ferrer and James A.R. Nicoll
11: 00 Correlation between levels of VEGF and insoluble A
1-42 in the cerebral cortex in
Alzheimer’s disease O24
T.L . Tho ma s , J.S. Miners, P.G. Kehoe, S. Love
11:15 Microinfarc ts, small vessel disease and dementia in the population-representative
CFAS brain donor cohort O25
P.G . I nc e , T. Minett, G. Forster, S.B. Wharton
11:3 0 Gene regulation of brain cytokines and mediators of immune response in aging and
rst stages of sporadic Alzheimer’s disease is not linked to
-amyloid plaques and
neurofi brillary tangles but is linked to soluble oligomers O26
I. Ferrer , I. López-González, A. Schlüter, A. Pujol, E . Aso
11: 45 A role for microglia in ageing and dementia O27
D. Boche , T. Minett, J. Classey, F.E. Matthews, M. Fahrenhold, M. Taga, C. Brayne, P.G. Ince,
J.A.R. Nicoll, and MRC CFAS
12: 00 Frontal white mat ter clasmatodendrosis and cognitive dysfunc tion in the elderly O28
A. Chen, R.O. Akinyemi, K. Washida, V. Foster, M.J. Firbank, A.E. Oakley, Y. Okamoto, J.T. O’Brien,
L.M. Allan, M. Ihara, R.N. Kalaria
12.15 – 13:15 Diagnostic Slide Session (Incorporating EQA)
13:15 – 14:30 Lunch and Poster Discussion
14:30 – 16:30 SIXTH SCIENTIFIC SESSION – Miscellaneous
Chairs: Seth Love and Raj N Kalaria
14 :3 0 Fine-mapping neurodegenerative milestones in the rTg4510 mouse model of tauopathy O29
S. Meftah, M.A. Ward, S. Wu, T.K. Murray, F.D. Tingley, M. Hayashi, R. Demattos, M.L. Hutton,
M.J. O’Neill, Z . Ahmed
14 : 45 Comparative clinical, genetic and pathological study of
C9or f72
expansion repeat cases O30
P. G a m i, C. Murray, L. Schottlaender, C. Bettencourt, E . Mudanohwo, J. Polke, T. Revesz,
H. Houlden, T. Lashley
15: 0 0 Investigating the mechanisms underlying oligodendrocyte dysfunction in C9ORF72 ALS O31
A. Lorente-Pons, J.D. Wood, P.J. Shaw, P.G. Ince, J. Cooper-Knock, A. Ramachandran,
J. Kirby, J.R. Highley
15:15 Complement activation and neurodegeneration in multiple sclerosis grey matter lesions O32
O. W. Howell, S. Loveless, J.W. Neal, M.I. Rees, R. Reynolds, N. Robertson, B. P.Morgan, L. M. Watkins
15: 30 Olfactory pathology in central nervous system demyelinating diseases O33
G.C. DeLuca, A. Joseph, J. George, R.L. Yates, M. Hamard, M. Hofer, M.M. Esiri
15: 45 Normobaric hyperoxia protects against demyelination in an experimental model of
pattern III multiple sclerosis lesions O34
R.A. Desai, A.L. Davies, M. Tachrount, X. Golay, K.J. Smith
16.00 Uncommon prion disease induced in macaque ten years after scrapieinoculation O35
J. Mikol, S. Luccantoni-Freire, E . Correia, N. Lescoutra-Etchegaray, V. Durand, C. Dehen,
J.P. Deslys, E. Comoy
16 :15 Dystonia with a dif ference: unusual pathologic fi ndings in a rare inherited O36
nephrocerebellar syndrome
B. Harding, R. Jinks, E . Puffenberger, K. Strauss
16 :3 0 Announcement of the poster prize winners and closure of the meeting
Ageing and Neurodegeneration
Profi lin 1 in ALS: neuropathology of 3 cases with PFN1 mutations/variants P01
A. King, B. Smith, C. Troakes, C. Vance, A. Al- Chalabi, I. Bodi, S. Maekawa, J. Landers, C.E. Shaw, S. Al-Sarraj
A reduced astrocyte response to
-amyloid plaques in the ageing brain associates with dementia and
cognitive impairment P02
R. Mathur, P.G. Ince, T. Minett, C.J. Garwood, P.J. Shaw, F.E. Matthews, C. Brayne, J.E. Simpson, S.B. Wharton, on behalf of the
MRC Cognitive Function and Ageing Neuropathology Study Group
Distinct clinical and neuropathological features of G51D
mutation cases compared with
duplication and H50Q mutation P03
A.P. Kiely, H. Ling, Y.T. Asi, E. Kara, P. Limousin, P. Lewis, C. Proukakis, A.H. Schapira, H.R. Morris, S. Lubbe, N. Quinn,
S. Love, A.J. Lees, J. Hardy, T. Revesz, H. Houlden, J.L. Holton
Neuronal senescence as a contributor to neurodegeneration P04
I. Vazquez-Villasenor, J.E. Simpson, C. Garwood, P.G. Ince, P. Heath, S.B. Wharton
The impact of systemic infection on neuroin ammation in human brain affected by Alzheimer’s disease P05
S. Rakic, J.A.R. Nicoll, S. Love, C. Holmes, V.H. Perry, W. Stewart, D. Boche
Could the parvopyramidal layer hold clues to protecting neurons from degeneration? P06
C.E. Murray, P. Gami, E. Portelius, J.L. Holton, H. Zetterberg, T. Revesz, T. Lashley
Beta-propeller protein associated neurodegeneration: neuropathological features P07
R. Paudel, C. Strand, R. Bandopadhyay, R. de Silva, S. Wiethoff, A. Li, H. Houlden, J.L. Holton
Differential expression of galanin in the basal forebrain in Lewy body disorders P08
A. Alexandris, A.K.L. Liu, R.K.B. Pearce, S.M. Gentleman
Where is the human nucleus basalis of Meynert? P09
A.K.L. Liu, R.C.C. Chang, R.K.B. Pearce, S.M. Gentleman
Using quantitative proteomics to investigate commonality between Alzheimer’s disease and
hyper tension in human brain tissue P10
K.A. Burnett, J.F.R. Paton, P. Kehoe
Old-age hippocampal sclerosis and Alzheimer’s disease present with similar clinical characteristics:
a population-based study P11
S.R.K. Hokkanen, S. Hunter, H.A. Keage, T.M. Polvikoski, F.E. Matthews, C. Brayne
Characterising the effect of Doxycycline treatment on tau associated degeneration in rTg4510 mice P12
A Fisher, M Heggenes, S Meftah, T Murray, N Colgan, O Ismail, ML Hutton, M Lythgoe, MJ O’Neill, Z Ahmed
Intracerebral injections of pathological tau from Alzheimer’s disease or corticobasal degeneration results
in cell-type specifi c tau pathology in PS19 mice P13
S. Boluda, M. Iba, B. Zhang, K.M. Raible, V. M-Y Lee, J.Q. Trojanowski
Global proteomic profi ling of brain leptomeningeal arteries from patients with cerebral amyloid angiopathy
reveals novel therapeutic targets P14
A. Manousopoulou, C. Smith, J.A.R. Nicoll, J. Attems, R. Kalaria, H.E. Johnston, C.H. Woelk, R.O. Weller,
S.D. Garbis, R.O. Carare
-Synuclein phosphorylation at Ser87 is upregulated by A
in vitro
but reduced in post-mortem
brain tissue in dementia with Lew y bodies P15
M.I. Swirski, J.S. Miners, R. de Silva, S. Love
Neuropathological diagnostic accuracy of cor ticobasal degeneration: A review of 140 cases P16
H. Ling, J.L. Holton, K. Davey, E. Gelpi, J. Hedreen, D. Mann, S. Al-Sarraj, G. Kovacs, J. Attems, G. Halliday, S. Love,
J. Xuereb, E. Kovari, T Revesz
Tumours of Central Nervous System
Potential markers of tumorigenesis and therapeutic targets in craniopharyngiomas: a study of 74 tumors P17
A. Tauziede-Espariat, M. Polivka, P. de Cremoux, G. Lot, S. Bouazza, D. Bresson, S. Froelich, H. Adle-Biassette
Giant cell glioblastoma: A study of six teen cases P18
A. Chakrabarty, F. Malta, C. Loughrey
BRAF V600E mutations in glioneuronal tumours in epilepsy P19
M. Thom, C. Schneider, B. Paradiso, J. Liu, C. Reeves, A. Jardim, S. An, S. Brandner
EGFR and EGFRvIII detection in glioblas toma: Method s to select patients for novel individualised therapies P20
C. Faulkner, A. Pal mer, H. Williams, C. Wragg, H.R. Haynes, P. White, R. deSouza, M. Williams, K. Hopkins, K.M. Kurian
A combined strategy for the detec tion of BRAF fusions in pilocytic astrocy toma using RT-PCR and FISH P21
C. Faulkner ; H.P. Ellis, A. Shaw; H.R. Haynes; H. Williams, S. Lowis, M. Williams, K.M. Kurian
Expression of mesothelioma-related markers in meningiomas: An immunohistochemical study P22
E. Abdelzaher, D.M. Abda llah
eMolNeuroPath: a new e -learning package focussing on the molecular pathology of brain tumours P23
A. Lawson McLean, D. Wang, J.E. Martin
Pathology of Skeletal Muscle
Using whole-exome sequencing to identify mutations of
in inclusion body myositis P24
Q. Gang, P. Machado, C. Bettencourt, S. Brady, E. Healy, M. Parton, J.L. Holton, D. Hilton-Jones, M.G. Hanna,
H. Houlden &The Muscle Study Group and The International IBM Genetics Consortium
Adult onset Pompe’s disease with LGMD phenotype P25
J.B. Cryan, R. Walsh, S. Lefter, M. Farrell
Extensive genetic investigation in recurrent rhabdomyolysis and vacuolar myopathy:
An undiagnosed case report P26
R.S. Scalco, A. Gardiner, R. Godfrey, S.E. Olpin, R. Kirk, A. Majumdar, E. Murphy, H. Houlden, J.L. Holton, R. Quinlivan
Pathological evaluation of myopathies with tubular aggregates and cylindrical spirals P27
S. Brady, E.G. Healy, Q. Gang, B. White, S. Jacob, H. Houlden, J.L. Holton
B cells correlate with histological and clinical features of muscle disease in patients with
juvenile dermatomyositis P28
S.A. Yasin, E. Sag, K. Arnold, C. Sawali, J.L. Holton, T.S. Jacques, L.R. Wedderburn
Tubuloreticular inclusions in juvenile dermatomyositis: A diagnostically useful marker? P29
S.A. Yasin, E. Sag, K. Arnold, G. Anderson, J.L. Holton, L.R. Wedderburn, T.S. Jacques
Dramatic and sustained response to rituximab therapy in anti-SRP related myopathy with
additional mitochondrial features P30
E. Matthews, M. Parton, R. Phadke
Confusing muscle pathology in a child with distal weakness P31
C.A. Sewry, L. Feng, R. Phadke, J. Poulton, I. Zaharieva, S. Robb, A. Manzur, F. Muntoni
Juvenile dermatomyositis: Repor t of three cases P32
V. P ap a, B. Romanin, R. Bergamaschi, C. Ceccarelli, R. Salaroli, L. Badiali De Giorgi, G. Cenacchi
Diagnostic Neuropathology
Isolated pituitary IgG4 -related autoimmune disease (IgG4-RD hypophysitis): A rare entity P33
A. Merve, A. Ramsay, M. Galloway, N. Dorward, R. Phadke
Neuropathological fi ndings in Bardet-Biedl syndrome P34
T.S . Jac ques, E. Forsythe, S. Christou- Savina, M. Hayes, P. Beales
Spinal intradural nerve sheath myxoma P35
M. Aizpurua, B. Cheserem, R. Gullen, I. Bodi
Malignant transformation in a desmoplastic non-infantile ganglioglioma P36
M. Aizpurua, I. Bodi, R. Laxton, C. Chandler, S. Al-Sarraj
Widespread neurotropic dissemination of metastatic pulmonary adenocarcinoma with
EGFR insertion mutation (p.Asp770_Asn771insGly) P37
U. Pohl, K. Tarver, A. Misbahuddin
Bilateral trigeminal sensory ganglioneuropathy, sensory axonal and autonomic neuropathy in
Hodgkin lymphoma: a new paraneoplastic syndrome? P38
W.J. Zhang, J.H. Rees, R. Phadke
Spindle cell cerebellar pseudotumour due to
Mycobacterium Avium
(MA) in a non-AIDS patient P39
C. Keohane, A. Beausang, D. Corcoran, M. Lim, C. Lim, N. Bermingham
Fatal cerebellar haemorrhage in 2 premature infants without germinal matrix haemorrhage P40
A. Beausang, N. Bermingham, B. Fitzgerald, C. Keohane
The role of the Merlin tumour suppressor in the developing and injured adult peripheral nerve P41
T. M in dos, S. Roberts, R. Doddrell, G. Mortimer, XP. Dun, P. Edwards, A. Shivane, D. Parkinson
Control tissue in brain banking: The importance of thorough neuropathological assessment P42
M. Nolan, C. Troakes, A. King, I. Bodi, S. Al-Sarraj
Mapping synaptic diversity in the human brain P43
O.E. Curran, C Smith, S.G.N. Grant
The mechanism and clinical-pathological correlation of traumatic dif fuse axonal injury (TDAI) in assaults P4 4
S. Al-Sarraj, V. Fitzpatrick-Swallow, R. Laxton, M. Biggs, N. Cary, R. Chapman, A. Fegan-Earl, S. Hamilton,
F. Hollingbury, N. Hunt, P Jerreat, A. Kolar, S. Poole, B. Swift
Prion protein protease sensitivity, stability and seeding activit y in variably protease sensitive
prionopathy suggests molecular overlaps with sporadic Creutzfeldt-Jakob disease P45
A.H. Peden, D.P. Sarode, C.R. Mulholland, M.A. Barria, D.L. Ritchie, J.W. Ironside, M.W. Head
Neuroinfl ammation, blood brain barrier disruption and acute neuronal injury in the amygdala in SUDEP P46
D. Obari, Z. Michalak, M. Thom, S. Sisodiya
A study of glial differentiation in pericy te-like cells in human cortical injuries P47
A. Prada-Jardim, J.Y.W. Liu, C. Reeves, S.M. Sisodiya, M. Thom
Localization of complement proteins as potential biomarkers of infl ammation in Multiple Sclerosis using
tissue microarray methodology P48
O. Howell, S. Loveless, L. Watkins, N. Robertson, J. Neal, B. Morgan
Oral presentations
First scientific session Neuropathology of Neurogeneration
E.L. Ashby, J.S. Miners, E. Dale, S. Love, P.G. Kehoe
Dementia Research Group, Institute of Clinical
Neurosciences, School of Clinical Sciences, University of
Bristol, Bristol, UK;
The effect of hypertension and anti-hypertensive
treatment on Abplaque load and on b- and c-secretase
activity in the frontal cortex
Introduction: Midlife hypertension has long been recog-
nised as a risk factor for Alzheimer’s disease (AD). While
the impact of hypertension on amyloid-b(Ab) pathology
is not well understood in human brain, in spontaneously
hypertensive stroke-prone rats hypertension led to age-
dependent accumulation of Abin the parenchyma (1).
Several studies showed that anti-hypertensive treatment
reduces the incidence of AD and evidence from more
recent studies suggests that certain classes of anti-hyper-
tensive therapies may decrease dementia risk by lower-
ing the level of Ab(2, 3). We performed a retrospective
investigation of the effect of hypertension and anti-
hypertensive treatment on Abplaque load and on the
activity of enzymes involved in Abproduction, b- and c-
secretase, in the frontal cortex.
Material and methods: We studied 82 AD brains from
the South West Dementia Brain Bank, Bristol, UK. The
cohort was stratified according to history of hyperten-
sion and of anti-hypertensive treatment. Frontal Ab
plaque load was measured by immunohistochemistry
and field fraction analysis, and b- and c-secretase activ-
ities were measured in the frontal cortex.
Results: Frontal Abplaque load was significantly
higher in AD cases with than without hypertension. It
was also significantly higher in treated than untreated
hypertensives, although frontal b- and c-secretase
activities were similar in the two groups.
Conclusion: Our results suggest that hypertension exac-
erbates Abdeposition in AD. Within the hypertensive
group, anti-hypertensive treatment was associated with
higher frontal Abload but we cannot exclude the pos-
sibility that the retrospective analysis obscured clinical
differences that influenced treatment decisions. The
similar b- and c-secretase activites in the different
groups argues against an effect of hypertension or anti-
hypertensive treatment on Absynthesis and suggests
they are more likely to influence Abclearance.
1. Bueche et al.Ann Clin Transl Neurol 2014; 1:124
2. Paris et al. Mol Med 2011; 17:149162
3. Hajjar et al. Arch Neurol 2012; 69:1632-38.
R. Vuono
, S. Winder-Rhodes
, R. de Silva
G. Cisbani
, J. Drouin-Ouellet
, M.G. Spillantini
, R.A. Barker
John van Geest Cambridge Centre for Brain Repair,
Department of Clinical Neuroscience, University of
Cambridge, Cambridge, UK;
Institute of Psychiatry,
Psychology & Neuroscience, King’s College London,
London, UK;
Reta Lila Weston Institute, UCL Institute
of Neurology, London, UK;
Centre de Recherche du
CHU de Qu
ebec (CHUQ), Axe Neuroscience and
epartement de Psychiatrie et Neurosciences, Qu
QC, Canada;
e Laval, Qu
ebec, QC, Canada;
The role of tau in the pathological process and clinical
expression of Huntington’s disease
Introduction: Huntington’s disease (HD) is a neurode-
generative disorder caused by an abnormal CAG repeat
expansion within exon-1 of the huntingtin gene. While
several genetic modifiers, distinct from the HD locus
itself, have been identified as being linked to the clini-
cal expression and progression of HD, the exact molec-
ular mechanisms driving its pathogenic cascade and
clinical features, especially the dementia, are not fully
©2015 The Authors
8 Neuropathology and Applied Neurobiology ©2015 British Neuropathological Society
Neuropathology and Applied Neurobiology (2015), 41 (Suppl. 1), 8–29
understood. Recently the tau gene, which is associated
with several neurodegenerative disorders, has been
reported to be involved in HD and so we explored in
more detail its contribution at thepathological, genetic
and clinical level.
Material and methods: Tau pathology was assessed in
post-mortem human brain tissue, provided by the Cam-
bridge Brain Bank, using standard immunohistochem-
istry and immunoblot procedures. In particular, we
looked at the presence of tau oligomers and hyper-
phosphorylated aggregates in HD subjects (n=16)
compared to tauopathies cases (Alzheimer’s disease,
corticobasal degeneration, Pick’s disease) and healthy
controls. We also undertook a genotype-phenotype
analysis of a large cohort of HD patients (n=960)
with a particular focus on cognitive decline.
Results: We report for the first time not only on the
extent of tau pathology in HD but also its importance
to the HD clinical expression and progression. We
found tau oligomers and extensive pathological inclu-
sions containing abnormally phosphorylated tau aggre-
gates that co-localize with mutant huntingtin. We
confirmed this related to the disease process rather
than age, by showing it was also present in young-
onset HD patients (26 and 40-years old at death).
Finally we highlighted the clinical significance of this
pathology by demonstrating that the tau haplotypes
affect the rate of cognitive decline in HD patients.
Conclusion: Our findings therefore highlight a novel
important role of tau in the pathogenic process and
clinical expression of HD, which in turn opens up new
therapeutic avenues for treating this incurable condi-
B. Hapuarachchi
, M. Roberts
, J. Staddon
, T. Warner
R. de Silva
Reta Lila Weston Institute, Department of Molecular
Neuroscience, UCL Institute of Neurology, London, UK;
Eisai Ltd, EKC Mosquito Way, Hatfield, UK;
A cell-based biosensor for pathological tau uptake and
Introduction: Pathological inclusions of aggregated tau
characterise the large group of neurodegenerative dis-
orders called the tauopathies. It is recognised that tau
pathology spreads along anatomically connected path-
ways with progression of disease (1). The agent of this
“prion-like” aggregation and trans-synaptic spread are
pathological conformers and oligomeric intermediates
of tau that are released by sick cells and endocytosed
by neighbouring healthy neurons which convert nor-
mal tau in a cascade-like fashion. Studies have shown
the potential therapeutic benefit of targeting the extra-
cellular tau with specific antibodies (2). We are investi-
gating two antibodies, RD3 and RD4 (3) that target
regions in the microtubule-binding repeat domain
(MTBR) of tau that are crucial for aggregation. We
demonstrate their efficacy in preventing pathological
tau uptake and aggregation in a cell-based model.
Material and methods: Sequences encoding the tau
MTBR were cloned into pEGFP-N1 and pDsRed-mono-
mer-N1 vectors so as to express the tau domain fused
to eGFP or RFP,at the C-terminus. In addition to the
wild-type (WT) sequence, we also expressed the highly
aggregation-prone DK280 (D) and P301L/V337M (LM)
double mutants. SH-SY5Y neuroblastoma cells were
co-transfected with the eGFP and RFP variants of both
mutant and WT tau constructs. After 48 hours, para-
formaldehyde fixed cells were subject to fluorescence
resonance energy transfer (FRET) analysis using both
acceptor photo bleaching microscopy and a fluores-
cence plate reader with fixed excitation/emission
Results: We observed the strongest FRET signals in
cells co-expressing the Dand LM mutants. Pre-incuba-
tion of the cells with dilutions of clarified AD brain
homogenate further increased the FRET signal. This
increased FRET signal was progressively abolished with
pre-incubation of the brain homogenate with increas-
ing concentrations of RD3 antibody with a more mod-
est efficacy of the RD4 antibody.
Conclusion: We have developed a robust cell-based
FRET biosensor for tau aggregation and high-through-
put testing of anti-aggregation therapies, including
antibodies. The well-characterised RD3 antibody
appears to be effective in preventing the cellular uptake
and seeding of tau aggregation. Given what is under-
stood about tau pathology spread, these findings sug-
gest that RD3 could be developed for passive
1. Braak&Braak. Neurobiol Aging. 1995, 16:271-278
2. Clavaguera et al. Neuropharmacology. 2014; 76:9-15
Oral presentations 9
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Neuropathology and Applied Neurobiology ©2015 British Neuropathological Society, 41 (Suppl. 1), 8–29
3. de Silva et al. Neuropathol Appl Neurobiol. 2003,
T. Lashley, P. Gami, R. Bandopadhyay, T. Revesz
The Queen Square Brain Bank for Neurological
Disorders, Department of Molecular Neuroscience,
Institute of Neurology, UCL, London, UK;
The presence of heterogeneous nuclear
ribonucleoproteins in frontotemporal dementia with
FUS positive inclusions
Introduction: Fused in sarcoma (FUS) has been identi-
fied as the major protein in the pathological lesions
in frontotemporal lobar degeneration with FUS-posi-
tive inclusions (FTLD-FUS). The disease pathogenesis
of FTLD-FUS remains poorly understood. However
transportin1 (TRN1) is abundantly found in FUS-posi-
tive inclusions. TRN1 is responsible for shuttling pro-
teins, containing an M9 nuclear localisation signal,
between the nuclear and cytoplasmic compartments.
FUS is a member of the FET protein family, which
also includes Ewing’s sarcoma and TATA-binding
protein-associated factor 15, both of which are pres-
ent in the pathological lesions in FTLD-FUS, suggest-
ing a disturbance of transportin-mediated nuclear
import of the FET proteins. FUS is also known to
belong to the heterogeneous nuclear ribonucleopro-
tein (hnRNP) protein family. In this study we wished
to investigate whether other members of this family
of proteins are associated with FUS pathology and
could be implicated in the pathogenesis of these
Material and methods: We studied the localization of
proteins of the hnRNP family in affected brain regions
in patients with FTLD-FUS (n=10) and normal control
brains (n=5) by immunohistochemistry and biochemi-
cal analysis.
Results: Here we demonstrated the presence of sev-
eral hnRNP proteins in a proportion of pathological
inclusions including neuronal cytoplasmic inclusions
and dystrophic neurites. Dense cytoplasmic staining
was also evident containing several hnRNP proteins.
Biochemical analysis also revealed a shift in the loca-
tion of the hnRNP proteins from the nucleus to the
cytoplasm which was not apparent in normal
Conclusion: These results implicate a wider dysregula-
tion of TRN1-associated nuclear import between intra-
cellular compartments, than mechanisms only affecting
the FET proteins.
J.S. Miners, S. Love
Dementia Research Group, School of Clinical Sciences,
University of Bristol, Learning and Research, Level 1,
Southmead Hospital, Bristol, UK;
Accumulation of a-synuclein in dementia with Lewy
bodies is associated with decline in the a-synuclein-
degrading enzymes kallikrein-6, calpain-1 and
endothelin-converting enzyme-1 and -2
Introduction: A number of CNS enzymes have been
identified that are able to cleave a-synuclein (a-syn)
but their role in the pathogenesis of Lewy body diseases
is unclear. We have explored the possibility that reduc-
tion in the level or activity of these enzymes might
contribute to the accumulation of a-syn in DLB.
Material and methods: We measured the levels of kallik-
rein-6 (KLK6), calpain-1 (CAPN1), endothelin-convert-
ing enzyme-1 and -2 (ECE-1 and -2) (which we show
for first time to be capable of cleaving a-syn), a-syn
and a-syn phosphorylated at serine-129 (a-syn-P129)
in the cingulate cortex in post-mortem brain tissue in
dementia with Lewy bodies (DLB, n=12) and age-
matched controls (n=19).
Results: The levels of KLK6, CAPN1, ECE-1 and ECE-2
were all significantly reduced in DLB compared to age-
matched controls and correlated inversely with a-syn
and a-syn-P129 levels. We also demonstrate partial co-
localisation of all four enzymes with a-syn in SHSY-5Y
cells overexpressing wild-type a-syn and found that siR-
NA-mediated knock-down of KLK6, CAPN1, ECE-1 or
ECE-2 increased the amount of a-syn within cell lysates
and the surrounding culture medium.
Conclusion: Our results indicate that reductions in a-
syn degrading proteases may contribute to the accu-
mulation and spread of a-syn in DLB.
10 Oral presentations
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Neuropathology and Applied Neurobiology ©2015 British Neuropathological Society, 41 (Suppl. 1), 8–29
C.E. Murray
, S.N. Pressey
, W.E. Heywood
I.P. Hargreaves
, V. Neergheen
, S. Wauters
M. Palkovits
, E. Gelpi
, C. Troakes
, S.M. Gentleman
K. Mills
, J.L. Holton
, T. Revesz
, S. Gandhi
Institute of Neurology, University College London,
Queen Square Brain Bank, UK;
Centre for
Translational Omics, Institute of Child Health, UCL,
London, UK;
Neurometabolic Unit, National Hospital
for Neurology and Neurosurgery, UK;
Human Brain
Tissue Bank, Budapest, Semmelweis Medical University,
Neurological Tissue bank, University of
Barcelona, Spain;
Institute of Psychiatry, Kings
College London, UK;
Department of Medicine, Imperial
College London, London, UK;
Mitochondrial dysfunction in Parkinson’s disease: Is it
the earliest feature?
Introduction: In Parkinson’s disease (PD), pathological
changes spread throughout the brain in a predictable
sequence (1). By examining early stage PD cases (Bra-
ak 3/4), we can compare pathologically affected
regions with pathologically unaffected regions predicted
to develop PD pathology later in the disease, thus
enabling investigation of the earliest molecular changes
that arise in disease.
Material and methods: A total of 66 control and 66 Bra-
ak stage 3/4 cases were selected, matched for age,
post-mortem delay and pH. Microdissection from 9
regions (substantia nigra, caudate, putamen, temporal
cortex, parahippocampus, cingulate cortex, frontal cor-
tex, parietal cortex and the cerebellum) was performed.
Proteins were extracted, digested and expression
changes investigated using quantitative label-free mass
spectrometry based proteomics. Validation was per-
formed using multiple reaction monitoring and func-
tional mitochondrial assays for Complex IIV.
Results: Our method provides in-depth coverage of the
human brain proteome from post-mortem brain, detect-
ing 1147 unique proteins. We identified candidate pro-
teins whose expression changed significantly in at least
5/9 of the affected regions in PD brain compared to
control. Further to this, proteins that had a >5 fold
change in expression in one region were also identified.
The majority of the top preliminary candidates are
mitochondrial constituents, and include proteins
involved in the TCA cycle, mitochondrial metabolism
and respiratory chain function. Preliminary results
from functional assays show reduced complex I activity
in frontal cortex of early PD compared to control.
Conclusion: Both application of mass-spectrometry
based proteomics and the complex I assay to our
unique collection of early stage Parkinson’s disease
cases, indicate that mitochondrial dysfunction is appar-
ent in both unaffected regions and affected regions
early in PD. This may reflect an early pathogenic pro-
cess in sporadic PD.
1. Braak et al. Neurobiol Aging 2003; 24:197211
A.K.L. Liu
, R.C.C. Chang
, R.K.B. Pearce
S.M. Gentleman
Neuropathology Unit, Division of Brain Sciences,
Imperial College London, UK;
Department of
Anatomy, LKS Faculty of Medicine, The University of
Hong Kong;
Sub-regional nucleus basalis of Meynert pathology in
Lewy body disorders
Introduction: Cortical acetylcholine is essential for nor-
mal cognitive functioning and its innervation origi-
nates from the nucleus basalis of Meynert (nbM).
Retrograde tracer studies on non-human primates have
shown a topographic innervation from different sub-
regions of the nbM with the anterior portion providing
afferents to the frontal and medial cortical regions;
intermediate nbM to the lateral cortical regions; and
posterior division innervating the temporal polar
region. In Alzheimer’s disease (AD), the posterior nbM
has shown the greatest degree of neuronal loss. How-
ever, detailed sub-regional analysis of the nbM has not
been performed on Lewy body disorders (LBD). With
functional imaging studies highlighting the difference
in cortical cholinergic deficits between AD and LBD, we
hypothesise a differential susceptibility to pathology in
Material and methods: Basal forebrain tissues from 43
Parkinson’s disease (PD). 20 PD with mild cognitive
impairment (PD-MCI), 61 PD with dementia (PDD), 8
Dementia with Lewy Bodies (DLB) and 9 age-matched
controls were obtained from the Parkinson’s UK Tissue
Bank. Tissues were stained with H&E for the determi-
Oral presentations 11
©2015 The Authors
Neuropathology and Applied Neurobiology ©2015 British Neuropathological Society, 41 (Suppl. 1), 8–29
nation of nbM sub-regions, and immunohistochemistry,
with choline acetyltransferase (ChAT) antibodies, for
the quantification of cholinergic neurons.
Results: A graded decrease of ChAT-positive neuronal
density was observed as PD cognitive disability
increased. In PDD, all nbM sub-regions appeared to be
equally affected, whereas the degree of neuronal loss in
PD without cognitive deficit was most severe in the
posterior nbM sub-region. No significant difference
between sub-regional cell loss in PDD and DLB was
Conclusion: Our results show that sub-regional pathol-
ogy exists in different LBD. Further work is now needed
to determine if this corresponds to the findings from
recent functional imaging studies.
Second scientific session Tumours of the Central Nervous
D.W. Ellison
, K.W. Pajtler
, T. Lin
, S.M. Pfister
T. Merchant
, A. Korshunov
Department of Pathology, St. Jude Children’s Research
Hospital, 262 Danny Thomas Place, Memphis, USA;
Pediatric Neuro-oncology, Deutsches
Krebsforschungszentrum, Heidelberg, Deutschland;
Department of Biostatistics, St. Jude Children’s
Research Hospital, Memphis, USA;
Department of
Radiation Oncology, St. Jude Children’s Research
Hospital, Memphis, USA;
Infant posterior fossa ependymoma comprises two
molecular subgroups
Introduction: The current molecular classification of
posterior fossa (PF) ependymomas suggests two princi-
pal subgroups, one presenting mainly in infants (PFA)
and a second presenting mainly in adults and adoles-
cents (PFB). We tested the hypothesis that PF disease
in infants comprises two molecular subgroups, having
observed supporting transcriptomic data from patients
at St. Jude (SJ) whose tumours were analysed as part
of the Pediatric Cancer Genome Project.
Material and methods: Transcriptomic and methylomic
data were generated on a series of PF ependymomas
from SJ infants (n=124) and children and adults from
the DKFZ (n=98) using Affymetrix U133 and Illu-
mina 450K arrays. Copy number alterations were dem-
onstrated using fluoresence in situ hybridization or
Affymetrix SNP6 or OncoScan arrays. Associations
between genomic and detailed clinicopathologic data
were sought.
Results: Among infants, two molecular subgroups in
transcriptomic and methylomic datasets were demon-
strated in cohorts from both centers. These subgroups
were shown to segregate with PFA tumours when
datasets for infants and the entire disease were com-
pared. Relative over-expression of HOX genes and
genes involved in angiogenesis and the immune
response characterized one subgroup (PFA-1), while
genes involved in the cytoskeleton and development of
the mid-brain / hind-brain boundary were over-
expressed in the other (PFA-2). Radiological and clini-
cal data have identified differences in the presentation
and outcome of tumours from the two subgroups.
Conclusion: Infant PF ependymomas comprise two
molecular subgroups with different transcriptomic and
methylomic profiles that suggest a distinct histogenesis.
While PFA-1 and PFA-2 present at the same age, other
clinicopathological characteristics are distinct, suggest-
ing that distinguishing tumors of the two subgroups
would have clinical utility.
12 Oral presentations
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Neuropathology and Applied Neurobiology ©2015 British Neuropathological Society, 41 (Suppl. 1), 8–29
S. Brandner
, Z. Jaunmuktane
, T.J. Stone
, J. Chalker
M. Hubank
, T.S. Jacques
Division of Neuropathology UCL Institute of
Neurology, London, UK;
Neural Development Unit,
UCL Institute of Child Health London, UK;
and Molecular Diagnostic Service, Great Ormond Street
Hospital for Children NHS Foundation Trust London,
UCL Genomics, UCL Institute of Child Health
London, UK;
Department of Histopathology, Great
Ormond Street Hospital for Children NHS Foundation
Trust, London, UK;
Establishing a diagnostic pipeline for methylome
analysis of paediatric and adult brain tumours in the
UK using the Heidelberg classifier
Introduction: Characteristic patterns of the DNA methyl-
ation are key features in various tumours. A promising
tool for DNA methylation studies is the Illumina Infini-
um 450k array that assesses the DNA methylation sta-
tus of 450,000 individual CpG sites. An algorithm,
developed in Heidelberg, is able to distinguish brain
tumour entities based on their methylation profile. As of
November 2014 it is based on over 2000 reference brain
tumour cases including almost all known entities, thus
comprising the largest brain tumour methylation refer-
ence set, yet it is still expanding with rare entities await-
ing more precise classification, or re-classification. The
aim is to improve the diagnostic accuracy, which is par-
ticularly important for paediatric tumours, and those
entities with unusual morphology or clinical course,
where molecular subgroups are important.
Material and methods: We are in the process of setting
up a diagnostic pipeline and are performing a trial run
on a set of morphologically well-characterized paediat-
ric and adult brain tumours and of a set of complex,
unresolved tumour cases. Unprocessed idat-files of Illu-
mina Infinium Human Methylation 450 Bead Chips
are uploaded to the Heidelberg v9 classifier. This tool
provides a molecular classification, based on the com-
parison to the reference set as well as a low resolution
copy number plot from the array data for assessment
of deletions, including 1p19q codeletion and amplifica-
tions, and provides reliable information on the MGMT
promoter methylation status.
Results: We present the feasibility of setting up a 450k
array platform in a diagnostic setting including valida-
tion steps and interpretation of the classifier results of
rare entities and approaches to refining or revising his-
tological diagnosis.
Conclusion: The molecular classification by Heidelberg
classifier is as yet a research tool, but it does show a
great potential for improving diagnostic accuracy, risk
stratification and a step closer to improved patient-tai-
lored therapy.
A. Merve, X. Zhang, S. Acquati, S. Marino
Blizard Institute, Barts and The London School of
Medicine and Dentistry, Queen Mary University,
London, UK;
c-Myc is expressed in a proportion of human choroid
plexus tumours and its overexpression in the
developing mouse CNS induces choroid plexus
Introduction: Choroid plexus tumours (CPT) are intra-
cranial tumours predominantly occurring in children.
They are classified into three prognostically relevant
histological categories - choroid plexus papillomas
(CPP), atypical choroid plexus papillomas (ACPP) and
choroid plexus carcinomas (CPC) (1). c-Myc is a proto-
oncogene deregulated in various malignancies, includ-
ing paediatric brain tumours (2). While modelling
c-Myc-driven brain tumorigenesis in the mouse, we
unexpectedly found a significant incidence of CPTs in
transgenic mice overexpressing c-Myc in neural pro-
genitor cells. Here, we test the hypothesis that deregu-
lation of c-Myc expression plays a role in human CPTs.
Material and methods: RosaMycIB12;NestinCre mice
were generated and kept under tumour watch until
symptomatic or termination of the experiment
(20 months of age), when histological analysis was
performed on their brains. 46 human CPT samples
were obtained from the MRC UK Brain Archive Infor-
mation Network (BRAIN UK) and tested for c-Myc
expression and c-Myc amplification by immunohisto-
chemistry (IHC) and Fluorescence In-~/mice was 41%
(21/51): 66% (14/21) CPP and 33% (7/21) CPC. No
tumours were detected in the control cohort (n=34).
A total of 37% (14/46) of human CPT cases expressed
c-Myc on IHC: 37.5% (3/8) CPC, 45.5% (5/11) ACPP
and 33.3% (9/27) CPP. 8 cases were tested for c-Myc
Oral presentations 13
©2015 The Authors
Neuropathology and Applied Neurobiology ©2015 British Neuropathological Society, 41 (Suppl. 1), 8–29
amplification by FISH but only 1showed gain of signal,
although no amplification.
Conclusion: Overexpression of c-Myc in neural progeni-
tor cells leads to CPT development in a good proportion
of the mutant mice. More than a third of the human
CPT tested express c-Myc, although this was not
caused by gene amplification. Further molecular char-
acterisation of the genetic events leading to c-MYC
expression in human CPTs are being analysed to assess
whether our mouse model faithfully recapitulate
human CPTs.
1. Louis et al.Acta Neuropathol 2007; 114:97-109
2. Wang et al.PLoS ONE 2008; 3:e3769
T.J. Stone
, A. Keeley
, A. Virasami
, W. Harkness
M. Tisdall
, D. Hargrave
, M. Hubank
, J.H. Cross
J. Ham
, T.S. Jacques
Developmental Biology & Cancer Programme, UCL
Institute of Child Health, London, UK;
Department of
Histopathology, Neurosurgery Great Ormond Street
Hospital, London, UK;
Neurosurgery Great Ormond
Street Hospital, London, UK;
Oncology, Neurosurgery
Great Ormond Street Hospital, London, UK;
and Genomic Medicine Programme, UCL Institute of
Child Health, London, UK;
Neuroscience Programme, UCL Institute of Child
Health, London, UK;
Glioneuronal tumours: Classification, outcome and
molecular genetics
Introduction: Glioneuronal tumours are common struc-
tural causes of drug-resistant epilepsy. They predomi-
nantly arise in childhood and frequently display
bizarreor mixed features that confound diagnosis, a
point reflected by marked variation in reported frequen-
cies between institutions. Little is known regarding the
biology that underlies their development or their epile-
ptogenesis. We lack robust biologically informed diag-
nostic tools that predict postoperative seizure outcome.
To investigate this problem, we have reviewed the his-
tology of these tumours, evaluated established predic-
tive markers and undertaken expression profiling.
Material and methods: We have retrospectively reviewed
histological and clinicaldata for 82 patients diagnosed
with glioneuronal tumours at Great Ormond Street
Hospital. We have undertaken RNASeq analysis to
investigate the molecular genetics of these tumours.
Results: We found current classification insufficient for
conclusive diagnosis: 50% of tumours displayed non-
typical features. All established predictors of seizure
outcome failed to predict seizure freedom at 1 year fol-
lowing treatment with the exception of residual
tumour on MRI, which was associated with continued
seizures (P=0.046). Moreover, molecular classification
was possible on the basis of the expression analysis.
Conclusion: Our data support the idea that current classi-
fication criteria are insufficient. We favour the develop-
ment of molecular classification based on expression
profiles that include biologically similar tumours, rather
than morphological classification based on expert opinion.
A. Tauziede-Espariat
, M. Polivka
, F. Labrousse
E. Aronica
, S. Bouazza
, H. Salle
, A. Laquerriere
S. Froelich
, H. Adle-Biassette
Department of Pathology, Lariboisiere Hospital, Paris,
Department of Pathology, Dupuytren
University Hospital, Limoges, France;
Department of
(Neuro)Pathology, Academic Medical Center, University
of Amsterdam, Amsterdam, The Netherlands;
Department of Surgery, Lariboisiere Hospital, Paris,
Department of Pathology, Charles Nicolle
Hospital, Rouen, France;
Prognostic and therapeutic markers in chordomas: A
study of 287 tumours
Introduction: Chordomas (CH) are rare slow-growing
malignant neoplasms derived from notochordal rem-
nants. The aim of this study was to identify prognostic
factors and molecular markers of responses to targeted
Material and methods: This retrospective and multi-cen-
tre study included 287 CH (primitives and at progres-
sion) from 111 patients. Clinical data and histological
pattern were reviewed, and immunohistochemical
analysis using Ki67, p53, E-cadherin, VEGF, EGFR,
pSTAT3, three proteins of mTOR pathway (pS6 ser
235/236, pS6 ser240/244 and P-4EBP1) was com-
pleted. The cut-off of p53, Ki67 and E-cadherin were
those used in the literature (respectively 25, 6 and 50
%). Molecular analyses of EGFR, KRAS, BRAF and
PI3KCA gene mutations were performed.
14 Oral presentations
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Neuropathology and Applied Neurobiology ©2015 British Neuropathological Society, 41 (Suppl. 1), 8–29
Results: The localization of the tumours, the extent of
resection, adjuvant proton therapy, the presence of de-
differentiated areas (0: absent; 1: present), necrosis (0:
absent; 1: present), apoptosis (0: <20 % tumours cells
with apoptotic bodies; 1: 20 % tumour cells with
apoptotic bodies), prominent nucleoli (0: absent; 1:
present), p53 (0: <25 %; 1: 25 %) and Ki67 (0: <6
%; 1: 6 %) labeling indexes significantly correlated
with the outcome. The sum of these six last factors
defined two groups of CH: low-grade (scores 03) and
high-grade (scores 46). Expression of STAT3p, VEGF
and activation of mTOR pathways were observed.
There was also a high expression of EGFR without
amplification, polysomy and mutation of EGFR gene.
In two cases, two different mutations of PI3KCA gene
were detected for the first time in CH.
Conclusion: This is the largest series of CH which iden-
tified clinical, histological and immunohistochemical
prognostic factors. A grading system correlated to the
prognostic is proposed. The expression of several bio-
markers were observed, in addition to mutations in
PI3KCA gene, and potentially implied in response to
molecularly targeted treatments.
R.C. Laxton
,M. Aizpurua
, L. Doey
, I. Bodi
, A. King
R. Bhangoo
, R. Beaney
, L. Brazil
, K. Ashkan
S. Al-Sarraj
Departments of Clinical Neuropathology, King’s
College Hospital, London, UK;
Neurosurgery, King’s
College Hospital, London, UK;
Department of
Oncology, St Thomas’ Hospital, London, UK;
The biological behaviour and prognosis of anaplastic
oligodendroglioma with necrosis
Introduction: Previously we have shown that glioblasto-
mas with an oligodendroglial component (GBMO) did
not differ from other glioblastomas in the frequency of
1p/19q deletion or isocitrate dehydrogenase mutation
(1). Here we seek to determine whether anaplastic oli-
godendrogliomas with necrosis and very prominent
endothelial cell hyperplasia (AO +N), often diagnosed
as GBMO, differ in prognosis from the classic grade III
counterpart (AOIII) and GBMO.
Material and methods: Anaplastic oligodendrogliomas
with 1p/19q co-deletion and mutation to IDH1 or
IDH2 were classed as either grade III or IV dependent
upon the presence of the above mentioned high grade
features. GBMO with neither 1p/19q co-deletion nor
mutation to IDH1 or IDH2 were also selected for com-
parison. Statistical analyses were performed using R-
Stats v2.15.2.
Results: AO +N(n=14) with a median survival of
65.5 months had a trend towards worse prognosis
than AOIII (n=17) (median not reached, P=0.18)
and a better prognosis than GBMO (n=43) (median
survival 9 months, P=4.3 910
). The difference in
survival between AO +N and GBMO remained signifi-
cant when adjusted for age and gender (HR 0.14 95%
CI 0.050.34, 3.4 910
Conclusion: The results suggest that anaplastic oligo-
dendroglioma with necrosis and prominent endothelial
cell hyperplasia behave worse than classic anaplastic
oligodendroglioma and better than GBMO. However
due to the relatively small sample size and short follow
up time we suggest that it would require that our
results were replicated in a larger cohort before proper
consideration is given to including these neoplasms as
a novel WHO grade IV classification.
1. Laxton et al.Neuro Oncol 2013; 12:1635-43.
Third scientific session Neuropathology of Epilepsy
O. Adegbaju
, I. Bodi
, M. Honavar
, S. Al-Sarraj
Department of Clinical Neuropathology, King’s College
Hospital NHS Foundation Trust, Denmark Hill, London,
Hospital Pedro Hispano, Matosinhos, Portugal;
A review of primary and secondary neuropathological
changes in autopsy epileptic brains
Introduction: Patients with epilepsy, particularly poorly-
controlled epilepsy, are at risk of early death, which
may be accidental or unexpected and unexplained.
Post-mortem examination of epileptic brains reveals
abnormalities that may be considered the cause (pri-
Oral presentations 15
©2015 The Authors
Neuropathology and Applied Neurobiology ©2015 British Neuropathological Society, 41 (Suppl. 1), 8–29
mary) and others considered the effects (secondary) of
epilepsy. We reviewed post-mortem reports to investi-
gate the frequency of primary and secondary pathologi-
cal changes in a series of autopsies in which epilepsy
was mentioned in the clinical history.
Material and methods: A cohort of 103 autopsy case
reports obtained by database search, were reviewed.
Primary pathological changes were grouped into the
following categories: brain malformation, hippocampal
sclerosis, old head injury, infarction, infection, vascular
malformation and Alzheimer’s disease. Secondary path-
ological changes included: recent head injury, ischae-
mia and congestion of blood vessels.
Results: Age range of cohort was between 389 years
old: male (63): female (40). Approximately 82%
revealed various primary lesions believed to be a proba-
ble cause of epilepsy such as hippocampal sclerosis
(20.4%), old infarction (15.5%), cortical malformation
(15%), old head injury (9.7%),infection (8.7%), Alzhei-
mer’s disease (7.7%) and vascular malformation
(4.8%).The most common secondary lesions were
recent ischaemia(46%) and contusions (17.5%).There
were other non-specific changes (21.4%) such as reac-
tive astrocytosis and increased numbers of microglial
Conclusion: Autopsy examination and detailed neuro-
pathological assessment identified frequent primary
lesions that may cause epilepsy and secondary patho-
logical changes which may be related to the terminal
event in a majority of patient cohort. Systematic study
of epileptic brains combined with detailed clinical his-
tory including classification of the seizure illness, anti-
epileptic medication and the circumstances of death
may provide a better understanding of the cause of epi-
lepsy and help identify the risk of premature death.
F. Scerif
, S.R. Picker
, S.A. Yasin
, A. Virasami
A. Alahdal
, W. Harkness
, M. Tisdall
, F. Guillemot
S.M.L. Paine
, J.H. Cross
, T.S. Jacques
Developmental Biology & Cancer Programme, UCL
Institute of Child Health, London, UK WC1N 1EH;
Department of Histopathology, Great Ormond Street
Hospital, Great Ormond Street, London, UK;
of Molecular Neurobiology, National Institute for
Medical Research, London, UK;
Neurosurgery, Great
Ormond Street Hospital, Great Ormond Street, London,
Developmental Neuroscience Programme, UCL
Institute of Child Health, London, UK;
Identifying novel cell types in focal cortical dysplasia
by gene network analysis
Introduction: Focal cortical dysplasia (FCD) is a malfor-
mation of cortical development that is a frequent cause
of multidrug resistant paediatric epilepsy. FCD type IIb
is characterised by a population of unique abnormal
cells known as balloon cells (BCs). The pathogenesis of
FCDIIb is poorly understood and it is unclear if BCs are
the key pathological cell or if there are other types of
cells that are important in driving the development of
the disease.
Material and methods: Analysis of Affymetrix
Exon 1.0ST microarray data revealed differentially
expressed genes (DEGs) between a BC group and a con-
trol non-BC group. Ingenuity Pathway Analysis (IPA;
bioinformatics software) was used to identify networks
of the DEGs. The expression of a micro-network was
validated using immunohistochemistry. Double immu-
nofluorescence was undertaken to identify the lineage
of cells expressing components of the network.
Results: We identified a network of interacting genes
that were dysregulated in FCDIIb compared to nor-
mally formed cortex or FCD lacking balloon cells
(FCDIIa). Some components of this network were
expressed in BCs but others were expressed in novel
cell populations. Double immunofluorescence identified
a cell with the phenotype of a glial progenitor that was
only present in FCDIIb but not in normally formed
Conclusion: We have identified a novel population of
glial progenitors found frequently adjacent to BCs in
FCDIIb. The gene network analysis suggests that this
cell has a role in the pathogenesis of FCD by secreting
16 Oral presentations
©2015 The Authors
Neuropathology and Applied Neurobiology ©2015 British Neuropathological Society, 41 (Suppl. 1), 8–29
factors that influence gene expression by BCs. Further
investigations into the role of these cells would give us
a better understanding of the molecular abnormalities
underlying FCD and possibly provide novel therapeutic
M. Thom
, J. Liu
, C. Reeves
, M. Matarin
S. Sisodiya
Department of Clinical and Experimental Epilepsy, UCL
Institute of Neurology and National Hospital for
Neurology and Neurosurgery, Queen Square, London,
Department of Neuropathology, UCL Institute of
Neurology and National Hospital for Neurology and
Neurosurgery, Queen Square, London, UK;
Society, Chesham Lane, Chalfont St Peter, Bucks, UK;
Distribution of nestin and doublecortin expressing cells
in temporal lobe epilepsy with hippocampal sclerosis
Introduction: Epilepsy can alter brain progenitor cell
(PC) populations. We have previously shown nestin-
expressing cells (NECs) as transient, proliferative popu-
lations responding to acute brain injury, glial scar for-
mation and possible neurogenesis (1). Doublecortin
(DCX) is also widely regarded as a marker of PCs. Our
aim was to explore the distribution of nestin and DCX-
expressing cells in temporal lobe epilepsy with hippo-
campal sclerosis (TLE/HS).
Material and methods: We selected adult surgical
(n=22), paediatric (n=5), and elderly post mortem
(n=5) epilepsy specimens representing TLE/HS and
controls (n=15). Samples of the hippocampus (pes
and body), parahippocampal gyrus (PHG), amygdala,
temporal cortex (pole and posterior lobe) were
examined in each case with anti-nestin and anti-DCX
immunohistochemistry and co-localization with
microglial markers (CD68, Iba1), astroglial markers
(GFAP, GFAP delta, Sox2), neuronal marker (NeuN),
CD34 and oligodendrocyte markers (Olig2, PDGFRb).
Histological data were correlated with gene
expression data from a parallel study of MTG in TLE/
Results: Multipolar NECs were identified, particularly in
the subpial region, cortical layer I/II, perivascular
white matter, subgranular zone (SGZ) of hippocampus,
subventricular zone, PHG white matter and fibre tracts
in the amygdala; occasional neuronal NECs were seen
in the amygdala and temporal pole. DCX antibodies
identified NeuN-positive cells in cortical layer II and
prominent ramified cells, particularly in the SGZ. There
was little co-localisation between DCX and Nestin.
Many DCX-cells however, co-labelled with Iba1, CD68
and PDGFRb, and occasional cells with Olig2 and
Sox2; no co-localisation was observed for DCX with
CD34, GFAP and GFAP delta. Results from gene
expression studies of adult TLE/HS samples (n=83)
supported ongoing DCX expression, not diminished
compared to control groups (n=73).
Conclusion: The distribution of NECs corresponds to
known PC niches and to regions most vulnerable to
gliosis in TLE/HS as well as developmental abnormali-
ties associated with epilepsy; they may representing sei-
zure-responsive PCs. Although DCX antibodies identify
small neurons in cortical layer II, expression in microg-
lial cells was apparent, supported by sustained DCX
gene expression in adults. This indicates that DCX is
not a reliable marker of PCs.
Goc et al. Eur J Neurosci 2014; 39:2151-62.
C. Reeves
, M. Tachrount
, D.Thomas
, Z. Micha-
, J. Liu
, M. Ellis
, S. Eriksson
, T. Yousry
M. Thom
Departments of Neuropathology, UCL, Institute of
Neurology, Queen Square, London, UK;
Clinical and
Experimental Epilepsy, UCL, Institute of Neurology,
Queen Square, London, UK;
Neuroradiology, UCL,
Institute of Neurology, Queen Square, London, UK;
Neurosurgery, UCL, Institute of Neurology, Queen
Square, London, UK;
Department of Brain Repair and
Rehabilitation, UCL, Institute of Neurology, Queen
Square, London, UK;
Combined ex-vivo 9.4Tesla MRI and quantitative
histopathological study in normal and pathological
surgical resections in focal epilepsy
Introduction: High resolution MRI and quantitative
methods may improve the pre-operative diagnosis of
focal malformations of cortical development (MCD)
(Focal cortical dysplasia (FCD) and mild MCD) in epi-
lepsy. Reactive cellular changes (gliosis, microgliosis
Oral presentations 17
©2015 The Authors
Neuropathology and Applied Neurobiology ©2015 British Neuropathological Society, 41 (Suppl. 1), 8–29
and blood brain barrier break down) may also be pres-
ent in epilepsy and influence MR signal.
Material and methods: 9.4Tesla MRI was carried out
(T1, T2, T2*and MTR) on 12 cortical tissue samples
representing pathologically confirmed FCD type II
(three cases) and normal cortex ; in three samples,
small intracranial electrode (ICE) implantation sites
were present. Quantitative immunohistochemistry for
myelin (SMI94), neuronal populations (MAP2, neurofi-
lament (SMI31, 32), synpatophysin, NeuN, calbindin),
reactive glia (GFAP), microglia (CD68) and blood brain
permeability (albumin) was carried out in regions of
interest (ROI) from normal and abnormal white matter
and cortex. Whole slide scanning (WSS) analysis of the
entire white matter was also carried out. MRI were
spatially aligned and quantitative analysis carried out
on corresponding ROI. Line profile analysis (LPA) of
intensity gradients through the cortex was also carried
Results: An inverse correlation was observed between
SMI94 and T1, T2 and T2*(P<0.05 to <0.005) and
a positive correlation between MAP2 and T1 and T2*
(P<0.05 to <0.005) in all ROI; conversely a positive
correlation was observed between SMI94 and MTR and
an inverse correlation between MAP2 and MTR. Simi-
lar pathology-MRI correlations were observed when
applied only to histologically normal white matter ROI
and were also noted for MAP2 using WSS methods.
LPA was altered in regions of FCD compared to normal
cortex, reflecting abnormal cortical lamination and my-
elo-architecture, including in pre-operatively undetect-
able FCD cases. Correlations were also noted between
qMRI values and GFAP, albumin values and with
MAP2 in vicinity of acute ICE injuries.
Conclusion: This study demonstrates the ability of
quantitative 9.4T MRI to detect subtle differences in
cortical and white matter neuronal numbers and mye-
lination in histologically normal appearing cortex and
white matter. LPA is useful tool in the evaluation of
cortical dyslamination. These methods may be applica-
ble in the pre-operative evaluation and in vivo detec-
tion of mild MCD and occult FCD cases.
Fourth scientific session Pathology of Skeletal Muscle and
W. Stenzel
, C. Preuße
, Y. Allenbach
, D. Pehl
R. Junckerstorff
, E. Aronica
, E. Rushing
O. Benveniste
, J. Weis
, H.-H. Goebel
Department of Neuropathology, Charit
atsmedizin Berlin, Germany;
epartement de
edecine Interne et Immunologie Clinique, Centre de
erence Maladies Neuro-Musculaires Paris Est,
Assistance Public H^
opitaux de Paris Universit
e Pierre
et Marie Curie, H^
opital Piti
ere, Paris, France;
Section of Neuropathology, Department of Anatomical
Pathology, Path West Laboratory Medicine, Royal
Perth Hospital, Perth, Western Australia;
School of
Pathology and Laboratory Medicine, University of
Western Australia, Nedlands, Western Australia;
Department of Pathology and Neuropathology, AMC
University, Amsterdam, The Netherlands;
of Neuropathology, University of Zurich, Zurich,
Institute of Neuropathology, RWTH
Aachen, Germany;
Nuclear actin aggregation is a hallmark of anti-
synthetase syndrome-induced dysimmune myopathy
Introduction: Idiopathic inflammatory myopathies com-
prise highly heterogeneous subgroups of diseases such
as dermatomyositis, polymyositis, sporadic inclusion
body myositis, necrotising autoimmune myopathy and
unspecific forms of myositis. The objective of this study
was to analyse antisynthetase syndrome (ASS)-associ-
ated myositis by modern myopathological methods and
to define its place in the spectrum of Idiopathic Inflam-
matory Myopathies (IIMs).
Material and methods: Skeletal muscle biopsies from
ASS-associated myositis and other IIMs from different
institutions worldwide were analysed by histopathol-
ogy, quantitative polymerase chain reaction and elec-
tron microscopy.
Results: Myonuclear actin filament inclusions were
identified as a unique morphological hallmark of ASS-
associated myositis. Nuclear actin inclusions were
never found in dermatomyositis, polymyositis, sporadic
inclusion body myositis, autoimmune necrotising
18 Oral presentations
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Neuropathology and Applied Neurobiology ©2015 British Neuropathological Society, 41 (Suppl. 1), 8–29
myopathy associated with SRP or HMGCR autoantibod-
ies, or nonspecific myositis associated with other sys-
temic diseases, harbouring myositis-associated
autoantibodies and presenting myofibre necrosis. We
show that molecules involved in actin filament forma-
tion and actin shuttling mechanisms are altered in
ASS, and may thus be involved in pathological myonu-
clear actin aggregation. In addition, we have identified
a typical topographic distribution of necrotic myofibres
predominantly located at the periphery of muscle fasci-
cles accompanied by inflammation and destruction of
the perimysial connective tissue.
Conclusion: ASS-associated myositis is characterized by
distinctive myonuclear actin filament inclusions,
including rod formations and a typical necrotising per-
imysial myositis. This supports the hypothesis that
ASS-associated myositis is unique and should not be
grouped among DM, PM, sIBM, NAM or nonspecific
C.T. Deakin
, S.A. Yasin
, K. Arnold
, S.L. Tansley
Z.E. Betteridge
, N.J. McHugh
, J.L. Holton
, T.S. Jac-
, C. Pilkington
, M. De Iorio
, L.R.Wedderburn
Infection, Inflammation and Rheumatology Section,
UCL Institute of Child Health, London, UK;
National Hospital for Rheumatic Diseases, Bath, UK;
Department of Molecular Neuroscience, MRC Centre
for Neuromuscular Diseases, UCL Institute of
Neurology, London, UK;
Developmental Biology &
Cancer Programme, UCL Institute of Child Health,
London, UK;
Rheumatology Unit, Great Ormond
Street Hospital, London, UK;
Department of Statistical
Science, UCL, London, UK;
Sub-phenotyping of juvenile dermatomyositis
Introduction: Juvenile Dermatomyositis (JDM) is a rare
serious disease (affecting 23 million children per year)
characterised by rash and proximal muscle weakness.
Serious complications can include calcinosis, gastroin-
testinal ulceration, interstitial lung disease (ILD) and
even death. It is increasingly clear that JDM is a heter-
ogeneous condition and therefore there is a need to
define clinical sub-phenotypes and to investigate the
biological mechanisms underpinning these subtypes.
Previously, associations have been identified between
certain clinical features and expression of the autoanti-
bodies anti-MDA5, anti-NXP2 and anti-TIF1[gamma].
We hypothesised that JDM patients with known au-
toantibodies would display distinct pathological pheno-
types on muscle biopsy.
Material and methods: Patients:Patients were included
from the Juvenile Dermatomyositis Cohort and Biomar-
ker Study, a multi-centre study including 13 centres
from across the UK (n=463 patients). Clinical data
were collected for these patients. Autoantibodies:Plasma
or serum from 285 patients were screened for the pres-
ence of autoantibodies by immunoprecipitation and
confirmed by ELISA. Muscle biopsies:101 Muscle biop-
sies were stained and scored using the JDM Muscle
biopsy score tool which measures the severity of mus-
cle pathology (1, 2). Principal component analysis
(PCA) was used as a clustering technique in order to
define JDM sub-phenotypes.
Results: PCA identified two distinct clusters that corre-
late with the autoantibodies anti-MDA5 and anti-Mi2,
reflecting mild and severe histological changes, respec-
Conclusion: These analyses represent the first step
towards the identification of JDM sub-phenotypes that
correlate with potential biomarkers. This will allow us
to have a better understanding of the disease mecha-
nisms, which will enable a more targeted therapeutic
approach for JDM.
1. Wedderburn et al. Arthritis & Rheum 2007;
2. Varsani et al. Ann Rheum Dis 2015; 74:204-10
J.L. Rinnenthal
, A. Hucko
, M. Schuelke
H.H. Goebel
, W. Stenzel
Department of Neuropathology, Charite
Universitaetsmedizin Berlin, Germany;
Department of
Neuropediatrics, Charite Universitaetsmedizin Berlin,
Congenital myopathy with Lamin A/C mutation
Introduction: Mutations in the LMNA gene are
responsible for a wide spectrum of clinically different
conditions. These mutations are usually autosomal-
dominantly inherited. Here we present data that
concern a homozygous LMNA mutation.
Oral presentations 19
©2015 The Authors
Neuropathology and Applied Neurobiology ©2015 British Neuropathological Society, 41 (Suppl. 1), 8–29
Case report: A 3-month-old boy presented with muscle
weakness, respiratory failure, dysphagia, and mild dys-
morphic features. Quadriceps muscle biopsy revealed
nonspecific findings such as increased variation in
muscle fibre diameters, numerical increase in internally
located nuclei, many immature muscle fibres, but no
further immunohistochemical abnormalities. Neuro-
muscular diseases were not known in the family.
Whole Exome Sequencing revealed a homozygous
mutation in the LMNA gene. Lamin A/C was immuno-
histochemically expressed in muscle fibre nuclei as was
Conclusion: To our knowledge, this is the fourth patient
reported with autosomal-recessive laminoA/Cpathy,
two without immunohistochemical information, one
with absence of immunohistochemical lamin A/C. Our
patient appears to be the first with preserved immuno-
histochemical lamin A/C expression indicating that
lamin A/C immunohistochemistry may diagnostically
not always be informative and suggesting that mutant
lamin A/C may be demonstrated by immunohistochem-
R. Phadke
, D. Chambers
, J. Hudson
, L. Feng
C. Timson
, D. Johnson
, A. Manzur
, F. Muntoni
C.A. Sewry
Dubowitz Neuromuscular Centre, Great Ormond Street
Hospital for Children and UCL, London, UK;
of Genetic Medicine, Newcastle University, Newcastle
upon Tyne, UK;
Unique brick-red auto-fluorescence of reducing bodies
and protein aggregates is a useful diagnostic biopsy
marker for FHL1-associated myopathies
Introduction: Mutations in the four and a half LIM
domain protein 1 (FHL1) gene are causative of four
distinct human myopathies. The severe early-onset
reducing body myopathy subgroup featuring reducing
bodies (RB) and reducing body material (RBME) in
biopsies is linked to LIM2 missense mutations. A biopsy
diagnosis can be difficult due to overlap with other pro-
tein aggregation myopathies (PAM), dystrophic
changes and non-specific menadione-NBT reduction.
Our aim was to assess and compare the auto-fluores-
cent (AF) characteristics of inclusions in biopsies from
molecularly confirmed cases of FHL1 and non-
FHL1PAM as a potential biopsy marker.
Material and methods: 21 muscle biopsies referred to
the DNC were reviewed retrospectively (FHL1 =7; 14
non-FHL1 including BAG3, desmin, myotilin, Alpha-B-
Crystallin, FKRP, acid maltase, AVM and minimal
change). Serial frozen sections were stained with HE
for bright field microscopy and AF followed by Desmin/
Bag3/FHL-1 fluorescent double-immunolabeling (BGR
multi-excitation filter, Leica DM2500) except in one
FHL1 case (paraffin sections). Relevant histochemistry,
immunostaining and electron microscopy (EM) were
Results: Unique brick-red AF of the inclusions includ-
ing discrete RB and diffuse RBME was seen only in fro-
zen sections of FHL1 cases. Non-overlapping, closely
interacting brick-red AF of FHL1 inclusions with yel-
low-orange AF of desmin and myotilin was noted.
Brick-red AF material was detectable in small quanti-
ties even in end-stage atrophic fibres. RB and diffuse
RBME were confirmed on EM. Protein aggregates in all
non-FHL1 cases showed variable yellow-orange AF.
Conclusion: In HE stained frozen sections examined
under multi-excitation BGR fluorescence, brick-red AF
appears to be a unique property of FHL1 containing
reducing bodies and protein aggregates and may be a
useful biopsy marker for early detection and diagnosis
of FHL1 pathology.
R. Phadke
, Z.A. Puthucheary
, J. Rawal
M.J.W. McPhail
, P.S. Sidhu
, A. Rowlerson
J. Moxham
, S. Harridge
, N. Hart
, H.E. Montgomery
UCL Institute of Neurology, National Hospital, UCLH,
London, UK;
Institute of Health and Human
Performance, UCL, London, UK;
St. Mary’s Hospital,
Imperial College, London, UK;
King’s College Hospital,
London, UK;
King’s College London, London, UK;
Fasciitis frequently accompanies myopathy in acute
critical illness muscle wasting: Evidence from
qualitative ultrasound and muscle biopsy analysis
Introduction: A rapid and early loss of skeletal muscle
mass underlies the physical disability that is common
amongst survivors of critical illness (CI). The functional
capacity of skeletal muscle depends on its quantity as
20 Oral presentations
©2015 The Authors
Neuropathology and Applied Neurobiology ©2015 British Neuropathological Society, 41 (Suppl. 1), 8–29
well as quality, which may be adversely affected. Our
main objectives were to characterise changes in muscle
echogenicity, pennation angle and fascial characteris-
tics that occur early in CI, and to relate these to histo-
logically defined myofibre necrosis and fascial
Patients and Methods: Subjects comprised a subgroup of
patients recruited to the Musculoskeletal Ultrasound in
CI: Longitudinal Evaluation (MUSCLE) study. Compari-
sons were made between sequential vastus lateralis
(VL) biopsy specimens and ultrasound assessment of
rectus femoris (RF) echogenicity. Change in RF penna-
tion angle was measured.
Results: In 30 patients, change in muscle echogenicity
was greater in patients who developed muscle necrosis
than in those who did not (8.2%, (95% CI 5.3 to
21.7), versus 15.0%, (95% CI 28.9 to 1.09),
P=0.016). The AUROC for prediction of myofibre
necrosis was 0.74 (95% CI 0.5650.919, P=0.024)
increasing to 0.85 (95% CI 0.7030.995, P=0.003)
with the removal of those with potential iatrogenic
muscle damage. Fasciitis was observed in 18 out of 30
biopsies (60%) and was dominated by macrophages by
day 7 or day 10. Mean pennation angle decreased from
7.6 4.0°to 5.5 2.1°(P=0.01) over the first
10 days of CI.
Conclusion: Myofibre necrosis and fascial inflammation
can be detected noninvasively using ultrasound in CI.
Fasciitis precedes and frequently accompanies muscle
necrosis and is dominated by macrophages in the late
acute phase. Rapid decreases in pennation angle are
seen. These findings may have functional implications
for survivors of critical illness.
I. Bodi
, R. Hadden
, P. Bannister
, A. Radunovic
Clinical Neuropathology, King’s College Hospital NHS
Foundation Trust, Denmark Hill, London, UK;
Neurology Departments, King’s College Hospital NHS
Foundation Trust, Denmark Hill, London, UK;
Neurology Department, Barts and the London MND
Centre Royal London Hospital, Barts Health NHS Trust,
London, UK;
The role of simultaneous proximal and distal skin
biopsies in the diagnosis of small fibre neuropathy
Introduction: Skin biopsy appears to be a sensitive and
specific test to confirm clinical suspicion of small fibre
neuropathy (SNP). Previous studies in large cohort of
control patients have shown age related decline of the
distal intraepidermal nerve fibre density (IENFD) which
is also influenced by gender. In the current study we
examined the usefulness of simultaneous proximal and
distal skin biopsy in the diagnosis of SNP.
Material and methods: Simultaneous 3 mm punch
biopsy samples from the upper thigh and the lower
outer leg were obtained from 113 patients. The sam-
ples were immediately fixed in freshly prepared 2%
paraformaldehyde lysine periodate (PLP) for 24 hours
at 4°C. Immunohistochemistry for PGP 9.5 was per-
formed on 3 randomly selected 50 lm serial cryostat
sections by immunoperoxidase method. The IENFD was
calculated by counting the fibres crossing the dermal-
epidermal junction (excluding secondary branching) as
fibres per millimetre SD. The IENFD were analysed
using age/sex matched normative values set by the
European Federation of Neurological Societies/Periph-
eral Nerve Society Guideline(1). The results were also
compared to the available distal IENFD data from 336
Results: 42% of the biopsies showed normal IENFD.
The cases with confirmed abnormal values revealed
two main pattern; 33% of the biopsies revealed length
dependent SNP (LD-SFN) and 12% showed non-length
dependent SNP (NLD-SFN). In a further 10% of LD-
SNP and 1% of NLD-SFN pattern was suspected, while
only 3% of the cases remained borderline.
Conclusion: Our findings revealed cases of NLD-SNP, in
addition to the more expected LD-SFN. The aetiology of
the NLD-SFN is more likely to be linked to ganglionop-
athy; therefore it may have clinical significance. The
number of borderline IENFD cases is also appears to be
reduced using proximal and distal biopsies.
1. Lauria et al. Eur J Neurol 2010; 17:90312
Oral presentations 21
©2015 The Authors
Neuropathology and Applied Neurobiology ©2015 British Neuropathological Society, 41 (Suppl. 1), 8–29
Fifth scientific session Neurodegeneration Beyond Misfolded
T.L. Thomas, S.J. Miners, P.G. Kehoe, S. Love
Dementia Research Group, Institute of Clinical
Neurosciences, School of Clinical Sciences, University of
Bristol, Bristol, UK;
Correlation between levels of VEGF and insoluble
in the cerebral cortex in Alzheimer’s disease
Introduction: Cerebral blood flow (CBF) is reduced in
patients with Alzheimer’s disease (AD). The reduction
precedes the development of dementia and predicts the
rate of cognitive decline. Vascular endothelial growth
factor-A (VEGF) is an endothelial mitogen and a key
regulator of angiogenesis, initiating the growth of new
blood vessels in response to tissue hypoxia. We previ-
ously demonstrated that VEGF protein level was
increased in AD but was not associated with an
increase in microvascular density. Other researchers
have reported that VEGF is present in Abplaques, sug-
gesting that plaques may sequester Aband limit its
biological availability. In the present study we have
investigated the relationship between VEGF and Ablev-
els in AD and control brains.
Material and methods: We studied AD, VaD and control
brains from the South West Dementia Brain Bank.
Total Ab,Ab
and Ab
were measured by sand-
wich ELISA insoluble and insoluble (guanidine-extract-
able) fractions of left parahippocampal, cingulate and
mid-frontal cortex and thalamus. The levels of Abwere
compared to VEGF protein level that had previously
been measured in the same regions.
Results: VEGF protein level in the mid-frontal region
correlated closely with insoluble (guanidine-HCl-
extractable) Ab
and insoluble Ab
not with insoluble Ab40. A positive association was
also demonstrated between VEGF and total insoluble
Abbut this did not reach statistical significance. VEGF
did not correlate with Ablevels in the soluble fractions.
When VEGF increased with Braak tangle stage and
was significantly higher in the V-VI than the 0-II
Conclusion: The close correlation between VEGF protein
and insoluble Ab
levels is in keeping with previous
findings suggesting that plaque-associated Abmay
sequester VEGF, reducing its biological availability in
the cerebral cortex in patients with AD.
P.G. Ince
, T. Minett
, G. Forster
, S.B. Wharton
Sheffield Institute for Translational Neuroscience,
University of Sheffield, Sheffield, UK;
University of
Microinfarcts, Small Vessel Disease and Dementia in
the population-representative CFAS brain donor cohort
Introduction: Microinfarcts are focal areas of ischaemic
brain damage not visible on macroscopical examina-
tion or by routine brain imaging methods. They are
claimed to be a major vascular substrate of cognitive
decline in older people. Medical Research Council Cog-
nitive Function and Ageing Study (MRC CFAS) is a
large UK population based study of ageing and demen-
tia with an autopsy brain donor cohort. Previous work
published by CFAS showed that small vessel disease
(SVD) may contribute up to 20% of the risk for demen-
tia but the analysis did not include systematic data on
microinfarcts. We reviewed brains from three CFAS
centres to assess: how microinfarcts relate to previously
acquired data on SVD; the relationship between micro-
infarcts, dementia, cognition, vascular risk factors and
Material and methods: CFAS brain donations from Cam-
bridge, Newcastle and Nottingham (n=331) were
assessed by light microscopy (H&E) to record the num-
ber of brain regions with microinfarcts. The impact of
the inclusion of microinfarcts into the CFAS opera-
tional diagnosis of SVD was analysed. The relationships
between vascular lesions and dementia, MMSE scores,
mobility scores, MRI WML and vascular risk factors
were analysed controlling by age of death and sex.
Results: Microinfarcts were present in 36% of the
brains examined (mean age at death: dementia
88.6 years; no-dementia 83.4 years). Cortical microin-
farcts were significantly associated with the risk of
dementia (OR 1.41; 95% CI 1.021.96; P=0.038),
22 Oral presentations
©2015 The Authors
Neuropathology and Applied Neurobiology ©2015 British Neuropathological Society, 41 (Suppl. 1), 8–29
and impaired mobility (OR 1.36; 95% CI 1.051.74;
P=0.018). Microinfarcts were significantly associated
with self-reported stroke (IRR 2.47; 95% CI 1.583.87;
P<0.001) and MRI deep white matted lesions (WML,
OR 1.31; 95% CI 1.011.70; P=0.044). Subcortical
microinfarcts were significantly associated with
impaired mobility (OR 1.96; 95% CI 1.113.43;
P=0.02) and MRI periventricular WML (OR 1.80;
95% CI 1.092.97; P=0.022). Inclusion of microin-
farcts into the operational diagnosis of SVD reassigned
11 cases to the SVD category and had minimal impact
on the relationship between an SVD diagnosis and risk
of dementia compared with previous analyses.
Conclusion: Microinfarction is common in older people
and is an independent risk factor for cognitive decline
and impaired mobility. In this study microinfarcts do
not dominate the pathological constellation of signifi-
cant SVD compared to assessment based on other
lesions (WML, moderate or severe arteriolar sclerosis
and lacunar infarcts). Nevertheless evaluation of the
presence of microinfarcts is recommended as part of
the assessment of small vessel vascular brain pathology
in older people.
I. Ferrer
, A. Schl
, A. Pujol
E. Aso
Institute of Neuropathology, IDIBELL-Bellvitge
University Hospital, University of Barcelona, Barcelona,
Neurometabolic Diseases Laboratory, IDIBELL,
Hospitalet de Llobregat, Barcelona, Spain;
Gene regulation of brain cytokines and mediators of
immune response in aging and first stages of sporadic
Alzheimer’s disease is not linked to b-amyloid plaques
and neurofibrillary tangles but is linked to soluble
Introduction: Profiles of gene regulation and protein
expression of cytokines and mediators of the immune
response are analysed in the aging brain and early
stages of sporadic Alzheimer’s disease (sAD) in compar-
ison with those seen in APP/PS1 transgenic mice and
AD with disease progression.
Material and methods: Middle-aged (MA) individuals
and sporadic Alzheimer’s disease (sAD) at stages I-II/0
(A), III-IV/A-B, and V-VI/C of Braak and Braak; wild
type (WT) and APP/PS1 transgenic mice. Regions
examined include entorhinal cortex, orbitofrontal cor-
tex, and frontal cortex area 8, and pars 1 and 2 in
humans and mice, respectively.
Results: Significant modifications of mRNA regulation
of cytokines and mediators of the immune response
were found in normal aging in WT mice and between
MA individuals and early stages of sAD-related pathol-
ogy accompanied by increased protein expression of
selected mediators in ramified microglia. Gene regula-
tion of cytokines and mediators at early stages of sAD-
related pathology is not related to hyper-phosphory-
lated tau deposition in neurofibrillary tangles, b-amy-
loid (Ab) plaque burden, soluble levels of Ab40 and
Ab42, and fibrillar Ablinked to membranes but with
increased levels of soluble oligomers. Inflammatory
changes occur in parallel with amyloid deposition in
APP/PS1 transgenic mice, but only increased levels of
soluble oligomers are found parallel with mRNA regu-
lation of cytokine and mediators in WT mice.
Conclusion: The present findings show (i) major
changes in the brain gene regulation of cytokines and
mediators of the immune response, some of them
expressed in ramified microglia occur with aging; (ii)
gene deregulation in APP/PS1 transgenic mice and
advanced stages of sAD is not merely non-specific
accelerated aging but rather species-specific, and regio-
nal- and stage-dependent; (iii) gene regulation of cyto-
kines and mediators of the immune response in aging
and first stages of sAD is not related to hyper-phos-
phorylated tau, Abplaque burden, soluble Ab40 and
Ab42 and Ablinked to membranes but rather to solu-
ble oligomers; and (iv) species differences, and regional-
and stage-dependent inflammatory responses in sAD,
particularly those occurring at early stages of sAD-
related pathology, highlight the need to identify new
anti-inflammatory compounds adapted to specific
molecular targets.
Oral presentations 23
©2015 The Authors
Neuropathology and Applied Neurobiology ©2015 British Neuropathological Society, 41 (Suppl. 1), 8–29
D. Boche
, T. Minett
, J. Classey
, F.E. Matthews
M. Fahrenhold
, M. Taga
, C. Brayne
, P.G. Ince
J.A.R. Nicoll
Clinical Neurosciences, Clinical and Experimental
Sciences, Faculty of Medicine, University of
Southampton, UK;
Institute of Public Health,
Department of Public Health and Primary Care,
University of Cambridge, UK;
MRC Biostatistics Unit,
Cambridge Institute of Public Health, UK;
Institute for Translational Neuroscience, Sheffield
University, UK;
A role for microglia in ageing and dementia
Introduction: Genetic risk factors for Alzheimer’s disease
(AD) recently identified imply that inflammation plays
a causal role in AD. Using the MRC Cognitive Function
and Ageing Study (CFAS), we investigated the role of
microglia in human brain ageing and dementia.
Material and methods: Frontal cortex from 298 cases
were analysed for CD68 (phagocytic activity); macro-
phage scavenger receptor (MSR)-A (plaque related),
CD64 (Fccreceptor I), Iba1 (resting and activated mi-
croglia), TREM2 (phagocytic versus proinflammatory
microglial activity) and HLA-DR (antigen presenting
function). All analyses were adjusted for age of death
and sex.
Results: Overall, MMSE was associated negatively with
CD68 and HLA-DR and positively with CD64 and Iba1.
Among the cases without dementia, associations were
observed for: diffuse plaques with all markers except
MSR-A which was strongly associated with neuritic
plaques. HLA-DR and Iba1 were negatively associated
with tangles. In the cases with dementia and AD
pathology, CD64 was strongly associated with all neu-
rodegenerative pathologies except tangles, CD68 with
plaques and tangles, and MSR-A with neuritic plaques
and tangles. HLA-DR was significantly related to pla-
ques and tangles and Iba1 with increase in all neuro-
pathological features. TREM2 recognized only
monocytes/macrophages. With regard to the APOE
polymorphism, e2 was associated with expression of
Iba1 and MSR-A and e4 with CD68, CD64 and HLA-
Conclusion: These data suggest that microglia may
respond differently to Aband tau in subjects with and
without dementia so that the microglial response may
influence the likelihood of developing dementia. Inter-
estingly the findings also suggest that APOE polymor-
phism may influence the microglial profile.
A. Chen
, R.O. Akinyemi
, K. Washida
, V. Foster
M.J. Firbank
, A.E. Oakley
, Y. Okamoto
J.T. O’Brien
, L.M. Allan
, M. Ihara
,R.N. Kalaria
Neurovascular Research Group, Institute of
Neuroscience, Newcastle University, Campus for
Ageing & Vitality, Newcastle Upon Tyne, UK;
Department of Stroke and Cerebrovascular Diseases,
National Cerebral and Cardiovascular Center, Osaka,
Frontal white matter clasmatodendrosis and cognitive
dysfunction in the elderly
Introduction: Clasmatodendrosis, a morphological
change attributed to irreversely injured astrocytes. We
investigated the location and incidence of clasmato-
dendrosis and establish the association between astro-
cytic pathology and cognitive function in post-stroke
survivors who develop dementia.
Material and methods: We assessed post-mortem brains
from n=1125 non-demented (PSND), demented