ArticlePDF Available

PO83DESMOPLASTIC NON-INFANTILE GANGLIOGLIOMA - A RARE CASE OF MALIGNANT TRANSFORMATION AND A REVIEW OF THE LITERATURE

November 2015
Neuro-Oncology 17(suppl 8):viii14.6-viii15

DOI:10.1093/neuonc/nov284.72

Authors:

Bhaskar Thakur

Barts Health NHS Trust

Bassel Zebian

King's College Hospital NHS Foundation Trust

Miren Aizpurua

Show all 7 authorsHide

Content uploaded by Istvan Bodi

Content may be subject to copyright.

Neuropathology

& Applied

Neurobiology

Proceedings of the 116th Meeting

of the

British Neuropathological Society

Institute of Child Health,

London, UK, 4–6 March 2015

Disclaimer

The following items have been produced using author-supplied copy. Editing has been restricted to some corrections of

spelling and style where appropriate. No responsibility is assumed for any claims, instructions, methods or drug dosages

contained in the abstracts or articles: it is recommended that these are verified independently.

nan_41_s1_title_ps 03-02-2015 20:01 Page 1

President: S. Love

EDITOR-IN-CHIEF

J. L. Holton

UCL Institute of Neurology, University

College London, UK

CONSULTING EDITORS

J. S. Lowe

University of Nottingham, UK

S. B. Wharton

University of Sheeld, UK

ExECUTIvE EDITORS

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

BOOK REvIEWS EDITOR

R. O. Weller

Southhampton, UK

SOCIaL MEDIa EDITOR

A. Li

London, UK

FORMER EDITORS

S. B. Wharton: 2007–2013

J. S. Lowe: 2000–2006

R. O. Weller: 1989–1999

J. B. Cavanagh: 1975–1988

INTERNaTIONaL EDITORIaL BOaRD

EDITORIaL BOaRD

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

Carolina

R. Melki,

Paris, France

J. Nicoll,

Southampton, UK

S. Paine,

London, UK

A. Rozemuller,

Amsterdam,

The Netherlands

W. Stenzel,

Berlin, Germany

M. Thom,

London, UK

P. Wesseling,

Amsterdam, The

Netherlands

A. Shivane,

Plymouth, UK,

Secretary of the Society,

ex ocio

A. Aguzzi, Zurich, Switzerland

R. Castellani, Baltimore,

Maryland

L. Chimelli, Rio de Janeiro,

Brazil

V. Collins, Cambridge, UK

M. Dalakas, Athens, Greece

D. Dickson, Rochester,

Minnesota

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,

Canada

C. Masters, Melbourne,

Australia

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,

California

O. Wiestler, Bonn, Germany

W. Zhang, Beijing, China

EDITORIaL aSSISTaNT

Tara Noonan

PRODUCTION EDITOR

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

PROGRAMME

WEDNESDAY, 4th MARCH 2015

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

18:30 RECEPTION

THURSDAY 5th MARCH 2015

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. Pﬁ 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

14 : 00 THE CAVANAGH PRIZE LECTURE

Chair: Seth Love

Development of molecular markers for brain tumour classiﬁ 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

17:30 – 18:30 PROFESSIONAL AFFAIRS MEETING

19:30 SOCIETY DINNER AT THE HONOURABLE SOCIETY OF LINCOLN’S INN

Southeast corner of Lincoln’s Inn Fields, junction with Serle Street, WC2A 3TL

http://www.lincolnsinn.org.uk

FRIDAY 6th MARCH 2015

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

ﬁ 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

ﬁ 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

POSTER PRESENTATIONS

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

SNCA

mutation cases compared with

SNCA

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 neuroinﬂ 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

SQSTM1

and

VCP

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

Miscellaneous

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

O01

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;

E-mail: emma.ashby@bristol.ac.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.

References:

1. Bueche et al.Ann Clin Transl Neurol 2014; 1:124–

2. Paris et al. Mol Med 2011; 17:149–162

3. Hajjar et al. Arch Neurol 2012; 69:1632-38.

O02

R. Vuono

, S. Winder-Rhodes

1,2

, R. de Silva

G. Cisbani

, J. Drouin-Ouellet

, M.G. Spillantini

F.Cicchetti

4,5

, 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

D

epartement de Psychiatrie et Neurosciences, Qu

ebec,

QC, Canada;

Universit

e Laval, Qu

ebec, QC, Canada;

E-mail: rv254@cam.ac.uk

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

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-

tion.

O03

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;

E-mail: bimali.hapuarachchi.11@ucl.ac.uk

A cell-based biosensor for pathological tau uptake and

aggregation

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

windows.

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

immunotherapy.

References:

1. Braak&Braak. Neurobiol Aging. 1995, 16:271-278

2. Clavaguera et al. Neuropharmacology. 2014; 76:9-15

Oral presentations 9

3. de Silva et al. Neuropathol Appl Neurobiol. 2003,

29:288-302

O04

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;

E-mail: t.lashley@ucl.ac.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

diseases.

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

controls.

Conclusion: These results implicate a wider dysregula-

tion of TRN1-associated nuclear import between intra-

cellular compartments, than mechanisms only affecting

the FET proteins.

O05

J.S. Miners, S. Love

Dementia Research Group, School of Clinical Sciences,

University of Bristol, Learning and Research, Level 1,

Southmead Hospital, Bristol, UK;

E-mail: scott.miners@bris.ac.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

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

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,

Hungary;

Neurological Tissue bank, University of

Barcelona, Spain;

Institute of Psychiatry, Kings

College London, UK;

Department of Medicine, Imperial

College London, London, UK;

E-mail: christina.murray@ucl.ac.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 I–IV.

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.

Reference:

1. Braak et al. Neurobiol Aging 2003; 24:197–211

O07

A.K.L. Liu

1,2

, 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;

E-mail: king.liu09@imperial.ac.uk

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

LBD.

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

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

observed.

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

System

O08

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;

E-mail: david.ellison@stjude.org

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

O09

S. Brandner

, Z. Jaunmuktane

, T.J. Stone

, J. Chalker

M. Hubank

, T.S. Jacques

2,5

Division of Neuropathology UCL Institute of

Neurology, London, UK;

Neural Development Unit,

UCL Institute of Child Health London, UK;

Cellular

and Molecular Diagnostic Service, Great Ormond Street

Hospital for Children NHS Foundation Trust London,

UK;

UCL Genomics, UCL Institute of Child Health

London, UK;

Department of Histopathology, Great

Ormond Street Hospital for Children NHS Foundation

Trust, London, UK;

E-mail: s.brandner@ucl.ac.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.

O10

A. Merve, X. Zhang, S. Acquati, S. Marino

Blizard Institute, Barts and The London School of

Medicine and Dentistry, Queen Mary University,

London, UK;

E-mail: a.merve@qmul.ac.uk

c-Myc is expressed in a proportion of human choroid

plexus tumours and its overexpression in the

developing mouse CNS induces choroid plexus

tumorigenesis

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

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.

References:

1. Louis et al.Acta Neuropathol 2007; 114:97-109

2. Wang et al.PLoS ONE 2008; 3:e3769

O11

T.J. Stone

1,2

, A. Keeley

, A. Virasami

, W. Harkness

M. Tisdall

, D. Hargrave

, M. Hubank

, J.H. Cross

J. Ham

, T.S. Jacques

1,2

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;

Genetic

and Genomic Medicine Programme, UCL Institute of

Child Health, London, UK;

Developmental

Neuroscience Programme, UCL Institute of Child

Health, London, UK;

E-mail: thomas.stone.12@ucl.ac.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.

O12

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,

France;

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,

France;

Department of Pathology, Charles Nicolle

Hospital, Rouen, France;

E-mail: arnault.tauziedeespariat@gmail.com

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

therapies.

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

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 0–3) and

high-grade (scores 4–6). 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.

O13

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;

E-mail: ross.laxton@nhs.net maizpurua@nhs.net

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

6

). The difference in

survival between AO +N and GBMO remained signiﬁ-

cant when adjusted for age and gender (HR 0.14 95%

CI 0.05–0.34, 3.4 910

5

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.

Reference:

1. Laxton et al.Neuro Oncol 2013; 12:1635-43.

Third scientiﬁc session –Neuropathology of Epilepsy

O14

O. Adegbaju

, I. Bodi

, M. Honavar

1,2

, S. Al-Sarraj

Department of Clinical Neuropathology, King’s College

Hospital NHS Foundation Trust, Denmark Hill, London,

UK;

Hospital Pedro Hispano, Matosinhos, Portugal;

E-mail: oluwayomi.adegbaju@nhs.net

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

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 3–89 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

cells.

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.

O15

F. Scerif

1,2

, S.R. Picker

1,2,3

, S.A. Yasin

1,2

, A. Virasami

A. Alahdal

, W. Harkness

, M. Tisdall

, F. Guillemot

S.M.L. Paine

1,2

, J.H. Cross

, T.S. Jacques

1,2

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;

Division

of Molecular Neurobiology, National Institute for

Medical Research, London, UK;

Neurosurgery, Great

Ormond Street Hospital, Great Ormond Street, London,

UK;

Developmental Neuroscience Programme, UCL

Institute of Child Health, London, UK;

E-mail: fatma.scerif.12@ucl.ac.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

Human

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

cortex.

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

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

targets.

O16

M. Thom

, J. Liu

1,2

, C. Reeves

1,2

, M. Matarin

1,2

S. Sisodiya

Department of Clinical and Experimental Epilepsy, UCL

Institute of Neurology and National Hospital for

Neurology and Neurosurgery, Queen Square, London,

UK;

Department of Neuropathology, UCL Institute of

Neurology and National Hospital for Neurology and

Neurosurgery, Queen Square, London, UK;

Epilepsy

Society, Chesham Lane, Chalfont St Peter, Bucks, UK;

E-mail: m.thom@ucl.ac.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/

HS.

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.

Reference:

Goc et al. Eur J Neurosci 2014; 39:2151-62.

O17

C. Reeves

1,2

, M. Tachrount

, D.Thomas

, Z. Micha-

lak

1,2

, J. Liu

1,2

, M. Ellis

, S. Eriksson

, T. Yousry

3,5

M. Thom

1,2

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;

E-mail: m.thom@ucl.ac.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

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

out.

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

Nerves

O18

W. Stenzel

, C. Preuße

, Y. Allenbach

, D. Pehl

R. Junckerstorff

3,4

, E. Aronica

, E. Rushing

O. Benveniste

, J. Weis

, H.-H. Goebel

Department of Neuropathology, Charit

e–

Universit€

atsmedizin Berlin, Germany;

D

epartement de

M

edecine Interne et Immunologie Clinique, Centre de

R

ef

erence Maladies Neuro-Musculaires Paris Est,

Assistance Public –H^

opitaux de Paris Universit

e Pierre

et Marie Curie, H^

opital Piti

e-Salp^

etri

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;

Department

of Neuropathology, University of Zurich, Zurich,

Switzerland;

Institute of Neuropathology, RWTH

Aachen, Germany;

E-mail: werner.stenzel@charite.de

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

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

myositis.

O19

C.T. Deakin

, S.A. Yasin

, K. Arnold

, S.L. Tansley

Z.E. Betteridge

, N.J. McHugh

, J.L. Holton

, T.S. Jac-

ques

, C. Pilkington

, M. De Iorio

, L.R.Wedderburn

1,5

Infection, Inﬂammation and Rheumatology Section,

UCL Institute of Child Health, London, UK;

Royal

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;

E-mail: c.deakin@ucl.ac.uk

Sub-phenotyping of juvenile dermatomyositis

Introduction: Juvenile Dermatomyositis (JDM) is a rare

serious disease (affecting 2–3 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-

tively.

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.

References:

1. Wedderburn et al. Arthritis & Rheum 2007;

57:1192-1201

2. Varsani et al. Ann Rheum Dis 2015; 74:204-10

O20

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,

Germany;

E-mail: jan-leo.rinnenthal@charite.de

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

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

emerin.

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-

istry.

O21

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;

Institute

of Genetic Medicine, Newcastle University, Newcastle

upon Tyne, UK;

E-mail: r.phadke@ucl.ac.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

assessed.

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.

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

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;

E-mail: r.phadke@ucl.ac.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

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

pathology.

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 0.565–0.919, P=0.024)

increasing to 0.85 (95% CI 0.7030.995, 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.

O23

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;

E-mail: istvan.bodi@nhs.net

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

patients.

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.

Reference:

1. Lauria et al. Eur J Neurol 2010; 17:903–12

Oral presentations 21

Fifth scientiﬁc session –Neurodegeneration –Beyond Misfolded

Proteins

O24

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;

E-mail: taya.thomas@bristol.ac.uk

Correlation between levels of VEGF and insoluble

1–42

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

1–40

and Ab

1–42

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

1–42

and insoluble Ab

1–42

:Ab

1–40

but

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

group.

Conclusion: The close correlation between VEGF protein

and insoluble Ab

1–42

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.

O25

P.G. Ince

, T. Minett

, G. Forster

, S.B. Wharton

Shefﬁeld Institute for Translational Neuroscience,

University of Shefﬁeld, Shefﬁeld, UK;

University of

Cambridge;

E-mail: p.g.ince@shefﬁeld.ac.uk

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

mobility.

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 1.02–1.96; P=0.038),

22 Oral presentations

and impaired mobility (OR 1.36; 95% CI 1.05–1.74;

P=0.018). Microinfarcts were signiﬁcantly associated

with self-reported stroke (IRR 2.47; 95% CI 1.58–3.87;

P<0.001) and MRI deep white matted lesions (WML,

OR 1.31; 95% CI 1.01–1.70; P=0.044). Subcortical

microinfarcts were signiﬁcantly associated with

impaired mobility (OR 1.96; 95% CI 1.11–3.43;

P=0.02) and MRI periventricular WML (OR 1.80;

95% CI 1.09–2.97; 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.

O26

I. Ferrer

,I.L



opez-Gonz

alez

, A. Schl€

uter

, A. Pujol

E. Aso

Institute of Neuropathology, IDIBELL-Bellvitge

University Hospital, University of Barcelona, Barcelona,

Spain;

Neurometabolic Diseases Laboratory, IDIBELL,

Hospitalet de Llobregat, Barcelona, Spain;

E-mail: 8082ifa@gmail.com

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

oligomers

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

O27

D. Boche

, T. Minett

, J. Classey

, F.E. Matthews

M. Fahrenhold

, M. Taga

, C. Brayne

, P.G. Ince

J.A.R. Nicoll

, MRC CFAS

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;

Shefﬁeld

Institute for Translational Neuroscience, Shefﬁeld

University, UK;

E-mail: d.boche@soton.ac.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-

DR.

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.

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

1,2

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,

Japan;

E-mail: r.n.kalaria@ncl.ac.uk

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=11–25 non-demented (PSND), demented

(PSD)