Download 2009 ANZSNP program and abstracts

Joint Scientific Meeting, May 16th, 2009
The Australian and New Zealand Society for Neuropathology
The Australian and New Zealand Paediatric Pathology Group
Prince of Wales Medical Research Institute, Sydney.
Final Program
8:30-9:00am
Registration
9:00-11:00am
Slide Seminar Case Presentations.
(Chair: Dr Chris Burke. Presenters: M. Rodriguez, E. Sugo, Q. Lau, J. Brewer).
11:00-11:30am
Morning Tea
11:30am-12:30pm
Invited Speaker. David Thorburn. “Mitochondrial diseases: 100 genes and counting.”
12:30-1:30pm
Lunch break
1:30-2:15pm
Oral Presentations I. (The Bill Evans Memorial Young Investigator Award).
Björn Espedido: Using Genome-Wide Methylation Mapping to Find Oligodendroglial Tumour Suppressor
1:30-1:45
Genes.
1:45-2:00
2:00-2:15
Suad R Al-Jahdhami: Giant Cell Glioblastoma; a Rare Variant of Glioblastoma.
Cindy Kersaitis: Inflammatory Responses In Tau-Positive And Tau-Negative Frontotemporal Lobar
Degeneration.
2:15-3:00pm
2:30-2:45
Oral Presentations II (ANZ Paediatric Pathology Group).
Adrian Charles: Fetal akinesia
Amanda Charlton: Centronuclear / myotubular myopathyina s 16 day male neonate.
2:45-3:00
FREE SLOT
2:15-2:30
3:00-3:30pm
Afternoon tea
3:30-5:00pm
Oral Presentations III (ANZ Society for Neuropathology).
Hans Goebel: Adult Neuronal Ceroid-Lipofuscinosis  The Genetic Spectrum is Enlarging.
Glenda Halliday: Degeneration in different parkinsonian syndromes relates directly to astrocyte type and
3:30-3:45
3:45-4:00
astrocyte protein expression
4:00-4:15
Yue Huang: The early macroautophagy marker Atg12 concentrates in neurons and endothelial cells in
Alzheimer’s disease.
4:15-4:30
4:30-4:45
Nina Sundqvist: Next of kin consent for brain donation over a 5-year period.
Greg Sutherland: A cross-study transcriptional analysis of Parkinson's disease.
CLOSE OF SCIENTIFIC PART OF THE MEETING.
5:00
ANZSNP Business Meeting.
(Includes announcement of the winner of the “Bill Evans Memorial Award”).
~7:00pm
ANZSNP Dinner.
1
Invited Speaker
Title: “Mitochondrial Diseases: 100 Genes and Counting.”
Author:
David Thorburn
Murdoch Childrens Research Institute. The Royal Children's Hospital, Parkville, and Department of Paediatrics, University of Melbourne,
Victoria, Australia.
Abstract:
Investigation and diagnosis of mitochondrial respiratory chain (RC) disorders poses problems at multiple levels. There is
an extraordinary diversity of clinical presentations, organ involvement and age of onset. Some patients present with
symptoms that are strongly suggestive of a mitochondrial cytopathy, but many have nonspecific symptoms that overlap
with other diagnoses. There is no single "Gold Standard" test that can be used for diagnosis of all suspected patients.
When a mitochondrial aetiology is suspected, the first decision is how to investigate the patient in the most efficient,
least invasive and least costly manner. Direct analysis for mitochondrial DNA (mtDNA) rearrangements or "common"
point mutations is worth attempting in patients suspected of classic conditions such as LHON, MELAS, MERRF,
CPEO, Kearns-Sayre, Pearson and Leigh syndromes. However, in other patients, the diagnostic yield of such analysis
can become vanishingly small. In addition to mtDNA genes, mutations in more than 70 nuclear genes are now known to
cause mitochondrial dysfunction. Apart from a few notable exceptions, clinical suspicion alone is usually not enough to
target mutation analysis of specific nuclear genes.
Two of the best known paediatric mitochondrial disorders are Leigh syndrome and Alpers syndrome. They provide
contrasting examples of some of the issues surrounding molecular diagnosis of mitochondrial disease. Leigh syndrome
is a neurodegenerative disease of early childhood with a characteristic neuropathology, particularly involving the basal
ganglia and brainstem. The neuropathology of Leigh syndrome presumably represents a common end-pathway of
pathogenesis since mutations in more than 30 different genes can cause Leigh syndrome, including autosomal, Xchromosomal and mtDNA genes. In contrast, most cases of Alpers syndrome (childhood psychomotor retardation,
intractable epilepsy and liver failure) are due to autosomal recessive mutations in a single gene, POLG, encoding the
mtDNA gamma polymerase. The pathogenesis involves a progressive loss of mtDNA in brain and liver. Liver biopsies
typically show deficiency of the RC Complexes with subunits encoded by mtDNA (Complexes I, III and IV) and gross
depletion of mtDNA levels. However, enzyme and mtDNA levels are typically normal in skeletal muscle and can be
normal in liver early in the disease course. Other mutations in the POLG gene can cause adult-onset ataxia or external
ophthalmoplegia with autosomal dominant or recessive inheritance. In populations of European descent, most cases of
Alpers syndrome can now be diagnosed by testing for three common POLG mutations. In Leigh syndrome and most
other paediatric mitochondrial diseases, diagnosis relies heavily on identifying deficient activity of one or more of the
mitochondrial RC enzymes. An enzyme diagnosis is often the starting point for further investigation of the underlying
molecular aetiology (reviewed by Kirby and Thorburn, 2008, Twin Res. Hum. Genet. 11: 395-411).
This presentation will describe our experience in diagnosis of over 400 children and smaller numbers of adults with
mitochondrial disease. Topics will include current approaches to diagnosis, diagnostic criteria, epidemiology and
molecular bases of mitochondrial disease. I will also describe new approaches to defining the complete repertoire of
mitochondrial “disease genes” and the potential impact of new technologies such as Next Generation sequencing.
2
Bill Evans Memorial Award Entrant
Title: “Using Genome-Wide Methylation Mapping to Find Oligodendroglial Tumour Suppressor Genes”
Authors:
Björn Espedido1,6, Kerrie McDonald2, David I.K. Martin3, Joseph Dhabhi3, Catherine Suter4 and Michael
1,4,5,6
Buckland
(1) Glioma Group, St. Vincent’s Centre for Applied Medical Research, St Vincent's Hospital, Darlinghurst, NSW 2010. (2) Kolling Institute, RNS
Hospital, Pacific Hwy., St Leonards, NSW 2065. (3) CHORI, Oakland, CA 94609, USA. (4) Victor Chang Cardiac Research Institute, 405
Liverpool St, Darlinghurst, NSW 2010. (5) Neuropathology Department, RPA Hospital, Camperdown, NSW 2050. (6) Department of Pathology,
University of Sydney, NSW 2006.
Abstract: Oligodendrogliomas (ODGs) make up 5-30% of gliomas, the most common type of primary brain tumour.
Most have allelic loss of the entire 1p and 19q chromosomal arms. This suggests that a tumour suppressor gene or
genes, involved in the early stages of ODG formation, may be present in 1p and/or 19q. According to Knudsen’s “twohit” hypothesis, tumourigenesis requires the inactivation of both alleles of a tumour suppressor gene; despite extensive
searches, mutations in the remaining copy of 1p and 19q are rarely found in ODG with 1p/19q loss. Our hypothesis is
that aberrant epigenetic silencing (epimutation), characterised by DNA methylation, is the mechanism by which the
remaining allele of tumour suppressor gene(s) on 1p and/or 19q is silenced. DNA methylation occurs at CpG
dinucleotides, which are often concentrated at gene promoters, and called CpG islands. Aberrant CpG island
methylation is strongly associated with transcriptional silence, thus an epimutation creates the functional equivalent of
an inactivating mutation. Using methylated DNA immunoprecipitation (MeDIP) and Nimblegen CpG island-pluspromoter arrays, we profiled the epigenetic state of all CpG islands and gene promoter regions in seven ODGs, and
compared them to four control brain samples. We have now obtained a comprehensive view of the methylation of all
gene promoters on 1p and 19q. We are currently validating these array data by Combined-Bisulphite Restriction
Analysis (COBRA) which provides a quantitative assessment of gene promoter methylation, and correlating our
findings with expression data from these same tumours. A number of genes have been identified as aberrantly
epigenetically silenced, and hence are candidate tumour suppressor genes for validation in a larger cohort of ODGs.
Bill Evans Memorial Award Entrant
Title: “Case Presentation: Giant Cell Glioblastoma, A Rare Variant Of Glioblastoma”.
Authors:
Suad R Al-Jahdhami and Maya Cherian
Anatomical Pathology Department, ACT Pathology, The Canberra Hospital. Woden, ACT 2606, Australia.
Abstract: A 63 year old lady presented to the Canberra hospital with a history of rapid onset of confusion associated
with dysphasia and limb weakness. Her past medical history was unremarkable apart from removal of a cutaneous lesion
(diagnosis unknown). MRI of her brain showed a 3.8cm left frontal lobe tumour which had a mixed solid and cystic
appearance. The clinical impression was a single metastatic deposit or a primary brain tumour. Multiple intra-operative
frozen sections were performed, all of which showed extensively necrotic tissue with no identifiable tumour. Cytological
smear preparations showed few single malignant large cells in a diffusely necrotic background. The surgeon was
informed of the findings and was advised to await the result of paraffin embedded tissue. Paraffin embedded fixed tissue
stained with haematoxylin and eosin, revealed a primary glial tumour composed almost entirely of bizarre
multinucleated giant cells in a setting of extensive non pallisading necrosis. The giant cells had alarming light
microscopic features including nuclear hyperchromasia and multilobation as well as frequent display of cytoplasmic
nuclear inclusions. They had abundant eosinophilic cytoplasm and exhibited several abnormal mitotic figures. Microvascular endothelial proliferation was not a feature of this tumour. Only about 2% of the tumour tissue showed a cellular
area with smaller cells resembling conventional astrocytoma. Focal increased stromal and perivascular reticulin staining
was observed. Immunohistochemical studies showed positive tumour cell staining with glial fibrillary acidic protein
(GFAP), confirming its glial origin, and S-100 protein, as expected in glioblastoma. The neoplastic cells showed
negative staining with melanocytic markers such as Melan-A, HMB-45, epithelial markers such as AE/AE3 and CK
8/18, as well as synaptophysin, chromogranin and neurofilament protein. A final diagnosis of Giant Cell Glioblastoma
(GC-GB), WHO grade IV, was made. GC-GB is a variant of glioblastoma (GB) with a marked predominance of bizarrelooking multinucleated giant cells, often prominent reticulin network and a high frequency of TP53 mutations. It is rare,
occurring in 1% of all brain tumours and 5% of GB, often in a slightly younger age group when compared to usual GB
(mean age 42 vs 53years, respectively). This tumour is typically well circumscribed and neuroimaging usually shows a
heterogeneous enhancement pattern with or without the usual peripheral intensification, and thus can be confused with a
metastatic deposit. Necrosis is commonly abundant, leading to the cystic areas visualized on MRI. GC-GBs are reported
to have a relatively more favourable clinical prognosis compared to usual GBs. They consistently express GFAP and are
usually S-100 positive as in our case. The formation of multinucleated giant cells in p53 gene deficient cells is linked to
Aurora-B kinase protein dysfunction, the latter is a mitotic activity regulator. GC-GBs have a distinctive
clinicopathological and molecular genetics profile: 70% have p53 mutations as in secondary GB, while 30% express
PTEN (phosphatase and tensin homologue) mutations as is seen in primary GB. Our patient’s brain tumor displayed the
typical histological features of GC-GB. She is slightly older than the usual median age reviewed in the literature (63 vs
42 years). She had an uneventful post operative recovery period.
3
Bill Evans Memorial Award Entrant
Title: “Inflammatory Responses in Tau-Positive and Tau-Negative Frontotemporal Lobar Degeneration”.
Authors:
Cindy Kersaitis1,3, Claire Stevens1, Glenda Halliday2 and Jillian Kril3,4
School of Biomedical & Health Sciences, University of Western Sydney 1; Prince of Wales Medical Research Institute and the University of
NSW2; Disciplines of Pathology3 and Medicine4, The University of Sydney.
Abstract: Purpose: Frontotemporal Lobar Degeneration (FTLD) comprises several neuropathological subtypes that can
be grouped into tau-negative cases (FTLD-U) and tau-positive cases. Although microglial activation is evident in both
groups, complement proteins capable of activating microglia have been identified in some cases of PiD. The absence of
Factor B in these cases suggests activation of the classical complement pathway, usually initiated by IgG or IgM. This
project evaluated the humoral and inflammatory responses in Frontotemporal Lobar Degeneration (FTLD). Method:
We examined 32 cases of sporadic FTLD and 6 normal control brains selected from regional donor programs in Sydney,
Australia and Cambridge, UK. The pattern of atrophy in two standardized coronal sections is used to determine the stage
of disease progression, and cases selected were limited to those in Stages 2 & 3. Tissue blocks from the inferior temporal
cortex were used for analysis. Immunohistochemistry with anti-sera to IgG, IgM, HLA-DR and CD68 was performed
and quantitation of activated microglia/macrophages, and immunoglobulin-positive cells undertaken. Results &
Conclusions: No IgM staining was observed in any of the cases examined. Immunoglobulin G immunoreactive neurons
were more abundant in cases of FTLD-U than tau-positive FTLD cases (p=0.0010). Neuronal loss (p=0.0078) and
microglial activation (p= 0.0058) correlated positively with the number of IgG-positive neurons, suggesting that
microglial activation may in part be a result of IgG binding, and that the increased microglial response may contribute to
loss of neurons in cases of tau-negative FTLD. While the extent of microglial activation increased with disease stage
(p=0.0091), the density of IgG-positive neurons was unchanged indicating that the humoral response is not progressive,
and may reflect an event occurring early in disease. The identification of a humoral immune response in FTLD helps
provide some direction for future studies of the mechanisms involved in FTLD, and introduces the possibility that
therapeutic interventions aimed at decreasing the immune response may be beneficial in slowing disease progression.
Oral Presentations II
Title: “Fetal Akinesia”.
Authors:
Adrian Charles
Department of Pathology, Princess Margaret Hospital, Roberts Road, Subiaco, Perth, WA 6008.
Abstract: Mother is in her 30's. During the pregnancy it was recognised that this fetus has severe neuro-muscular
abnormalities, with absent fetal movements and abnormal positioning of the limbs. Following discussion the baby was
delivered at 35 weeks gestation. The baby was elected to be intubated to allow muscle biopsy. Post mortem summary
A slightly premature neonate weighing 2300g delivered at 35 weeks gestation following a prenatal diagnosis of fetal
akinesia, who lived for two hours with a muscle biopsy, showing;
Features of fetal akinesia sequence.
1.
2. Extremely atrophic muscles showing markedly abnormal development.
3.
4. No other congenital anatomical abnormalities noted.
5.
6. Evidence of terminal petechial haemorrhages and subarachnoid haemorrhage.
The muscle biopsy showed no significant muscle. Post mortem muscle biopsies discussed as above. Comment. It can
be difficult to clearly identify the underlying pathology in these cases. The fetal akinesia with fixed flexion have
characteristic appearances of the facies. The causes are due to usually muscle or spinal cord changes, occasionally
nerves or neuromuscular junction, and rarely due to a cerebral abnormality at this gestational age. I do not see the
change of spinal muscular atrophy in the cord, and the muscle changes are very marked for this. I favour a primary
muscle pathology. There are not typical features of centronuclear or myotubular myopathy, but this needs to be
correlated with the muscle biopsy. Congenital muscular dystrophy is possible, but the changes seen in Fukuyama
dystrophy are not clearly seen in the brain. Congenital muscular dystrophy is a complex group of disorders, some with
cerebral changes. Discussion for meeting These cases are challenging from legal/ethical, management,pathological
and normalnd abnormal development issues. I wish to discuss the findings, and the approach to these cases with this
case in point and for the meeting to discuss the ideal workup of these cases.
4
Oral Presentations II
Title: “X linked neonatal onset myotubular myopathy”.
Authors:
Amanda Charlton
Histopathology Department, The Children’s Hospital at Westmead, NSW, Australia. NSW.2145.
Abstract: Case report: A 2 week old male infant was floppy with global muscle weakness. His older brother died of a
similar disease. A muscle biopsy was taken. Muscle shows small sized fibres, with large central nuclei, in both type 1
and type 2 fibres. Glycogen and mitochondria accumulate in the perinuclear, myofibril-free zone. In the correct clinical
context, this myopathy can be identified on H&E sections alone.
Oral Presentations III
Title: “Adult Neuronal Ceroid-Lipofuscinosis  The Genetic Spectrum is Enlarging”.
Authors:
Hans H. Goebel1, Margaret Jaynes2, Ludwig Gutmann2, Sydney Schochet ()3, David E. Sleat
Katherine B. Sims 5
4
and
1
Department of Neuropathology, University Medicine, Johannes Gutenberg University, Mainz, Germany
Department of Neurology, West Virginia University, Morgantown (WV), USA
3
Department of Pathology, West Virginia University, Morgantown (WV), USA
4
Department of Pharmacology, University of Medicine and Dentistry of New Jersey  Robert Wood Johnson Medical School, Piscataway (NJ),
USA
5
Department of Molecular Neurogenetics, Massachusetts General Hospital, Boston (MA), USA
2
Abstract: Introduction  Among the now at least ten different genetic forms of neuronal ceroid-lipofuscinosis (NCL)
and the various clinical subtypes, adult NCL (ANCL) is the rarest and least nosologically and genetically clarified type,
having been assigned, so far, to only two known genes of NCL while CLN4 is still unidentified. We describe clinical,
morphological (by biopsy and autopsy), and genetic findings in a patient with sporadic ANCL. Results  A 33-year-old
woman revealed impairment in cognitive skills and language at the age of 17 years, which further aggravated at the age
of 20 years by seizures following an automobile accident. MRI at the age of 30 years showed diffuse cerebral cortical
atrophy. Histologically, she had accumulation of NCL-specific lipopigments marked by fingerprint and curvilinear
profiles in skin, muscle, brain which were confirmed by extensive autopsy studies. Lipopigments contained ample
subunit C of mitochondrial ATPase. Her retina appeared preserved, but was intraneuronally loaded with lipopigments.
Other members of the family do not seem to be affected by NCL. Molecular analysis revealed compound heterozygosity
mutations in the CLN5 gene. Conclusion  This appears to be the first molecularly identified ANCL patient with
extensive clinical, ante-mortem as well as post-mortem morphological analysis having mutations in the CLN5 gene.
5
Oral Presentations III
Title: “Degeneration in Different Parkinsonian Syndromes Relates Directly to Astrocyte Type and Astrocyte Protein
Expression”.
Authors:
Glenda M Halliday1, Yun Ju C Song1, Janice L Holton2, Tammaryn Lashley2, Heather McCann1 and
Tamas R Revesz2
1
Prince of Wales Medical Research Institute (POWMRI) and the University of New South Wales, Sydney, Australia; 2Queen Square Brain Bank
(QSBB), Institute of Neurology, University College London, UK
Abstract: The present study aims to assess reactive changes in different types of astrocytes in Parkinson’s disease (PD),
multiple system atrophy (MSA), progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) to
determine any common relationship/s to the severity of degenerative changes. Formalin-fixed, paraffin-embedded brain
tissue from the putamen, pons and substantia nigra was used from 13 PD, 29 MSA, 34 PSP, 10 CBD and 13 controls.
Classic astrocytic reactivity was observed in MSA, PSP and CBD but not PD, and directly correlated with indices of
neurodegeneration and disease stage. About 40-45% of subcortical astrocytes accumulated pathological proteins in PD
(-synuclein) and PSP (phospho-tau) but not MSA or CBD. Protoplasmic but not fibrous astrocytes constitutively
expressed parkin co-regulated gene (PACRG), as well as apolipoprotein D, and accumulated abnormal proteins in PD,
PSP and CBD but not MSA. PACRG-immunoreactive protoplasmic astrocytes had significantly different responses and
severities, which directly correlated with indices of neurodegeneration in PSP and CBD (correlated with parkin
expression) but not PD, suggesting different underlying pathogenic cellular mechanisms. Non-reactive protoplasmic
astrogliosis occurred in PD and MSA, although in PD these astrocytes abnormally accumulated -synuclein. This
suggests an attenuated response in PD and MSA, possibly due to increased levels of -synuclein.
Oral Presentations III
Title: “The Early Macroautophagy Marker Atg12 Concentrates in Neurons and Endothelial Cells in Alzheimer’s
Disease”.
Authors:
Jian-Fang Ma1, Yue Huang2, Sheng-Di Chen1 and Glenda Halliday2
1.Department of Neurology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, 200025, P.R. China
2. Prince of Wales Medical Research Institute and University of New South Wales, Baker Street, Randwick, 2031, New South Wales, Australia
Abstract: Aim: To determine the pathological structures associated with macroautophagy in Alzheimer’s disease and
the relationship to disease progression. Methods: Atg12, the earliest macroautophagy marker, was localised in
formalin-fixed, paraffin-embedded medial temporal lobe sections from eleven AD cases at variable neuritic disease
stages. Double immunofluorescence labeling was used to colocalise Atg12 and A and phospho-tau (AT8) and
correlations performed using Spearman rank tests. Results: Atg12 immunoreactivity occurred in the majority of tauimmunoreactive dystrophic neurites (~70%) and some neurofibrillary tangles (~5%). Atg12-immunoreactive endothelial
cells were found spatially associated with A-positive plaques, with more Atg12-immunoreactive capillary endothelial
cells with higher neuritic disease stage. Conclusion: The data confirm that macroautophagy occurs in neurons
undergoing neuritic degeneration in AD, identified macroautophagy in capillary endothelial cells in close proximity to
A plaques, and has found that macroautophagy contributes to disease progression.
Key words: Ab Alzheimer’s disease, autophagy, endothelial cells, neurofibrillary tangles, senile plaques
6
Oral Presentations III
Title: “Next of Kin Consent for Brain Donation over a 5-Year Period”.
Authors:
Sundqvist N 1,2, Garrick T 2, Dobbins T 3, Azizi L 1,2 and Harper C 2,4
1
Schizophrenia Research Institute, Sydney, Australia; 2 Discipline of Pathology, The University of Sydney, Australia; 3 School of Public Health,
The University of Sydney, Australia; 4 Royal Prince Alfred Hospital, Sydney, Australia..
Abstract: Background and Aim: Post-mortem brain tissue is becoming increasingly valuable to psychiatric research,
enabling progress in the understanding and treatment of psychiatric disorders. The purpose of this study was to
investigate responses of the next-of-kin (NOK) of deceased persons to the question of brain donation for research over a
five-year period, and to identify factors that influence NOK decision-making. Method: Standard NSW Tissue Resource
Centre (NSW TRC) processes for brain donation were carried out. On the day of autopsy a phone call was made to the
deceased's family. The senior available NOK was asked to consider donating the deceased's brain tissue to research.
Responses to 200 calls were tabulated over five years and analysed. Results: Donation ratios were high (54%) over the
five-year period, and the presence or absence of a psychiatric illness in the deceased did not affect the response. Most
families who decided to donate did so because the donation allowed an 'altruistic' outcome to the death. Many families
also donated because they believed that their deceased relative would have wanted to be a donor. Factors that were
associated with the likelihood of donation were NOK relationship to the deceased, and post-mortem interval. Parents of
the deceased were the most likely group to donate, with spouses being least likely. The longer the interval from death to
the time of the phone call, the more likely the NOK was to consent. Conclusion: This study highlights the importance of
prior discussion about organ donation amongst family members, to help facilitate and ease the NOK decision-making
process.
Acknowledgement: This work was supported by the Schizophrenia Research Institute, utilising infrastructure funding from NSW Health.
Oral Presentations III
Title: “A Cross-Study Transcriptional Analysis of Parkinson's Disease”.
Authors:
G.T. Sutherland, N. A. Matigian, A.M. Chalk , M.J. Anderson, P.A. Silburn , A. Mackay-Sim, C.A Wells
and G.D. Mellick.
National Centre for Adult Stem Cell Research, Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, QLD 4111,
Australia
Abstract: The study of Parkinson’s disease (PD), like other complex neurodegenerative disorders, is limited by access
to brain tissue from patients with a confirmed diagnosis. Alternatively the study of peripheral tissues may offer some
insight into the molecular basis of disease susceptibility and progression, but this approach still relies on brain tissue to
benchmark relevant molecular changes against. Several studies have carried out whole-genome expression profiling in
post-mortem brain but reported concordance between these analyses is lacking. We have applied a standardised
pathway analysis to seven independent case-control studies, and demonstrated increased concordance between data sets.
A prominent theme among substantia nigra (SN) data sets was the down regulation of dopamine receptor signaling and
insulin-like growth factor 1 (IGF1) signaling pathways. However the implementation of a correction factor for
dopaminergic neuronal loss resulted in the loss of significance of the dopamine signaling pathway while axon guidance
pathways increased in significance. Interestingly the IGF1 signaling pathway was also over-represented in non-SN areas.
In addition we have recently re-analysed two microarray studies investigating SNc laser-microdissected DA neurons that
had published quite disparate results. Our combined re-analysis not only suggests that one study is quite superior to the
other but also raises some interesting issues about methodologies involved in generating these data and the implications
for patient-derived cellular models.
7
SLIDE SEMINAR
JOINT SCIENTIFIC MEETING OF THE
AUSTRALIAN AND NEW ZEALAND SOCIETY OF NEUROPATHOLOGY INC,
AND THE
AUSTRAIAN AND NEW ZEALAND PAEDIATRIC PATHOLOGY GROUP
SYDNEY, May 16th, 2009.
CLINICAL CASE SUMMARIES
8
Case 1 EX09-097 (07/31368-K) Presented by Dr Michael Rodriguez, Central Sydney Laboratory Service
Department of Forensic Medicine
This 62 year old woman lived alone. She had been homeless four years ago. Visited by a community carer about twice a
month until 18 months ago and then less frequently. Usually in good health and spirits and appeared to be able to look
after herself. She had no significant past medical history, was on no medications and did not smoke or drink. She was
found dead at home. The unit was very neat and well maintained.
Post mortem findings: She was unkempt, looking older than 62 years (BMI 12.1). A 3.5 cm invasive ductal carcinoma
was identified in the left breast without metastatic disease. The liver was fatty. The brain (1100 g) showed mild frontal
atrophy.
A section of rostral pons is submitted
Case 2 EX09-098 (08/34074-3A9) Presented by Dr Michael Rodriguez, Central Sydney Laboratory Service
Department of Forensic Medicine
This otherwise well 61 year old woman presented with a one week history of headache, dizziness and ataxia. An MRI
demonstrated a 45 x 39 x 31 mm intra axial mass in the right cerebellar hemisphere/cerebellar peduncle with mixed
internal signal on T2 weighted images. Intraoperatively the surgeon described the lesion as being largely extra-axial,
extended out of the pons into the cerebellum with a plane between much of the cerebellum and the tumour. The tumour
was not attached to the dura and it could be dissected away from the arachnoid. Although not particularly vascular on
angiogram, intraoperatively the surgeon commented that the tumour vessels were similar to those of a glioma. The
patient had an unprovoked run of supraventricular tachycardia preoperatively and an episode of hypertension (systolic to
200) after induction of anaesthesia but prior to manipulation of the tumour. Another similar episode occurred at the end
of the operation and postoperatively the blood pressure was somewhat labile.
A section of the lesion is submitted.
Case 3 EX09-099 (05/25533-S) Presented by Dr Michael Rodriguez, Central Sydney Laboratory Service
Department of Forensic Medicine
This 31 year old woman was admitted with a one week history of increasing headache and confusion. On examination
she was hyperreflexic with bilateral ankle clonus. There was no neck stiffness or photophobia. A lumbar puncture
revealed increased neutrophils but no infectious agent was identified. A non-contrast CT scan showed ill defined
densities in the posterior right temporal white matter and the left temporal white matter. An MRI the following day
showed multiple lesions in both cerebral hemispheres involving the cortex and white matter consistent with acute
encephalitis with some haemorrhagic conversion. Some of the lesions enhanced and some showed a small amount of
vasogenic oedema.
Sudden deterioration the following day with papilloedema and a GCS of 8 prompted admission to ICU and intubation.
A repeat non-contrast CT scan demonstrated increased mass effect with general effacement of cortical sulci and the
basal cisterns and evidence of cerebellar tonsil herniation without midline shift. The ill defined low density changes in
the temporal lobes, the right parafalcine frontal region and the left centrum semiovale were essentially unchanged.
Areas of low density in the deep right frontal white matter were slightly more marked. CT scan the next day showed
diffuse cerebral swelling and she died the following day, 6 days after presentation.
Her past medical history included a renal transplant (aged 25) for end-stage renal failure following preeclampsia. She
had disseminated Varicella zoster infection with complicating hepatitis and pneumonia about 6 months prior to death
and recurrent Varicella zoster complicated by TTP, splenic vein thrombosis and splenic infarction requiring splenectomy
5 months prior to death.
At autopsy there were multiple pulmonary emboli and a deep vein thrombosis in the calf. A few CMV positive cells
were identified in the native kidney. The brain was swollen (1231 g) with bilateral uncal and cerebellar tonsillar
herniation.
9
Case 4 EX09-100 (SP08-11896-2A) Presented by Dr Michael Rodriguez, Central Sydney Laboratory Service
Department of Forensic Medicine
This previously well 29yr old man presented with acute onset of severe frontal headache, persistent vomiting, lethargy
and general malaise following 2 days of mild frontotemporal headache. On examination he was very drowsy but
rousable, obeying commands. Pupils were equal and reactive. A non-contrast CT brain showed gross dilation of lateral
and third ventricles, and a 2cm x 2cm x 2cm hypodense mass in the pineal region. After insertion of an extra ventricular
drain he was more awake, the headaches were less severity and the vomiting subsided.
MRI showed a heterogeneous 1.8cm x 2.0cm x 2.3cm lesion in the pineal region with a nodule in the aqueduct. The
lesion was hyperintense on T2, with slight peripheral enhancement after gadolinium. High T2 signal extended into both
thalami. A cystic lesion within the left thalamus was consistent with recent intralesional haemorrhage.
Using a suboccipital transtentorial approach, a complete macroscopic resection was achieved.
Case 5 EX09-101 (1764-B5) Presented by Dr Suad Al Jahdhami, The Canberra Hospital.
(This case is being presented in Oral Presentations Session I as an entrant for the Bill Evans Memorial Young
Investigator Award).
Female 63 years
Presents with:
 Rapid onset confusion
 Dysphasia
 Limb weakness
 Past history of removal of a cutaneous lesion on left leg, nature of which is unknown by patient of family
members.
Case 6 EX09-102 (09P00391-G) Presented by Dr Ella Sugo, Sydney Children’s Hospital.
Male 22 months old, with an enhancing nodule in posterior fossa; post treatment of posterior fossa tumour
(chemotherapy and radiotherapy); ? Recurrence.
Case 7 EX09-103 (03A00031 & 03P00503) Presented by Dr Ella Sugo, Sydney Children’s Hospital.
Male 9 months old. History of ‘floppy’ baby with progressive muscle weakness.
2 slides: Autopsy brain and ante-mortem muscle biopsy.
Case 8 EX09-104 (08-07444-A) Presented by Dr Queenie Lau, Gold Coast Hospital and Royal Brisbane &
Women’s Hospital.
Female 71 years. Large posterior fossa (CPA) tumour. No significant past medical history.
Case 9 EX09-105 (RNS08P4119) Presented by Dr Janice Brewer, Royal North Shore Hospital.
Female 70 years with right parieto-occipital lesion typical of cavernoma on imaging. Past history of brain aneurysm.
Otherwise well.
Case 10 EX09-106 (RNS08P19386) Presented by Dr Janice Brewer, Royal North Shore Hospital.
Female 27 years, with enhancing thalamic/ventricular lesion.
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