The Canadian Association of Neuropathologists (CANP) held their 57th annual meeting at the Inn at the Forks Hotel in Winnipeg, Manitoba from October 12th-14th, 2017, under the leadership of Dr. Marc Del Bigio, CANP president, who also handled the local arrangements. The annual banquet was held at the Assiniboine Park Conservancy where the polar bears captivated the crowd of Neuropathologists.

The academic program of 14 scientific abstracts and 11 unknown cases were compiled by the CANP Secretary-Treasurer Dr. Julia Keith into 4 sessions; Infectious/Immune Mediated and Epilepsy Neuropathology, Tumour Neuropathology, Developmental Neuropathology and Neurodegenerative/Neuromuscular Neuropathology. The program also included a guided interactive forum on Quality Assurance and Professional Affairs for Neuropathologists led by Dr Del Bigio.

The digital pathology images from the 11 unknown cases are available for viewing online (www.canp.ca) thanks to the CANP webmaster, Dr. Jason Karamchandani. All submitted abstracts were peer reviewed by the CANP Abstract Review committee comprised of Drs. Marie-Christine Guiot, David Munoz, and Harvey Sarnat.

The Presidential Symposium explored the theme of Pediatric Head Injuries and Forensic Neuropathology. Dr. Michael J. Ellis (Section of Neurosurgery, University of Manitoba) delivered an invited lecture entitled Current Concepts in Pediatric Concussion. The Dr. Gordon Mathieson invited member lecturer was Dr. David Ramsay (Western University) who spoke on the subject of Observations on Selected Neuropathological Aspects of Suspected Inflicted Head and Spinal Injury in Young Children. The Dr. David Robertson invited lecture was delivered by Dr. Paul Kadar (Department of Pediatrics, Hospital for Sick Children, University of Toronto) Child Maltreatment/Abusive Head Trauma in a “Pre-” and “Post-Goudge” World. The Dr. Jerzy Olszewski guest lecturer was Dr. Waney Squier (Oxford University, UK) who explained the Impact of Legal Changes in the UK on Brain Retention, Evolving Opinions and Controversies about “Shaken Baby Syndrome”. The symposium concluded with a panel discussion and group Question and Answer session with the symposium speakers.

The resident awards committee was comprised of Drs. Sidney Croul and Sherry Krawitz. The Mary Tom Award for best clinical science paper was awarded to Dr. Randy van Ommeren (supervisor Dr. Patrick Shannon) for his presentation of Unknown Case #8 and the Morrison H. Finlayson Award went to Dr. Andrew Gao (supervisor Dr. Lili Hazrati) for his presentation Abstract #14 The Role of ATP and P2X Purinoreceptor 7 in the Pathogenesis of Cerebral Tau.

The following abstracts were presented at the 2017 Canadian Association of Neuropathologists (CANP) 57th Annual Meeting in October. The material presented contains the abstracts submitted as part of the 2017 Canadian Association of Neuropathologists (CANP) 57th Annual Meeting, as part of the standard processes of The Canadian Journal of Neurological Sciences, and may contain promotional content that does not represent the views or policies of the journal or publisher. The content and the views expressed therein are those of the presenting entity and not the Editors of The Canadian Journal of Neurological Sciences, the Canadian Neurological Sciences Federation, or Cambridge University Press. Authors have not provided standard disclosure forms as part of their submission, although these would have been evident at the time of the meeting.

SVcPACNS is a rare inflammatory/immune disorder that typically affects the small blood vessels of the brain. SVcPACNS differs from most adult forms of PACNS by being predominantly lymphocytic, non-granulomatous and non-necrotizing. Previously healthy children are typically affected by range of signs and symptoms, including: seizures, headache, cognitive decline, behavior/personality change, focal neurological deficits and potentially a decreased level of consciousness. Treatment protocols featuring induction (steroids and cyclophosphamide) and subsequent maintenance phases (e.g., mycophenolate mofetil) have been demonstrated to yield favorable outcomes. Since SVcPACNS is characteristically angiography negative, the diagnostic gold standard is brain biopsy. Interpretation of these biopsies is often challenging given the histologic overlap between SVcPACNS and encephalitis. Distinguishing the foregoing is critical since the treatment of these entities is significantly different.

Herein, a rare autopsy case of SVcPACNS in a 4 year old male is presented. This case provides a unique opportunity to review the Alrawi criteria for the histologic diagnosis of PACNS and establish/refine criteria specific to SVcPACNS. Generally, such criteria should feature: 1) an intramural and lymphocyte predominant infiltrate devoid of multinucleated giant cells; 2) structural vessel alterations lacking fibrinoid necrosis; 3) perivascular pathology supportive of an angiocentric process; 4) the absence of encephalitis; and, 5) the absence of a concurrent systemic or rheumatic illness that could account for the CNS findings.

The classification system for gliomas has undergone significant revisions in the last several years, with the incorporation of molecular criteria and removal of mixed histologic diagnoses. Large-scale molecular studies have elucidated the biological characteristics of low grade gliomas, and enabled grouping based on IDH mutational and 1p19q codeletion status that outperforms histology in predicting patient outcomes. Mutations in ATRX and TP53 are largely mutually exclusive of 1p19q- codeletion in the context of mutant IDH, and are useful in screening patients for further molecular studies.

At our institution, new testing methods for 1p19q codeletion and ATRX were implemented in 2014, and in this presentation we review all cases submitted for 1p19q testing since this time. In comparing histologic to molecular diagnoses, the majority of histologic oligodendrogliomas indeed have 1p19q codeletion, while oligoastrocytomas and GBMOs largely are re-classified as astrocytomas and glioblastomas, respectively. We have also found that loss of ATRX nuclear expression associated with ATRX mutation is highly indicative of 1p19q retention, however the immunohistochemical test can be challenging to interpret and there have been a small number of discordant results.

Anaplastic ependymomas are relatively uncommon, WHO grade III tumours that can occur in any location of the central nervous system. Low, as well as high grade tumours may show an additional component, most frequently cartilage or bone. Ganglionic differentiation has been demonstrated in only very few cases, usually young individuals. The purpose of this communication is to describe six examples of anaplastic ependymomas with a definite ganglionic component. All tumours were supratentorial and occurred in adults, 36-81 years of age. With the exception of one with a cystic component, all showed a diffuse MRI pattern and variable enhancement. All tumours displayed necrosis, vascular proliferation and marked pleomorphism, due to a mixture of epithelioid, giant, rhabdoid and gemistocytic, as well as clear and undifferentiated cells. Immunohistochemistry revealed reactivity for EMA (often atypical), GFAP and markers of neuronal differentiation, usually synaptophysin and chromogranin. All displayed high MIB-1 and occasional P53-positive nuclei. Two cases showed sarcomatous differentiation with desmin, smooth muscle actin and very rich reticulin staining. Electron microscopy revealed “zippering” intercellular junctions, basal bodies and cilia. Neuronal differentiation was expressed by neurosecretory granules and/or rich endoplasmic reticulin, large nuclei with nucleoli, and rare neuritic processes with microtubules. Differentiation of these rare tumours from glioblastomas might be important for the future development of tumour-specific molecular therapies. Electron microscopy is highly recommended for correct diagnosis of atypical variants of Anaplastic Ependymoma.

Pleomorphic xanthoastrocytoma (PXA) is a rare tumour comprising <1% of all primary central nervous system tumours and the majority (~98%) occur supratentorially. We report on a 40-year-old female with a past medical history of a rare posterior fossa/cerebellar PXA who presented with a right-sided neck mass, decreased shoulder power and longstanding right tongue deviation with right-sided hemi-atrophy. The patient had prior tumour debulking. Recent MRI demonstrated an enhancing posterior fossa mass extending to the skull base at the jugular foramen and another mass in the upper neck along the jugular bulb with displacement and encasement of the right common carotid artery down to C5. Resection of the neck mass reveals an anaplastic PXA. The tumour has close approximation with adjacent peripheral nerves and is positive in 2 lymph nodes. Comparison with the original tumour molecular and immunohistochemical profiles reveals a conserved BRAF V600E mutation but the transformed malignant glioma now expresses dot-like EMA positivity and ATRX is completely lost (mutated). Transformation of a PXA (WHO Grade II) into an anaplastic PXA (WHO Grade III) has been well documented, but extracranial extension is extraordinarily rare. We report herein the first documented case of a posterior fossa PXA that underwent malignant transformation and extracranial invasion to the parapharyngeal space.

Molecular studies suggest that anaplastic oligodendrogliomas (OIII) can be subdivided into clinically relevant subgroups. We analyzed a retrospective series of 40 consecutive OIII operated at our institution and compared them to 10 grade II oligodendrogliomas (OII). Chromosome 9p status was compared to Bcl1, Myc and p16 expression by immunohistochemistry, clinical and histological data, and to event free survival (EFS) and overall survival (OS).

Chromosome 9p deletion was observed in 55 % of OIII (22/40) but not in OII, and correlated with both OS and EFS. Bcl1 expression was significantly higher in OIII (45 % versus 14% for OII) and correlated with MIB-1 expression, vascular proliferation, tumour necrosis and a shorter EFS. Myc expression was correlated with histologic grade (27% in OII, 35% in OIII) and to a shorter EFS in chromosome 9p non-deleted OIII. p16 expression was not correlated with grade but revealed two distinct expression profiles according to chromosome 9p status. In 9p non-deleted oligodendrogliomas, p16 hyperexpression was correlated with shorter OS in both OII and OIII whereas absence of p16 expression was correlated with shorter OS and EFS in 9p deleted OIII.

Eosinophils may affect each stage of tumor development. The presence of eosinophils appears to correlate with longer patient survival in several non-CNS malignant tumors. Tumor-associated tissue eosinophilia (TATE) has been increasingly recognized. Two previous studies (Hayes RL, et al. 1995; 2001) revealed eosinophils in the intracavitary tissues of malignant gliomas following the infusion of IL-2 combined with activated autologous killer cells, but not in the primary operative specimens. Our recent study (Lu JQ, et al. 2014) demonstrated the infiltration of eosinophils in 19 of 44 pilocytic astrocytomas but not in 10 ependymomas. In the present study, we examined 7 cases of subependymal giant cell astrocytoma (SEGA; 4 with tuberous sclerosis; age range: 13 – 33 years; 4 males and 3 females), as SEGA is well known to contain infiltrating mast cells and lymphocytes. Five of 7 SEGA contained eosinophils that were focally scattered to rare in frequency; intratumoral and/or perivascular in location. In comparison, only one of 8 consecutive cases of glioblastoma showed infiltrating eosinophils. The incidence of TATE is significantly higher in SEGA than that in glioblastoma (71.4 % versus 12.5%; p=0.04, by Fisher’s exact test) but is not significantly different from that in pilocytic astrocytoma (71.4 % versus 43.2%, previously reported; p=0.232). Our findings support the concept that eosinophils may play a functional role in the development of astrocytic tumors, especially those with longer patient survival.

Neuroaxonal Dystrophies (NAD) are neurodegenerative diseases characterized by axonal “spheroids” occurring in different age groups. The identification of mutations delineated new molecular entities in these disorders. We report neuropathological data of a new form of NAD, characterized by a precocious prenatal onset, different from classical and connatal Infantile Neuroaxonal Dystrophy (INAD).

We studied 5 fetuses examined after pregnancy termination and 2 term neonates deceased just after birth, 4/7 from consanguineous parents. All subjects presented severe fetal akinesia sequence with microcephaly. In 4/7 cases, a molecular study was performed. In all cases, “spheroids” with typical immunohistochemical features were identified, with variable spreading in the central and peripheral nervous system. Basal ganglia, brainstem, cerebellum and spinal cord involvement was constant. Associated CNS malformations, unusual in INAD, were associated including hydrocephalus (2), callosal agenesis/hypoplasia (2), olfactory agenesis (1), cortical (3) and retinal (1) anomalies. None cases demonstrated mutations in PLA2G6, found in INAD.

The clinical and neuropathological features of these fetal cases are different from those of “classical” INAD. The absence of mutations of PLA2G6, in addition, suggests that the fetal NAD is a new entity, distinct from INAD, with different molecular basis. Associated malformations suggest a wide phenotypic spectrum and probable genetic heterogeneity. Finally, fetal NAD is an additional etiology of fetal akinesia.

By contrast to infantile spinal muscular atrophy, which usually links to deletions in the SMN genes, fetal onset motor neuron disease is poorly reported. We collected a series of twelve cases of fetal arthrogryposis (16-31 weeks gestational age) with fetal motor neuron disease and excluded infectious diseases, lysosomal storage disease and neuroaxonal dystrophy. Of these twelve, 3 were thought to be ischemic in nature with microvascular alterations and systemic or central nervous system ischemic injury. The remaining 9 all displayed marked reduction in anterior horn motor neurons. Of these 9, four demonstrated mineralised neurons, four demonstrated either neuronal loss or cavitation in the globus pallidus, and in two, degenerating neurons were detectable in the brainstem or globus pallidus. Specific sequencing of SMN1 was performed in 6 of 9 and was reported as normal. Whole exome sequencing was performed in 4 without definitive diagnosis. We conclude that fetal motor neuron disease can be distinguished from ischemic injury, is morphologically heterogeneous, may affect the globus pallidus and is rarely linked to SMN1 mutations.

We review the central nervous system anatomy in nine cases of amniotic rupture sequence, all of which had neuropathological examinations. Of these, four had normal brains, and in none of these was the cranial vault involved, and one had cleft lip and palate. Of the remaining five, all had portions of the scalp, calvarium and dura replaced by amnionic membrane directly overlying arachnoid. In one, the membrane covered a narrow necked large encephalocele, and the contained brain demonstrated extensive disruption and degeneration. In the remaining four, one demonstrated cranioplacental adhesion, and in three there was a broad based encephalocele covered in large part by amnion. Two of these four cases demonstrated holoprosencephaly. One case with holoprosencephaly and one without demonstrated marked aqueductal stenosis, and two of the four demonstrated aqueductal occlusion or near occlusion by neuroglial excrescences. None demonstrated ventriculomegaly. Three of these four cases demonstrate varying degrees of mechanical distortion and secondary pathology. We conclude that brains with amnionic rupture sequence demonstrate both malformation and deformation, which likely points to the embryonic stage origin of the lesion.

Chronic traumatic encephalopathy (CTE) is suggested to be a progressive neurodegenerative disease, characterized by tau deposits in the depth of cortical sulci in neurons and in glioneuronal complexes around blood vessels. Few studies have suggested that it is caused by multiple concussions or subconcussive brain injuries. A recent publication showed that most American football players whose brain were donated to the Boston University concussion center had CTE (Mez et al. 2017). Over the last 6 years, with the help of neuropathologist colleagues across Canada, we have collected the brains of 33 high level professional and amateur athletes. These include 5 National hockey league (NHL) players, 15 Canadian football league (CFL) players, 3 College football players, 3 College hockey players, 2 professional boxers, 1 professional bull rider, 1 BMX champion, 1 rugby player and 2 skiers. All were male and the ages ranging from 15 to 87 years. Our results indicate that only a small portion of cases have CTE. Moreover, most cases are low stage (stage 1 or 2) and this pathology is mainly seen in some of the younger players. Older players either have no pathological findings or have other neurodegenerative diseases such as Alzheimer’s disease. The disparity of results between the 2 groups will be discussed.

Most basic science research has focused on overt stroke caused by blockage of major blood vessels. Less attention has been paid to small vessel disease giving rise to covert stroke that often leads to vascular cognitive impairment (VCI). One reason for this may be the relative lack of relevant animal models. This talk will describe a model of VCI induced in middle-aged Sprague-Dawley rats exposed to a diet high in saturated fats, salt and refined sugar (HFSS). In Experiment 1, rats fed HFSS and subjected to a small mediodorsal (MD) thalamic stroke with or without concomitant cerebral hypoperfusion experienced significant executive dysfunction. In Experiment 2, dietary influences on functional, physiological and anatomical parameters were assessed. We found significant hypertension, blockage of brain microvessels (2-photon microscopy) and white matter atrophy in HFSS diet animals. As in Experiment 1, profound, specific set-shifting executive dysfunction was noted following both small MD infarcts (0.332 mm3) and the HFSS diet. In summary, these data describe a middle-aged animal model of VCI that includes clinically-relevant metabolic disturbances and small vessel disease and as such may be helpful in developing new cognitive therapies.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) represent a disease continuum with common genetic causes and molecular pathology. We recently identified mutations in the T-cell restricted intracellular antigen-1 (TIA1) protein as a cause of ALS +/− FTD. TIA1 is an RNA-binding protein containing a low complexity domain (LCD) that promotes the assembly of membrane-less organelles, such as stress granules (SG). Whole exome sequencing of two family members with fALS/FTD revealed a novel missense mutation in the TIA1 LCD (P362L). Subsequent screening identified five more TIA1 mutations in six additional ALS patients, but none in controls. All mutation carriers presented with weakness, behavioral abnormalities or language impairments and had a final diagnosis of ALS +/− FTD. Autopsy on five TIA1 mutation carriers showed widespread neurodegeneration with TDP-43 pathology. Round eosinophilic inclusions in lower motor neurons were a consistent feature. Cellular assays revealed abnormal SG dynamics in the presence of TIA1 mutations. In summary, missense mutations in the LCD of TIA1 are a newly recognized cause of ALS/FTD with TDP-43 pathology and strengthen the role of RNA metabolism in the pathogenesis in this disease.

With the financial assistance from two donors, we have established a neurodegenerative disease brain bank at the University of Calgary. At autopsy, tissues from anatomically specific regions are frozen in liquid nitrogen vapour and stored in small, bar-coded cryovials. Cases include patients with dementia, movement disorders, demyelinating diseases, and normal controls. We prepare additional FFPE blocks for diagnosis or banking. Sampling includes all major areas of cortex and most subcortical structures. All brains, including “normal” controls, are characterized with a basic set of stains and major classification schemata are used for Alzheimer and Lewy body diseases. These tissues are available to investigators with IRB-approved research on human tissues

Control tissue is important in the study of age-associated neurodegeneration. We preserve tissues from areas of brain that either are severely or minimally affected by neurodegeneration (e.g. in Alzheimer disease, Brodmann areas 9 and 17, respectively). In our “normal” aging cohort, which includes patients with no described neurodegenerative diseases, we find frequent evidence of low-stage Alzheimer or Lewy body related pathological changes. We also find relatively frequent small vessel disease, which in part relates to our preferential selection of patient’s who died suddenly.

In preliminary studies, we have examined amyloid plaque structure with confocal microscopy using beta-sheet sensitive dyes and have studied the distribution of different chaperones in normal brain.

The tauopathies are a group of neurodegenerative diseases characterized by abnormal deposition of hyperphosphorylated-tau. The pathogenesis of these changes remains uncertain. In chronic traumatic encephalopathy, tauopathy is hypothesized to occur after repeated mild traumatic brain injury (TBI). Post-traumatic extracellular ATP release and signalling via the P2X purinoceptor 7 (P2RX7) has been shown to be important in mediating pathological changes in TBI. We hypothesized that ATP-P2RX7 is involved in the development of tauopathy.

We injected ATP analogue bzATP or vehicle intraventricularly into C57BL/6 mice, pre-treated with either intraperitoneal P2RX7 antagonist Brilliant Blue G (BBG) or vehicle. At 2 weeks and 3 months, behavioural change was assessed with the tail suspension test, accelerating rotatrod, and fear conditioning; mice were then sacrificed for immunohistochemistry and western blot.

We observed increased immobile time in the tail suspension test for mice treated with bzATP at 3 months. Similarly, for rotarod, mice treated with bzATP showed poorer performance at 3 months. These effects were diminished by BBG pre-treatment. Fear conditioning, however, did not demonstrate a significant difference between groups. Immunohistochemical staining for GFAP showed increased intensity at both 2 weeks and 3 months for bzATP-treated mice compared to those pre-treated with BBG. Levels of phosphorylated tau (AT8) were increased in bzATP-treated mice compared to controls.

In summary, ATP-P2RX7-mediated mechanisms may play a role in the development of behavioural deficits and tauopathy.