Publications by authors named "Lee-Cyn Ang"

60 Publications

Globular glial tauopathy, a newly recognized white matter tauopathy, with depression/anxiety disorder: report and review of classification.

Folia Neuropathol 2021 ;59(1):98-103

Department of Pathology, Schulich School of Medicine and Dentistry, Western University, London, Canada.

Several studies have recently described 4-repeat tauopathies that are characterized by the presence of globular glial inclusions. These inclusions are astrocytic or oligodendroglial, show extensive white matter involvement, and have a wide range of neuropathological and clinical presentations. Globular glial tauopathy (GGT) is classified into three subtypes according to clinical manifestations. Type I is characterized by frontotemporal lobar degeneration and represents a group of diseases with diverse clinical and histopathological features. Some of these disorders are associated with abnormal microtubule-associated protein tau gene. Type II presents as motor impairment due to pyramidal involvement, whereas type III is a combination of the features of types I and II. This report describes a rare case of GGT that manifested as depression and anxiety and demonstrates its neuropathological features. We have also compared the features of this case with those of previously reported cases and have revisited the classification.
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http://dx.doi.org/10.5114/fn.2021.104396DOI Listing
January 2021

Vagus nerve stimulation does not alter brainstem nuclei morphology in patients with refractory epilepsy.

Epilepsy Behav 2021 May 7;118:107940. Epub 2021 Apr 7.

Department of Clinical Neurological Sciences, London Health Sciences Centre, Western University, London, Ontario, Canada; Department of Pathology and Lab Medicine, London Health Sciences Centre, Western University, London, Ontario, Canada. Electronic address:

Objective: To describe morphological characteristics of the brainstem nuclei in response to chronic vagus nerve stimulation (VNS) in patients with refractory epilepsy.

Background: VNS is a treatment option for individuals with medically refractory epilepsy. While treatment with VNS may achieve up to 50% seizure reduction and is protective against sudden unexpected death in epilepsy (SUDEP), its mechanism of action is not fully understood. Long-term structural and cellular changes in response to VNS have rarely been addressed in humans.

Methods: Four autopsy cases with history of chronic epilepsy treated with VNS (VNS+) and 4 age- and sex-matched chronic epilepsy-related death cases without VNS (VNS-) were included. Detailed clinical and postmortem data were obtained. Serial horizontal sections of the brainstem were prepared and stained with hematoxylin, eosin, and luxol fast blue (HE/LFB). Three regions of interest (ROIs) were delineated, including nucleus tractus solitarius (NTS), locus coeruleus (LC), and the rostral pontine group of raphe nuclei (rRN). Immunohistochemistry studies were performed using antibodies to GFAP, NeuN, HLA-DR, and IBA-1. Immunolabeling index was analyzed.

Results: Three of the 4 VNS+ patients and all 4 control (VNS-) patients died of SUDEP. There was no laterality difference in the NeuN, GFAP, HLA-DR and IBA-1 expression in LC and NTS of VNS+ patients. Similarly, there was no difference in the rRN, LC, and NTS between the VNS+ and VNS- groups.

Conclusion: This study represents the first histopathological study of the long-term effects of VNS therapy in the human brain. There was no difference observed in the neuronal cell number, degree of astrocytosis, and neuroinflammation in the main brainstem vagal afferent nuclei after prolonged VNS treatment in patients with refractory epilepsy.
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http://dx.doi.org/10.1016/j.yebeh.2021.107940DOI Listing
May 2021

α-tropomyosin gene (TPM3) mutation in an infant with nemaline myopathy.

Clin Case Rep 2021 Mar 3;9(3):1672-1676. Epub 2021 Feb 3.

Department of Paediatrics Children's Hospital London Health Sciences Centre London ON Canada.

We report a case of neonatal nemaline myopathy with a de novo mutation, which has been classified as a likely pathogenic mutation. With the expanding use of genetic testing in congenital myopathies, genotype-phenotype descriptions of novel variants are important to inform clinical care, diagnosis, genetic counseling, and management of disease.
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http://dx.doi.org/10.1002/ccr3.3866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7981619PMC
March 2021

Spinal Intradural Phosphaturic Mesenchymal Tumor.

Can J Neurol Sci 2021 Mar 10:1-3. Epub 2021 Mar 10.

Department of Radiology, Department of Medical Imaging, Western University, London, ON, Canada.

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http://dx.doi.org/10.1017/cjn.2021.44DOI Listing
March 2021

Evidence of synergism among three genetic variants in a patient with LMNA-related lipodystrophy and amyotrophic lateral sclerosis leading to a remarkable nuclear phenotype.

Mol Cell Biochem 2021 Mar 4. Epub 2021 Mar 4.

Molecular Medicine, Robarts Research Institute, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.

Neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), can be clinically heterogeneous which may be explained by the co-inheritance of multiple genetic variants that modify the clinical course. In this study we examine variants in three genes in a family with one individual presenting with ALS and lipodystrophy. Sequencing revealed a p.Gly602Ser variant in LMNA, and two additional variants, one each in SETX (g.intron10-13delCTT) and FUS (p.Gly167_Gly168del). These latter genes have been linked to ALS. All family members were genotyped and each variant, and each combination of variants detected, were functionally evaluated in vitro regarding effects on cell survival, expression patterns and cellular phenotype. Muscle biopsy retrieved from the individual with ALS showed leakage of chromatin from the nucleus, a phenotype that was recapitulated in vitro with expression of all three variants simultaneously. Individually expressed variants gave cellular phenotypes there were unremarkable. Interestingly the FUS variant appears to be protective against the effects of the SETX and the LMNA variants on cell viability and may indicate loss of interaction of FUS with SETX and/or R-loops. We conclude that these findings support genetic modifications as an explanation of the clinical heterogeneity observed in human disease.
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http://dx.doi.org/10.1007/s11010-021-04103-7DOI Listing
March 2021

Serotonin transporter protein in autopsied brain of chronic users of cocaine.

Psychopharmacology (Berl) 2020 Sep 3;237(9):2661-2671. Epub 2020 Jun 3.

Human Brain Laboratory, Brain Health Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Rationale: The long-held speculation that the brain serotonin system mediates some behavioral effects of the psychostimulant cocaine is supported in part by the high affinity of cocaine for the serotonin transporter (SERT) and by reports that the serotonin transporter (SERT), estimated by SERT binding, is increased in brain of human chronic cocaine users. Excessive SERT activity and consequent synaptic serotonin deficiency might cause a behavioral (e.g., mood) abnormality in chronic users of the drug.

Objective And Methods: Previous studies focused on changes in SERT binding, which might not necessarily reflect changes in SERT protein. Therefore, we compared levels of SERT protein, using a quantitative Western blot procedure, in autopsied brain (striatum, cerebral cortices) of chronic human cocaine users (n = 9), who all tested positive for the drug/metabolite in brain, to those in control subjects (n = 15) and, as a separate drug of abuse group, in chronic heroin users (n = 11).

Results: We found no significant difference in protein levels of SERT or the serotonin synthesizing enzyme tryptophan hydroxylase-2 among the control and drug abuse groups. In the cocaine users, no significant correlations were observed between SERT and brain levels of cocaine plus metabolites, or with levels of serotonin or its metabolite 5-hydroxyindoleacetic acid.

Conclusion: Our postmortem data suggest that a robust increase in striatal/cerebral cortical SERT protein is not a common characteristic of chronic, human cocaine users.
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http://dx.doi.org/10.1007/s00213-020-05562-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502513PMC
September 2020

Clinicopathological overlap of neurodegenerative diseases: A comprehensive review.

J Clin Neurosci 2020 Aug 27;78:30-33. Epub 2020 Apr 27.

Department of Pathology and Laboratory Medicine, Western University, London, Canada.

Clinical and neuropathological overlap of two or more neurodegenerative diseases (ND) is not an uncommon occurrence yet is still underdiagnosed in clinical neurological and neuropathological. The authors present a clinicopathological overview of the current understanding of overlapping ND's with the hope that this review will encourage further studies that are required to investigate the effect of such overlaps on clinical presentations and how often clinical presentations raise the suspicion of multiple ND's. The authors suggest that as more patients with overlapping ND's come to light, traditional classification system of ND's may need to be modified.
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http://dx.doi.org/10.1016/j.jocn.2020.04.088DOI Listing
August 2020

Limbic encephalitis following intracranial radiation for suprasellar meningioma.

Neurooncol Pract 2019 Mar 2;6(2):156-158. Epub 2019 Jan 2.

Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada.

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http://dx.doi.org/10.1093/nop/npy055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6656332PMC
March 2019

Concentration, distribution, and influence of aging on the 18 kDa translocator protein in human brain: Implications for brain imaging studies.

J Cereb Blood Flow Metab 2020 05 20;40(5):1061-1076. Epub 2019 Jun 20.

Human Brain Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Positron emission tomography (PET) imaging of the translocator protein (TSPO) is widely used as a biomarker of microglial activation. However, TSPO protein concentration in human brain has not been optimally quantified nor has its regional distribution been compared to TSPO binding. We determined TSPO protein concentration, change with age, and regional distribution by quantitative immunoblotting in autopsied human brain. Brain TSPO protein concentration (>0.1 ng/µg protein) was higher than those reported by binding assays by at least 2 to 70 fold. TSPO protein distributed widely in both gray and white matter regions, with distribution in major gray matter areas ranked generally similar to that of PET binding in second-generation radiotracer studies. TSPO protein concentration in frontal cortex was high at birth, declined precipitously during the first three months, and increased modestly during adulthood/senescence (10%/decade; vs. 30% for comparison astrocytic marker GFAP). As expected, TSPO protein levels were significantly increased (+114%) in degenerating putamen in multiple system atrophy, providing further circumstantial support for TSPO as a gliosis marker. Overall, findings show some similarities between TSPO protein and PET binding characteristics in the human brain but also suggest that part of the TSPO protein pool might be less available for radioligand binding.
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http://dx.doi.org/10.1177/0271678X19858003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7181090PMC
May 2020

Toxic diffuse isolated cerebellar edema from over-the-counter health supplements.

Neurology 2019 05 10;92(20):965-966. Epub 2019 Apr 10.

From the Department of Clinical Neurological Sciences (D.D.K., C.S.) and Division of Neuropathology, Department of Pathology and Laboratory Medicine (L.-C.A.), Western University, London, Canada.

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http://dx.doi.org/10.1212/WNL.0000000000007510DOI Listing
May 2019

Mutation Interrupts Nucleolin-mTOR-P70S6K Signaling in Rett Syndrome Patients.

Front Genet 2018 19;9:635. Epub 2018 Dec 19.

Regenerative Medicine Program, and Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

Rett syndrome (RTT) is a severe and rare neurological disorder that is caused by mutations in the X-linked (methyl CpG-binding protein 2) gene. MeCP2 protein is an important epigenetic factor in the brain and in neurons. In -deficient neurons, nucleoli structures are compromised. Nucleoli are sites of active ribosomal RNA () transcription and maturation, a process mainly controlled by nucleolin and mechanistic target of rapamycin (mTOR)-P70S6K signaling. Currently, it is unclear how nucleolin--mTOR-P70S6K signaling from RTT cellular model systems translates into human RTT brain. Here, we studied the components of nucleolin--mTOR-P70S6K signaling in the brain of RTT patients with common T158M and R255X mutations. Immunohistochemical examination of T158M brain showed disturbed nucleolin subcellular localization, which was absent in -deficient homozygous male or heterozygote female mice, compared to wild type (WT). We confirmed by Western blot analysis that nucleolin protein levels are altered in RTT brain, but not in -deficient mice. Further, we studied the expression of transcripts in -deficient mice and RTT patients, as downstream molecules that are controlled by nucleolin. By data mining of published ChIP-seq studies, we showed MeCP2-binding at the multi-copy genes in the mouse brain, suggesting that might be a direct MeCP2 target gene. Additionally, we observed compromised mTOR-P70S6K signaling in the human RTT brain, a molecular pathway that is upstream of -nucleolin molecular conduits. RTT patients showed significantly higher phosphorylation of active mTORC1 or mTORC2 complexes compared to age- and sex-matched controls. Correlational analysis of mTORC1/2-P70S6K signaling pathway identified multiple points of deviation from the control tissues that may result in abnormal ribosome biogenesis in RTT brain. To our knowledge, this is the first report of deregulated nucleolin--mTOR-P70S6K signaling in the human RTT brain. Our results provide important insight toward understanding the molecular properties of human RTT brain.
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http://dx.doi.org/10.3389/fgene.2018.00635DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305968PMC
December 2018

Microtomy: Cutting Formalin-Fixed, Paraffin-Embedded Sections.

Methods Mol Biol 2019 ;1897:269-278

Department of Pathology (Neuropathology) and Laboratory Medicine, University Hospital - London Health Sciences Centre, Western University, Ontario, London, ON, Canada.

Formalin-fixed, paraffin-embedded tissue (FFPE) still plays an important role in biobanking, since it is comparatively easy to obtain and store in comparison to fresh frozen tissue. They are stored as paraffin or FFPE blocks. Unstained slides derived from FFPE blocks may be used for hematoxylin and eosin histology, special stains, immunohistochemistry, and chromogenic or fluorescent in situ hybridization. In addition, tissue scraped off FFPE slides or from scrolls of FFPE tissue may be used for molecular or proteomic analyses. Hematoxylin and eosin staining of FFPE sections reviewed by a pathologist are highly valuable to ensure the presence of adequate lesional cells for molecular and other analyses. Therefore, proper microtomy technique is essential in the preparation of formalin-fixed, paraffin-embedded tissue for biobanking purposes. Here we describe the process of cutting paraffin embedded sections using a rotary microtome. We also highlight the possible pitfalls that may arise and discuss how to avoid them.
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http://dx.doi.org/10.1007/978-1-4939-8935-5_23DOI Listing
June 2019

Laboratory Safety: Chemical and Physical Hazards.

Methods Mol Biol 2019 ;1897:243-252

Department of Pathology (Neuropathology) and Laboratory Medicine, University Hospital-London Health Sciences Center, London, ON, Canada.

Chemical and physical hazards are part of the daily routine when working in biorepositories. This chapter provides a brief overview of some common physical and chemical hazards encountered in biorepositories, with some basic principles to help eliminate and control these hazards by implementing safe work practices.
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http://dx.doi.org/10.1007/978-1-4939-8935-5_21DOI Listing
June 2019

[ F]AV-1451 binding and postmortem pathology of CBD.

Mov Disord 2018 08 23;33(8):1360-1361. Epub 2018 Aug 23.

Research Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, University of Toronto, Ontario, Canada.

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http://dx.doi.org/10.1002/mds.27356DOI Listing
August 2018

Normal glutathione levels in autopsied brain of chronic users of heroin and of cocaine.

Drug Alcohol Depend 2018 09 23;190:20-28. Epub 2018 Jun 23.

Human Brain Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, ON, Canada.

Background: Animal studies suggest that exposure to either of the two widely used drugs of abuse, heroin or cocaine, causes depletion of the antioxidant, reduced glutathione, a hallmark of oxidative stress, in the brain. However, the relevance of the animal findings to the human is uncertain and clinical trials with the antioxidant GSH precursor n-acetylcysteine have produced mixed results in cocaine dependence.

Methods: Our major objective was to compare glutathione levels, determined by an HPLC-coulometric procedure, in autopsied brain of chronic heroin (n = 11) and cocaine users (n = 9), who were positive for the drugs in the brain, to those of matched controls (n = 16). Six brain regions were examined, including caudate, hippocampus, thalamus and frontal, temporal and insular cortices.

Results: In contrast to experimental animal findings, we found no statistically significant difference between mean levels of reduced or oxidized glutathione in the drug user vs. control groups. Moreover, no correlation was found between levels of drugs in the brain and those of glutathione.

Conclusions: Acknowledging the many generic limitations of an autopsied human brain study and the preliminary nature of the findings, our data nevertheless suggest that any oxidative stress caused by heroin or cocaine in chronic users of the drugs might not be sufficient to cause substantial loss of stores of glutathione in the human brain, at least during early withdrawal. These findings, requiring replication, might also have some relevance to future clinical trials employing glutathione supplement therapy as an anti-oxidative strategy in chronic users of the two abused drugs.
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http://dx.doi.org/10.1016/j.drugalcdep.2018.05.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6078812PMC
September 2018

Claustral neurons are vulnerable to ischemic insults in cardiac arrest encephalopathy.

Int J Clin Exp Pathol 2018 1;11(5):2735-2741. Epub 2018 May 1.

London Health Sciences Centre London, Ontario, Canada.

Cardiac arrest encephalopathy is the major cause of global brain ischemia which is the main cause of death in these cases. Morphological assessment of the ischemic changes is important to prove the extent of the brain injury and its effects. Selective vulnerability is the common form of ischemic injury in these cases and commonly affects the CA1 of hippocampus, cerebral cortex in watershed zone and Purkinje cells of the cerebellum. In this retrospective study, we reviewed the clinical and pathological data for the 135 retrieved cases and only 16/135 cases met the selection criteria (i.e. confirmed cardiac arrest episode with known survival time, autopsy performed in less than 24 hours after death, compatible gray matter ischemic changes with the survival period, and no pathological changes of other diseases that could confound the result). We found that the claustrum is the most sensitive area for ischemic changes. This represents a novel finding, as up to our knowledge, the neurons of the claustrum have not been considered before as common area to show selective vulnerability. In the 3 cases with a short survival (6-9 hours), the hippocampus showed no or mild ischemic changes and as such was not a good area for assessment of global ischemia. Another unexplained novel finding was prominent vacuolar changes predominantly around both sides of the gray-white matter junction of the cerebellar dentate nucleus and focally inside the dentate nucleus.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958261PMC
May 2018

Intrasellar cavernous hemangioma presenting as pituitary adenoma: A report of two cases and review of the literature.

Clin Neuropathol 2018 Mar/Apr;37(2):64-67

Cavernous hemangioma in the sellar region is quite rare with only a handful of cases being reported in the English literature. Its clinical manifestations and imaging characteristics can mimic those of a pituitary adenoma. We report two cases of recurrent sellar lesions, both of which were clinically suspected of being pituitary adenomas but histologically confirmed as cavernous hemangiomas. The first case is of a 67-year-old female whose initial resection was diagnosed as "venous angioma". Neuroimaging performed 27 years later demonstrated significant growth of the lesion involving the right cavernous sinus and encasing the right internal carotid artery. The patient then underwent transsphenoidal endoscopic resection of the mass. At the time of the surgery, the lesion was noted to be quite vascular. The second case is a 48-year-old female who underwent emergency resection of a pituitary mass following an apoplectic event. On follow-up 4 years later, the patient reported recurrence of galactorrhea, and MRI had demonstrated regrowth of the mass. She subsequently underwent subtotal resection of the mass. At the time of surgery, brisk bleeding was noted in the operative area. The above two cases demonstrate that cavernous hemangiomas in the sellar region can clinically and radiologically mimic pituitary adenoma and should be considered in the differential diagnosis of hemorrhagic sellar mass.
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http://dx.doi.org/10.5414/NP301012DOI Listing
August 2018

Brain monoamine oxidase B and A in human parkinsonian dopamine deficiency disorders.

Brain 2017 Sep;140(9):2460-2474

Human Brain Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

See Jellinger (doi:10.1093/awx190) for a scientific commentary on this article. The enzyme monoamine oxidases (B and A subtypes, encoded by MAOB and MAOA, respectively) are drug targets in the treatment of Parkinson's disease. Inhibitors of MAOB are used clinically in Parkinson's disease for symptomatic purposes whereas the potential disease-modifying effect of monoamine oxidase inhibitors is debated. As astroglial cells express high levels of MAOB, the enzyme has been proposed as a brain imaging marker of astrogliosis, a cellular process possibly involved in Parkinson's disease pathogenesis as elevation of MAOB in astrocytes might be harmful. Since brain monoamine oxidase status in Parkinson's disease is uncertain, our objective was to measure, by quantitative immunoblotting in autopsied brain homogenates, protein levels of both monoamine oxidases in three different degenerative parkinsonian disorders: Parkinson's disease (n = 11), multiple system atrophy (n = 11), and progressive supranuclear palsy (n = 16) and in matched controls (n = 16). We hypothesized that if MAOB is 'substantially' localized to astroglial cells, MAOB levels should be generally associated with standard astroglial protein measures (e.g. glial fibrillary acidic protein). MAOB levels were increased in degenerating putamen (+83%) and substantia nigra (+10%, non-significant) in multiple system atrophy; in caudate (+26%), putamen (+27%), frontal cortex (+31%) and substantia nigra (+23%) of progressive supranuclear palsy; and in frontal cortex (+33%), but not in substantia nigra of Parkinson's disease, a region we previously reported no increase in astrocyte protein markers. Although the magnitude of MAOB increase was less than those of standard astrocytic markers, significant positive correlations were observed amongst the astrocyte proteins and MAOB. Despite suggestions that MAOA (versus MAOB) is primarily responsible for metabolism of dopamine in dopamine neurons, there was no loss of the enzyme in the parkinsonian substantia nigra; instead, increased nigral levels of a MAOA fragment and 'turnover' of the enzyme were observed in the conditions. Our findings provide support that MAOB might serve as a biochemical imaging marker, albeit not entirely specific, for astrocyte activation in human brain. The observation that MAOB protein concentration is generally increased in degenerating brain areas in multiple system atrophy (especially putamen) and in progressive supranuclear palsy, but not in the nigra in Parkinson's disease, also distinguishes astrocyte behaviour in Parkinson's disease from that in the two 'Parkinson-plus' conditions. The question remains whether suppression of either MAOB in astrocytes or MAOA in dopamine neurons might influence progression of the parkinsonian disorders.
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http://dx.doi.org/10.1093/brain/awx172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6669411PMC
September 2017

Papillary thyroid carcinoma metastasizing to anaplastic meningioma: an unusual case of tumor-to-tumor metastasis.

Brain Tumor Pathol 2017 Jul 9;34(3):130-134. Epub 2017 Jun 9.

Department of Clinical Neurological Sciences, London Health Sciences Centre, London, ON, Canada.

Tumor-to-tumor metastasis is a relatively uncommon entity, whereby the so-called 'recipient' tumor is involved by another biologically unrelated 'donor' tumor. Intracranially, meningioma (WHO grade 1) is the most common recipient tumor, while breast and lung cancers are the most common donor tumors. We present an unusual case of intracranial tumor-to-tumor metastasis involving papillary thyroid carcinoma (PTC) believed to have metastasized to an anaplastic meningioma (WHO grade 3). The patient is a 64-year-old female with a history of PTC, whose neuroimaging, performed as part of her staging workup, revealed a right parietal scalp lesion. The lesion was resected to reveal metastatic PTC with spindle cell component believed to represent sarcomatoid differentiation. Follow-up neuroimaging 2 months later revealed regrowth of the lesion under the previous craniotomy site. PET scan showed increased uptake in this area consistent with metastasis. Resection of this lesion revealed primarily features of an anaplastic meningioma. The combination of pathologic findings from both resections in conjunction with findings from the PET scan led to the suggestion that the PTC had metastasized into the anaplastic meningioma. To the authors' knowledge, this is the first example in the literature of a donor tumor metastasizing to a high-grade recipient tumor.
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http://dx.doi.org/10.1007/s10014-017-0289-5DOI Listing
July 2017

Pathology of toxic leucoencephalopathy in drug abuse supports hypoxic-ischemic pathophysiology/etiology.

Neuropathology 2017 Aug 9;37(4):321-328. Epub 2017 Mar 9.

London Health Sciences Centre (LHSC), London, Ontario, Canada.

The histopathological features of leucoencephalopathy caused by illicit drugs (such as opioids and cocaine) are well documented in acute cases but not in long-survival cases. There are several hypotheses about the pathogenesis of this disorder, including hypoperfusion, direct drug toxicity resulting from the neurotoxic effects of the drug itself or contaminants in the illicit drug vehicle. We reviewed the post mortem findings in five males (aged 24 to 56 years, with survival intervals ranging from 7 days to 5 months) with a history of illicit drug use and concomitant fatal white matter changes. The histological characteristics of leucoencephalopathy vary with survival period. Prominent axonal injury and axonal spheroids were observed with shorter survival and spongiform changes becoming apparent with longer survival (acute and chronic incomplete infarct pattern). Necrosis was present in all cases and its appearance changed with longer survival (acute and chronic complete infarct pattern). Significant primary demyelination was not observed. These observations suggest that the primary defect in this leucoencephalopathy is hypoxic-ischemic injury, predominantly in the white matter. Spongiform leucoencephalopathy likely represents the longer-survival incomplete infarct pattern and is observed with polydrug abuse.
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http://dx.doi.org/10.1111/neup.12377DOI Listing
August 2017

Threonine, a novel pathological phosphorylation site on tau protein linked to multiple tauopathies.

Acta Neuropathol Commun 2017 01 11;5(1). Epub 2017 Jan 11.

Molecular Medicine Research Group, Robarts Research Institute, 1151 Richmond Street North, London, N6A 5B7, ON, Canada.

Microtubule associated protein tau (tau) deposition is associated with a spectrum of neurodegenerative diseases collectively termed tauopathies. We have previously shown that amyotrophic lateral sclerosis (ALS) with cognitive impairment (ALSci) is associated with tau phosphorylation at Thr and that this leads to activation of GSK3β which then induces phosphorylation at tau Thr. This latter step leads to dissociation of tau from microtubules and pathological tau fibril formation. To determine the extent to which this pathway is unique to ALS, we have investigated the expression of pThr tau and pThr tau across a range of frontotemporal degenerations. Representative sections from the superior frontal cortex, anterior cingulate cortex (ACC), amygdala, hippocampal formation, basal ganglia, and substantia nigra were selected from neuropathologically confirmed cases of Alzheimer's disease (AD; n = 3), vascular dementia (n = 2), frontotemporal lobar degeneration (FTLD; n = 4), ALS (n = 5), ALSci (n = 6), Parkinson's disease (PD; n = 5), corticobasal degeneration (CBD; n = 2), diffuse Lewy body dementia (DLBD; n = 2), mixed DLBD (n = 3), multisystem atrophy (MSA; n = 6) and Pick's disease (n = 1) and three neuropathologically-normal control groups aged 50-60 (n = 6), 60-70 (n = 6) and 70-80 (n = 8). Sections were examined using a panel of phospho-tau antibodies (pSer, pThr, pThr, pThr, pSer and T22 (oligomeric tau)). Across diseases, phospho-tau load was most prominent in layers II/III of the entorhinal cortex, amygdala and hippocampus. This is in contrast to the preferential deposition of phospho-tau in the ACC and frontal cortex in ALSci. Controls showed pThr tau expression only in the 7 decade of life and only in the presence of tau pathology and tau oligomers. With the exception of DLBD, we observed pThr co-localizing with pThr in the same cell populations as T22 positivity. This suggests that this pathway may be a common mechanism of toxicity across the tauopathies.
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http://dx.doi.org/10.1186/s40478-016-0406-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5225652PMC
January 2017

Granulovacuolar Degeneration in Hippocampus of Neurodegenerative Diseases: Quantitative Study.

J Neurodegener Dis 2016 23;2016:6163186. Epub 2016 Oct 23.

Department of Pathology, Schulich School of Medicine & Dentistry, Western University, London, ON, Canada N6A 5C1.

. Granulovacuolar degeneration (GVD) is one of the pathological features long associated with Alzheimer's disease (AD) and normal aging. . We investigate the frequency of GVDs in AD, other neurodegenerative diseases, and normal aging, with attempt to determine whether the GVD has preponderance in any particular neurodegenerative disease other than AD. . A retrospective review of 111 autopsied cases with a variety of neurodegenerative diseases and 70 control cases without pathological evidence of neurodegeneration was evaluated quantitatively. The microscopic examination was applied on coronal sections of hippocampi using Hematoxylin and Eosin (H&E) and Bielschowsky silver impregnation. The mean percentage of neurons with GVDs was calculated through all sectors of Ammon's horn for each case. . We found that neurons with GVD, in cases with or without neurodegenerative diseases, were found predominantly in CA1 and CA2 sectors of hippocampus. The GVD count in AD was significantly increased in CA1 and CA2 compared to other neurodegenerative cases as well as normal aging controls. In AD/LBD there was a significant increase in GVD in CA1 whereas in LBD there was no significant change in GVD. The frequency of GVD in AD is due to the disease process and attributes the increase for AD/LBD to the AD component.
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http://dx.doi.org/10.1155/2016/6163186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097825PMC
October 2016

Acute hypoxic-ischemia in cardiac arrest encephalopathy causes only minimal demyelination.

Neuropathology 2016 Oct 2;36(5):413-420. Epub 2016 Mar 2.

London Health Sciences Centre (LHSC), London, ON, Canada.

The underlying pathological process of "ischemic leukoencephalopathy" is not well studied in humans and "demyelination" is thought to represent a major component. We selected brains from autopsy cases with definite histories of recent cardiac arrest, in which the autopsy findings demonstrated gray matter ischemic changes consistent with the survival time. We excluded cases with clinical or pathological evidence of other diseases that may affect the white matter, specifically those with moderate-severe edema. The selected cases were then subjected to a review of the gross pathology (photographs) and microscopy. We used the normal white matter areas in the same brains as internal controls to exclude artefactual changes. Sixteen cases were selected. The pathological changes in acute ischemic leukoencephalopathy include: white matter pallor with separation of myelinated fibers and fine vacuoles, coarse vacuoles with or without attenuated axons, apoptotic nuclei, axonal abnormalities, focal scattered demyelinated axons and infarcts. The interpretation of these findings is controversial (i.e. ischemia, edema, artifact or combination) due to the postmortem nature of the specimens. However, these factors should not affect our interpretation of minimal demyelination in the pathological process. The major underlying pathological process in acute ischemic leukoencephalopathy is axonal degeneration, while demyelination represents only a minor component.
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http://dx.doi.org/10.1111/neup.12287DOI Listing
October 2016

Do glutathione levels decline in aging human brain?

Free Radic Biol Med 2016 Apr 1;93:110-7. Epub 2016 Feb 1.

Human Brain Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, 250 College Street, Toronto, Ontario, Canada M5T 1R8.

For the past 60 years a major theory of "aging" is that age-related damage is largely caused by excessive uncompensated oxidative stress. The ubiquitous tripeptide glutathione is a major antioxidant defense mechanism against reactive free radicals and has also served as a marker of changes in oxidative stress. Some (albeit conflicting) animal data suggest a loss of glutathione in brain senescence, which might compromise the ability of the aging brain to meet the demands of oxidative stress. Our objective was to establish whether advancing age is associated with glutathione deficiency in human brain. We measured reduced glutathione (GSH) levels in multiple regions of autopsied brain of normal subjects (n=74) aged one day to 99 years. Brain GSH levels during the infancy/teenage years were generally similar to those in the oldest examined adult group (76-99 years). During adulthood (23-99 years) GSH levels remained either stable (occipital cortex) or increased (caudate nucleus, frontal and cerebellar cortices). To the extent that GSH levels represent glutathione antioxidant capacity, our postmortem data suggest that human brain aging is not associated with declining glutathione status. We suggest that aged healthy human brains can maintain antioxidant capacity related to glutathione and that an age-related increase in GSH levels in some brain regions might possibly be a compensatory response to increased oxidative stress. Since our findings, although suggestive, suffer from the generic limitations of all postmortem brain studies, we also suggest the need for "replication" investigations employing the new (1)H MRS imaging procedures in living human brain.
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http://dx.doi.org/10.1016/j.freeradbiomed.2016.01.029DOI Listing
April 2016

Low levels of astroglial markers in Parkinson's disease: relationship to α-synuclein accumulation.

Neurobiol Dis 2015 Oct 21;82:243-253. Epub 2015 Jun 21.

Human Brain Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Although gliosis is a normal response to brain injury, reports on the extent of astrogliosis in the degenerating substantia nigra in Parkinson's disease (PD) are conflicting. It has also been recently suggested that accumulation of nigral α-synuclein in this disorder might suppress astrocyte activation which in turn could exacerbate the degenerative process. This study examined brain protein levels (intact protein, fragments, and aggregates, if any) of astroglial markers and their relationship to α-synuclein in PD and in the positive control parkinson-plus conditions multiple system atrophy (MSA) and progressive supranuclear palsy (PSP). Autopsied brain homogenates of patients with PD (n=10), MSA (n=11), PSP (n=11) and matched controls (n=10) were examined for the astroglial markers glial fibrillary acidic protein (GFAP), vimentin, and heat shock protein-27 (Hsp27) by quantitative immunoblotting. As expected, both MSA (putamen>substantia nigra>caudate>frontal cortex) and PSP (substantia nigra>caudate>putamen, frontal cortex) showed widespread but regionally specific pattern of increased immunoreactivity of the markers, in particular for the partially proteolyzed fragments (all three) and aggregates (GFAP). In contrast, immunoreactivity of the three markers was largely normal in PD in brain regions examined with the exception of trends for variably increased levels of cleaved vimentin in substantia nigra and frontal cortex. In patients with PD, GFAP levels in the substantia nigra correlated inversely with α-synuclein accumulation whereas the opposite was true for MSA. Our biochemical findings of generally normal protein levels of astroglial markers in substantia nigra of PD, and negative correlation with α-synuclein concentration, are consistent with some recent neuropathology reports of mild astroglial response and with the speculation that astrogliosis might be suppressed in this disorder by excessive α-synuclein accumulation. Should astrogliosis protect, to some extent, the degenerating substantia nigra from damage, therapeutics aimed at normalization of astrocyte reaction in PD could be helpful.
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http://dx.doi.org/10.1016/j.nbd.2015.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641013PMC
October 2015

Catheter based selective hypothermia reduces stroke volume during focal cerebral ischemia in swine.

J Neurointerv Surg 2016 Apr 12;8(4):418-22. Epub 2015 Feb 12.

Department of Clinical Neurological Sciences, Western University, London, Ontario, Canada Department of Medical Imaging, Western University, London, Ontario, Canada.

Background: Total body hypothermia is an established neuroprotectant in global cerebral ischemia. The role of hypothermia in acute ischemic stroke remains uncertain. Selective application of hypothermia to a region of focal ischemia may provide similar protection with more rapid cooling and elimination of systemic side effects. We studied the effect of selective endovascular cooling in a focal stroke model in adult domestic swine.

Methods: After craniotomy under general anesthesia, a proximal middle cerebral artery branch was occluded for 3 h, followed by 3 h of reperfusion. In half of the animals, selective hypothermia was induced during reperfusion using a dual lumen balloon occlusion catheter placed in the ipsilateral common carotid artery. Following reperfusion, the animals were sacrificed. Brain MRI and histology were evaluated by experts who were blinded to the intervention.

Results: 25 animals were available for analysis. Using selective hypothermia, hemicranial temperature was successfully cooled to a mean of 26.5 °C. Average time from start of perfusion to attainment of moderate hypothermia (<30 °C) was 25 min. Mean MRI stroke volumes were significantly reduced by selective cooling (0.050±0.059 control, 0.005±0.011 hypothermia (ratio stroke:hemisphere volume) (p=0.046). Stroke pathology volumes were reduced by 42% compared with controls (p=0.256).

Conclusions: Selective moderate hypothermia was rapidly induced using endovascular techniques in a clinically realistic swine stroke model. A significant reduction in stroke volume on MRI was observed. Endovascular selective hypothermia can provide neuroprotection within time frames relevant to acute ischemic stroke treatment.
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http://dx.doi.org/10.1136/neurintsurg-2014-011562DOI Listing
April 2016

Pathologic staging of white matter lesions in adult-onset leukoencephalopathy/leukodystrophy with axonal spheroids.

J Neuropathol Exp Neurol 2015 Mar;74(3):233-40

From the London Health Sciences Center (MA, L-CA) and Western University (MA, L-CA), London; and Sunnybrook Health Sciences Center, University of Toronto (JK), and Tanz Center for Research in Neurodegenerative Diseases (L-NH), Toronto, Ontario, Canada; Department of Neuroscience, Mayo Clinic Florida, Jacksonville, Florida (RR); and Department of Pathology, King Abdulaziz University and Hospital, Jeddah, Saudi Arabia (MA).

The pathologic features of adult-onset leukoencephalopathy/leukodystrophy with axonal spheroids (ALAS) are variable, and this has led to different hypotheses as to whether primarily demyelination or axonopathy may underlie this disorder. Typical ALAS pathology is rarely accompanied by focal multiple sclerosis (MS)-like plaques. In ALAS pathology accompanied by focal multiple sclerosis (MS)-like plaques cases, the pathologic features cannot be distinguished from those of progressive MS with diffusely abnormal white matter. To clarify these issues, we examined neuropathologic features in 159 representative samples from 5 ALAS cases (3 men and 2 women aged 39-61 years) and in 95 representative samples from 3 chronic MS cases (1 man and 2 women aged 50-73 years). The white matter abnormalities in ALAS cases were characterized by 3 evolving stages: 1) white matter with numerous spheroids in a background of well-myelinated fibers; 2) moderate loss of myelinated fibers with sparse to moderate number of spheroids; and 3) leukodystrophy-like pattern of confluent axonal and myelin loss. The application of this staging system suggests that myelin loss in ALAS is preceded by axonopathy. In progressive MS cases, the diffusely abnormal white matter pathology could be attributed to both primary demyelination and axonopathy. Some cases with predominant axonopathy are difficult to distinguish from cases with ALAS.
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http://dx.doi.org/10.1097/NEN.0000000000000168DOI Listing
March 2015

Is brain gliosis a characteristic of chronic methamphetamine use in the human?

Neurobiol Dis 2014 Jul 2;67:107-18. Epub 2014 Apr 2.

Human Brain Laboratory, Research Imaging Centre, Centre for Addiction and Mental Health, Toronto, Ontario, Canada.

Animal data show that high doses of the stimulant drug methamphetamine can damage brain dopamine neurones; however, it is still uncertain whether methamphetamine, at any dose, is neurotoxic to human brain. Since gliosis is typically associated with brain damage and is observed in animal models of methamphetamine exposure, we measured protein levels (intact protein and fragments, if any) of markers of microgliosis (glucose transporter-5, human leukocyte antigens HLA-DRα [TAL.1B5] and HLA-DR/DQ/DPβ [CR3/43]) and astrogliosis (glial fibrillary acidic protein, vimentin, and heat shock protein-27) in homogenates of autopsied brain of chronic methamphetamine users (n=20) and matched controls (n=23). Intact protein levels of all markers were, as expected, elevated (+28%-1270%, P<0.05) in putamen of patients with the neurodegenerative disorder multiple system atrophy (as a positive control) as were concentrations of fragments of glial fibrillary acidic protein, vimentin and heat shock protein-27 (+170%-4700%, P<0.005). In contrast, intact protein concentrations of the markers were normal in dopamine-rich striatum (caudate, putamen) and in the frontal cortex of the drug users. However, striatal levels of cleaved vimentin and heat shock protein-27 were increased (by 98%-211%, P<0.05), with positive correlations (r=0.41-0.60) observed between concentrations of truncated heat shock protein-27 and extent of dopamine loss (P=0.006) and levels of lipid peroxidation products 4-hydroxynonenal (P=0.046) and malondialdehyde (P=0.11). Our failure to detect increased intact protein levels of commonly used markers of microgliosis and astrogliosis could be explained by exposure to methamphetamine insufficient to cause a toxic process associated with overt gliosis; however, about half of the subjects had died of drug intoxication suggesting that "high" drug doses might have been used. Alternatively, drug tolerance to toxic effects might have occurred in the subjects, who were all chronic methamphetamine users. Nevertheless, the finding of above-normal levels of striatal vimentin and heat shock protein-27 fragments (which constituted 10-28% of the intact protein), for which changes in the latter correlated with those of several markers possibly suggestive of damage, does suggest that some astrocytic "disturbance" had occurred, which might in principle be related to methamphetamine neurotoxicity or to a neuroplastic remodeling process. Taken together, our neurochemical findings do not provide strong evidence for either marked microgliosis or astrogliosis in at least a subgroup of human recreational methamphetamine users who used the drug chronically and shortly before death. However, a logistically more difficult quantitative histopathological study is needed to confirm whether glial changes occur or do not occur in brain of human methamphetamine (and amphetamine) users.
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http://dx.doi.org/10.1016/j.nbd.2014.03.015DOI Listing
July 2014

Clinical Neuropathology practice guide 6-2013: morphology and an appropriate immunohistochemical screening panel aid in the identification of synovial sarcoma by neuropathologists.

Clin Neuropathol 2013 Nov-Dec;32(6):461-70

Aims: Pathologists are under increasing pressure to accurately subclassify sarcomas, yet neuropathologists have limited collective experience with rare sarcoma types such as synovial sarcoma. We reviewed 9 synovial sarcomas affecting peripheral nerve diagnosed by neuropathologists and explored the morphologic and immunohistochemical differences between these and MPNST. Our goal was to make practical recommendations for neuropathologists regarding which spindle cell tumors affecting nerve should be sent for SYT-SSX testing.

Methods: Clinical records and genetics were reviewed retrospectively and central pathology review of 9 synovial sarcomas and 6 MPNST included immunohistochemistry for SOX10, S100, BAF47, CK (lmw, pan, CK7, CK19), EMA, CD34, bcl2, CD99, and neurofilament.

Results: Common synovial sarcoma sites were brachial plexus, spinal and femoral nerve, none were "intra-neural", all had the SYTSSX1 translocation, and 6/9 were monophasic with myxoid stroma and distinct collagen. Half of the monophasic synovial sarcomas expressed CK7, CK19 or panCK in a "rare positive cells pattern", 8/9 (89%) expressed EMA, and all were SOX10 immunonegative with reduced but variable BAF47 expression.

Conclusions: We recommend that upon encountering a cellular spindle cell tumor affecting nerve neuropathologists consider the following: 1) SYT-SSX testing should be performed on any case with morphology suspicious for monophasic synovial sarcoma including wiry or thick bands of collagen and relatively monomorphous nuclei; 2) neuropathologists should employ a screening immunohistochemical panel including one of CK7, panCK or CK19, plus EMA, S100 and SOX10, and 3) SYT-SSX testing should be performed on any spindle cell tumor with CK and/or EMA immunopositivity if SOX10 immunostaining is negative or only labels entrapped nerve elements.
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http://dx.doi.org/10.5414/NP300685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3852132PMC
March 2014