Arthur W. Clark

The University of Calgary, Calgary, Alberta, Canada

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Publications (32)141.54 Total impact

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    ABSTRACT: To describe the clinical, molecular, and neuropathological findings of a patient with aquaporin 4-positive relapsing myelitis who developed extensive brain involvement followed by death. Case report. Foothills Medical Center, Calgary, Alberta, Canada. A 51-year-old woman with neuromyelitis optica spectrum disorder. Neuropathological examination disclosed neuromyelitis optica lesions, even in areas that appeared normal radiologically and grossly. Immunostaining confirmed the massive disintegration of astrocytes in the acute and chronic lesions, indicating that astrocytes are targeted early in the disease process. Induction of the immune response was demonstrated by reverse-transcriptase polymerase chain reaction analysis of relevant immune response genes. This article supports and supplements current concepts of astrocyte disintegration in neuromyelitis optica and of immune mechanisms in its pathogenesis.
    Full-text · Article · Apr 2011 · Archives of neurology
  • Jian-Qiang Lu · Arthur W. Clark
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    ABSTRACT: Tumor-to-tumor metastasis (TTM) is a relatively rare but well-documented phenomenon. When malignant tumor metastasizes to an intracranial tumor, meningiomas are most often the recipient; and breast or lung carcinoma the most common donor (primary tumor). The diagnosis of TTM can be made only by histopathological examination. Awareness of TTM is essential in clinical practice for timely diagnosis and early detection of malignant disease. The pathogenesis of TTM is related to various factors including vascularity and indolent growth of the recipient tumor; and simultaneous occurrence of the particular donor and recipient tumors (most notably breast carcinoma and meningioma). Most essential for understanding pathogenesis, however, are current concepts in the pathogenesis of metastatic cancer, an edifice rising on the concept of “seed and soil” expressed by Paget in 1889. The recently developed metastatic niche model is built on “seed and soil” theory, and describes the evolution of a conducive microenvironment in which disseminated tumor cells engraft and proliferate at the secondary sites. Early interventions that target both the disseminating seed and the metastatic soil may enable improvements in prognosis of malignant tumors. KeywordsMetastasis-TTM-Extracranial-Intracranial-Pathogenesis-Gliomas
    No preview · Chapter · Dec 2010
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    ABSTRACT: To evaluate the effects of allogeneic hematopoietic stem cell transplantation (allo-HSCT) on the brains of persons with and without multiple sclerosis (MS) by means of postmortem histopathological examination. Postmortem histopathology, case studies, and case-control studies. Patients Four patients with MS who died at a median of 4.5 months (range, 3-9 months) after allo-HSCT for a concomitant hematologic malignant neoplasm; 5 patients without MS who died at a median of 10.0 months (1-29 months) after allo-HSCT; and 5 control subjects without MS who did not undergo allo-HSCT. Referral centers. Intervention Allogeneic hematopoietic stem cell transplantation. Morphological features and immunohistochemical features, including the quantitative measures of chronic inflammatory cells. Demyelinating and inflammatory activities of MS persisted after allo-HSCT in all of the patients with MS. Active and chronic active MS lesions exhibited significantly higher numbers of CD3+ T cells and CD8+ cytotoxic T cells and significantly higher scores of CD68+ microglia/macrophages than did chronic inactive lesions or normal-appearing white matter. The normal-appearing brains of allo-HSCT recipients who did not have MS were found to have significantly higher numbers of CD3+ T cells and CD8+ cytotoxic T cells and higher scores of CD68+ microglia/macrophages compared with the controls; however, no demyelination was identified in these non-MS samples. Allo-HSCT fails to halt the demyelination and inflammation of MS.
    No preview · Article · Jun 2010 · Archives of neurology
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    ABSTRACT: The clinicopathological spectra of a dysembryoplastic neuroepithelial tumor (DNT) and a rosette-forming glioneuronal tumor (RGNT) are expanding. We report here the autopsy findings of a case of complex glioneuronal tumor with combined histological features of both a DNT and an RGNT. A 79-year-old man presented with a 1-month history of confusion and gait difficulties. A magnetic resonance imaging scan revealed obstructive hydrocephalus attributed to a mass in the posterior third ventricle. A third ventriculostomy was performed. Postoperatively, the mass remained unchanged in size for more than 14 months. Thirty-eight months after his initial manifestations, he experienced minor head trauma and was then hospitalized. Despite placement of an external ventricular drain and other supportive treatment, he deteriorated and died. A full autopsy was performed, with emphasis on the brain. The mass lesion and a few independent microfoci situated primarily around the third ventricle showed histological features of pilocytic astrocytoma with recurrent hemorrhage. Far more numerous were microfoci with histological features of a DNT, including floating neurons, as well as typical RGNT-associated, synaptophysin-positive rosettes and perivascular pseudorosettes. The advanced age of the patient, the coexisting histological features of the DNT and RGNT, and the distinctive anatomic distribution of the lesions, being centered on the third ventricle, may lend insight into the histogenetic relationship of a DNT, an RGNT, and mixed glioneuronal tumors.
    No preview · Article · Jul 2009 · Neurosurgery
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    ABSTRACT: Tumor-to-tumor metastasis (TTM) is a relatively rare but well-documented phenomenon. The authors report a unique case of esophageal carcinoma metastatic to an intracranial paraganglioma. A sellar and suprasellar tumor was found using MR imaging in an 81-year-old man who presented with a 3-week history of progressive headache and blurred vision. A subtotal excision of the tumor was achieved. Histopathological examination of the tumor disclosed a neoplasm with two distinct components: one showing the classic Zellballen pattern of a paraganglioma, the other exhibiting malignant features leading to the diagnosis of a poorly differentiated carcinoma metastatic to a sellar/suprasellar paraganglioma. The primary esophageal carcinoma was not uncovered until 2 months later, after the patient presented with upper gastrointestinal bleeding. The patient died 4 months after initial presentation. This case expands the spectrum of TTM, and emphasizes the importance of TTM in the practice of pathology.
    No preview · Article · Apr 2009 · Journal of Neurosurgery

  • No preview · Article · Apr 2008 · The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques
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    ABSTRACT: Primary angiitis of the central nervous system (CNS) is a rare vasculitic disorder that typically involves the brain and, less frequently, the spinal cord without involvement of the blood vessels outside the CNS. We present a case of a 52-year-old woman who developed a conus syndrome linked to an enhancing mass of her lower thoracic spinal cord, lumbar cord, and conus. Spinal cord biopsy performed for diagnostic purposes in the setting of progressive neurological deficit confirmed angiitis of the spinal cord. Therapy with steroid and cyclophosphamide was associated with long-term (3 years) clinical and imaging remission of the lesion. The prognosis of primary CNS angiitis is dismal with most cases progressing to death. Long-term remission is unusual. Aggressive therapy with steroid and cytotoxic agents may improve survival.
    No preview · Article · Jan 2007 · Surgical Neurology

  • No preview · Article · Dec 2006 · Annals of the New York Academy of Sciences
  • Arthur W Clark · Harvey B Sarnat
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    ABSTRACT: Ontogenic development of granule cells in the hippocampal dentate gyrus is influenced by genes including WNT3, EMX2, NEUROD, and LEF1. Dentate granule cells continue to be generated from stem cell precursors postnatally and during adult life, and are implicated in normal and abnormal neurological function. Developmental privation of dentate granule cells is rare and essentially always occurs in the context of other neurodevelopmental abnormalities. We have found no previous reports of severe, selective agenesis of dentate granule cells in humans. A gross and microscopic examination of the brain included appropriate histochemical and immunohistochemical preparations and examination of the hippocampal formation at multiple levels bilaterally. This neurologically normal 82-year-old man was found to have bilateral agenesis of the hippocampal dentate gyrus, no identifiable dentate granule cells, and moderate disorganization of the pyramidal cell layer of Ammon's horn. We found no neurodevelopmental abnormalities outside the hippocampus. The hippocampal architectural alterations in this patient are similar to those associated with a murine Lef1 mutation, but our human case does not have the other congenital deficits reported in the Lef1-null mouse. Bilateral agenesis of the hippocampal dentate gyrus, and apparent failure of regeneration of dentate granule cells from stem cells in adult life, may occur without overt clinical neurological deficits.
    No preview · Article · Sep 2006 · The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques
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    ABSTRACT: We report the treatment and follow-up, including MRI, of two patients with idiopathic hypertrophic pachymeningitis and review the English language literature, with emphasis on management and outcome in this rare disorder. The files of two patients were reviewed, with relevant histopathology and imaging (MRI). The first patient has been followed for sixteen years (the longest MRI-documented postoperative course reported for this condition) and the second for two years. The English language literature was reviewed, including a summary of all reported patients that have been followed with MRI or CT imaging. Despite extensive investigation, no underlying etiology was determined in either patient. Histopathological studies revealed a chronic inflammatory dural infiltrate in both patients, with granulomas in the first but not the second patient. The first patient underwent surgery twice and has remained stable for sixteen years, despite persistent neurologic deficits. The second patient was managed with dexamethasone after a surgical biopsy, and experienced complete resolution of all neurological deficits and abnormalities seen with MRI. Although prompt and extensive surgery has been recommended for this condition, the results from our second patient indicate that complete remission can be achieved in some patients with biopsy and steroid therapy. This also supports the view that autoimmune mechanisms underlie idiopathic hypertrophic pachymeningitis. The first patient illustrates that extensive laminectomies may be an effective therapeutic option but chronic discomfort may result. If extensive surgery must be performed, laminoplasty should be done because of the potential for reduced pain and improved long-term spinal stability.
    Full-text · Article · Dec 2000 · The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques
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    James N. Scott · Arthur W. Clark · Douglas W. Zochodne
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    ABSTRACT: In human and experimental diabetes, the relationship between molecular abnormalities in perikarya of sensory neurons and structural abnormalities in their distal axons is largely unexplored. In this study we examined neurofilament (Nf) and tubulin messenger RNA (mRNA) expression and their incorporation into distal sensory axons during progressive streptozotocin-induced diabetes in rats. After 2 and 6 months of diabetes, we measured mRNA levels of all three Nf subunits, B50 [growth associated protein-43 (GAP-43)] and alpha-tubulin in L4-L6 dorsal root ganglia using Northern analysis. The same animals underwent morphometric studies of myelinated fibres by light microscopy and quantitative analysis of Nf and microtubule numbers and density within sural myelinated and unmyelinated axons. Multifibre in vivo sensory and motor conduction nerve recordings confirmed slowing of conduction velocities in diabetic rats indicating experimental neuropathy. mRNA levels for the three Nf subunits, B50 (GAP-43) and alpha-tubulin were unchanged from controls at 2 months, but were decreased by 26-46% at 6 months. These changes accompanied declines in Nf numbers and densities within large myelinated sensory axons, and Nf numbers in unmyelinated fibres by 6 months. Microtubule numbers and densities were similarly reduced in large myelinated axons, and microtubule numbers reduced in small myelinated and unmyelinated axons in diabetes at 6, but not 2 months. Axonal atrophy was observed in unmyelinated fibres at 6 months. Our findings indicate that decreased mRNA expression of cytoskeletal proteins in sensory neurons accompanies a reduction in their incorporation into distal axons. These changes imply that there is a direct link between pathological changes in the sensory neuron and alterations of its distal branches from experimental diabetes. The changes in gene expression in diabetes are unique and differ from those that develop after axotomy.
    Full-text · Article · Dec 1999 · Brain
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    ABSTRACT: Neurofibrillary tangles (NFT) in Alzheimer's disease (AD) consist largely of hyperphosphorylated tau protein. Many of the phosphorylation sites on tau are serine/threonine-proline sequences, several of which are phosphorylated in vitro by neuronal Cdc2-like kinase (Nclk), a kinase composed of Cdk5 and its activator(s). Thus, tau hyperphosphorylation in AD may result in part from deregulation of Nclk. To test this hypothesis, we examined Nclk activity in prefrontal and cerebellar cortex from 15 postmortem AD and 16 age-matched control subjects, and corrected either for Cdk5 level or for neuronal loss. The ratio of Nclk activity in prefrontal versus cerebellar cortex was then compared. When corrections were made for neuronal loss, the ratios of kinase activity in prefrontal versus cerebellar cortex were significantly higher in AD (6.45+/-0.86) than the controls (3.13+/-0.46; P = 0.003). This finding is consistent with a role for Nclk in the pathogenesis of NFT in AD.
    Full-text · Article · Jun 1999 · Neuroscience Research
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    ABSTRACT: The authors present a case in which a symptomatic hamartoma was found in the spinal cord of a patient with neurofibromatosis type 1 (NF-1). This 52-year-old woman presented with painful urinary incontinence. Magnetic resonance (MR) imaging revealed an intramedullary lesion within the lower thoracic spinal cord and conus medullaris, which was surgically removed. Pathological investigation showed a hamartomatous lesion consisting of glial cells, ganglion cells, abundant disoriented axons, and thin-walled vessels. This case provides a pathological correlate to the hamartomatous lesions demonstrated on MR imaging in patients with NF-1 and illustrates that these benign lesions may become symptomatic and require neurosurgical intervention.
    No preview · Article · Jul 1998 · Journal of Neurosurgery
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    ABSTRACT: Matrix metalloproteinases (MMPs) are involved in remodelling extracellular matrix. Gelatinase B (MMP-9) is an inducible 92 kDa MMP expressed by neutrophils, microglia, and endothelial cells. Gelatinase A (MMP-2) is a 72 kDa MMP, constitutively expressed in brain. Elevated MMP activity has been linked to various pathologic conditions, and the therapeutic benefit of MMP inhibitors is under study in a few experimental models. Using gelatin zymography, we have compared activities of these MMPs in infarcted and matched non-infarcted cerebral tissue from eight subjects dying at intervals of less than 2 h to several years after a stroke. Gelatinase B activity was markedly elevated in the infarcted tissue at two days post-infarction, and remained elevated in cases dying months after the event. Increases in gelatinase A activity were subtle at 2-5 days; they were marked and significant in cases dying at 4 months and later. The findings indicate distinct temporal profiles of post-ischemic gelatinase activity in human brain, with earlier but equally persistent elevation in gelatinase B when compared to gelatinase A.
    No preview · Article · Dec 1997 · Neuroscience Letters
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    ABSTRACT: Classification of inherited neurodegenerative diseases is increasingly based on their genetic features, which supplement, clarify, and sometimes replace the older clinical and pathologic schemata. This change has been particularly rapid and impressive for the CAG repeat disorders. In Huntington's disease, X-linked spinobulbar muscular atrophy, dentatorubropallidoluysian atrophy, and a series of autosomal dominant cerebellar atrophies, genetic advances have resolved many nosologic issues, and opened new avenues for exploration of pathogenesis. In this review, we summarize classic and current concepts in neuropathology of these CAG repeat diseases.
    No preview · Article · Aug 1997 · Brain Pathology
  • Albert R. La Spada · Arthur W. Clark
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    ABSTRACT: At the beginning of this decade, the American Association of Neurology decided that the 1990's should be labelled “the decade of the brain” for expected advances in our understanding of neurological disorders and neuroscience. By the end of this decade, clinicians and researchers who work in the field of inherited neurological disorders might well remember the 1990's as “the decade of the trinucleotide repeat”. At the time of writing this introduction, eleven inherited neurological disorders have been found to be caused by expansions of trinucleotide repeats, and a twelfth trinucleotide repeat expansion mutation has been identified (6), although the gene containing this mutant triplet repeat has not been cloned to our knowledge (Table 1).
    No preview · Article · Aug 1997 · Brain Pathology
  • Craig A. Krekoski · Irma M. Parhad · Tak S. Fung · Arthur W. Clark
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    ABSTRACT: We studied the effects of advancing age on the expression of several proteins important in the structure and function of the nervous system. Brains of young (3 month), middle-aged (13 month), and old (29 month) male Fischer 344 rats were examined. Run-on transcription and Northern blot hybridizations were used to determine gene-specific transcription rates and mRNA levels, respectively. With advancing age, there was a decrement in the transcription rate and mRNA levels for neurofilament-light subunit (Nf-L), but an increment in the transcription rate and mRNA levels for glial fibrillary acidic protein (GFAP). Proteolipid protein (PLP) mRNA levels were attenuated between 3 and 13 months of age, whereas amyloid precursor protein (APP) mRNA levels were attenuated in the middle-aged but not the old animals. Transcription rates for alpha-actin and fos, and mRNA levels for alpha-actin, were unaffected. These observations indicate divergent transcriptional regulation of several genes, notably Nf-L and GFAP, in the aging mammalian forebrain.
    No preview · Article · Nov 1996 · Neurobiology of Aging
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    ABSTRACT: Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are found in 15 to 20% of patients with familial amyotrophic lateral sclerosis (FALS). Increased levels of neurofilament subunits in transgenic mouse models of ALS also suggests a key role for these proteins in the pathogenesis of the disease. We report the coexistence of an Ile113-->Thr substitution in exon 4 of the SOD1 gene and marked neurofilamentous pathology in the same FALS patient. These observations suggest that two mechanisms, SOD1-induced toxicity and neurofilament disruption, are acting together.
    No preview · Article · Jan 1996 · Annals of Neurology
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    ABSTRACT: The association cortex of Down's syndrome (DS) predictably and prematurely undergoes neurofibrillary degeneration of Alzheimer type. Hence studies of DS are potentially useful in defining the earliest pathogenetic events in Alzheimer's disease (AD). Previous reports have described altered expression of several mRNAs in AD cortex; but the pathogenetic stage at which expression of these mRNAs begins to deviate from the norm has not been defined. We have examined this issue in neocortex of DS. Expression of mRNAs, known to be altered in AD cortex, was studied by Northern analysis, comparing frontal cortex of DS (15-45 years) with age-matched controls and with AD. Chromosome 21- and non-21-encoded mRNAs were studied, including transcripts expressed preferentially in neurons (neurofilament light subunit and amyloid precursor transcripts) and in glia (glial fibrillary acidic protein [GFAP] and S100[beta]). Chromosome 21-encoded mRNAs were increased in DS cortex as expected. Except in the DS case with extensive neurofibrillary degeneration, GFAP was expressed at levels significantly below the control, suggesting that trisomy 21 exerts a suppressive effect on GFAP gene expression. We found no instance in which AD-type changes of transcript expression preceded the appearance of neurofibrillary degeneration. The findings indicate that in trisomy 21, certain changes of mRNA prevalence previously described for AD neocortex are not a necessary antecedent to neurofibrillary degeneration.
    No preview · Article · May 1993 · Journal of Neuropathology and Experimental Neurology
  • Irma M. Parhad · Roderick Oishi · Arthur W. Clark
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    ABSTRACT: In amyotrophic lateral sclerosis (ALS), neuronal loss and axonal degeneration occur in motor neurons. Although there is limited axonal regeneration, surviving motor neurons send collateral sprouts to denervated muscle fibers. GAP-43, a protein enriched in growth cones and synaptic terminals, is thought to have a role in axonal elongation and synaptogenesis. GAP-43 messenger RNA (mRNA) expression was evaluated in ALS spinal cords using Northern blot analysis and in situ hybridization to assess whether surviving neurons can mount an appropriate response to injury. There was a two- to four-fold increase in GAP-43 mRNA in ALS that localized to the anterior horn cells. The increase in GAP-43 mRNA indicates that the mechanism which leads to degeneration in ALS does not compromise the neuron's capacity for vigorous expression of growth-associated proteins.
    No preview · Article · Jun 1992 · Annals of Neurology

Publication Stats

3k Citations
141.54 Total Impact Points


  • 1989-2011
    • The University of Calgary
      • • Department of Pathology and Laboratory Medicine
      • • Department of Clinical Neurosciences
      • • Department of Cell Biology and Anatomy
      • • Division of Neurosurgery
      Calgary, Alberta, Canada
  • 1980-1986
    • Johns Hopkins University
      • • Department of Pathology
      • • Department of Neurology
      Baltimore, Maryland, United States
  • 1985
    • Johns Hopkins Medicine
      Baltimore, Maryland, United States