Person: Hedley-Whyte, E.
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Hedley-Whyte
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Hedley-Whyte, E.
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Publication Phylogenetic and epidemiologic evidence of multiyear incubation in human rabies(Wiley-Blackwell, 2014) Boland, Torrey A.; McGuone, Declan; Jindal, Jenelle; Rocha, Marcelo; Cumming, Melissa; Rupprecht, Charles E.; Barbosa, Taciana Fernandes Souza; de Novaes Oliveira, Rafael; Chu, Catherine; Cole, Andrew; Kotait, Ivanete; Kuzmina, Natalia A.; Yager, Pamela A.; Kuzmin, Ivan V.; Hedley-Whyte, E.; Brown, Catherine M.; Rosenthal, EricEight years after emigrating from Brazil, an otherwise healthy man developed rabies. An exposure prior to immigration was reported. Genetic analysis revealed a canine rabies virus variant found only in the patient’s home country, and the patient had not traveled internationally since immigrating to the United States. We describe how epidemiological, phylogenetic, and viral sequencing data provided confirmation that rabies encephalomyelitis may present after a long, multiyear incubation period, a consideration that previously has been hypothesized without the ability to exclude a more recent exposure. Accordingly, rabies should be considered in the diagnosis of any acute encephalitis, myelitis, or encephalomyelitis.Publication A 44-year-old man with eye, kidney, and brain dysfunction(Wiley-Blackwell, 2016) Vodopivec, Ivana; Oakley, Derek; Perugino, Cory; Venna, Nagagopal; Hedley-Whyte, E.; Stone, JohnRetinal vasculopathy with cerebral leukodystrophy (RVCL) is a rare, autosomal dominant condition caused by mutations of the three-prime repair exonuclease-1 (TREX1). The phenotypic expressions range from isolated retinal involvement to varying degrees of retinopathy, cerebral infarction with calcium depositions, nephropathy, and hepatopathy. We report a case of RVCL caused by a novel TREX1 mutation. This patient’s multisystem presentation, retinal involvement interpreted as “retinal vasculitis”, and improvement of neuroimaging abnormalities with dexamethasone led to the accepted diagnosis of a rheumatologic disorder resembling Behçet’s disease. Clinicians should consider RVCL in any patient with retinal capillary obliterations associated with tumefactive brain lesions or nephropathy.Publication Ataxia, Dementia, and Hypogonadotropism Caused by Disordered Ubiquitination(New England Journal of Medicine (NEJM/MMS), 2013) Margolin, David H.; Kousi, Maria; Chan, Yee-Ming; Lim, Elaine T.; Schmahmann, Jeremy; Hadjivassiliou, Marios; Hall, Janet E.; Adam, Ibrahim; Dwyer, Andrew; Plummer, Lacey; Aldrin, Stephanie V.; O, Julia; Kirby, Andrew; Lage, Kasper; Milunsky, Aubrey; Milunsky, Jeff M.; Chan, Jennifer; Hedley-Whyte, E.; Daly, Mark; Katsanis, Nicholas; Seminara, StephanieIn recent years, we have seen great advances in the elucidation of genetic causes of cerebellar ataxia, with newly identified genes regulating a wide spectrum of cellular functions, including intracellular signaling, tau regulation, and mitochondrial function.1 However, a genetic defect cannot be found in approximately 40% of patients with ataxia,1 including those in whom ataxia is associated with reproductive endocrine failure, a syndrome first reported by Gordon Holmes in 1908.2 Most patients with this syndrome have a hypogonadotropic condition, with defective secretion of gonadotropins by the pituitary gland.3-12 Strikingly, genes associated with ataxia have little functional overlap with genes associated with hypogonadotropic hypogonadism, which encode proteins involved in the biologic function of the neurons that secrete gonadotropin-releasing hormone (GnRH).13 A decade ago, we described a consanguineous family with a syndrome of cerebellar ataxia, dementia, and hypogonadotropic hypogonadism.12 Here we report the results of whole-exome and targeted sequencing performed to identify mutations that underlie the syndrome in this kindred and in unrelated patients.Publication Glioblastoma Recurrence after Cediranib Therapy in Patients: Lack of "Rebound" Revascularization as Mode of Escape(American Association for Cancer Research (AACR), 2011) di Tomaso, E.; Snuderl, M.; Kamoun, W. S.; Duda, Dan; Auluck, P. K.; Fazlollahi, L.; Andronesi, Ovidiu; Frosch, Matthew; Wen, Patrick; Plotkin, Scott; Hedley-Whyte, E.; Sorensen, Alma Gregory; Batchelor, Tracy; Jain, RadhikaRecurrent glioblastomas (rGBM) invariably relapse after initial response to anti-VEGF therapy. There are two prevailing hypotheses on how these tumors escape antiangiogenic therapy: switch to VEGF-independent angiogenic pathways and vessel co-option. However, direct evidence in rGBM patients is lacking. Thus, we compared molecular, cellular and vascular parameters in autopsy tissues from five rGBM patients who had been treated with the pan-VEGF receptor tyrosine kinase inhibitor cediranib versus seven patients who received no therapy or chemoradiation but no antiangiogenic agents. After cediranib treatment, endothelial proliferation and glomeruloid vessels were decreased, and vessel diameters and perimeters were reduced to levels comparable to the unaffected contralateral brain hemisphere. In addition, tumor endothelial cells expressed molecular markers specific to the blood-brain barrier, indicative of a lack of revascularization despite the discontinuation of therapy. Surprisingly, in cediranib-treated GBM cellular density in the central area of the tumor was lower than in control cases and gradually decreased towards the infiltrating edge, indicative of a change in growth pattern of rGBMs after cediranib treatment, unlike that after chemo-radiation. Finally, cediranib treated GBMs showed high levels of PDGF-C and c-Met expression and infiltration by myeloid cells, which may potentially contribute to resistance to anti-VEGF therapy. In summary, we show that rGBMs switch their growth pattern after anti-VEGF therapy – characterized by lower tumor cellularity in the central area, decreased pseudopalisading necrosis and blood vessels with normal molecular expression and morphology without a second wave of angiogenesis.Publication Nodular bilateral amygdala degeneration in demented individuals(Springer Nature, 2010) Lain, Aurelio Hernandez; Lieberman, Andrew P.; Pfannl, Rolf; Hedley-Whyte, E.Among more than 2050 brains in our Alzheimer disease brain banks we came across three brains with well demarcated indurated white-yellow nodules in the amygdalas. Microscopically, these nodules were composed of numerous lipid-laden macrophages located in the central region surrounded by an eosinophilic hyaline-like material with minimal reactive gliosis in the periphery. Neurons within these lesions had a normal appearance but were moderately decreased in number. Beta-amyloid, tau and alpha-synuclein immunostaining revealed no abnormal deposits within the nodules. The three patients had long histories of dementia (one linked to a presenilin-1 mutation). The neuropathological diagnoses were Alzheimer disease in two of them and an unclassified tauopathy with argyrophilic grains in the third.Publication TDP-43 Proteinopathy and Motor Neuron Disease in Chronic Traumatic Encephalopathy(Oxford University Press (OUP), 2010) McKee, Ann C.; Gavett, Brandon E.; Stern, Robert A.; Nowinski, Christopher J.; Cantu, Robert C.; Kowall, Neil; Perl, Daniel P.; Hedley-Whyte, E.; Price, Bruce; Sullivan, Chris; Morin, Peter; Lee, Hyo-Soon; Kubilus, Caroline A.; Daneshvar, Daniel H.; Wulff, Megan; Budson, AndrewEpidemiological evidence suggests that the incidence of amyotrophic lateral sclerosis is increased in association with head injury. Repetitive head injury is also associated with the development of chronic traumatic encephalopathy (CTE), a tauopathy characterized by neurofibrillary tangles throughout the brain in the relative absence of β-amyloid deposits. We examined 12 cases of CTE and, in 10, found a widespread TAR DNA-binding protein of approximately 43 kd (TDP-43) proteinopathy affecting the frontal and temporal cortices, medial temporal lobe, basal ganglia, diencephalon, and brainstem. Three athletes with CTE also developed a progressive motor neuron disease with profound weakness, atrophy, spasticity, and fasciculations several years before death. In these 3 cases, there were abundant TDP-43–positive inclusions and neurites in the spinal cord in addition to tau neurofibrillary changes, motor neuron loss, and corticospinal tract degeneration. The TDP-43 proteinopathy associated with CTE is similar to that found in frontotemporal lobar degeneration with TDP-43 inclusions, in that widespread regions of the brain are affected. Akin to frontotemporal lobar degeneration with TDP-43 inclusions, in some individuals with CTE, the TDP-43 proteinopathy extends to involve the spinal cord and is associated with motor neuron disease. This is the first pathological evidence that repetitive head trauma experienced in collision sports might be associated with the development of a motor neuron disease.Publication Scapuloperoneal spinal muscular atrophy and CMT2C are allelic disorders caused by alterations in TRPV4(Springer Nature, 2009) Deng, Han-Xiang; Klein, Christopher J; Yan, Jianhua; Shi, Yong; Wu, Yanhong; Fecto, Faisal; Yau, Hau-Jie; Yang, Yi; Zhai, Hong; Siddique, Nailah; Hedley-Whyte, E.; DeLong, Robert; Martina, Marco; Dyck, Peter J; Siddique, TeepuScapuloperoneal spinal muscular atrophy (SPSMA) and hereditary motor and sensory neuropathy type IIC (HMSN IIC, also known as HMSN2C or Charcot-Marie-Tooth disease type 2C (CMT2C)) are phenotypically heterogeneous disorders involving topographically distinct nerves and muscles. We originally described a large New England family of French-Canadian origin with SPSMA and an American family of English and Scottish descent with CMT2C1,2. We mapped SPSMA and CMT2C risk loci to 12q24.1–q24.31 with an overlapping region between the two diseases3,4. Further analysis reduced the CMT2C risk locus to a 4-Mb region5. Here we report that SPSMA and CMT2C are allelic disorders caused by mutations in the gene encoding the transient receptor potential cation channel, subfamily V, member 4 (TRPV4). Functional analysis revealed that increased calcium channel activity is a distinct property of both SPSMA- and CMT2C-causing mutant proteins. Our findings link mutations in TRPV4 to altered calcium homeostasis and peripheral neuropathies, implying a pathogenic mechanism and possible options for therapy for these disorders.Publication Chronic Traumatic Encephalopathy in Athletes: Progressive Tauopathy After Repetitive Head Injury(Oxford University Press (OUP), 2009) McKee, Ann C.; Cantu, Robert C.; Nowinski, Christopher J.; Hedley-Whyte, E.; Gavett, Brandon E.; Budson, Andrew; Santini, Veronica E.; Lee, Hyo-Soon; Kubilus, Caroline A.; Stern, Robert A.Since the 1920s, it has been known that the repetitive brain trauma associated with boxing may produce a progressive neurological deterioration, originally termed “dementia pugilistica” and more recently, chronic traumatic encephalopathy (CTE). We review the 47 cases of neuropathologically verified CTE recorded in the literature and document the detailed findings of CTE in 3 professional athletes: one football player and 2 boxers. Clinically, CTE is associated with memory disturbances, behavioral and personality changes, Parkinsonism, and speech and gait abnormalities. Neuropathologically, CTE is characterized by atrophy of the cerebral hemispheres, medial temporal lobe, thalamus, mammillary bodies, and brainstem, with ventricular dilatation and a fenestrated cavum septum pellucidum. Microscopically, there are extensive tau-immunoreactive neurofibrillary tangles, astrocytic tangles, and spindle-shaped and threadlike neurites throughout the brain. The neurofibrillary degeneration of CTE is distinguished from other tauopathies by preferential involvement of the superficial cortical layers, irregular, patchy distribution in the frontal and temporal cortices, propensity for sulcal depths, prominent perivascular, periventricular and subpial distribution, and marked accumulation of tau-immunoreactive astrocytes. Deposition of beta amyloid, most commonly as diffuse plaques, occurs in fewer than half the cases. CTE is a neuropathologically distinct, slowly progressive tauopathy with a clear environmental etiology.Publication Preservation of Neuronal Number Despite Age-Related Cortical Brain Atrophy in Elderly Subjects Without Alzheimer Disease(Oxford University Press (OUP), 2008) Freeman, Stefanie H.; Kandel, Ruth; Cruz, Luis; Rozkalne, Anete; Newell, Kathy; Frosch, Matthew; Hedley-Whyte, E.; Locascio, Joseph; Lipsitz, Lewis; Hyman, BradleyCerebral volume loss has long been associated with normal aging but whether this is due to aging itself or to age-related diseases including incipient Alzheimer disease (AD) is uncertain. To understand the changes that occur in the aging brain, we examined the cerebral cortex of 27 normal individuals ranging in age from 56 to 103 years. None fulfilled the criteria for the neuropathological diagnosis of AD or other neurodegenerative disease. Seventeen of the elderly participants had cognitive testing an average of 6.7 months prior to death. We used quantitative approaches to analyze cortical thickness, neuronal number, and density. Frontal and temporal neocortical regions had clear evidence of cortical thinning with age but total neuronal numbers in frontal and temporal neocortical regions remained relatively constant over a 50-year age range. These data suggest that loss of neuronal and dendritic architecture, rather than loss of neurons, underlies neocortical volume loss with increasing age in the absence of AD.Publication Adult Onset Leukodystrophy with Neuroaxonal Spheroids: Clinical, Neuroimaging and Neuropathologic Observations(Wiley-Blackwell, 2009) Freeman, Stefanie H.; Hyman, Bradley; Sims, Katherine Bustin; Hedley-Whyte, E.; Vossough, Arastoo; Frosch, Matthew; Schmahmann, JeremyPigmented orthochromatic leukodystrophy (POLD) and Hereditary diffuse leukoencephalopathy with spheroids HDLS are two adult onset leukodystrophies with neuroaxonal spheroids presenting with prominent neurobehavioral, cognitive, and motor symptoms. These are familial or sporadic disorders characterized by cerebral white matter degeneration including myelin and axonal loss, gliosis, macrophages, and axonal spheroids. We report clinical, neuroimaging and pathological correlations of four women ages 34–50 years with adult onset leukodystrophy. Their disease course ranged from 1.5–8 years. Three patients had progressive cognitive and behavioral changes whereas one had acute onset. Neuroimaging revealed white matter abnormalities characterized by symmetric, bilateral, T2 hyperintense and T1 hypointense MRI signal involving frontal lobe white matter in all patients. Extensive laboratory investigations were negative apart from abnormalities in some mitochondrial enzymes and immunologic parameters. Autopsies demonstrated severe leukodystrophy with myelin and axonal loss, axonal spheroids, and macrophages with early and severe frontal white matter involvement. The extent and degree of changes outside the frontal lobe appeared to correlate with disease duration. The prominent neurobehavioral deficits and frontal white matter disease provides clinical-pathologic support for association pathways linking distributed neural circuits subserving cognition. These observations lend further support to the notion that white matter disease alone can account for dementia.