Person: Folkerth, Rebecca D.
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Folkerth
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Rebecca D.
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Folkerth, Rebecca D.
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Publication HIV-2 Encephalitis: Case Report and Literature Review(Mary Ann Liebert, 2012) Wood, Brian R.; Klein, Joshua; Lyons, Jennifer L; Milner, Danny; Phillips, Richard Edmund; Schutten, Martin; Folkerth, Rebecca D.; Ciarlini, Pedro; Henrich, Timothy J.; Johnson, JenniferWe report the case of a 59-year-old man who moved from Cape Verde to Massachusetts at the age of 29. He had multiple sexual contacts with female partners in Cape Verde and with West African women in Massachusetts, as well as multiple past indeterminate HIV-1 antibody tests. He presented to our facility with 2–3 months of inappropriate behaviors, memory impairment, weight loss, and night sweats, at which time he was found to have an abnormal enhancing lesion of the corpus collosum on brain magnetic resonance imaging (MRI). Laboratory testing revealed a CD4 count of \(63 cells/mm^3\), positive HIV-2 Western blot, serum HIV-2 RNA polymerase chain reaction (PCR) of 1160 copies per milliliter and cerebrospinal fluid (CSF) HIV-2 RNA PCR of 2730 copies per milliliter. Brain biopsy demonstrated syncytial giant cells centered around small blood vessels and accompanied by microglia, which correlated with prior pathologic descriptions of HIV-2 encephalitis and with well-described findings of HIV-1 encephalitis. Based on genotype resistance assay results, treatment guidelines, and prior studies validating success with lopinavir-ritonavir, he was treated with tenofovir-emtricitabine and lopinavir-ritonavir, which has led to virologic suppression along with steady neurologic and radiologic improvement, although he continues to have deficits.Publication A TSC signaling node at the peroxisome regulates mTORC1 and autophagy in response to ROS(2013) Zhang, Jiangwei; Kim, Jinhee; Alexander, Angela; Cai, Shengli; Tripathi, Durga Nand; Dere, Ruhee; Tee, Andrew R.; Tait-Mulder, Jacqueline; Di Nardo, Alessia; Han, Juliette M.; Kwiatkowski, Erica; Dunlop, Elaine A.; Dodd, Kayleigh M.; Folkerth, Rebecca D.; Faust, Phyllis L.; Kastan, Michael B.; Sahin, Mustafa; Walker, Cheryl LynSubcellular localization is emerging as an important mechanism for mTORC1 regulation. We report that the tuberous sclerosis complex (TSC) signaling node, TSC1, TSC2 and Rheb, localizes to peroxisomes, where it regulates mTORC1 in response to reactive oxygen species (ROS). TSC1 and TSC2 were bound by PEX19 and PEX5, respectively, and peroxisome-localized TSC functioned as a Rheb GAP to suppress mTORC1 and induce autophagy. Naturally occurring pathogenic mutations in TSC2 decreased PEX5 binding, abrogated peroxisome localization, Rheb GAP activity, and suppression of mTORC1 by ROS. Cells lacking peroxisomes were deficient in mTORC1 repression by ROS and peroxisome-localization deficient TSC2 mutants caused polarity defects and formation of multiple axons in neurons. These data identify a role for TSC in responding to ROS at the peroxisome, and identify the peroxisome as a signaling organelle involved in regulation of mTORC1.Publication Angiomatous meningiomas have a distinct genetic profile with multiple chromosomal polysomies including polysomy of chromosome 5(Impact Journals LLC, 2014) Abedalthagafi, Malak; Merrill, Parker H.; Bi, Wenya; Jones, Robert T.; Listewnik, Marc L.; Ramkissoon, Shakti H.; Thorner, Aaron R.; Dunn, Ian; Beroukhim, Rameen; Alexander, Brian; Brastianos, Priscilla; Francis, Joshua M.; Folkerth, Rebecca D.; Ligon, Keith; Hummelen, Paul Van; Ligon, Azra; Santagata, SandroMeningiomas are a diverse group of tumors with a broad spectrum of histologic features. There are over 12 variants of meningioma, whose genetic features are just beginning to be described. Angiomatous meningioma is a World Health Organization (WHO) meningioma variant with a predominance of blood vessels. They are uncommon and confirming the histopathologic classification can be challenging. Given a lack of biomarkers that define the angiomatous subtype and limited understanding of the genetic changes underlying its tumorigenesis, we compared the genomic characteristics of angiomatous meningioma to more common meningioma subtypes. While typical grade I meningiomas demonstrate monosomy of chromosome 22 or lack copy number aberrations, 13 of 14 cases of angiomatous meningioma demonstrated a distinct copy number profile – polysomies of at least one chromosome, but often of many, especially in chromosomes 5, 13, and 20. WHO grade II atypical meningiomas with angiomatous features have both polysomies and genetic aberrations characteristic of other atypical meningiomas. Sequencing of over 560 cancer-relevant genes in 16 cases of angiomatous meningioma showed that these tumors lack common mutations found in other variants of meningioma. Our study demonstrates that angiomatous meningiomas have distinct genomic features that may be clinically useful for their diagnosis.Publication Atypical presentation of cerebral schistosomiasis four years after exposure to Schistosoma mansoni☆(Elsevier, 2014) Rose, Matthew; Zimmerman, Eli E.; Hsu, Liangge; Golby, Alexandra; Saleh, Emam; Folkerth, Rebecca D.; Santagata, Sandro; Milner, Danny; Ramkissoon, Shakti H.Schistosomiasis is the second most socioeconomically devastating parasitic disease worldwide, affecting over 240 million people in 77 countries on 5 continents and killing 300,000 people annually in sub-Saharan Africa alone. Neuroschistosomiasis is caused by granuloma formation around eggs that lodge in the CNS, with Schistosoma mansoni and Schistosoma haematobium usually affecting the spinal cord and Schistosoma japonicum causing most reported cerebral disease. We report a case of a previously healthy 25-year-old woman native to the United States who presented with a single generalized tonic–clonic seizure without other neurologic symptoms four years after spending a semester in Ghana where she went swimming once in a river. Brain MRI showed areas of signal abnormality and mottled nodular linear enhancement in the left temporal and right posterior temporal/parietal lobes and right cerebellum without mass effect. A biopsy of the left temporal lesion showed prominent granulomas with dense mixed inflammatory infiltrates composed of eosinophils, plasma cells, and lymphocytes surrounding refractile egg shells containing characteristic embryonal cells and von Lichtenberg's envelope and displaying the pathognomonic spine shape of S. mansoni. Serum ELISA and antibody immunoblots confirmed exposure to S. mansoni. In summary, we describe the atypical combination of cerebral schistosomiasis due to S. mansoni, after a prolonged interval of four years, from a single known exposure.Publication The first NINDS/NIBIB consensus meeting to define neuropathological criteria for the diagnosis of chronic traumatic encephalopathy(Springer Berlin Heidelberg, 2015) McKee, Ann C.; Cairns, Nigel J.; Dickson, Dennis W.; Folkerth, Rebecca D.; Dirk Keene, C.; Litvan, Irene; Perl, Daniel P.; Stein, Thor D.; Vonsattel, Jean-Paul; Stewart, William; Tripodis, Yorghos; Crary, John F.; Bieniek, Kevin F.; Dams-O’Connor, Kristen; Alvarez, Victor E.; Gordon, Wayne A.Chronic traumatic encephalopathy (CTE) is a neurodegeneration characterized by the abnormal accumulation of hyperphosphorylated tau protein within the brain. Like many other neurodegenerative conditions, at present, CTE can only be definitively diagnosed by post-mortem examination of brain tissue. As the first part of a series of consensus panels funded by the NINDS/NIBIB to define the neuropathological criteria for CTE, preliminary neuropathological criteria were used by 7 neuropathologists to blindly evaluate 25 cases of various tauopathies, including CTE, Alzheimer’s disease, progressive supranuclear palsy, argyrophilic grain disease, corticobasal degeneration, primary age-related tauopathy, and parkinsonism dementia complex of Guam. The results demonstrated that there was good agreement among the neuropathologists who reviewed the cases (Cohen’s kappa, 0.67) and even better agreement between reviewers and the diagnosis of CTE (Cohen’s kappa, 0.78). Based on these results, the panel defined the pathognomonic lesion of CTE as an accumulation of abnormal hyperphosphorylated tau (p-tau) in neurons and astroglia distributed around small blood vessels at the depths of cortical sulci and in an irregular pattern. The group also defined supportive but non-specific p-tau-immunoreactive features of CTE as: pretangles and NFTs affecting superficial layers (layers II–III) of cerebral cortex; pretangles, NFTs or extracellular tangles in CA2 and pretangles and proximal dendritic swellings in CA4 of the hippocampus; neuronal and astrocytic aggregates in subcortical nuclei; thorn-shaped astrocytes at the glial limitans of the subpial and periventricular regions; and large grain-like and dot-like structures. Supportive non-p-tau pathologies include TDP-43 immunoreactive neuronal cytoplasmic inclusions and dot-like structures in the hippocampus, anteromedial temporal cortex and amygdala. The panel also recommended a minimum blocking and staining scheme for pathological evaluation and made recommendations for future study. This study provides the first step towards the development of validated neuropathological criteria for CTE and will pave the way towards future clinical and mechanistic studies. Electronic supplementary material The online version of this article (doi:10.1007/s00401-015-1515-z) contains supplementary material, which is available to authorized users.Publication Mutations in the substrate binding glycine-rich loop of the mitochondrial processing peptidase-α protein (PMPCA) cause a severe mitochondrial disease(Cold Spring Harbor Laboratory Press, 2016) Joshi, Mugdha; Anselm, Irina; Shi, Jiahai; Bale, Tejus A.; Towne, Meghan; Schmitz-Abe, Klaus; Crowley, Laura; Giani, Felix C.; Kazerounian, Shideh; Markianos, Kyriacos; Lidov, Hart; Folkerth, Rebecca D.; Sankaran, Vijay; Agrawal, PankajWe describe a large Lebanese family with two affected members, a young female proband and her male cousin, who had multisystem involvement including profound global developmental delay, severe hypotonia and weakness, respiratory insufficiency, blindness, and lactic acidemia—findings consistent with an underlying mitochondrial disorder. Whole-exome sequencing was performed on DNA from the proband and both parents. The proband and her cousin carried compound heterozygous mutations in the PMPCA gene that encodes for α-mitochondrial processing peptidase (α-MPP), a protein likely involved in the processing of mitochondrial proteins. The variants were located close to and postulated to affect the substrate binding glycine-rich loop of the α-MPP protein. Functional assays including immunofluorescence and western blot analysis on patient's fibroblasts revealed that these variants reduced α-MPP levels and impaired frataxin production and processing. We further determined that those defects could be rescued through the expression of exogenous wild-type PMPCA cDNA. Our findings link defective α-MPP protein to a severe mitochondrial disease.Publication Serotonin Receptors in the Medulla Oblongata of the Human Fetus and Infant: The Analytic Approach of the International Safe Passage Study(Oxford University Press, 2016) Haynes, Robin; Folkerth, Rebecca D.; Paterson, David S.; Broadbelt, Kevin G.; Dan Zaharie, S.; Hewlett, Richard H.; Dempers, Johan J.; Burger, Elsie; Wadee, Shabbir; Schubert, Pawel; Wright, Colleen; Sens, Mary Ann; Nelsen, Laura; Randall, Bradley B.; Tran, Hoa; Geldenhuys, Elaine; Elliott, Amy J.; Odendaal, Hein J.; Kinney, HannahThe Safe Passage Study is an international, prospective study of approximately 12 000 pregnancies to determine the effects of prenatal alcohol exposure (PAE) upon stillbirth and the sudden infant death syndrome (SIDS). A key objective of the study is to elucidate adverse effects of PAE upon binding to serotonin (5-HT) 1A receptors in brainstem homeostatic networks postulated to be abnormal in unexplained stillbirth and/or SIDS. We undertook a feasibility assessment of 5-HT1A receptor binding using autoradiography in the medulla oblongata (6 nuclei in 27 cases). 5-HT1A binding was compared to a reference dataset from the San Diego medical examiner’s system. There was no adverse effect of postmortem interval ≤100 h. The distribution and quantitated values of 5-HT1A binding in Safe Passage Study cases were essentially identical to those in the reference dataset, and virtually identical between stillbirths and live born fetal cases in grossly non-macerated tissues. The pattern of binding was present at mid-gestation with dramatic changes in binding levels in the medullary 5-HT nuclei over the second half of gestation; there was a plateau at lower levels in the neonatal period and into infancy. This study demonstrates feasibility of 5-HT1A binding analysis in the medulla in the Safe Passage Study.Publication Alzheimer's Disease Amyloid-\(\beta\) Links Lens and Brain Pathology in Down Syndrome(Public Library of Science, 2010) Moncaster, Juliet A.; Lu, Suqian; Burton, Mark A.; Ghosh, Joy G.; Soscia, Stephanie J.; Mocofanescu, Anca; Kuszak, Jer R.; Pineda, Roberto; Moir, Robert; Ericsson, Maria; Folkerth, Rebecca D.; Robb, Richard; Clark, John I.; Tanzi, Rudolph; Hunter, David; Goldstein, LeeDown syndrome (DS, trisomy 21) is the most common chromosomal disorder and the leading genetic cause of intellectual disability in humans. In DS, triplication of chromosome 21 invariably includes the APP gene (21q21) encoding the Alzheimer's disease (AD) amyloid precursor protein (APP). Triplication of the APP gene accelerates APP expression leading to cerebral accumulation of APP-derived amyloid-\(\beta\) peptides (A\(\beta\)), early-onset AD neuropathology, and age-dependent cognitive sequelae. The DS phenotype complex also includes distinctive early-onset cerulean cataracts of unknown etiology. Previously, we reported increased A\(\beta\) accumulation, co-localizing amyloid pathology, and disease-linked supranuclear cataracts in the ocular lenses of subjects with AD. Here, we investigate the hypothesis that related AD-linked A\(\beta\) pathology underlies the distinctive lens phenotype associated with DS. Ophthalmological examinations of DS subjects were correlated with phenotypic, histochemical, and biochemical analyses of lenses obtained from DS, AD, and normal control subjects. Evaluation of DS lenses revealed a characteristic pattern of supranuclear opacification accompanied by accelerated supranuclear A\(\beta\) accumulation, co-localizing amyloid pathology, and fiber cell cytoplasmic A\(\beta\) aggregates (\(\sim\)5 to 50 nm) identical to the lens pathology identified in AD. Peptide sequencing, immunoblot analysis, and ELISA confirmed the identity and increased accumulation of A\(\beta\) in DS lenses. Incubation of synthetic A\(\beta\) with human lens protein promoted protein aggregation, amyloid formation, and light scattering that recapitulated the molecular pathology and clinical features observed in DS lenses. These results establish the genetic etiology of the distinctive lens phenotype in DS and identify the molecular origin and pathogenic mechanism by which lens pathology is expressed in this common chromosomal disorder. Moreover, these findings confirm increased A\(\beta\) accumulation as a key pathogenic determinant linking lens and brain pathology in both DS and AD.Publication Gray Matter Injury Associated with Periventricular Leukomalacia in the Premature Infant(Springer-Verlag, 2007) Pierson, Christopher R.; Folkerth, Rebecca D.; Billiards, Saraid S.; Trachtenberg, Felicia L.; Drinkwater, Mark E.; Volpe, Joseph; Kinney, HannahNeuroimaging studies indicate reduced volumes of certain gray matter regions in survivors of prematurity with periventricular leukomalacia (PVL). We hypothesized that subacute and/or chronic gray matter lesions are increased in incidence and severity in PVL cases compared to non-PVL cases at autopsy. Forty-one cases of premature infants were divided based on cerebral white matter histology: PVL (n = 17) with cerebral white matter gliosis and focal periventricular necrosis; diffuse white matter gliosis (DWMG) (n = 17) without necrosis; and “Negative” group (n = 7) with no abnormalities. Neuronal loss was found almost exclusively in PVL, with significantly increased incidence and severity in the thalamus (38%), globus pallidus (33%), and cerebellar dentate nucleus (29%) compared to DWMG cases. The incidence of gliosis was significantly increased in PVL compared to DWMG cases in the deep gray nuclei (thalamus/basal ganglia; 50–60% of PVL cases), and basis pontis (100% of PVL cases). Thalamic and basal ganglionic lesions occur almost exclusively in infants with PVL. Gray matter lesions occur in a third or more of PVL cases suggesting that white matter injury generally does not occur in isolation, and that the term “perinatal panencephalopathy” may better describe the scope of the neuropathology.