Browsing by Author "Epperson, Francine"
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Item [(11)C]PiB PET in Gerstmann-Sträussler-Scheinker disease(e-Century Publishing Corporation, 2016) Deters, Kacie D.; Risacher, Shannon L.; Yoder, Karmen K.; Oblak, Adrian L.; Unverzagt, Frederick W.; Murrell, Jill R.; Epperson, Francine; Tallman, Eileen F.; Quaid, Kimberly A.; Farlow, Martin R.; Saykin, Andrew J.; Ghetti, Bernardino; Department of Pathology & Laboratory Medicine, IU School of MedicineGerstmann-Sträussler-Scheinker Disease (GSS) is a familial neurodegenerative disorder characterized clinically by ataxia, parkinsonism, and dementia, and neuropathologically by deposition of diffuse and amyloid plaques composed of prion protein (PrP). The purpose of this study was to evaluate if [(11)C]Pittsburgh Compound B (PiB) positron emission tomography (PET) is capable of detecting PrP-amyloid in PRNP gene carriers. Six individuals at risk for GSS and eight controls underwent [(11)C]PiB PET scans using standard methods. Approximately one year after the initial scan, each of the three asymptomatic carriers (two with PRNP P102L mutation, one with PRNP F198S mutation) underwent a second [(11)C]PiB PET scan. Three P102L carriers, one F198S carrier, and one non-carrier of the F198S mutation were cognitively normal, while one F198S carrier was cognitively impaired during the course of this study. No [(11)C]PiB uptake was observed in any subject at baseline or at follow-up. Neuropathologic study of the symptomatic individual revealed PrP-immunopositive plaques and tau-immunopositive neurofibrillary tangles in cerebral cortex, subcortical nuclei, and brainstem. PrP deposits were also numerous in the cerebellar cortex. This is the first study to investigate the ability of [(11)C]PiB PET to bind to PrP-amyloid in GSS F198S subjects. This finding suggests that [(11)C]PiB PET is not suitable for in vivo assessment of PrP-amyloid plaques in patients with GSS.Item Barriers and facilitators to participating in Alzheimer’s disease biomarker research in Black and White older adults(Wiley, 2023-06-05) Eliacin, Johanne; Polsinelli, Angelina J.; Epperson, Francine; Gao, Sujuan; Van Heiden, Sarah; Westmoreland, Glenda; Richards, Ralph; Richards, Mollie; Campbell, Christopher; Hendrie, Hugh; Risacher, Shannon L.; Saykin, Andrew J.; Wang, Sophia; Medicine, School of MedicineIntroduction: The study examined Black and White prospective participants' views of barriers to and facilitators of participation in Alzheimer's disease (AD) biomarker research. Methods: In a mixed-methods study, 399 community-dwelling Black and White older adults (age ≥55) who had never participated in AD research completed a survey about their perceptions of AD biomarker research. Individuals from lower socioeconomic and education backgrounds and Black men were over-sampled to address perspectives of traditionally under-represented groups. A subset of participants (n = 29) completed qualitative interviews. Results: Most participants expressed interest in biomarker research (overall 69%). However, Black participants were comparatively more hesitant than White participants (28.9% vs 15.1%), were more concerned about study risks (28.9% vs 15.1%), and perceived multiple barriers to participating in brain scans. These results persisted even after adjusting for trust and perceived knowledge of AD. Information was a primary barrier (when absent) and incentive (when provided) for AD biomarker research participation. Black older adults desired more information about AD (eg, risk, prevention), general research processes, and specific biomarker procedures. They also desired return of results to make informed decisions about their health, research-sponsored community awareness events, and for researchers to mitigate the burden placed on participants in research (eg, transportation, basic needs). Conclusion: Our findings increase representativeness in the literature by focusing on individuals with no history of AD research experience and those from traditionally underrepresented groups in research. Results suggest that the research community needs to improve information sharing and raising awareness, increase their presence in the communities of underrepresented groups, reduce incidental costs, and provide valuable personal health information to participants to increase interest. Specific recommendations for improving recruitment are addressed. Future studies will assess the implementation of evidence-based, socioculturally sensitive recruitment strategies to increase enrollment of Black older adults into AD biomarker studies. HIGHLIGHTS: Individuals from under-represented groups are interested in Alzheimer's disease (AD) biomarker research. After adjusting for trust and AD knowledge, Black participants were still more hesitant .Information is a barrier (when absent) to and incentive (when given) for biomarker studies. Reducing burden (e.g., transportation) is essential for recruiting Black older adults.Item Cerebral hypometabolism and grey matter density in MAPT intron 10 +3 mutation carriers(e-Century Publishing Corporation, 2014) Deters, Kacie D.; Risacher, Shannon L.; Farlow, Martin R.; Unverzagt, Frederick W.; Kareken, David A.; Hutchins, Gary D.; Yoder, Karmen K.; Murrell, Jill R.; Spina, Salvatore; Epperson, Francine; Gao, Sujuan; Saykin, Andrew J.; Ghetti, Bernardino; Department of Radiology and Imaging Sciences, IU School of MedicineMultiple systems tauopathy with presenile dementia (MSTD), a form of frontotemporal dementia with parkinsonism-17 with tau inclusions (FTDP-17T), is a neurodegenerative disorder caused by an (a) to (g) transition at position +3 of intron 10 of the microtubule associated protein tau (MAPT) gene. The mutation causes overexpression of 4 repeat (4R) tau isoforms with increased 4R/3R ratio leading to neurodegeneration. Clinically, these patients primarily present with behavioral variant FTD (bvFTD) and show disinhibition, disordered social comportment, and impaired executive function, memory, and speech. While altered glucose metabolism has been reported in subjects with sporadic bvFTD, it has yet to be investigated in an FTDP-17 sample of this size. In this study, eleven mutation carriers (5 males; mean age = 48.0 ± 6.9 years) and eight non-carriers (2 males; mean age = 43.7 ± 12.0 years) from a MSTD family were imaged using [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET). Eight of the MAPT intron 10 +3 mutation carriers met diagnostic criteria for bvFTD at the time of the PET scan, while three MAPT intron 10 +3 carriers were not cognitively impaired at the time of scan. Non-carriers had no clinically-relevant cognitive impairment at the time of the PET scan. Additionally, ten mutation carriers (5 males; mean age = 48.04 ± 2.1 years) and seven non-carriers (2 males; mean age 46.1 ± 4.1 years) underwent magnetic resonance imaging (MRI) which is an expanded sample size from a previous study. Seven MAPT mutation carriers met diagnostic criteria for bvFTD at the time of the MRI scan. Images were assessed on a voxel-wise basis for the effect of mutation carrier status. SPM8 was used for preprocessing and statistical analyses. Compared to non-carriers, MAPT mutation carriers showed lower [(18)F]FDG uptake bilaterally in the medial temporal lobe, and the parietal and frontal cortices. Anatomical changes were predominantly seen bilaterally in the medial temporal lobe areas which substantially overlapped with the hypometabolism findings. These anatomical and metabolic changes overlap previously described patterns of neurodegeneration in MSTD patients and are consistent with the characteristics of their cognitive dysfunction. These results suggest that neuroimaging can describe the neuropathology associated with this MAPT mutation.Item Cerebral hypometabolism in carriers of the intron 10 +3 MAPT mutation(Office of the Vice Chancellor for Research, 2014-04-11) Deters, K. D.; Risacher, Shannon L.; Farlow, Martin R.; Unverzagt, F. W.; Kareken, D. A.; Hutchins, Gary D.; Yoder, K. K.; Murrell, J. R.; Spina, S.; Epperson, Francine; Saykin, Andrew J.; Ghetti, B.Introduction: Multiple systems tauopathy with presenile dementia (MSTD), a form of frontotemporal dementia with parkinsonism-17 (FTDP-17), is a neurodegenerative disorder caused by an (a) to (g) transition at position +3 of intron 10 of the microtubule associated protein tau (MAPT) gene. The mutation causes over-expression of 4 repeat (4R) tau isoforms with increased 4R/3R ratio leading to neurodegeneration. Clinically, these patients primarily present with behavior variant FTD (bvFTD), showing disinhibition, and disordered social comportment, as well as impaired executive function, memory, and speech. While altered glucose metabolism has been reported in subjects with sporadic bvFTD, it has yet to be reported in an MSTD sample of this size carrying the intron 10 + 3 mutation. In this study, we used voxel-based analysis to assess brain metabolism using fluorodeoxyglucose (FDG) positron emission tomography (PET) in eleven mutation carriers and eight non-carriers. Methods: Eleven MAPT intron 10 + 3 mutation carriers (5 males; mean age = 48.0 +/- 6.9 years) and eight non-carriers (2 males; mean age = 43.7 +/- 12.0 years) were imaged using FDG PET with standard techniques. Briefly, dynamic PET imaging for 60 minutes followed an intravenous injection of 5-10 mCi of FDG. Scans were then reconstructed using standard techniques, pre-processed for motion correction, and normalized to MNI space. A static FDG image from 30-60 minutes was created from the appropriate frames and normalized to a cerebellar gray matter reference region to create an SUVR image for each participant. These SUVR images were then assessed on a voxel-wise basis for the effect of mutation carrier status, covaried for age at scan and gender and masked using a whole-brain mask. Results were displayed at a voxel-wise threshold of p<0.01 (uncorrected) and minimum cluster size (k) = 50 voxels. SPM8 was used for all pre-processing and voxel-wise statistical analyses. Results: Eight of the MAPT intron 10 + 3 mutation carriers showed mild cognitive impairment at the time of the PET scan (MMSE = 25.3 +/- 2.4), while three MAPT intron 10 + 3 carriers were not impaired at the time of scan (MMSE = 28.0 +/- 0.0). Non-carriers had no cognitive impairment at the time of PET scan (MMSE = 27.1 +/- 1.6). Overall, MAPT mutation carriers showed lower FDG uptake bilaterally in the hippocampus, parahippocampal gyrus, amygdala, superior parietal lobule, and in the prefrontal cortex compared to non-carriers. Conclusions: The present findings suggest individuals with the MAPT mutation at position +3 of intron 10 show symmetrical glucose hypometabolism relative to non-carriers in the medial temporal lobe, parietal cortex, and frontal cortex. These metabolic changes overlap previously described patterns of neurodegeneration in MSTD patients and are consistent with the characteristics of their cognitive dysfunction.Item Detection of tau in Gerstmann-Sträussler-Scheinker disease (PRNP F198S) by [18F]Flortaucipir PET(Biomed Central, 2018-10-29) Risacher, Shannon L.; Farlow, Martin R.; Bateman, Daniel R.; Epperson, Francine; Tallman, Eileen F.; Richardson, Rose; Murrell, Jill R.; Unverzagt, Frederick W.; Apostolova, Liana G.; Bonnin, Jose M.; Ghetti, Bernardino; Saykin, Andrew J.; Radiology and Imaging Sciences, School of MedicineThis study aimed to determine the pattern of [18F]flortaucipir uptake in individuals affected by Gerstmann-Sträussler-Scheinker disease (GSS) associated with the PRNP F198S mutation. The aims were to: 1) determine the pattern of [18F]flortaucipir uptake in two GSS patients; 2) compare tau distribution by [18F]flortaucipir PET imaging among three groups: two GSS patients, two early onset Alzheimer's disease patients (EOAD), two cognitively normal older adults (CN); 3) validate the PET imaging by comparing the pattern of [18F]flortaucipir uptake, in vivo, with that of tau neuropathology, post-mortem. Scans were processed to generate standardized uptake value ratio (SUVR) images. Regional [18F]flortaucipir SUVR was extracted and compared between GSS patients, EOADs, and CNs. Neuropathology and tau immunohistochemistry were carried out post-mortem on a GSS patient who died 9 months after the [18F]flortaucipir scan. The GSS patients were at different stages of disease progression. Patient A was mildly to moderately affected, suffering from cognitive, psychiatric, and ataxia symptoms. Patient B was moderately to severely affected, suffering from ataxia and parkinsonism accompanied by psychiatric and cognitive symptoms. The [18F]flortaucipir scans showed uptake in frontal, cingulate, and insular cortices, as well as in the striatum and thalamus. Uptake was greater in Patient B than in Patient A. Both GSS patients showed greater uptake in the striatum and thalamus than the EOADs and greater uptake in all evaluated regions than the CNs. Thioflavin S fluorescence and immunohistochemistry revealed that the anatomical distribution of tau pathology is consistent with that of [18F]flortaucipir uptake. In GSS patients, the neuroanatomical localization of pathologic tau, as detected by [18F]flortaucipir, suggests correlation with the psychiatric, motor, and cognitive symptoms. The topography of uptake in PRNP F198S GSS is strikingly different from that seen in AD. Further studies of the sensitivity, specificity, and anatomical patterns of tau PET in diseases with tau pathology are warranted.Item Diffuse Lewy Body Disease and Alzheimer Disease: Neuropathologic Phenotype Associated With the PSEN1 p.A396T Mutation(Oxford, 2019-06-05) Gondim, Dibson D; Oblak, Adrian; Murrell, Jill R; Richardson, Rose; Epperson, Francine; Ross, Owen A; Ghetti, Bernardino; Pathology and Laboratory Medicine, School of MedicineIn sporadic and dominantly inherited Alzheimer disease (AD), aggregation of both tau and α-synuclein may occur in neurons. Aggregates of either protein occur separately or coexist in the same neuron. It is not known whether the coaggregation of tau and α-synuclein in dominantly inherited AD occurs in association with specific mutations of the APP, PSEN1, or PSEN2 genes. The aim of this study was to provide the first characterization of the neuropathologic phenotype associated with the PSEN1 p.A396T mutation in a man who was clinically diagnosed as having AD, but for whom the PSEN1 mutation was found postmortem. The proband, who was 56 years old when cognitive impairment first manifested, died at 67 years of age. Neuropathologically, 3 proteinopathies were present in the brain. Widespread α-synuclein-immunopositive neuronal inclusions suggested a diagnosis of diffuse Lewy body disease (DLBD), while severe and widespread tau and amyloid-β pathologies confirmed the clinical diagnosis of AD. Immunohistochemistry revealed the coexistence of tau and α-synuclein aggregates in the same neuron. Neuropathologic and molecular studies in brains of carriers of the PSEN1 p.A396T mutation or other PSEN1 or PSEN2 mutations associated with the coexistence of DLBD and AD are needed to clarify whether tau and α-synuclein proteinopathies occur independently or whether a relationship exists between α-synuclein and tau that might explain the mechanisms of coaggregation.Item PET of Brain Prion Protein Amyloid in Gerstmann–Sträussler–Scheinker Disease(Wiley, 2010-03) Kepe, Vladimir; Ghetti, Bernardino; Farlow, Martin R.; Bresjanac, Mara; Miller, Karen; Huang, Sung-Cheng; Wong, Koon-Pong; Murrell, Jill R.; Piccardo, Pedro; Epperson, Francine; Repovš, Grega; Smid, Lojze M.; Petrič, Andrej; Siddarth, Prabha; Liu, Jie; Satyamurthy, Nagichettiar; Small, Gary W.; Barrio, Jorge R.; Pathology and Laboratory Medicine, School of MedicineIn vivo amyloid PET imaging was carried out on six symptomatic and asymptomatic carriers of PRNP mutations associated with the Gerstmann-Sträussler-Scheinker (GSS) disease, a rare familial neurodegenerative brain disorder demonstrating prion amyloid neuropathology, using 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile ([F-18]FDDNP). 2-Deoxy-2-[F-18]fluoro-d-glucose PET ([F-18]FDG) and magnetic resonance imaging (MRI) scans were also performed in each subject. Increased [F-18]FDDNP binding was detectable in cerebellum, neocortex and subcortical areas of all symptomatic gene carriers in close association with the experienced clinical symptoms. Parallel glucose metabolism ([F-18]FDG) reduction was observed in neocortex, basal ganglia and/or thalamus, which supports the close relationship between [F-18]FDDNP binding and neuronal dysfunction. Two asymptomatic gene carriers displayed no cortical [F-18]FDDNP binding, yet progressive [F-18]FDDNP retention in caudate nucleus and thalamus was seen at 1- and 2-year follow-up in the older asymptomatic subject. In vitro FDDNP labeling experiments on brain tissue specimens from deceased GSS subjects not participating in the in vivo studies indicated that in vivo accumulation of [F-18]FDDNP in subcortical structures, neocortices and cerebellum closely related to the distribution of prion protein pathology. These results demonstrate the feasibility of detecting prion protein accumulation in living patients with [F-18]FDDNP PET, and suggest an opportunity for its application to follow disease progression and monitor therapeutic interventions.