Browsing by Author "Matthews, Brandy R."
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Item Apolipoprotein ε4 Is Associated with Lower Brain Volume in Cognitively Normal Chinese but Not White Older Adults(PLoS, 2016-06-17) Yokoyama, Jennifer S.; Lee, Allen K.L.; Takada, Leonel T.; Busovaca, Edgar; Bonham, Luke W.; Chao, Steven Z.; Tse, Marian; He, Jing; Schwarz, Christopher G.; Carmichael, Owen T.; Matthews, Brandy R.; Karydas, Anna; Weiner, Michael W.; Coppola, Giovanni; DeCarli, Charles S.; Miller, Bruce L.; Rosen, Howard J.; Department of Neurology, IU School of MedicineStudying ethnically diverse groups is important for furthering our understanding of biological mechanisms of disease that may vary across human populations. The ε4 allele of apolipoprotein E (APOE ε4) is a well-established risk factor for Alzheimer's disease (AD), and may confer anatomic and functional effects years before clinical signs of cognitive decline are observed. The allele frequency of APOE ε4 varies both across and within populations, and the size of the effect it confers for dementia risk may be affected by other factors. Our objective was to investigate the role APOE ε4 plays in moderating brain volume in cognitively normal Chinese older adults, compared to older white Americans. We hypothesized that carrying APOE ε4 would be associated with reduced brain volume and that the magnitude of this effect would be different between ethnic groups. We performed whole brain analysis of structural MRIs from Chinese living in America (n = 41) and Shanghai (n = 30) and compared them to white Americans (n = 71). We found a significant interaction effect of carrying APOE ε4 and being Chinese. The APOE ε4xChinese interaction was associated with lower volume in bilateral cuneus and left middle frontal gyrus (Puncorrected<0.001), with suggestive findings in right entorhinal cortex and left hippocampus (Puncorrected<0.01), all regions that are associated with neurodegeneration in AD. After correction for multiple testing, the left cuneus remained significantly associated with the interaction effect (PFWE = 0.05). Our study suggests there is a differential effect of APOE ε4 on brain volume in Chinese versus white cognitively normal elderly adults. This represents a novel finding that, if verified in larger studies, has implications for how biological, environmental and/or lifestyle factors may modify APOE ε4 effects on the brain in diverse populations.Item Characterizing neurodegeneration in the human connectome: a network science study of hereditary diffuse leukoencephalopathy with spheroids(Office of the Vice Chancellor for Research, 2015-04-17) Contreras, Joey; Rishacher, Shannon L.; West, John D.; Wu, Yu-Chien; Wang, Yang; Murrell, Jill R.; Dzemidzic, Mario; Farlow, Martin R.; Unverzagt, Frederik; Ghetti, Bernardino; Matthews, Brandy R.; Quaid, Kimberly A.; Sporns, Olaf; Saykin, Andrew J.; Goñi, JoaquínAbstract The effect of white matter neurodegeneration on the human connectome and its functional implications is an important topic with clinical applicability of advanced brain network analysis. The aim of this study was to evaluate integration and segregation changes in structural connectivity (SC) that arise as consequence of white matter lesions in hereditary diffuse leukoencephalopathy with spheroids (HDLS). Also, we assessed the relationship between HDLS induced structural changes and changes in restingstate functional connectivity (rsFC). HDLS is a rare autosomal dominant neurodegenerative disorder caused by mutations in the CSF1R gene. HDLS is characterized by severe white matter damage leading to prominent subcortical lesions detectable by structural MRI. Spheroids, an important feature of HDLS, are axonal swellings indicating damage. HDLS causes progressive motor and cognitive decline. The clinical symptoms of HDLS are often mistaken for other diseases such as Alzheimer’s disease, frontotemporal dementia, atypical Parkinsonism or multiple sclerosis. Our study is focused on the follow-up of two siblings, one being a healthy control (HC) and the other one being an HDLS patient. In this study, deterministic fiber-tractography of diffusion MRI with multi-tensor modeling was used in order to obtain reliable and reproducible SC matrices. Integration changes were measured by means of SC shortest-paths (including distance and number of edges), whereas segregation and community organization were measured by means of a multiplex modularity analysis on the SC matrices. Additionally, rsFC was modeled using state of the art preprocessing methods including motion regressors and scrubbing. This allowed us to characterize functional changes associated to the disease. Major integration disruption involved superior frontal (L,R), caudal middle frontal (R), precentral (L,R), inferior parietal (R), insula (R) and paracentral (L) regions. Major segregation changes were characterized by the disruption of a large bilateral module that was observed in the HC that includes the frontal pole (L,R), medial orbitofrontal (L,R), rostral middle frontal (L), superior frontal (L,R), precentral (L,R), paracentral (L,R), rostral anterior cingulate (L,R), caudal anterior cingulate (L,R), posterior cingulate (L,R), postcentral (L), precuneus (L,R), lateral orbitofrontal (R) and parsorbitalis (R). The combination of tractography and network analysis permitted the detection and characterization of profound cortical to cortical changes in integration and segregation associated with HDLS white matter lesions and its relationship with rsFC. Our preliminary findings suggest that advanced network analytic approaches show promising sensitivity to known white matter pathology and progression. Further Indiana Alzheimer Disease Center Symposium. March 6, 2015. research is needed to address the specificity of network profiles for differentiation among white matter pathologies and diseases.Item Clinicopathological correlations in behavioural variant frontotemporal dementia(Oxford University Press, 2017-12-01) Perry, David C.; Brown, Jesse A.; Possin, Katherine L.; Datta, Samir; Trujillo, Andrew; Radke, Anneliese; Karydas, Anna; Kornak, John; Sias, Ana C.; Rabinovici, Gil D.; Gorno-Tempini, Maria Luisa; Boxer, Adam L.; May, Mary De; Rankin, Katherine P.; Sturm, Virginia E.; Lee, Suzee E.; Matthews, Brandy R.; Kao, Aimee W.; Vossel, Keith A.; Tartaglia, Maria Carmela; Miller, Zachary A.; Seo, Sang Won; Sidhu, Manu; Gaus, Stephanie E.; Nana, Alissa L.; Vargas, Jose Norberto S.; Hwang, Ji-Hye L.; Ossenkoppele, Rik; Brown, Alainna B.; Huang, Eric J.; Coppola, Giovanni; Rosen, Howard J.; Geschwind, Daniel; Trojanowski, John Q.; Grinberg, Lea T.; Kramer, Joel H.; Miller, Bruce L.; Seely, William W.; Neurology, School of MedicineAccurately predicting the underlying neuropathological diagnosis in patients with behavioural variant frontotemporal dementia (bvFTD) poses a daunting challenge for clinicians but will be critical for the success of disease-modifying therapies. We sought to improve pathological prediction by exploring clinicopathological correlations in a large bvFTD cohort. Among 438 patients in whom bvFTD was either the top or an alternative possible clinical diagnosis, 117 had available autopsy data, including 98 with a primary pathological diagnosis of frontotemporal lobar degeneration (FTLD), 15 with Alzheimer's disease, and four with amyotrophic lateral sclerosis who lacked neurodegenerative disease-related pathology outside of the motor system. Patients with FTLD were distributed between FTLD-tau (34 patients: 10 corticobasal degeneration, nine progressive supranuclear palsy, eight Pick's disease, three frontotemporal dementia with parkinsonism associated with chromosome 17, three unclassifiable tauopathy, and one argyrophilic grain disease); FTLD-TDP (55 patients: nine type A including one with motor neuron disease, 27 type B including 21 with motor neuron disease, eight type C with right temporal lobe presentations, and 11 unclassifiable including eight with motor neuron disease), FTLD-FUS (eight patients), and one patient with FTLD-ubiquitin proteasome system positive inclusions (FTLD-UPS) that stained negatively for tau, TDP-43, and FUS. Alzheimer's disease was uncommon (6%) among patients whose only top diagnosis during follow-up was bvFTD. Seventy-nine per cent of FTLD-tau, 86% of FTLD-TDP, and 88% of FTLD-FUS met at least 'possible' bvFTD diagnostic criteria at first presentation. The frequency of the six core bvFTD diagnostic features was similar in FTLD-tau and FTLD-TDP, suggesting that these features alone cannot be used to separate patients by major molecular class. Voxel-based morphometry revealed that nearly all pathological subgroups and even individual patients share atrophy in anterior cingulate, frontoinsula, striatum, and amygdala, indicating that degeneration of these regions is intimately linked to the behavioural syndrome produced by these diverse aetiologies. In addition to these unifying features, symptom profiles also differed among pathological subtypes, suggesting distinct anatomical vulnerabilities and informing a clinician's prediction of pathological diagnosis. Data-driven classification into one of the 10 most common pathological diagnoses was most accurate (up to 60.2%) when using a combination of known predictive factors (genetic mutations, motor features, or striking atrophy patterns) and the results of a discriminant function analysis that incorporated clinical, neuroimaging, and neuropsychological data.Item Improvement in Function after Lasmiditan Treatment: Post Hoc Analysis of Data from Phase 3 Studies(Springer, 2020-12) Smith, Timothy; Krege, John H.; Rathmann, Suchitrita S.; Dowsett, Sherie A.; Hake, Ann; Nery, Emel S. M.; Matthews, Brandy R.; Doty, Erin G.; Neurology, School of MedicineIntroduction: Migraine is associated with substantial functional impairment and affects many aspects of daily life. Methods: Using data from SAMURAI and SPARTAN (double-blind, placebo-controlled, phase 3 studies) and GLADIATOR (an open-label, phase 3 study enrolling patients who had completed SAMURAI or SPARTAN), we assessed the effects of lasmiditan on migraine-related functional disability at multiple time points from 0.5 to 48 h post dose by asking patients to rate how much the migraine was interfering with normal activities. Pooled data from SAMURAI and SPARTAN (SAMURAI + SPARTAN) and data from GLADIATOR were analyzed using the intention-to-treat populations. Results: For SPARTAN + SAMURAI, significantly more patients who received lasmiditan at any dose versus placebo reported freedom from migraine-related functional disability at every timepoint from 2 h post dose, and this difference persisted to 48 h (p < 0.05). Significant differences from placebo in freedom from migraine-related functional disability commenced at 1 h post dose for lasmiditan 200 mg, 1.5 h for lasmiditan 100 mg, and 2 h for lasmiditan 50 mg. Findings from GLADIATOR supported those from SAMURAI + SPARTAN. Conclusion: All doses of lasmiditan resulted in an improvement in migraine-related functional disability that persisted to 48 h. In SAMURAI + SPARTAN, a significant difference from placebo was observed as early as 1 h post dose. TRIAL REGISTRATION AT CLINICALTRIALS.GOV: SAMURAI (NCT02439320), SPARTAN (NCT02605174), and GLADIATOR (NCT02565186).Item Journal Club: comparison of symptomatic and asymptomatic persons with Alzheimer disease neuropathology.(American Academy of Neurology, 2014-03-04) Brosch, Jared R.; Matthews, Brandy R.; Department of Neurology, IU School of MedicineAdvances in neuroimaging, biomarkers, and clinical data have led to the hypothesis that the pathologic process of Alzheimer dementia begins decades prior to functional decline and diagnosis.1–3 High-profile clinical trial results have shown that biomarker changes can be made via pharmacologic intervention; however, the timing of this intervention has likely been too late to impact the cascade of neurodegenerative changes.4,5 In “Comparison of symptomatic and asymptomatic persons with Alzheimer disease neuropathology” by Monsell et al.,6 neuropathologic and clinical data were used to determine the risk of developing clinically significant cognitive impairment. This work represents a significant contribution because it examines a large cohort of autopsy data, which includes patients with Alzheimer dementia neuropathology who were clinically normal or diagnosed with mild cognitive impairment and Alzheimer-type dementia. The authors report a 3-fold increase in the risk of cognitive symptoms in association with quantifiable increases in neurofibrillary tangle pathology. Additionally, several other factors including APOE gene status, history of depression, and age impacted the clinical presentation. The ultimate goal of this investigation and similar studies is to facilitate the early and accurate identification of those at risk of developing Alzheimer dementia, such that potentially disease-modifying therapies may be considered.Item Memory Dysfunction.(Wolters Kluwer, 2015-06) Matthews, Brandy R.; Department of Neurology, IU School of MedicinePurpose of Review:: This article highlights the dissociable human memory systems of episodic, semantic, and procedural memory in the context of neurologic illnesses known to adversely affect specific neuroanatomic structures relevant to each memory system. Recent Findings:: Advances in functional neuroimaging and refinement of neuropsychological and bedside assessment tools continue to support a model of multiple memory systems that are distinct yet complementary and to support the potential for one system to be engaged as a compensatory strategy when a counterpart system fails. Summary:: Episodic memory, the ability to recall personal episodes, is the subtype of memory most often perceived as dysfunctional by patients and informants. Medial temporal lobe structures, especially the hippocampal formation and associated cortical and subcortical structures, are most often associated with episodic memory loss. Episodic memory dysfunction may present acutely, as in concussion; transiently, as in transient global amnesia (TGA); subacutely, as in thiamine deficiency; or chronically, as in Alzheimer disease. Semantic memory refers to acquired knowledge about the world. Anterior and inferior temporal lobe structures are most often associated with semantic memory loss. The semantic variant of primary progressive aphasia (svPPA) is the paradigmatic disorder resulting in predominant semantic memory dysfunction. Working memory, associated with frontal lobe function, is the active maintenance of information in the mind that can be potentially manipulated to complete goal-directed tasks. Procedural memory, the ability to learn skills that become automatic, involves the basal ganglia, cerebellum, and supplementary motor cortex. Parkinson disease and related disorders result in procedural memory deficits. Most memory concerns warrant bedside cognitive or neuropsychological evaluation and neuroimaging to assess for specific neuropathologies and guide treatment.Item Resting state network profiles of Alzheimer disease and frontotemporal dementia: A preliminary examination(Cambridge University Press, 2018-05-10) Contreras, Joey Annette; Risacher, Shannon L.; Dzemidzic, Mario; West, John D.; McDonald, Brenna C.; Farlow, Martin R.; Matthews, Brandy R.; Apostolova, Liana G.; Brosch, Jared; Ghetti, Bernard; GoÑi, Joaquin; Medicine, School of MedicineOBJECTIVES/SPECIFIC AIMS: Recent evidence from resting-state fMRI studies have shown that brain network connectivity is altered in patients with neurodegenerative disorders. However, few studies have examined the complete connectivity patterns of these well-reported RSNs using a whole brain approach and how they compare between dementias. Here, we used advanced connectomic approaches to examine the connectivity of RSNs in Alzheimer disease (AD), Frontotemporal dementia (FTD), and age-matched control participants. METHODS/STUDY POPULATION: In total, 44 participants [27 controls (66.4±7.6 years), 13 AD (68.5.63±13.9 years), 4 FTD (59.575±12.2 years)] from an ongoing study at Indiana University School of Medicine were used. Resting-state fMRI data was processed using an in-house pipeline modeled after Power et al. (2014). Images were parcellated into 278 regions of interest (ROI) based on Shen et al. (2013). Connectivity between each ROI pair was described by Pearson correlation coefficient. Brain regions were grouped into 7 canonical RSNs as described by Yeo et al. (2015). Pearson correlation values were then averaged across pairs of ROIs in each network and averaged across individuals in each group. These values were used to determine relative expression of FC in each RSN (intranetwork) and create RSN profiles for each group. RESULTS/ANTICIPATED RESULTS: Our findings support previous literature which shows that limbic networks are disrupted in FTLD participants compared with AD and age-matched controls. In addition, interactions between different RSNs was also examined and a significant difference between controls and AD subjects was found between FP and DMN RSNs. Similarly, previous literature has reported a disruption between executive (frontoparietal) network and default mode network in AD compared with controls. DISCUSSION/SIGNIFICANCE OF IMPACT: Our approach allows us to create profiles that could help compare intranetwork FC in different neurodegenerative diseases. Future work with expanded samples will help us to draw more substantial conclusions regarding differences, if any, in the connectivity patterns between RSNs in various neurodegenerative diseases.