Browsing by Author "Schultz, Stephanie A."

Now showing 1 - 3 of 3
  • Thumbnail Image
    Item
    Presenilin-1 mutation position influences amyloidosis, small vessel disease, and dementia with disease stage
    (Wiley, 2024) Joseph-Mathurin, Nelly; Feldman, Rebecca L.; Lu, Ruijin; Shirzadi, Zahra; Toomer, Carmen; Saint Clair, Junie R.; Ma, Yinjiao; McKay, Nicole S.; Strain, Jeremy F.; Kilgore, Collin; Friedrichsen, Karl A.; Chen, Charles D.; Gordon, Brian A.; Chen, Gengsheng; Hornbeck, Russ C.; Massoumzadeh, Parinaz; McCullough, Austin A.; Wang, Qing; Li, Yan; Wang, Guoqiao; Keefe, Sarah J.; Schultz, Stephanie A.; Cruchaga, Carlos; Preboske, Gregory M.; Jack, Clifford R., Jr.; Llibre-Guerra, Jorge J.; Allegri, Ricardo F.; Ances, Beau M.; Berman, Sarah B.; Brooks, William S.; Cash, David M.; Day, Gregory S.; Fox, Nick C.; Fulham, Michael; Ghetti, Bernardino; Johnson, Keith A.; Jucker, Mathias; Klunk, William E.; la Fougère, Christian; Levin, Johannes; Niimi, Yoshiki; Oh, Hwamee; Perrin, Richard J.; Reischl, Gerald; Ringman, John M.; Saykin, Andrew J.; Schofield, Peter R.; Su, Yi; Supnet-Bell, Charlene; Vöglein, Jonathan; Yakushev, Igor; Brickman, Adam M.; Morris, John C.; McDade, Eric; Xiong, Chengjie; Bateman, Randall J.; Chhatwal, Jasmeer P.; Benzinger, Tammie L. S.; Dominantly Inherited Alzheimer Network; Pathology and Laboratory Medicine, School of Medicine
    Introduction: Amyloidosis, including cerebral amyloid angiopathy, and markers of small vessel disease (SVD) vary across dominantly inherited Alzheimer's disease (DIAD) presenilin-1 (PSEN1) mutation carriers. We investigated how mutation position relative to codon 200 (pre-/postcodon 200) influences these pathologic features and dementia at different stages. Methods: Individuals from families with known PSEN1 mutations (n = 393) underwent neuroimaging and clinical assessments. We cross-sectionally evaluated regional Pittsburgh compound B-positron emission tomography uptake, magnetic resonance imaging markers of SVD (diffusion tensor imaging-based white matter injury, white matter hyperintensity volumes, and microhemorrhages), and cognition. Results: Postcodon 200 carriers had lower amyloid burden in all regions but worse markers of SVD and worse Clinical Dementia Rating® scores compared to precodon 200 carriers as a function of estimated years to symptom onset. Markers of SVD partially mediated the mutation position effects on clinical measures. Discussion: We demonstrated the genotypic variability behind spatiotemporal amyloidosis, SVD, and clinical presentation in DIAD, which may inform patient prognosis and clinical trials. Highlights: Mutation position influences Aβ burden, SVD, and dementia. PSEN1 pre-200 group had stronger associations between Aβ burden and disease stage. PSEN1 post-200 group had stronger associations between SVD markers and disease stage. PSEN1 post-200 group had worse dementia score than pre-200 in late disease stage. Diffusion tensor imaging-based SVD markers mediated mutation position effects on dementia in the late stage.
  • Thumbnail Image
    Item
    Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease
    (Nature Research, 2019-02) Preische, Oliver; Schultz, Stephanie A.; Apel, Anja; Kuhle, Jens; Kaeser, Stephan A.; Barro, Christian; Gräber, Susanne; Kuder-Buletta, Elke; LaFougere, Christian; Laske, Christoph; Vöglein, Jonathan; Levin, Johannes; Masters, Colin L.; Martins, Ralph; Schofield, Peter R.; Rossor, Martin N.; Graff-Radford, Neill R.; Salloway, Stephen; Ghetti, Bernardino; Ringman, John M.; Noble, James M.; Chhatwal, Jasmeer; Goate, Alison M.; Benzinger, Tammie L. S.; Morris, John C.; Bateman, Randall J.; Wang, Guoqiao; Fagan, Anne M.; McDade, Eric M.; Gordon, Brian A.; Jucker, Mathias; Alzheimer Network; Allegri, Ricardo; Amtashar, Fatima; Bateman, Randall; Benzinger, Tammie; Berman, Sarah; Bodge, Courtney; Brandon, Susan; Brooks, William; Buck, Jill; Buckles, Virginia; Chea, Sochenda; Chhatwal, Jasmeer; Chrem, Patricio; Chui, Helena; Cinco, Jake; Clifford, Jack; Cruchaga, Carlos; D’Mello, Mirelle; Donahue, Tamara; Douglas, Jane; Edigo, Noelia; Erekin-Taner, Nilufer; Fagan, Anne; Farlow, Marty; Farrar, Angela; Feldman, Howard; Flynn, Gigi; Fox, Nick; Franklin, Erin; Fujii, Hisako; Gant, Cortaiga; Gardener, Samantha; Ghetti, Bernardino; Goate, Alison; Goldman, Jill; Gordon, Brian; Graff-Radford, Neill; Gray, Julia; Gurney, Jenny; Hassenstab, Jason; Hirohara, Mie; Holtzman, David; Hornbeck, Russ; DiBari, Siri Houeland; Ikeuchi, Takeshi; Ikonomovic, Snezana; Jerome, Gina; Jucker, Mathias; Karch, Celeste; Kasuga, Kensaku; Kawarabayashi, Takeshi; Klunk, William; Koeppe, Robert; Kuder-Buletta, Elke; Laske, Christoph; Lee, Jae-Hong; Levin, Johannes; Marcus, Daniel; Martins, Ralph; Mason, Neal Scott; Masters, Colin; Maue-Dreyfus, Denise; McDade, Eric; Montoya, Lucy; Mori, Hiroshi; Morris, John; Nagamatsu, Akem; Neimeyer, Katie; Noble, James; Norton, Joanne; Perrin, Richard; Raichle, Marc; Ringman, John; Roh, Jee Hoon; Salloway, Stephen; Schofield, Peter; Shimada, Hiroyuki; Shiroto, Tomoyo; Shoji, Mikio; Sigurdson, Wendy; Sohrabi, Hamid; Sparks, Paige; Suzuki, Kazushi; Swisher, Laura; Taddei, Kevin; Wang, Jen; Wang, Peter; Weiner, Mike; Wolfsberger, Mary; Xiong, Chengjie; Xu, Xiong; Pathology and Laboratory Medicine, School of Medicine
    Neurofilament light chain (NfL) is a promising fluid biomarker of disease progression for various cerebral proteopathies. Here we leverage the unique characteristics of the Dominantly Inherited Alzheimer Network and ultrasensitive immunoassay technology to demonstrate that NfL levels in the cerebrospinal fluid (n = 187) and serum (n = 405) are correlated with one another and are elevated at the presymptomatic stages of familial Alzheimer's disease. Longitudinal, within-person analysis of serum NfL dynamics (n = 196) confirmed this elevation and further revealed that the rate of change of serum NfL could discriminate mutation carriers from non-mutation carriers almost a decade earlier than cross-sectional absolute NfL levels (that is, 16.2 versus 6.8 years before the estimated symptom onset). Serum NfL rate of change peaked in participants converting from the presymptomatic to the symptomatic stage and was associated with cortical thinning assessed by magnetic resonance imaging, but less so with amyloid-β deposition or glucose metabolism (assessed by positron emission tomography). Serum NfL was predictive for both the rate of cortical thinning and cognitive changes assessed by the Mini-Mental State Examination and Logical Memory test. Thus, NfL dynamics in serum predict disease progression and brain neurodegeneration at the early presymptomatic stages of familial Alzheimer's disease, which supports its potential utility as a clinically useful biomarker.
  • Thumbnail Image
    Item
    Serum neurofilament light chain levels are associated with white matter integrity in autosomal dominant Alzheimer's disease
    (Elsevier, 2020-08-01) Schultz, Stephanie A.; Strain, Jeremy F.; Adedokun, Adedamola; Wang, Qing; Preische, Oliver; Kuhle, Jens; Flores, Shaney; Keefe, Sarah; Dincer, Aylin; Ances, Beau M.; Berman, Sarah B.; Brickman, Adam M.; Cash, David M.; Chhatwal, Jasmeer; Cruchaga, Carlos; Ewers, Michael; Fox, Nick N.; Ghetti, Bernardino; Goate, Alison; Graff-Radford, Neill R.; Hassenstab, Jason J.; Hornbeck, Russ; Jack, Clifford; Johnson, Keith; Joseph-Mathurin, Nelly; Karch, Celeste M.; Koeppe, Robert A.; Lee, Athene K. W.; Levin, Johannes; Masters, Colin; McDade, Eric; Perrin, Richard J.; Rowe, Christopher C.; Salloway, Stephen; Saykin, Andrew J.; Sperling, Reisa; Su, Yi; Villemagne, Victor L.; Vöglein, Jonathan; Weiner, Michael; Xiong, Chengjie; Fagan, Anne M.; Morris, John C.; Bateman, Randall J.; Benzinger, Tammie L. S.; Jucker, Mathias; Gordon, Brian A.; Pathology and Laboratory Medicine, School of Medicine
    Neurofilament light chain (NfL) is a protein that is selectively expressed in neurons. Increased levels of NfL measured in either cerebrospinal fluid or blood is thought to be a biomarker of neuronal damage in neurodegenerative diseases. However, there have been limited investigations relating NfL to the concurrent measures of white matter (WM) decline that it should reflect. White matter damage is a common feature of Alzheimer's disease. We hypothesized that serum levels of NfL would associate with WM lesion volume and diffusion tensor imaging (DTI) metrics cross-sectionally in 117 autosomal dominant mutation carriers (MC) compared to 84 non-carrier (NC) familial controls as well as in a subset (N = 41) of MC with longitudinal NfL and MRI data. In MC, elevated cross-sectional NfL was positively associated with WM hyperintensity lesion volume, mean diffusivity, radial diffusivity, and axial diffusivity and negatively with fractional anisotropy. Greater change in NfL levels in MC was associated with larger changes in fractional anisotropy, mean diffusivity, and radial diffusivity, all indicative of reduced WM integrity. There were no relationships with NfL in NC. Our results demonstrate that blood-based NfL levels reflect WM integrity and supports the view that blood levels of NfL are predictive of WM damage in the brain. This is a critical result in improving the interpretability of NfL as a marker of brain integrity, and for validating this emerging biomarker for future use in clinical and research settings across multiple neurodegenerative diseases.