Browsing by Author "Heller, Carolin"

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    Functional connectivity associations with markers of disease progression in GRN mutation carriers
    (Wiley, 2025-01-03) Flagan, Taru M.; Chu, Stephanie A.; Häkkinen, Suvi; Zhang, Liwen; McFall, David; Heller, Carolin; Rohrer, Jonathan D.; Brown, Jesse A.; Lee, Alex Jihun; Fernhoff, Kristen; Pasquini, Lorenzo; Mandelli, Maria Luisa; Gorno Tempini, Maria Luisa; Yokoyama, Jennifer S.; Sturm, Virginia; Appleby, Brian; Dickerson, Brad C.; Domoto-Reilly, Kimiko; Foroud, Tatiana M.; Geschwind, Daniel H.; Ghoshal, Nupur; Graff-Radford, Neill R.; Grossman, Murray; Hsiung, Ging-Yuek Robin; Huang, Eric J.; Huey, Edward D.; Kantarci, Kejal; Karydas, Anna M.; Kaufer, Daniel; Knopman, David S.; Litvan, Irene; MacKenzie, Ian R.; Mendez, Mario F.; Onyike, Chiadi U.; Petrucelli, Leonard; Ramos, Eliana Marisa; Roberson, Erik D.; Rojas, Julio C.; Tartaglia, Maria Carmela; Toga, Arthur W.; Weintraub, Sandra; Forsberg, Leah K.; Heuer, Hilary W.; Boeve, Brad F.; Boxer, Adam L.; Rosen, Howard J.; Miller, Bruce L.; Moreno, Fermin; Seeley, William W.; Lee, Suzee E.; ARTFL/LEFFTDS Consortia; Medicine, School of Medicine
    Background: Autosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN‐related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset. However, whether hyperconnectivity arises concomitantly with markers of neurodegeneration remains unclear. Method: Utilizing T1 and task‐free functional magnetic resonance imaging (tf‐fMRI) from 49 presymptomatic and 26 symptomatic GRN mutation carriers, we determined the relationships between functional connectivity as measured by voxel‐wise whole brain degree and GRN‐relevant markers of disease progression, which included plasma neurofilament light chain (NfL) concentrations, CSF complement C1q and C3b protein levels, grey matter atrophy, and OCD symptom severity. Result: NfL concentrations were associated with frontotemporoparietal and thalamic hyperconnectivity in presymptomatic GRN carriers and extensive regions of atrophy in symptomatic carriers. Complement levels were associated with regions of hyperconnectivity, but not gray matter, in symptomatic carriers. Presymptomatic carriers with thalamic hyperconnectivity tended to have lower grey matter volume in bilateral insula and left lateral parietal cortex, which are among regions that deteriorate in GRN‐FTD. OCD symptom severity was associated with hypoconnectivity across all GRN carriers. Conclusion: In presymptomatic carriers, the co‐occurrence of hyperconnectivity, high NfL, and low gray matter suggests that tf‐fMRI hyperconnectivity may portend the onset of the neurodegenerative phase. These findings point toward hyperconnectivity as an indicator of approaching symptomatic onset.
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    Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration
    (American Academy of Neurology, 2021-05-04) Rojas, Julio C.; Wang, Ping; Staffaroni, Adam M.; Heller, Carolin; Cobigo, Yann; Wolf, Amy; Goh, Sheng-Yang M.; Ljubenkov, Peter A.; Heuer, Hilary W.; Fong, Jamie C.; Taylor, Joanne B.; Veras, Eliseo; Song, Linan; Jeromin, Andreas; Hanlon, David; Yu, Lili; Khinikar, Arvind; Sivasankaran, Rajeev; Kieloch, Agnieszka; Valentin, Marie-Anne; Karydas, Anna M.; Mitic, Laura L.; Pearlman, Rodney; Kornak, John; Kramer, Joel H.; Miller, Bruce L.; Kantarci, Kejal; Knopman, David S.; Graff-Radford, Neill; Petrucelli, Leonard; Rademakers, Rosa; Irwin, David J.; Grossman, Murray; Ramos, Eliana Marisa; Coppola, Giovanni; Mendez, Mario F.; Bordelon, Yvette; Dickerson, Bradford C.; Ghoshal, Nupur; Huey, Edward D.; Mackenzie, Ian R.; Appleby, Brian S.; Domoto-Reilly, Kimiko; Hsiung, Ging-Yuek R.; Toga, Arthur W.; Weintraub, Sandra; Kaufer, Daniel I.; Kerwin, Diana; Litvan, Irene; Onyike, Chiadikaobi U.; Pantelyat, Alexander; Roberson, Erik D.; Tartaglia, Maria C.; Foroud, Tatiana; Chen, Weiping; Czerkowicz, Julie; Graham, Danielle L.; van Swieten, John C.; Borroni, Barbara; Sanchez-Valle, Raquel; Moreno, Fermin; Laforce, Robert; Graff, Caroline; Synofzik, Matthis; Galimberti, Daniela; Rowe, James B.; James B., Mario; Finger, Elizabeth; Vandenberghe, Rik; de Mendonça, Alexandre; Tagliavini, Fabrizio; Santana, Isabel; Ducharme, Simon; Butler, Chris R.; Gerhard, Alexander; Levin, Johannes; Danek, Adrian; Otto, Markus; Sorbi, Sandro; Cash, David M.; Convery, Rhian S.; Bocchetta, Martina; Foiani, Martha; Greaves, Caroline V.; Peakman, Georgia; Russell, Lucy; Swift, Imogen; Todd, Emily; Rohrer, Jonathan D.; Boeve, Bradley F.; Rosen, Howard J.; Boxer, Adam L.; Neurology, School of Medicine
    Objective: We tested the hypothesis that plasma neurofilament light chain (NfL) identifies asymptomatic carriers of familial frontotemporal lobar degeneration (FTLD)-causing mutations at risk of disease progression. Methods: Baseline plasma NfL concentrations were measured with single-molecule array in original (n = 277) and validation (n = 297) cohorts. C9orf72, GRN, and MAPT mutation carriers and noncarriers from the same families were classified by disease severity (asymptomatic, prodromal, and full phenotype) using the CDR Dementia Staging Instrument plus behavior and language domains from the National Alzheimer's Disease Coordinating Center FTLD module (CDR+NACC-FTLD). Linear mixed-effect models related NfL to clinical variables. Results: In both cohorts, baseline NfL was higher in asymptomatic mutation carriers who showed phenoconversion or disease progression compared to nonprogressors (original: 11.4 ± 7 pg/mL vs 6.7 ± 5 pg/mL, p = 0.002; validation: 14.1 ± 12 pg/mL vs 8.7 ± 6 pg/mL, p = 0.035). Plasma NfL discriminated symptomatic from asymptomatic mutation carriers or those with prodromal disease (original cutoff: 13.6 pg/mL, 87.5% sensitivity, 82.7% specificity; validation cutoff: 19.8 pg/mL, 87.4% sensitivity, 84.3% specificity). Higher baseline NfL correlated with worse longitudinal CDR+NACC-FTLD sum of boxes scores, neuropsychological function, and atrophy, regardless of genotype or disease severity, including asymptomatic mutation carriers. Conclusions: Plasma NfL identifies asymptomatic carriers of FTLD-causing mutations at short-term risk of disease progression and is a potential tool to select participants for prevention clinical trials. Trial registration information: ClinicalTrials.gov Identifier: NCT02372773 and NCT02365922. Classification of evidence: This study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.
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    Temporal order of clinical and biomarker changes in familial frontotemporal dementia
    (Springer Nature, 2022) Staffaroni, Adam M.; Quintana, Melanie; Wendelberger, Barbara; Heuer, Hilary W.; Russell, Lucy L.; Cobigo, Yann; Wolf, Amy; Goh, Sheng-Yang Matt; Petrucelli, Leonard; Gendron, Tania F.; Heller, Carolin; Clark, Annie L.; Taylor, Jack Carson; Wise, Amy; Ong, Elise; Forsberg, Leah; Brushaber, Danielle; Rojas, Julio C.; VandeVrede, Lawren; Ljubenkov, Peter; Kramer, Joel; Casaletto, Kaitlin B.; Appleby, Brian; Bordelon, Yvette; Botha, Hugo; Dickerson, Bradford C.; Domoto-Reilly, Kimiko; Fields, Julie A.; Foroud, Tatiana; Gavrilova, Ralitza; Geschwind, Daniel; Ghoshal, Nupur; Goldman, Jill; Graff-Radford, Jonathon; Graff-Radford, Neill; Grossman, Murray; Hall, Matthew G. H.; Hsiung, Ging-Yuek; Huey, Edward D.; Irwin, David; Jones, David T.; Kantarci, Kejal; Kaufer, Daniel; Knopman, David; Kremers, Walter; Lago, Argentina Lario; Lapid, Maria I.; Litvan, Irene; Lucente, Diane; Mackenzie, Ian R.; Mendez, Mario F.; Mester, Carly; Miller, Bruce L.; Onyike, Chiadi U.; Rademakers, Rosa; Ramanan, Vijay K.; Ramos, Eliana Marisa; Rao, Meghana; Rascovsky, Katya; Rankin, Katherine P.; Roberson, Erik D.; Savica, Rodolfo; Tartaglia, M. Carmela; Weintraub, Sandra; Wong, Bonnie; Cash, David M.; Bouzigues, Arabella; Swift, Imogen J.; Peakman, Georgia; Bocchetta, Martina; Todd, Emily G.; Convery, Rhian S.; Rowe, James B.; Borroni, Barbara; Galimberti, Daniela; Tiraboschi, Pietro; Masellis, Mario; Finger, Elizabeth; van Swieten, John C.; Seelaar, Harro; Jiskoot, Lize C.; Sorbi, Sandro; Butler, Chris R.; Graff, Caroline; Gerhard, Alexander; Langheinrich, Tobias; Laforce, Robert; Sanchez-Valle, Raquel; de Mendonça, Alexandre; Moreno, Fermin; Synofzik, Matthis; Vandenberghe, Rik; Ducharme, Simon; Le Ber, Isabelle; Levin, Johannes; Danek, Adrian; Otto, Markus; Pasquier, Florence; Santana, Isabel; Kornak, John; Boeve, Bradley F.; Rosen, Howard J.; Rohrer, Jonathan D.; Boxer, Adam L.; Frontotemporal Dementia Prevention Initiative (FPI) Investigators; Medicine, School of Medicine
    Unlike familial Alzheimer’s disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN, and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes, and plasma neurofilament light chain (NfL) in 796 carriers and 412 non-carrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations employing model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. F-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.