Selected Publications
Our selected publications below are grouped by topic: genetic frontotemporal dementia, the MAPT p.A152T genetic risk variant for neurodegenerative disease, and clinicopathological correlations to refine the diagnosis of corticobasal degeneration.
Genetic frontotemporal dementia (FTD)
The emergence of recent therapies for neurodegenerative diseases, such as Alzheimer’s disease, has transformed the landscape of clinical care. Treatments are most effective during the earliest symptomatic stages, and growing evidence suggests that intervening before symptoms arise will yield greater benefit-- well before substantial neurodegeneration takes hold. Thus, early diagnosis during the asymptomatic phase remains crucial, yet for frontotemporal dementia (FTD), validated biomarkers are lacking. Studying carriers of pathogenic FTD genetic variants remains the only opportunity to study abnormalities before symptoms begin.
Our lab uses advanced neuroimaging techniques, such as structural brain imaging and resting-state fMRI, to map the neural circuits targeted in genetic FTD. We found that differences in resting-state fMRI neural network profiles can be detected decades before symptoms are expected to appear for asymptomatic carriers of each of the most common genetic variants. Our work focuses on families with genetic variants in microtubule-associated protein tau (MAPT), progranulin (GRN) and the hexanucleotide expansion in the C9orf72 gene, the most common genetic cause of FTD and amyotrophic lateral sclerosis. By pairing neuroimaging measures with biofluid markers such as neurofilament light chain, poly(GP) for the C9orf72 repeat expansion, and proteomic signatures, we are building a comprehensive picture of how novel biomarkers evolve over the lifespan, long before symptoms emerge. Our long-term goal is to map the natural history of genetic FTD across the lifespan from childhood through adulthood.
Lee SE, Khazenzon AM, Trujillo AJ, Guo C, Yokoyama JS, Sha SJ, Takada LT, Karydas AM, Block NR, Coppola G, Pribadi M, Geschwind DH, Rademakers R, Fong JC, Weiner MW, Boxer AL, Kramer JH, Rosen HJ, Miller BL, Seeley WW. Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion. Brain. 2014;137(11):3047–3060. PMCID: PMC4208465.
Ng AS, Sias AC, Pressman PS, Fong JC, Karydas AM, Zanto TP, De May MG, Coppola G, Geschwind DH, Miller BL, Lee SE. Young-onset frontotemporal dementia in a homozygous tau R406W mutation carrier. Ann Clin Transl Neurol. 2015;2(12):1124–1128. PMCID: PMC4693591.
Lee SE, Sias AC, Mandelli ML, Brown JA, Brown AB, Khazenzon AM, Vidovszky AA, Zanto TP, Karydas AM, Pribadi M, Dokuru D, Coppola G, Geschwind DH, Rademakers R, Gorno-Tempini ML, Rosen HJ, Miller BL, Seeley WW. Network degeneration and dysfunction in presymptomatic C9orf72 expansion carriers. Neuroimage Clin. 2016;14:286–297. PMCID: PMC5349617.
Sha SJ, Khazenzon AM, Ghosh PM, Rankin KP, Pribadi M, Coppola G, Geschwind DH, Rabinovici GD, Miller BL, Lee SE. Early-onset Alzheimer’s disease versus frontotemporal dementia: resolution with genetic diagnoses? Neurocase. 2016;22(2):161–167. PMCID: PMC4733403.
Meeter LH, Gendron TF, Sias AC, Jiskoot LC, Russo SP, Donker Kaat L, Papma JM, Panman JL, van der Ende EL, Dopper EG, Franzen S, Graff C, Boxer AL, Rosen HJ, Sanchez-Valle R, Galimberti D, Pijnenburg YAL, Benussi L, Ghidoni R, Borroni B, Laforce R Jr, Del Campo M, Teunissen CE, van Minkelen R, Rojas JC, Coppola G, Geschwind DH, Rademakers R, Karydas AM, Öijerstedt L, Scarpini E, Binetti G, Padovani A, Cash DM, Dick KM, Bocchetta M, Miller BL, Rohrer JD, Petrucelli L, van Swieten JC, Lee SE. Poly(GP), neurofilament and grey matter deficits in C9orf72 expansion carriers. Ann Clin Transl Neurol. 2018;5(5):583–597. PMCID: PMC5945959.
Caverzasi E, Battistella G, Chu SA, Rosen H, Zanto TP, Karydas AM, Shwe W, Coppola G, Geschwind DH, Rademakers R, Miller BL, Gorno-Tempini ML, Lee SE. Gyrification abnormalities in presymptomatic C9orf72 expansion carriers. J Neurol Neurosurg Psychiatry. 2019;90(9):1005–1010. PMCID: PMC6820159.
Lee SE, Sias AC, Kosik EL, Flagan TM, Deng J, Chu SA, Brown JA, Vidovszky AA, Ramos EM, Gorno-Tempini ML, Karydas AM, Coppola G, Geschwind DH, Rademakers R, Boeve BF, Boxer AL, Rosen HJ, Miller BL, Seeley WW. Thalamo-cortical network hyperconnectivity in preclinical progranulin mutation carriers. Neuroimage Clin. 2019;22:101751. PMCID: PMC6438992.
Chu SA, Flagan TM, Staffaroni AM, Jiskoot LC, Deng J, Spina S, Zhang L, Sturm VE, Yokoyama JS, Seeley WW, Papma J, Geschwind MD DH, Rosen HJ, Boeve B, Boxer AL, Heuer HW, Forsberg LK, Brushaber DE, Grossman M, Coppola G, Dickerson BC, Bordelon YM, Faber KF, Feldman HF, Fields JA, Fong JC, Foroud T, Gavrilova RH, Ghoshal N, Graff-Radford NR, Hsiung GYR, Huey ED, Irwin DI, Kantarci K, Kaufer DI, Karydas AM, Knopman DS, Kornak J, Kramer JH, Kukull WA, Lapid MI, Litvan I, Mackenzie IRA, Mendez MM, Miller BL, Onyike CU, Pantelyat AY, Rademakers R, Ramos EM, Roberson ED, Tartaglia MC, Tatton NA, Toga AW, Vetor A, Weintraub S, Wong B, Wszolek ZK, Van Swieten JC, Lee SE. Brain volumetric deficits in MAPT mutation carriers: a multisite study. Ann Clin Transl Neurol. 2021;8(1):95–110. PMCID: PMC7818091.
Zhang L, Flagan TM, Häkkinen S, Chu SA, Brown JA, Lee AJ, Pasquini L, Mandelli ML, Gorno-Tempini ML, Sturm VE, Yokoyama JS, Appleby BS, Cobigo Y, Dickerson BC, Domoto-Reilly K, Geschwind DH, Ghoshal N, Graff-Radford NR, Grossman M, Hsiung GY, Huey ED, Kantarci K, Lario Lago A, Litvan I, Mackenzie IR, Mendez MF, Onyike CU, Ramos EM, Roberson ED, Tartaglia MC, Toga AW, Weintraub S, Wszolek ZW, Forsberg LK, Heuer HW, Boeve BF, Boxer AL, Rosen HJ, Miller BL, Seeley WW, Lee SE; ARTFL/LEFFTDS Consortia. Network connectivity alterations across the MAPT mutation clinical spectrum. Ann Neurol. 2023; 10;94(4):632-646. PMCID: PMC10727479.
Saloner R, Staffaroni AM, Dammer EB, Johnson ECB, Paolillo EW, Wise A, Heuer HW, Forsberg LK, Lario-Lago A, Webb JD, Vogel JW, Santillo AF, Hansson O, Kramer JH, Miller BL, Li J, Loureiro J, Sivasankaran R, Worringer KA, Seyfried NT, Yokoyama JS, Spina S, Grinberg LT, Seeley WW, VandeVrede L, Ljubenkov PA, Bayram E, Bozoki A, Brushaber D, Considine CM, Day GS, Dickerson BC, Domoto-Reilly K, Faber K, Galasko DR, Gendron T, Geschwind DH, Ghoshal N, Graff-Radford N, Hales CM, Honig LS, Hsiung G-Y R, Huey ED, Kornak J, Kremers W, Lapid MI, Lee SE, Litvan I, McMillan CT, Mendez MF, Miyagawa T, Pantelyat A, Pascual B, Masdeu J, Paulson HL, Petrucelli L, Pressman P, Rademakers R, Ramos EM, Rascovsky K, Roberson ED, Savica R, Snyder A, Sullivan AC, Tartaglia MC, Vandebergh M, Boeve BF, Rosen HJ, Rojas JC, Boxer AL, Casaletto KB; ALLFTD Consortium. Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration. Nat Aging. 2025 Jun;5(6):1143-1158. PMID:40380000.
Flagan TM, Chu SA, Häkkinen S, Zhang L, McFall D, Rohrer JD, Brown JA, Lee AJ, Fernhoff K, Pasquini L, Rankin KP, Mandelli ML, Gorno-Tempini ML, Yokoyama JS, Sturm VE, Appleby B, Dickerson BC, Domoto-Reilly K, Foroud T, Geschwind DH, Ghoshal N, Graff-Radford NR, Hsiung G-R, Huang EJ, Huey E, Kantarci K, Litvan I, Mackenzie IR, Mendez MF, Onyike CU, Petrucelli L, Ramos EM, Roberson ED, Rojas JC, Tartaglia MC, Toga AW, Weintraub S, Forsberg LK, Heuer HW, Boeve BF, Boxer AL, Rosen HJ, Miller BL, Moreno F, Seeley WW, Lee SE on behalf of the ALLFTD Consortium. Functional Connectivity Associations With Markers of Disease Progression in GRN Pathogenic Variant Carriers. Ann Clin Transl Neurol. 2025 Sep 16;21(9):e70670. PMID: 40958169.
The MAPT p.A152T genetic risk variant for neurodegenerative disease
We discovered that a rare MAPT variant, p.A152T (Coppola et al. Hum Mol Gen 2012), is associated with various neurodegenerative disease syndromes (Lee et al. Alzheimer Dis Assoc Disord 2013). In a replication cohort of 7,451 participants, we validated p.A152T association with FTD and progressive supranuclear palsy, and determined that transgenic p.A152T zebrafish showed neurodegeneration and proteasome compromise (Lopez et al. Brain 2016). This work involved collaboration between 15 international centers for neurodegenerative disease. Unexpectedly, we also discovered a high frequency of p.A152T in a large Basque kindred carrying a pathogenic GRN variant (Moreno et al. Plos One 2017).
Coppola G, Chinnathambi S, Lee JJ, Dombrowski BA, Baker MC, Soto-Ortolaza AI, Lee SE, et al. Evidence for a Role of The Rare p.A152T Variant in MAPT in increasing the Risk for FTD-Spectrum and Alzheimer’s Diseases. Hum Mol Gen 2012 Aug 1;21(15):3500-12. PMCID: 3392107.
Lee SE, Tartaglia MC, Yener G, Genc S, Seeley WW, Sanchez-Juan P, Moreno F, Mendez M, Klein E, Rademakers R, de Munain AL, Combarros O, Kramer J, Kenet R, Boxer AL, Geschwind MD, Gorno-Tempini ML, Karydas AM, Rabinovici GD, Coppola G, Geschwind DH, Miller BL. Neurodegenerative disease phenotypes in carriers of MAPT p.A152T, a risk factor for frontotemporal dementia spectrum disorders and Alzheimer’s disease. Alzheimer Dis Assoc Disord 2013 Mar 25. PMCID: 3796183.
Lopez A#, Lee SE#, Wojta K#, Ramos EM, Klein E, Chen J, Boxer AL, Gorno-Tempini ML, Geschwind DH, Schlotowa L, Ogryzko NV, Bigio EH, Rogalski E, Weintraub S, Mesulam MM, Fleming A, Coppola G*, Miller BL*, Rubinsztein DC.* A152T tau allele causes neurodegeneration which can be ameliorated in a zebrafish model by autophagy induction. Brain 2016 Apr 1;140(4):1128-1146. PMID: 28334843.
#joint first author, *joint last author
Moreno F, Indakoetxea B, Barandiaran M, Caballero MC, Gorostidi A, Calafell F, Gabilondo A, Tainta M, Zulaica M, Martí Massó JF, López de Munain A, Sánchez-Juan P, Lee SE. The unexpected co-occurrence of GRN and MAPT p.A152T in Basque families: Clinical and pathological characteristics. PLoS One. 2017 Jun 8;12(6):e0178093. PMID: 28594853.
Clinicopathological correlations to refine the diagnosis of corticobasal degeneration
The clinical diagnosis of corticobasal degeneration (CBD) is challenging; only about one-third of patients believed to have CBD during life show CBD at autopsy. In our study, we systematically examined cognitive, behavioral, and motor symptoms in autopsy-proven CBD to define its full clinical spectrum (Lee et al. Ann Neurol 2011). We discovered that pathologically-proven CBD most commonly presents as one of three major frontal lobe clinical syndromes: behavioral variant FTD, nonfluent primary progressive aphasia, or corticobasal syndrome accompanied by executive dysfunction. Importantly, we determined that CBD can present without early motor symptoms and with symmetric patterns of brain atrophy—features previously thought to be inconsistent with the diagnosis. As part of a multicenter effort, our findings contributed to the first international CBD consensus criteria (Armstrong et al., Neurology 2013), which for the first time incorporated behavioral symptoms into the diagnostic framework.
Lee SE, Rabinovici GD, Mayo MC, Wilson SM, Seeley WW, DeArmond SJ, Huang EJ, Trojanowski JQ, Growdon ME, Jang JY, Sidhu M, See TM, Karydas AM, Gorno-Tempini ML, Boxer AL, Weiner MW, Geschwind MD, Rankin KJ, Miller BL. Clinicopathological correlations in corticobasal degeneration. Ann Neurol 2011 Aug;70(2):327-40. PMCID: 3154081.
Armstrong MJ, Litvan I, Lang AE, Bak TH, Bhatia K, Borroni B, Boxer AL, Dickson D, Grossman M, Hallett, M, Josephs K, Kertesz A, Lee SE, Miller BL, Reich S, Riley DE, Tolosa E, Tröster A, Vidailhet M, Weiner WJ. Criteria for the diagnosis of corticobasal degeneration. Neurology 2013; 80(5):496-503. PMCID: 3590050.
Sha, SJ, Ghosh PM, Lee SE, Corbetta-Rastelli C, Jagust WJ, Kornak J, Rankin KP, Grinberg LT, Vinters HV, Mendez MF, Dickson DW, Seeley WW, Gorno-Tempini M, Kramer JH, Miller BL, Boxer AL, Rabinovici GD. Predicting amyloid status in corticobasal syndrome using modified clinical criteria, magnetic resonance imaging and fluorodeoxyglucose positron emission tomography. Alzheimers Res Ther 2015 1–12. PMCID: 4346122.
Selected Review Articles and Book Chapters
Review Articles
Lee SE. Guam dementia syndrome revisited in 2011. Curr Opin Neurol 2011, 24:517–524. PMID: 21986681.
Hakkinen S, Chu SA, Lee SE. Neuroimaging in genetic frontotemporal dementia and amyotrophic lateral sclerosis. Neurobiol Dis. 2020 Sep 2;145:105063. PMCID: PMC7572920.
Lee SE. Frontotemporal dementia: Clinical features and diagnosis. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA.
Lee SE. Frontotemporal dementia: Pathogenesis and Pathology. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA.
Lee SE, Ljubenkov P. Frontotemporal dementia: Treatment. In: UpToDate, Rose, BD (Ed), UpToDate, Waltham, MA.
Book Chapters
Lee SE, Miller BL. Corticobasal syndrome and progressive supranuclear palsy. In: Geschwind MD, editor. Atypical and Non-Alzheimer’s Dementias. Oxford, UK: Wiley-Blackwell; 2011.
Viskontas IV, Lee SE. The creation of art in the setting of dementia. In: Nadal M, Pearce MT, editors. Art, Aesthetics, and the Brain. Oxford, UK: Oxford University Press; 2013.
Fredericks CA, Lee SE. Corticobasal degeneration and progressive supranuclear palsy. In: Miller BL, Boeve BF, editors. The Behavioral Neurology of Dementia. 2nd ed. Cambridge, UK: Cambridge University Press; 2014.
Yokoyama JS, Lee SE. Clinical and basic science perspectives on frontotemporal dementia. In: Geschwind MD, Cummings JL, Miller BL, editors. Genomics, Circuits, and Pathways for the Clinical Neuroscientist. Amsterdam, Netherlands: Elsevier; 2014.
Lee SE. Greg was still Greg. In: Prioleau C, Merrilees J, editors. Hear/Say: Stories About Aging, Dementia, Art, and Life. San Francisco, CA: Norfolk Press; 2017. p. 11-19.
