1,660 results on '"Boxer, Adam L."'
Search Results
52. Author Correction: Safety and efficacy of anti-tau monoclonal antibody gosuranemab in progressive supranuclear palsy: a phase 2, randomized, placebo-controlled trial
- Author
-
Dam, Tien, Boxer, Adam L., Golbe, Lawrence I., Höglinger, Günter U., Morris, Huw R., Litvan, Irene, Lang, Anthony E., Corvol, Jean-Christophe, Aiba, Ikuko, Grundman, Michael, Yang, Lili, Tidemann-Miller, Beth, Kupferman, Joseph, Harper, Kristine, Kamisoglu, Kubra, Wald, Michael J., Graham, Danielle L., Gedney, Liz, O’Gorman, John, and Haeberlein, Samantha Budd
- Published
- 2023
- Full Text
- View/download PDF
53. The impact of demographic, clinical, genetic, and imaging variables on tau PET status
- Author
-
Ossenkoppele, Rik, Leuzy, Antoine, Cho, Hanna, Sudre, Carole H, Strandberg, Olof, Smith, Ruben, Palmqvist, Sebastian, Mattsson-Carlgren, Niklas, Olsson, Tomas, Jögi, Jonas, Stormrud, Erik, Ryu, Young Hoon, Choi, Jae Yong, Boxer, Adam L, Gorno-Tempini, Maria L, Miller, Bruce L, Soleimani-Meigooni, David, Iaccarino, Leonardo, La Joie, Renaud, Borroni, Edilio, Klein, Gregory, Pontecorvo, Michael J, Devous, Michael D, Villeneuve, Sylvia, Lyoo, Chul Hyoung, Rabinovici, Gil D, and Hansson, Oskar
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Biomedical Imaging ,Aging ,Alzheimer's Disease ,Dementia ,Brain Disorders ,Neurodegenerative ,Clinical Research ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Acquired Cognitive Impairment ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Alzheimer Disease ,Amyloid beta-Peptides ,Cognitive Dysfunction ,Demography ,Humans ,Positron-Emission Tomography ,tau Proteins ,PET ,Tau ,Aβ ,Alzheimer’ ,s disease ,MCI ,Alzheimer’s Disease Neuroimaging Initiative ,PREVENT-AD research group ,Alzheimer’s disease ,Aβ ,Other Physical Sciences ,Nuclear Medicine & Medical Imaging ,Clinical sciences - Abstract
PurposeA substantial proportion of amyloid-β (Aβ)+ patients with clinically diagnosed Alzheimer's disease (AD) dementia and mild cognitive impairment (MCI) are tau PET-negative, while some clinically diagnosed non-AD neurodegenerative disorder (non-AD) patients or cognitively unimpaired (CU) subjects are tau PET-positive. We investigated which demographic, clinical, genetic, and imaging variables contributed to tau PET status.MethodsWe included 2338 participants (430 Aβ+ AD dementia, 381 Aβ+ MCI, 370 non-AD, and 1157 CU) who underwent [18F]flortaucipir (n = 1944) or [18F]RO948 (n = 719) PET. Tau PET positivity was determined in the entorhinal cortex, temporal meta-ROI, and Braak V-VI regions using previously established cutoffs. We performed bivariate binary logistic regression models with tau PET status (positive/negative) as dependent variable and age, sex, APOEε4, Aβ status (only in CU and non-AD analyses), MMSE, global white matter hyperintensities (WMH), and AD-signature cortical thickness as predictors. Additionally, we performed multivariable binary logistic regression models to account for all other predictors in the same model.ResultsTau PET positivity in the temporal meta-ROI was 88.6% for AD dementia, 46.5% for MCI, 9.5% for non-AD, and 6.1% for CU. Among Aβ+ participants with AD dementia and MCI, lower age, MMSE score, and AD-signature cortical thickness showed the strongest associations with tau PET positivity. In non-AD and CU participants, presence of Aβ was the strongest predictor of a positive tau PET scan.ConclusionWe identified several demographic, clinical, and neurobiological factors that are important to explain the variance in tau PET retention observed across the AD pathological continuum, non-AD neurodegenerative disorders, and cognitively unimpaired persons.
- Published
- 2021
54. Recognition memory and divergent cognitive profiles in prodromal genetic frontotemporal dementia.
- Author
-
Barker, Megan S, Manoochehri, Masood, Rizer, Sandra J, Appleby, Brian S, Brushaber, Danielle, Dev, Sheena I, Devick, Katrina L, Dickerson, Bradford C, Fields, Julie A, Foroud, Tatiana M, Forsberg, Leah K, Galasko, Douglas R, Ghoshal, Nupur, Graff-Radford, Neill R, Grossman, Murray, Heuer, Hilary W, Hsiung, Ging-Yuek, Kornak, John, Litvan, Irene, Mackenzie, Ian R, Mendez, Mario F, Pascual, Belen, Rankin, Katherine P, Rascovsky, Katya, Staffaroni, Adam M, Tartaglia, Maria Carmela, Weintraub, Sandra, Wong, Bonnie, Boeve, Bradley F, Boxer, Adam L, Rosen, Howard J, Goldman, Jill, Huey, Edward D, Cosentino, Stephanie, and ALLFTD consortium
- Subjects
ALLFTD consortium ,Humans ,Pick Disease of the Brain ,Cognition ,Neuropsychological Tests ,Heterozygote ,Mutation ,Frontotemporal Dementia ,Progranulins ,Behavioral variant frontotemporal dementia ,Episodic memory ,Genetic frontotemporal dementia ,Neuropsychology ,Prodromal disease ,Behavioral variant frontotemporal ,dementia ,Frontotemporal Dementia (FTD) ,Alzheimer's Disease ,Rare Diseases ,Alzheimer's Disease Related Dementias (ADRD) ,Behavioral and Social Science ,Dementia ,Neurosciences ,Genetics ,Aging ,Acquired Cognitive Impairment ,Brain Disorders ,Clinical Research ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurodegenerative ,Genetic Testing ,Basic Behavioral and Social Science ,2.1 Biological and endogenous factors ,Neurological ,Mental health ,Experimental Psychology ,Psychology ,Cognitive Sciences - Abstract
Although executive dysfunction is the characteristic cognitive marker of behavioral variant frontotemporal dementia (bvFTD), episodic memory deficits are relatively common, and may be present even during the prodromal disease phase. In a cohort of mutation carriers with mild behavioral and/or cognitive symptoms consistent with prodromal bvFTD, we aimed to investigate patterns of performance on an abbreviated list learning task, with a particular focus on recognition memory. We further aimed to characterize the cognitive prodromes associated with the three major genetic causes of frontotemporal dementia, as emerging evidence suggests there may be subtle differences in cognitive profiles among carriers of different genetic mutations. Participants included 57 carriers of a pathogenic mutation in microtubule-associated protein tau (MAPT, N = 23), or progranulin (GRN, N = 15), or a or a hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72, N = 19), with mild cognitive and/or behavioral symptoms consistent with prodromal bvFTD. Familial non-carriers were included as controls (N = 143). All participants completed a comprehensive neuropsychological examination, including an abbreviated list learning test assessing episodic memory recall and recognition. MAPT mutation carriers performed worse than non-carriers in terms of list recall, and had difficulty discriminating targets from distractors on the recognition memory task, primarily due to the endorsement of distractors as targets. MAPT mutation carriers also showed nonverbal episodic memory and semantic memory dysfunction (object naming). GRN mutation carriers were variable in performance and overall the most dysexecutive. Slowed psychomotor speed was evident in C9orf72 repeat expansion carriers. Identifying the earliest cognitive indicators of bvFTD is of critical clinical and research importance. List learning may be a sensitive cognitive marker for incipient dementia in MAPT and potentially a subset of GRN carriers. Our results highlight that distinct cognitive profiles may be evident in carriers of the three disease-causing genes during the prodromal disease stage.
- Published
- 2021
55. Plasma Neurofilament Light for Prediction of Disease Progression in Familial Frontotemporal Lobar Degeneration
- Author
-
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, Masellis, 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, and consortia, on behalf of the ALLFTD and GENFI
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Neurodegenerative ,Genetics ,Prevention ,Dementia ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Clinical Research ,Alzheimer's Disease ,Frontotemporal Dementia (FTD) ,Aging ,Acquired Cognitive Impairment ,Clinical Trials and Supportive Activities ,2.1 Biological and endogenous factors ,Aetiology ,Adult ,Aged ,Aged ,80 and over ,Biomarkers ,Cohort Studies ,Disease Progression ,Female ,Frontotemporal Lobar Degeneration ,Humans ,Magnetic Resonance Imaging ,Male ,Middle Aged ,Neurofilament Proteins ,Predictive Value of Tests ,Young Adult ,ALLFTD and GENFI consortia ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
ObjectiveWe 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.MethodsBaseline 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.ResultsIn 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.ConclusionsPlasma 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 informationClinicalTrials.gov Identifier: NCT02372773 and NCT02365922.Classification of evidenceThis study provides Class I evidence that in carriers of FTLD-causing mutations, elevation of plasma NfL predicts short-term risk of clinical progression.
- Published
- 2021
56. Development and validation of the Uniform Data Set (v3.0) executive function composite score (UDS3‐EF)
- Author
-
Staffaroni, Adam M, Asken, Breton M, Casaletto, Kaitlin B, Fonseca, Corrina, You, Michelle, Rosen, Howard J, Boxer, Adam L, Elahi, Fanny M, Kornak, John, Mungas, Dan, and Kramer, Joel H
- Subjects
Biological Psychology ,Psychology ,Behavioral and Social Science ,Aging ,Alzheimer's Disease ,Dementia ,Brain Disorders ,Neurodegenerative ,Clinical Research ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Acquired Cognitive Impairment ,Neurological ,Aged ,Alzheimer Disease ,Brain ,Cognitive Dysfunction ,Datasets as Topic ,Executive Function ,Female ,Gray Matter ,Humans ,Magnetic Resonance Imaging ,Male ,Neuropsychological Tests ,Psychometrics ,Alzheimer&apos ,s disease ,cognition ,composite score ,executive function ,item response theory ,mild cognitive impairment ,National Alzheimer&apos ,s Coordinating Center ,uniform data set ,Alzheimer's disease ,National Alzheimer's Coordinating Center ,Clinical Sciences ,Geriatrics ,Clinical sciences ,Biological psychology - Abstract
IntroductionCognitive composite scores offer a means of precisely measuring executive functioning (EF).MethodsWe developed the Uniform Data Set v3.0 EF composite score (UDS3-EF) in 3507 controls from the National Alzheimer's Coordinating Center dataset using item-response theory and applied nonlinear and linear demographic adjustments. The UDS3-EF was validated with other neuropsychological tests and brain magnetic resonance imaging from independent research cohorts using linear models.ResultsFinal model fit was good-to-excellent: comparative fit index = 0.99; root mean squared error of approximation = 0.057. UDS3-EF scores differed across validation cohorts (controls > mild cognitive impairment > Alzheimer's disease-dementia ≈ behavioral variant frontotemporal dementia; P
- Published
- 2021
57. Plasma Tau and Neurofilament Light in Frontotemporal Lobar Degeneration and Alzheimer Disease.
- Author
-
Illán-Gala, Ignacio, Lleo, Alberto, Karydas, Anna, Staffaroni, Adam M, Zetterberg, Henrik, Sivasankaran, Rajeev, Grinberg, Lea T, Spina, Salvatore, Kramer, Joel H, Ramos, Eliana M, Coppola, Giovanni, La Joie, Renaud, Rabinovici, Gil D, Perry, David C, Gorno-Tempini, Maria Luisa, Seeley, William W, Miller, Bruce L, Rosen, Howard J, Blennow, Kaj, Boxer, Adam L, and Rojas, Julio C
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Acquired Cognitive Impairment ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurodegenerative ,Frontotemporal Dementia (FTD) ,Alzheimer's Disease ,Aging ,Clinical Trials and Supportive Activities ,Clinical Research ,Dementia ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Adult ,Aged ,Alzheimer Disease ,Amyloid beta-Peptides ,Brain ,Case-Control Studies ,DNA-Binding Proteins ,Disease Progression ,Female ,Frontotemporal Lobar Degeneration ,Humans ,Magnetic Resonance Imaging ,Male ,Middle Aged ,Neurofilament Proteins ,Neuropsychological Tests ,Positron-Emission Tomography ,RNA-Binding Protein FUS ,Sensitivity and Specificity ,Survival Rate ,tau Proteins ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
ObjectiveTo test the hypothesis that plasma total tau (t-tau) and neurofilament light chain (NfL) concentrations may have a differential role in the study of frontotemporal lobar degeneration syndromes (FTLD-S) and clinically diagnosed Alzheimer disease syndromes (AD-S), we determined their diagnostic and prognostic value in FTLD-S and AD-S and their sensitivity to pathologic diagnoses.MethodsWe measured plasma t-tau and NfL with the Simoa platform in 265 participants: 167 FTLD-S, 43 AD-S, and 55 healthy controls (HC), including 82 pathology-proven cases (50 FTLD-tau, 18 FTLD-TDP, 2 FTLD-FUS, and 12 AD) and 98 participants with amyloid PET. We compared cross-sectional and longitudinal biomarker concentrations between groups, their correlation with clinical measures of disease severity, progression, and survival, and cortical thickness.ResultsPlasma NfL, but not plasma t-tau, discriminated FTLD-S from HC and AD-S from HC. Both plasma NfL and t-tau were poor discriminators between FLTD-S and AD-S. In pathology-confirmed cases, plasma NfL was higher in FTLD than AD and in FTLD-TDP compared to FTLD-tau, after accounting for age and disease severity. Plasma NfL, but not plasma t-tau, predicted clinical decline and survival and correlated with regional cortical thickness in both FTLD-S and AD-S. The combination of plasma NfL with plasma t-tau did not outperform plasma NfL alone.ConclusionPlasma NfL is superior to plasma t-tau for the diagnosis and prediction of clinical progression of FTLD-S and AD-S.Classification of evidenceThis study provides Class III evidence that plasma NfL has superior diagnostic and prognostic performance vs plasma t-tau in FTLD and AD.
- Published
- 2021
58. Accelerating Alzheimer’s therapeutic development: The past and future of clinical trials
- Author
-
Boxer, Adam L. and Sperling, Reisa
- Published
- 2023
- Full Text
- View/download PDF
59. Uniform data set language measures for bvFTD and PPA diagnosis and monitoring
- Author
-
Staffaroni, Adam M, Weintraub, Sandra, Rascovsky, Katya, Rankin, Katherine P, Taylor, Jack, Fields, Julie A, Casaletto, Kaitlin B, Hillis, Argye E, Lukic, Sladjana, Gorno‐Tempini, Maria Luisa, Heuer, Hilary, Teylan, Merilee A, Kukull, Walter A, Miller, Bruce L, Boeve, Bradley F, Rosen, Howard J, Boxer, Adam L, and Kramer, Joel H
- Subjects
Biological Psychology ,Psychology ,Alzheimer's Disease Related Dementias (ADRD) ,Aging ,Clinical Research ,Neurodegenerative ,Neurosciences ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Acquired Cognitive Impairment ,Rare Diseases ,Clinical Trials and Supportive Activities ,Aphasia ,Frontotemporal Dementia (FTD) ,Dementia ,clinical trials ,cognition ,differential diagnosis ,endpoints ,frontotemporal dementia ,FTLD module ,longitudinal ,neuropsychology ,primary progressive aphasia ,speech ,Genetics ,Biological psychology - Abstract
IntroductionThe Frontotemporal Lobar Degeneration Module (FTLD-MOD) includes a neuropsychological battery designed to assess the clinical features of FTLD, although much is unknown about its utility. We investigated FTLD-MOD and Uniform Data Set 3.0 (UDS) language tests for differential diagnosis and disease monitoring.MethodsLinear regressions compared baseline performances in 1655 National Alzheimer's Coordinating Center participants (behavioral variant frontotemporal dementia (bvFTD, n = 612), semantic variant primary progressive aphasia (svPPA, n = 168), non-fluent/agrammatic variant PPA (nfvPPA, n = 168), logopenic variant PPA (lvPPA, n = 109), and controls (n = 581)). Sample sizes to detect treatment effects were estimated using longitudinal data.ResultsAmong PPAs, the FTLD-MOD language tasks and UDS Multilingual Naming Test accurately discriminated svPPA. Number Span Forward best discriminated lvPPA; Phonemic:Semantic Fluency ratio was excellent for nfvPPA classification. UDS fluency and naming measures required the smallest sample size to detect meaningful change.DiscussionThe FTLD-MOD and UDS differentiated among PPA subtypes. UDS 3.0 measures performed best for longitudinal monitoring.
- Published
- 2021
60. Best Practices in the Clinical Management of Progressive Supranuclear Palsy and Corticobasal Syndrome: A Consensus Statement of the CurePSP Centers of Care
- Author
-
Bluett, Brent, Pantelyat, Alexander Y, Litvan, Irene, Ali, Farwa, Apetauerova, Diana, Bega, Danny, Bloom, Lisa, Bower, James, Boxer, Adam L, Dale, Marian L, Dhall, Rohit, Duquette, Antoine, Fernandez, Hubert H, Fleisher, Jori E, Grossman, Murray, Howell, Michael, Kerwin, Diana R, Leegwater-Kim, Julie, Lepage, Christiane, Ljubenkov, Peter Alexander, Mancini, Martina, McFarland, Nikolaus R, Moretti, Paolo, Myrick, Erica, Patel, Pritika, Plummer, Laura S, Rodriguez-Porcel, Federico, Rojas, Julio, Sidiropoulos, Christos, Sklerov, Miriam, Sokol, Leonard L, Tuite, Paul J, VandeVrede, Lawren, Wilhelm, Jennifer, Wills, Anne-Marie A, Xie, Tao, and Golbe, Lawrence I
- Subjects
Biomedical and Clinical Sciences ,Ophthalmology and Optometry ,Clinical Trials and Supportive Activities ,Neurosciences ,Neurodegenerative ,Rare Diseases ,Clinical Research ,Eye Disease and Disorders of Vision ,Brain Disorders ,Neurological ,progressive supranuclear palsy ,corticobasal syndrome ,management ,consensus ,CurePSP ,treatment ,symptomatic ,palliative ,Clinical Sciences ,Psychology ,Clinical sciences ,Biological psychology - Abstract
Progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS; the most common phenotype of corticobasal degeneration) are tauopathies with a relentless course, usually starting in the mid-60s and leading to death after an average of 7 years. There is as yet no specific or disease-modifying treatment. Clinical deficits in PSP are numerous, involve the entire neuraxis, and present as several discrete phenotypes. They center on rigidity, bradykinesia, postural instability, gait freezing, supranuclear ocular motor impairment, dysarthria, dysphagia, incontinence, sleep disorders, frontal cognitive dysfunction, and a variety of behavioral changes. CBS presents with prominent and usually asymmetric dystonia, apraxia, myoclonus, pyramidal signs, and cortical sensory loss. The symptoms and deficits of PSP and CBS are amenable to a variety of treatment strategies but most physicians, including many neurologists, are reluctant to care for patients with these conditions because of unfamiliarity with their multiplicity of interacting symptoms and deficits. CurePSP, the organization devoted to support, research, and education for PSP and CBS, created its CurePSP Centers of Care network in North America in 2017 to improve patient access to clinical expertise and develop collaborations. The directors of the 25 centers have created this consensus document outlining best practices in the management of PSP and CBS. They formed a writing committee for each of 12 sub-topics. A 4-member Steering Committee collated and edited the contributions. The result was returned to the entire cohort of authors for further comments, which were considered for incorporation by the Steering Committee. The authors hope that this publication will serve as a convenient guide for all clinicians caring for patients with PSP and CBS and that it will improve care for patients with these devastating but manageable disorders.
- Published
- 2021
61. Brain volumetric deficits in MAPT mutation carriers: a multisite study
- Author
-
Chu, Stephanie A, Flagan, Taru M, Staffaroni, Adam M, Jiskoot, Lize C, Deng, Jersey, Spina, Salvatore, Zhang, Liwen, Sturm, Virginia E, Yokoyama, Jennifer S, Seeley, William W, Papma, Janne M, Geschwind, Dan H, Rosen, Howard J, Boeve, Bradley F, Boxer, Adam L, Heuer, Hilary W, Forsberg, Leah K, Brushaber, Danielle E, Grossman, Murray, Coppola, Giovanni, Dickerson, Bradford C, Bordelon, Yvette M, Faber, Kelley, Feldman, Howard H, Fields, Julie A, Fong, Jamie C, Foroud, Tatiana, Gavrilova, Ralitza H, Ghoshal, Nupur, Graff‐Radford, Neill R, Hsiung, Ging‐Yuek Robin, Huey, Edward D, Irwin, David J, Kantarci, Kejal, Kaufer, Daniel I, Karydas, Anna M, Knopman, David S, Kornak, John, Kramer, Joel H, Kukull, Walter A, Lapid, Maria I, Litvan, Irene, Mackenzie, Ian RA, Mendez, Mario F, Miller, Bruce L, Onyike, Chiadi U, Pantelyat, Alexander Y, Rademakers, Rosa, Ramos, Eliana Marisa, Roberson, Erik D, Tartaglia, Maria Carmela, Tatton, Nadine A, Toga, Arthur W, Vetor, Ashley, Weintraub, Sandra, Wong, Bonnie, Wszolek, Zbigniew K, Consortium, the ARTFL LEFFTDS, Van Swieten, John C, and Lee, Suzee E
- Subjects
Biological Psychology ,Biomedical and Clinical Sciences ,Psychology ,Aging ,Rare Diseases ,Acquired Cognitive Impairment ,Neurosciences ,Neurodegenerative ,Dementia ,Frontotemporal Dementia (FTD) ,Brain Disorders ,Clinical Research ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Adult ,Aged ,Brain ,Female ,Frontotemporal Dementia ,Heterozygote ,Humans ,Male ,Middle Aged ,Mutation ,tau Proteins ,ARTFL/LEFFTDS Consortium ,Clinical Sciences ,Clinical and health psychology - Abstract
ObjectiveMAPT mutations typically cause behavioral variant frontotemporal dementia with or without parkinsonism. Previous studies have shown that symptomatic MAPT mutation carriers have frontotemporal atrophy, yet studies have shown mixed results as to whether presymptomatic carriers have low gray matter volumes. To elucidate whether presymptomatic carriers have lower structural brain volumes within regions atrophied during the symptomatic phase, we studied a large cohort of MAPT mutation carriers using a voxelwise approach.MethodsWe studied 22 symptomatic carriers (age 54.7 ± 9.1, 13 female) and 43 presymptomatic carriers (age 39.2 ± 10.4, 21 female). Symptomatic carriers' clinical syndromes included: behavioral variant frontotemporal dementia (18), an amnestic dementia syndrome (2), Parkinson's disease (1), and mild cognitive impairment (1). We performed voxel-based morphometry on T1 images and assessed brain volumetrics by clinical subgroup, age, and mutation subtype.ResultsSymptomatic carriers showed gray matter atrophy in bilateral frontotemporal cortex, insula, and striatum, and white matter atrophy in bilateral corpus callosum and uncinate fasciculus. Approximately 20% of presymptomatic carriers had low gray matter volumes in bilateral hippocampus, amygdala, and lateral temporal cortex. Within these regions, low gray matter volumes emerged in a subset of presymptomatic carriers as early as their thirties. Low white matter volumes arose infrequently among presymptomatic carriers.InterpretationA subset of presymptomatic MAPT mutation carriers showed low volumes in mesial temporal lobe, the region ubiquitously atrophied in all symptomatic carriers. With each decade of age, an increasing percentage of presymptomatic carriers showed low mesial temporal volume, suggestive of early neurodegeneration.
- Published
- 2021
62. Studying the natural history of frontotemporal lobar degeneration (FTLD): The ARTFL LEFFTDS longitudinal FTLD (ALLFTD) protocol
- Author
-
Boeve, Bradley F, Boxer, Adam L, Rosen, Howard J, Forsberg, Leah K, Heuer, Hilary W, Brushaber, Danielle, Appleby, Brian, Biernacka, Joanna M, Bordelon, Yvette M, Botha, Hugo, Brannelly, Patrick, Dickerson, Brad C, Dickson, Dennis W, Kimiko, Domoto‐Reilly, Faber, Kelley, Fagan, Anne, Fields, Julie A, Fishman, Ann, Foroud, Tatiana M, Galasko, Doug R, Gavrilova, Ralitza H, Gendron, Tania F, Geschwind, Daniel H, Ghoshal, Nupur, Goldman, Jill, Graff‐Radford, Jonathan, Graff‐Radford, Neill R, Grant, Ian, Grossman, Murray, Hsiung, Ging‐Yuek Robin, Huang, Eric J, Huey, Edward, Irwin, David J, Jones, David T, Kantarci, Kejal, Karydas, Anna M, Kaufer, Daniel, Knopman, David S, Kramer, Joel H, Kremers, Walter K, Kornak, John, Kukull, Walter A, Lagone, Emma, Leger, Gabriel C, Litvan, Irene, Ljubenkov, Peter A, Lucente, Diane E, Mackenzie, Ian R, Manoochehri, Masood, Masdeu, Joseph C, McGinnis, Scott, Mendez, Mario F, Miller, Bruce L, Miyagawa, Toji, Nelson, Kevin M, Onyike, Chiadi U, Pantelyat, Alex, Pascual, Belen, Pearlman, Rodney, Petrucelli, Leonard, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine, Rascovsky, Katya, Rexach, Jessica E, Ritter, Aaron, Roberson, Erik D, Rojas, Julio C, Sabbagh, Marwan N, Salmon, David P, Savica, Rodolfo, Seeley, William W, Staffaroni, Adam M, Syrjanen, Jeremy, Tartaglia, Carmela, Tatton, Nadine, Taylor, Joanne, Toga, Arthur W, Weintraub, Sandra, Wheaton, Diana, Wong, Bonnie, and Wszolek, Zbigniew
- Subjects
Brain Disorders ,Rare Diseases ,Acquired Cognitive Impairment ,Neurodegenerative ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Clinical Trials and Supportive Activities ,Clinical Research ,Frontotemporal Dementia (FTD) ,Alzheimer's Disease Related Dementias (ADRD) ,Genetics ,Neurosciences ,Dementia ,2.1 Biological and endogenous factors ,Geriatrics ,Clinical Sciences - Published
- 2020
63. Plasma neurofilament light chain levels reflect caregiver burden and social cognition measures in familial frontotemporal lobar degeneration (FTLD)
- Author
-
Heuer, Hilary W, Rojas, Julio C, Toller, Gianina, Rankin, Katherine, Brushaber, Danielle, Appleby, Brian, Bordelon, Yvette M, Dickerson, Brad C, Kimiko, Domoto‐Reilly, Faber, Kelley, Foroud, Tatiana M, Forsberg, Leah K, Ghoshal, Nupur, Grant, Ian, Graff‐Radford, Neill R, Grossman, Murray, Hsiung, Ging‐Yuek Robin, Huey, Edward D, Karydas, Anna M, Kaufer, Daniel, Kerwin, Diana R, Lagone, Emma, Litvan, Irene, Ljubenkov, Peter A, Mackenzie, Ian R, Mendez, Mario F, Miller, Bruce L, Onyike, Chiadi U, Ramos, Eliana Marisa, Rascovsky, Katya, Roberson, Erik D, Tartaglia, Carmela, Weintraub, Sandra, Boeve, Bradley F, Rosen, Howard J, and Boxer, Adam L
- Subjects
Neurodegenerative ,Clinical Trials and Supportive Activities ,Acquired Cognitive Impairment ,Genetics ,Aging ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Alzheimer's Disease ,Neurosciences ,Dementia ,Clinical Research ,Brain Disorders ,Behavioral and Social Science ,Neurological ,Geriatrics ,Clinical Sciences - Published
- 2020
64. Promoting tau secretion and propagation by hyperactive p300/CBP via autophagy-lysosomal pathway in tauopathy
- Author
-
Chen, Xu, Li, Yaqiao, Wang, Chao, Tang, Yinyan, Mok, Sue-Ann, Tsai, Richard M, Rojas, Julio C, Karydas, Anna, Miller, Bruce L, Boxer, Adam L, Gestwicki, Jason E, Arkin, Michelle, Cuervo, Ana Maria, and Gan, Li
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Dementia ,Alzheimer's Disease Related Dementias (ADRD) ,Frontotemporal Dementia (FTD) ,Neurosciences ,Acquired Cognitive Impairment ,Neurodegenerative ,Alzheimer's Disease ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Aging ,Brain Disorders ,Aetiology ,2.1 Biological and endogenous factors ,Animals ,Autophagy ,Humans ,Lysosomes ,Mice ,Mice ,Transgenic ,Neurons ,Rats ,Sprague-Dawley ,Tauopathies ,p300-CBP Transcription Factors ,tau Proteins ,Tauopathy ,Tau secretion ,Tau spreading ,Autophagy-lysosomal pathway ,p300 ,CBP ,p300/CBP ,Genetics ,Clinical Sciences ,Neurology & Neurosurgery ,Biochemistry and cell biology - Abstract
BackgroundThe trans-neuronal propagation of tau has been implicated in the progression of tau-mediated neurodegeneration. There is critical knowledge gap in understanding how tau is released and transmitted, and how that is dysregulated in diseases. Previously, we reported that lysine acetyltransferase p300/CBP acetylates tau and regulates its degradation and toxicity. However, whether p300/CBP is involved in regulation of tau secretion and propagation is unknown.MethodWe investigated the relationship between p300/CBP activity, the autophagy-lysosomal pathway (ALP) and tau secretion in mouse models of tauopathy and in cultured rodent and human neurons. Through a high-through-put compound screen, we identified a new p300 inhibitor that promotes autophagic flux and reduces tau secretion. Using fibril-induced tau spreading models in vitro and in vivo, we examined how p300/CBP regulates tau propagation.ResultsIncreased p300/CBP activity was associated with aberrant accumulation of ALP markers in a tau transgenic mouse model. p300/CBP hyperactivation blocked autophagic flux and increased tau secretion in neurons. Conversely, inhibiting p300/CBP promoted autophagic flux, reduced tau secretion, and reduced tau propagation in fibril-induced tau spreading models in vitro and in vivo.ConclusionsWe report that p300/CBP, a lysine acetyltransferase aberrantly activated in tauopathies, causes impairment in ALP, leading to excess tau secretion. This effect, together with increased intracellular tau accumulation, contributes to enhanced spreading of tau. Our findings suggest that inhibition of p300/CBP as a novel approach to correct ALP dysfunction and block disease progression in tauopathy.
- Published
- 2020
65. 18F-flortaucipir PET to autopsy comparisons in Alzheimer’s disease and other neurodegenerative diseases
- Author
-
Soleimani-Meigooni, David N, Iaccarino, Leonardo, La Joie, Renaud, Baker, Suzanne, Bourakova, Viktoriya, Boxer, Adam L, Edwards, Lauren, Eser, Rana, Gorno-Tempini, Maria-Luisa, Jagust, William J, Janabi, Mustafa, Kramer, Joel H, Lesman-Segev, Orit H, Mellinger, Taylor, Miller, Bruce L, Pham, Julie, Rosen, Howard J, Spina, Salvatore, Seeley, William W, Strom, Amelia, Grinberg, Lea T, and Rabinovici, Gil D
- Subjects
Biomedical and Clinical Sciences ,Health Sciences ,Psychology ,Brain Disorders ,Alzheimer's Disease ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Rare Diseases ,Biomedical Imaging ,Aging ,Acquired Cognitive Impairment ,Frontotemporal Dementia (FTD) ,Alzheimer's Disease Related Dementias (ADRD) ,Neurosciences ,Neurodegenerative ,Dementia ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Adult ,Aged ,Alzheimer Disease ,Autopsy ,Carbolines ,Disease Progression ,Female ,Frontotemporal Lobar Degeneration ,Gray Matter ,Humans ,Magnetic Resonance Imaging ,Male ,Middle Aged ,Neurodegenerative Diseases ,Neurofibrillary Tangles ,Positron-Emission Tomography ,Radiopharmaceuticals ,Supranuclear Palsy ,Progressive ,Tauopathies ,tau ,neurofibrillary tangle ,Alzheimer's disease ,positron emission tomography ,neuropathology ,Alzheimer’s disease ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery ,Biomedical and clinical sciences ,Health sciences - Abstract
Few studies have evaluated the relationship between in vivo18F-flortaucipir PET and post-mortem pathology. We sought to compare antemortem 18F-flortaucipir PET to neuropathology in a consecutive series of patients with a broad spectrum of neurodegenerative conditions. Twenty patients were included [mean age at PET 61 years (range 34-76); eight female; median PET-to-autopsy interval of 30 months (range 4-59 months)]. Eight patients had primary Alzheimer's disease pathology, nine had non-Alzheimer tauopathies (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, and frontotemporal lobar degeneration with MAPT mutations), and three had non-tau frontotemporal lobar degeneration. Using an inferior cerebellar grey matter reference, 80-100-min 18F-flortaucipir PET standardized uptake value ratio (SUVR) images were created. Mean SUVRs were calculated for progressive supranuclear palsy, corticobasal degeneration, and neurofibrillary tangle Braak stage regions of interest, and these values were compared to SUVRs derived from young, non-autopsy, cognitively normal controls used as a standard for tau negativity. W-score maps were generated to highlight areas of increased tracer retention compared to cognitively normal controls, adjusting for age as a covariate. Autopsies were performed blinded to PET results. There was excellent correspondence between areas of 18F-flortaucipir retention, on both SUVR images and W-score maps, and neurofibrillary tangle distribution in patients with primary Alzheimer's disease neuropathology. Patients with non-Alzheimer tauopathies and non-tau frontotemporal lobar degeneration showed a range of tracer retention that was less than Alzheimer's disease, though higher than age-matched, cognitively normal controls. Overall, binding across both tau-positive and tau-negative non-Alzheimer disorders did not reliably correspond with post-mortem tau pathology. 18F-flortaucipir SUVRs in subcortical regions were higher in autopsy-confirmed progressive supranuclear palsy and corticobasal degeneration than in controls, but were similar to values measured in Alzheimer's disease and tau-negative neurodegenerative pathologies. Quantification of 18F-flortaucipir SUVR images at Braak stage regions of interest reliably detected advanced Alzheimer's (Braak VI) pathology. However, patients with earlier Braak stages (Braak I-IV) did not show elevated tracer uptake in these regions compared to young, tau-negative controls. In summary, PET-to-autopsy comparisons confirm that 18F-flortaucipir PET is a reliable biomarker of advanced Braak tau pathology in Alzheimer's disease. The tracer cannot reliably differentiate non-Alzheimer tauopathies and may not detect early Braak stages of neurofibrillary tangle pathology.
- Published
- 2020
66. Four-Repeat Tauopathies: Current Management and Future Treatments
- Author
-
VandeVrede, Lawren, Ljubenkov, Peter A, Rojas, Julio C, Welch, Ariane E, and Boxer, Adam L
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Rare Diseases ,Dementia ,Frontotemporal Dementia (FTD) ,Neurodegenerative ,Neurosciences ,Aging ,Clinical Research ,Mental Health ,Alzheimer's Disease ,Clinical Trials and Supportive Activities ,Brain Disorders ,Acquired Cognitive Impairment ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurological ,Clinical Trials as Topic ,Disease Management ,Forecasting ,Humans ,Motor Disorders ,Tauopathies ,Treatment Outcome ,4R-tauopathy ,progressive supranuclear palsy ,Richardson's syndrome ,corticobasal syndrome ,corticobasal degeneration ,atypical parkinsonism ,Richardson’s syndrome ,Pharmacology and Pharmaceutical Sciences ,Public Health and Health Services ,Neurology & Neurosurgery ,Pharmacology and pharmaceutical sciences ,Biological psychology - Abstract
Four-repeat tauopathies are a neurodegenerative disease characterized by brain parenchymal accumulation of a specific isoform of the protein tau, which gives rise to a wide breadth of clinical syndromes encompassing diverse symptomatology, with the most common syndromes being progressive supranuclear palsy-Richardson's and corticobasal syndrome. Despite the lack of effective disease-modifying therapies, targeted treatment of symptoms can improve quality of life for patients with 4-repeat tauopathies. However, managing these symptoms can be a daunting task, even for those familiar with the diseases, as they span motor, sensory, cognitive, affective, autonomic, and behavioral domains. This review describes current approaches to symptomatic management of common clinical symptoms in 4-repeat tauopathies with a focus on practical patient management, including pharmacologic and nonpharmacologic strategies, and concludes with a discussion of the history and future of disease-modifying therapeutics and clinical trials in this population.
- Published
- 2020
67. Longitudinal structural and metabolic changes in frontotemporal dementia.
- Author
-
Bejanin, Alexandre, Tammewar, Gautam, Marx, Gabe, Cobigo, Yann, Iaccarino, Leonardo, Kornak, John, Staffaroni, Adam M, Dickerson, Bradford C, Boeve, Bradley F, Knopman, David S, Gorno-Tempini, Marilu, Miller, Bruce L, Jagust, William J, Boxer, Adam L, Rosen, Howard J, and Rabinovici, Gil D
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Brain Disorders ,Biomedical Imaging ,Frontotemporal Dementia (FTD) ,Dementia ,Neurodegenerative ,Acquired Cognitive Impairment ,Aging ,Clinical Research ,Alzheimer's Disease ,Aphasia ,Neurosciences ,Rare Diseases ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Aged ,Atrophy ,Cerebral Cortex ,Disease Progression ,Female ,Fluorodeoxyglucose F18 ,Frontotemporal Dementia ,Humans ,Longitudinal Studies ,Magnetic Resonance Imaging ,Male ,Middle Aged ,Neuroimaging ,Neuropsychological Tests ,Positron-Emission Tomography ,Radiopharmaceuticals ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences - Abstract
ObjectiveTo compare the sensitivity of structural MRI and 18F-fludeoxyglucose PET (18FDG-PET) to detect longitudinal changes in frontotemporal dementia (FTD).MethodsThirty patients with behavioral variant FTD (bvFTD), 7 with nonfluent/agrammatic variant primary progressive aphasia (nfvPPA), 16 with semantic variant primary progressive aphasia (svPPA), and 43 cognitively normal controls underwent 2-4 MRI and 18FDG-PET scans (total scans/visit = 270) as part of the Frontotemporal Lobar Degeneration Neuroimaging Initiative study. Linear mixed-effects models were carried out voxel-wise and in regions of interest to identify areas showing decreased volume or metabolism over time in patients as compared to controls.ResultsAt baseline, patients with bvFTD showed bilateral temporal, dorsolateral, and medial prefrontal atrophy/hypometabolism that extended with time into adjacent structures and parietal lobe. In nfvPPA, baseline atrophy/hypometabolism in supplementary motor cortex extended with time into left greater than right precentral, dorsolateral, and dorsomedial prefrontal cortex. In svPPA, baseline atrophy/hypometabolism encompassed the anterior temporal and medial prefrontal cortex and longitudinal changes were found in temporal, orbitofrontal, and lateral parietal cortex. Across syndromes, there was substantial overlap in the brain regions showing volume and metabolism loss. Even though the pattern of metabolic decline was more extensive, metabolic changes were also more variable and sample size estimates were similar or higher for 18FDG-PET compared to MRI.ConclusionOur findings demonstrated the sensitivity of 18FDG-PET and structural MRI for tracking disease progression in FTD. Both modalities showed highly overlapping patterns of longitudinal change and comparable sample size estimates to detect longitudinal changes in future clinical trials.
- Published
- 2020
68. Targeting tau: Clinical trials and novel therapeutic approaches
- Author
-
VandeVrede, Lawren, Boxer, Adam L, and Polydoro, Manuela
- Subjects
Biochemistry and Cell Biology ,Biological Sciences ,Aging ,Neurosciences ,Clinical Research ,Rare Diseases ,Pick's Disease ,Clinical Trials and Supportive Activities ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Dementia ,Alzheimer's Disease ,Brain Disorders ,Acquired Cognitive Impairment ,Genetics ,Neurodegenerative ,Alzheimer's Disease Related Dementias (ADRD) ,Orphan Drug ,Frontotemporal Dementia (FTD) ,2.1 Biological and endogenous factors ,5.1 Pharmaceuticals ,Neurological ,Alzheimer Disease ,Brain ,Clinical Trials as Topic ,Frontotemporal Dementia ,Humans ,Tauopathies ,tau Proteins ,Tau ,Alzheimer's disease ,Frontotemporal dementia ,Progressive supranuclear palsy ,Pick's disease ,Corticobasal degeneration ,Parkinsonism ,Psychology ,Cognitive Sciences ,Biochemistry and cell biology ,Biological psychology - Abstract
Tauopathies are a group of over 20 clinicopathological neurodegenerative diseases including Alzheimer's disease (AD), the most common type of dementia, progressive supranuclear palsy, Pick's disease, corticobasal degeneration, among others. Tauopathies are defined by neurodegeneration and the presence of tau aggregates in affected brains regions. Interestingly, regional tau aggregation burden correlates with clinical phenotype and predicts cognitive status. Autosomal dominant mutations in the MAPT gene lead to tau deposition and clinical FTD syndromes with cognitive, behavioral, and motor impairment. Polymorphisms in or around the MAPT gene have also been strongly linked to other proteinopathies including synucleinopathies. Taken together these findings suggests that tau plays a critical role in neurodegeneration and proteinopathies, supporting the idea that tau targeted approaches can be disease-modifying and lead to clinically meaningful benefits in slowing or reversing disease progression. Increasingly, human clinical trials are testing this hypothesis. This article reviews tau-targeted therapies tested in clinical trials as well as agents currently in active development based on publicly disclosed information. We describe the therapeutic approaches of these trials based on the potential pathogenic mechanism they target.
- Published
- 2020
69. Assessment of Demographic, Genetic, and Imaging Variables Associated With Brain Resilience and Cognitive Resilience to Pathological Tau in Patients With Alzheimer Disease
- Author
-
Ossenkoppele, Rik, Lyoo, Chul Hyoung, Jester-Broms, Jonas, Sudre, Carole H, Cho, Hanna, Ryu, Young Hoon, Choi, Jae Yong, Smith, Ruben, Strandberg, Olof, Palmqvist, Sebastian, Kramer, Joel, Boxer, Adam L, Gorno-Tempini, Maria L, Miller, Bruce L, La Joie, Renaud, Rabinovici, Gil D, and Hansson, Oskar
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Acquired Cognitive Impairment ,Behavioral and Social Science ,Biomedical Imaging ,Clinical Research ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Alzheimer's Disease ,Dementia ,Neurodegenerative ,Brain Disorders ,Aging ,Aetiology ,2.1 Biological and endogenous factors ,Mental health ,Neurological ,Age Factors ,Aged ,Alzheimer Disease ,Brain ,Cognition ,Cognitive Reserve ,Cross-Sectional Studies ,Disease Progression ,Female ,Humans ,Image Interpretation ,Computer-Assisted ,Longitudinal Studies ,Magnetic Resonance Imaging ,Male ,Neuroimaging ,Positron Emission Tomography Computed Tomography ,Risk Factors ,Sex Characteristics ,tau Proteins - Abstract
ImportanceBetter understanding is needed of the degree to which individuals tolerate Alzheimer disease (AD)-like pathological tau with respect to brain structure (brain resilience) and cognition (cognitive resilience).ObjectiveTo examine the demographic (age, sex, and educational level), genetic (APOE-ε4 status), and neuroimaging (white matter hyperintensities and cortical thickness) factors associated with interindividual differences in brain and cognitive resilience to tau positron emission tomography (PET) load and to changes in global cognition over time.Design, setting, an participantsIn this cross-sectional, longitudinal study, tau PET was performed from June 1, 2014, to November 30, 2017, and global cognition monitored for a mean [SD] interval of 2.0 [1.8] years at 3 dementia centers in South Korea, Sweden, and the United States. The study included amyloid-β-positive participants with mild cognitive impairment or AD dementia. Data analysis was performed from October 26, 2018, to December 11, 2019.ExposuresStandard dementia screening, cognitive testing, brain magnetic resonance imaging, amyloid-β PET and cerebrospinal fluid analysis, and flortaucipir (tau) labeled with fluor-18 (18F) PET.Main outcomes and measuresSeparate linear regression models were performed between whole cortex [18F]flortaucipir uptake and cortical thickness, and standardized residuals were used to obtain a measure of brain resilience. The same procedure was performed for whole cortex [18F]flortaucipir uptake vs Mini-Mental State Examination (MMSE) as a measure of cognitive resilience. Bivariate and multivariable linear regression models were conducted with age, sex, educational level, APOE-ε4 status, white matter hyperintensity volumes, and cortical thickness as independent variables and brain and cognitive resilience measures as dependent variables. Linear mixed models were performed to examine whether changes in MMSE scores over time differed as a function of a combined brain and cognitive resilience variable.ResultsA total of 260 participants (145 [55.8%] female; mean [SD] age, 69.2 [9.5] years; mean [SD] MMSE score, 21.9 [5.5]) were included in the study. In multivariable models, women (standardized β = -0.15, P = .02) and young patients (standardized β = -0.20, P = .006) had greater brain resilience to pathological tau. Higher educational level (standardized β = 0.23, P
- Published
- 2020
70. Open‐Label Phase 1 Futility Studies of Salsalate and Young Plasma in Progressive Supranuclear Palsy
- Author
-
VandeVrede, Lawren, Dale, Marian L, Fields, Scott, Frank, Megan, Hare, Emma, Heuer, Hilary W, Keith, Kellie, Koestler, Mary, Ljubenkov, Peter A, McDermott, Dana, Ohanesian, Noelle, Richards, Jennifer, Rojas, Julio C, Thijssen, Elisabeth H, Walsh, Christine, Wang, Ping, Wolf, Amy, Quinn, Joseph F, Tsai, Richard, and Boxer, Adam L
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Clinical Research ,Rare Diseases ,Orphan Drug ,Clinical Trials and Supportive Activities ,Evaluation of treatments and therapeutic interventions ,6.1 Pharmaceuticals ,Neurological ,progressive supranuclear palsy ,salsalate ,young plasma ,4RTNI ,PSPRS ,Clinical sciences - Abstract
BackgroundProgressive supranuclear palsy (PSP) is a neurodegenerative disease without approved therapies, and therapeutics are often tried off-label in the hope of slowing disease progression. Results from these experiences are seldom shared, which limits evidence-based knowledge to guide future treatment decisions.ObjectivesTo describe an open-label experience, including safety/tolerability, and longitudinal changes in biomarkers of disease progression in PSP-Richardson's syndrome (PSP-RS) patients treated with either salsalate or young plasma and compare to natural history data from previous multicenter studies.MethodsFor 6 months, 10 PSP-RS patients received daily salsalate 2,250 mg, and 5 patients received monthly infusions of four units of young plasma. Every 3 months, clinical severity was assessed with the Progressive Supranuclear Palsy Rating Scale (PSPRS), and MRI was obtained for volumetric measurement of midbrain. A range of exploratory biomarkers, including cerebrospinal fluid levels of neurofilament light chain, were collected at baseline and 6 months. Interventional data were compared to historical PSP-RS patients from the davunetide clinical trial and the 4-Repeat Tauopathy Neuroimaging Initiative.ResultsSalsalate and young plasma were safe and well tolerated. PSPRS change from baseline (mean ± standard deviation [SD]) was similar in salsalate (+5.6 ± 9.6), young plasma (+5.0 ± 7.1), and historical controls (+5.6 ± 7.1), and change in midbrain volume (cm3 ± SD) did not differ between salsalate (-0.07 ± 0.03), young plasma (-0.06 ± 0.03), and historical controls (-0.06 ± 0.04). No differences were observed between groups on any exploratory endpoint.ConclusionsNeither salsalate nor young plasma had a detectable effect on disease progression in PSP-RS. Focused open-label clinical trials incorporating historical clinical, neuropsychological, fluid, and imaging biomarkers provide useful preliminary data about the promise of novel PSP-directed therapies.
- Published
- 2020
71. Cognitive decline on the Repeatable Battery for the Assessment of Neuropsychological Status in progressive supranuclear palsy
- Author
-
Duff, Kevin, Randolph, Christopher, and Boxer, Adam L
- Subjects
Brain Disorders ,Aging ,Clinical Research ,Rare Diseases ,Neurosciences ,Clinical Trials and Supportive Activities ,Neurological ,Adult ,Aged ,Aged ,80 and over ,Cognitive Dysfunction ,Cohort Studies ,Female ,Humans ,Longitudinal Studies ,Male ,Middle Aged ,Neuropsychological Tests ,Prognosis ,Supranuclear Palsy ,Progressive ,Young Adult ,Progressive supranuclear palsy ,RBABS ,cognitive change ,Psychology ,Cognitive Sciences ,Clinical Psychology - Abstract
Objective: Progressive supranuclear palsy (PSP) is associated with a variety of cognitive deficits, but few studies have reported on its cognitive trajectory across time, especially on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS).Methods: Two hundred twenty participants diagnosed with Richardson's syndrome of PSP (PSP-RS) were evaluated with the RBANS at baseline, six months, and one year with alternate forms.Results: When using dependent t-tests, significant declines were observed on all Indexes of the RBANS from baseline to six months (ps < 0.01). Between six months and one year, significant declines were observed on three Indexes of the RBANS (ps < 0.05). Using existing regression-based change formulae from cognitively intact older adults, these participants with PSP showed significant decline on all RBANS Indexes (ps < 0.01) across one year. Finally, new regression-based change formulae were developed on this sample of individuals with PSP-RS to more precisely evaluate cognitive change in this condition.Conclusion: In this large, longitudinal cohort of participants with PSP-RS, many (but not all) showed notable cognitive decline across six months and one year on the RBANS. The different methods of examining change across time yielded different results, with regression-based methods appearing to more accurately capture decline in this sample. These findings are expected to allow clinicians to more accurately evaluate cognitive trajectories in patients with PSP, as well as make better estimates of prognosis and offer more appropriate treatment recommendations. Such findings are also expected to inform clinical trials as to the changes in cognitive outcomes with this neurological condition.
- Published
- 2020
72. Trajectory of lobar atrophy in asymptomatic and symptomatic GRN mutation carriers: a longitudinal MRI study
- Author
-
Chen, Qin, Boeve, Bradley F, Senjem, Matthew, Tosakulwong, Nirubol, Lesnick, Timothy, Brushaber, Danielle, Dheel, Christina, Fields, Julie, Forsberg, Leah, Gavrilova, Ralitza, Gearhart, Debra, Graff-Radford, Jonathan, Graff-Radford, Neill, Jack, Clifford R, Jones, David, Knopman, David, Kremers, Walter K, Lapid, Maria, Rademakers, Rosa, Ramos, Eliana Marisa, Syrjanen, Jeremy, Boxer, Adam L, Rosen, Howie, Wszolek, Zbigniew K, and Kantarci, Kejal
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Brain Disorders ,Biomedical Imaging ,Neurosciences ,Alzheimer's Disease Related Dementias (ADRD) ,Aging ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Frontotemporal Dementia (FTD) ,Dementia ,Acquired Cognitive Impairment ,Neurodegenerative ,Neurological ,Adult ,Asymptomatic Diseases ,Atrophy ,Female ,Frontotemporal Lobar Degeneration ,Heterozygote ,Humans ,Loss of Function Mutation ,Magnetic Resonance Imaging ,Male ,Middle Aged ,Progranulins ,Temporal Lobe ,Young Adult ,Magnetic resonance image ,GRN ,Asymptomatic ,Frontotemporal dementia ,Longitudinal ,Neurology & Neurosurgery ,Biological psychology - Abstract
Loss-of-function mutations in the progranulin gene (GRN) are one of the major causes of familial frontotemporal lobar degeneration. Our objective was to determine the rates and trajectories of lobar cortical atrophy from longitudinal structural magnetic resonance imaging in both asymptomatic and symptomatic GRN mutation carriers. Individuals in this study were from the ADRC and LEFFTDS studies at the Mayo Clinic. We identified 13 GRN mutation carriers (8 asymptomatic, 5 symptomatic) and noncarriers (n = 10) who had at least 2 serial T1-weighted structural magnetic resonance images and were followed annually with a median of 3 years (range 1.0-9.8 years). Longitudinal changes in lobar cortical volume were analyzed using the tensor-based morphometry with symmetric normalization (TBM-SyN) algorithm. Linear mixed-effect models were used to model cortical volume change over time among 3 groups. The annual rates of frontal (p < 0.05) and parietal (p < 0.01) lobe cortical atrophy were higher in asymptomatic GRN mutation carriers than noncarriers. The symptomatic GRN mutation carriers also had increased rates of atrophy in the frontal (p < 0.01) and parietal lobe (p < 0.01) cortices than noncarriers. In addition, greater rates of cortical atrophy were observed in the temporal lobe cortices of symptomatic GRN mutation carriers than noncarriers (p < 0.001). We found that a decline in frontal and parietal lobar cortical volume occurs in asymptomatic GRN mutation carriers and continues in the symptomatic GRN mutation carriers, whereas an increased rate of temporal lobe cortical atrophy is observed only in symptomatic GRN mutation carriers. This sequential pattern of cortical involvement in GRN mutation carriers has important implications for using imaging biomarkers of neurodegeneration as an outcome measure in potential treatment trials involving GRN mutation carriers.
- Published
- 2020
73. Progressive supranuclear palsy and primary lateral sclerosis secondary to globular glial tauopathy: a case report and a practical theoretical framework for the clinical prediction of this rare pathological entity
- Author
-
Liu, Andy J, Chang, Jessica E, Naasan, Georges, Boxer, Adam L, Miller, Bruce L, and Spina, Salvatore
- Subjects
Biomedical and Clinical Sciences ,Biological Psychology ,Clinical and Health Psychology ,Neurosciences ,Psychology ,Rare Diseases ,Brain Disorders ,Orphan Drug ,Acquired Cognitive Impairment ,Frontotemporal Dementia (FTD) ,Dementia ,Neurodegenerative ,Neurological ,Aged ,80 and over ,Fatal Outcome ,Frontotemporal Dementia ,Gait Disorders ,Neurologic ,Humans ,Male ,Motor Neuron Disease ,Neuroglia ,Ocular Motility Disorders ,Supranuclear Palsy ,Progressive ,Tauopathies ,Globular glial tauopathy ,primary lateral sclerosis ,frontotemporal dementia ,progressive supranuclear palsy ,neuropathology ,Clinical Sciences ,Cognitive Sciences ,Experimental Psychology ,Biological psychology ,Clinical and health psychology - Abstract
Globular glial tauopathy (GGT) is a rare 4-repeat tauopathy characterized by the accumulation of tau globular inclusions in astrocytes and oligodendrocytes. Several clinical phenotypes have been associated with GGT, making the prediction of this rare pathological entity difficult. We report the case of a patient with eye-movement abnormalities and gait instability, reminiscent of progressive supranuclear palsy-Richardson's syndrome (PSP-RS), who later developed upper motor neuron symptoms suggestive of primary lateral sclerosis (PLS). Neuropathological assessment revealed GGT type III pathology. A theoretical framework is proposed to help clinicians predict GGT in subjects with coexistent features of PSP-RS and PLS.
- Published
- 2020
74. Diagnostic value of plasma phosphorylated tau181 in Alzheimer's disease and frontotemporal lobar degeneration.
- Author
-
Thijssen, Elisabeth H, La Joie, Renaud, Wolf, Amy, Strom, Amelia, Wang, Ping, Iaccarino, Leonardo, Bourakova, Viktoriya, Cobigo, Yann, Heuer, Hilary, Spina, Salvatore, VandeVrede, Lawren, Chai, Xiyun, Proctor, Nicholas K, Airey, David C, Shcherbinin, Sergey, Duggan Evans, Cynthia, Sims, John R, Zetterberg, Henrik, Blennow, Kaj, Karydas, Anna M, Teunissen, Charlotte E, Kramer, Joel H, Grinberg, Lea T, Seeley, William W, Rosen, Howie, Boeve, Bradley F, Miller, Bruce L, Rabinovici, Gil D, Dage, Jeffrey L, Rojas, Julio C, Boxer, Adam L, and Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) investigators
- Subjects
Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) investigators ,Humans ,Alzheimer Disease ,Amyloid ,Neurofilament Proteins ,tau Proteins ,Positron-Emission Tomography ,Severity of Illness Index ,Cognition ,Phosphorylation ,Heterozygote ,Mutation ,Aged ,Middle Aged ,Female ,Male ,Frontotemporal Lobar Degeneration ,Amyloid beta-Peptides ,Gray Matter ,Biomarkers ,Neurosciences ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Frontotemporal Dementia (FTD) ,Neurodegenerative ,Alzheimer's Disease ,Acquired Cognitive Impairment ,Aging ,Dementia ,Biomedical Imaging ,Brain Disorders ,4.1 Discovery and preclinical testing of markers and technologies ,4.2 Evaluation of markers and technologies ,Neurological ,Immunology ,Medical and Health Sciences - Abstract
With the potential development of new disease-modifying Alzheimer's disease (AD) therapies, simple, widely available screening tests are needed to identify which individuals, who are experiencing symptoms of cognitive or behavioral decline, should be further evaluated for initiation of treatment. A blood-based test for AD would be a less invasive and less expensive screening tool than the currently approved cerebrospinal fluid or amyloid β positron emission tomography (PET) diagnostic tests. We examined whether plasma tau phosphorylated at residue 181 (pTau181) could differentiate between clinically diagnosed or autopsy-confirmed AD and frontotemporal lobar degeneration. Plasma pTau181 concentrations were increased by 3.5-fold in AD compared to controls and differentiated AD from both clinically diagnosed (receiver operating characteristic area under the curve of 0.894) and autopsy-confirmed frontotemporal lobar degeneration (area under the curve of 0.878). Plasma pTau181 identified individuals who were amyloid β-PET-positive regardless of clinical diagnosis and correlated with cortical tau protein deposition measured by 18F-flortaucipir PET. Plasma pTau181 may be useful to screen for tau pathology associated with AD.
- Published
- 2020
75. Association of Cognitive and Behavioral Features Between Adults With Tuberous Sclerosis and Frontotemporal Dementia
- Author
-
Liu, Andy J, Staffaroni, Adam M, Rojas-Martinez, Julio C, Olney, Nicholas T, Alquezar-Burillo, Carolina, Ljubenkov, Peter A, La Joie, Renaud, Fong, Jamie C, Taylor, Joanne, Karydas, Anna, Ramos, Eliana Marisa, Coppola, Giovanni, Boxer, Adam L, Rabinovici, Gil D, Miller, Bruce L, and Kao, Aimee W
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Clinical Sciences ,Aging ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Mental Health ,Rare Diseases ,Neurodegenerative ,Brain Disorders ,Clinical Research ,Tuberous Sclerosis ,Alzheimer's Disease Related Dementias (ADRD) ,Acquired Cognitive Impairment ,Biomedical Imaging ,Dementia ,2.1 Biological and endogenous factors ,Aetiology ,Detection ,screening and diagnosis ,4.1 Discovery and preclinical testing of markers and technologies ,Neurological ,Adult ,Aged ,Biomarkers ,Case-Control Studies ,Female ,Frontotemporal Dementia ,Humans ,Male ,Middle Aged ,Neuroimaging ,Neuropsychological Tests ,Positron-Emission Tomography - Abstract
ImportanceIndividuals with tuberous sclerosis complex can develop a progressive neuropsychiatric syndrome known as tuberous sclerosis-associated neuropsychiatric disorders. Tuberous sclerosis-associated neuropsychiatric disorders symptoms overlap with clinical criteria for frontotemporal dementia, yet the association between the 2 has not been explored.ObjectiveTo investigate the potential association between tuberous sclerosis-associated neuropsychiatric disorders and frontotemporal dementia.Design, setting, and participantsCase-control study that enrolled patients with tuberous sclerosis complex with normal IQs in an observational clinical study at the University of California, San Francisco, from 2017 to 2019 where they underwent a comprehensive clinical evaluation including neuropsychologic testing, cerebral spinal fluid biomarker profiling, and structural neuroimaging. The study included adults who fulfilled the clinical criteria for tuberous sclerosis complex and had normal IQs, had frontotemporal dementia, or were healthy control individuals.Main outcomes and measuresTuberous sclerosis-associated neuropsychiatric disorders checklist severity score, neuropsychologic test scores, cerebral spinal fluid concentrations of phosphorylated tau181, total tau, amyloid-β 42, and neurofilament light chain. Amyloid and tau positron emission tomography scans were obtained in a subset of patients.ResultsEighteen patients with tuberous sclerosis complex (mean [SD] age, 48 years [9.54]; 13 women [72%]), 16 with frontotemporal dementia (60 [6.93] years; 7 women [44%]) and 18 healthy control individuals (63 [3.85] years; 9 women [50%]) were included. The tuberous sclerosis-associated neuropsychiatric disorders checklist and neuropsychological test results were not significantly different when the tuberous sclerosis complex and frontotemporal dementia cohorts were compared. The tuberous sclerosis complex cohort exhibited elevated cerebral spinal fluid phosphorylated tau181 and neurofilament light chain with a mean of 32 pg/mL and 2300 pg/mL, respectively, when compared to healthy control individuals. All 3 patients with tuberous sclerosis complex who underwent fluorine 1B-labeled flortaucipir tau positron emission tomographic neuroimaging showed punctate foci of elevated [18F]flortaucipir binding in the frontal and temporal regions.Conclusions and relevanceAdults with tuberous sclerosis complex showed phenotypic overlap with frontotemporal dementia. The results support a possible clinical continuum between tuberous sclerosis-associated neuropsychiatric disorders and frontotemporal dementia and highlights a potential pathophysiological link between neurodevelopmental and neurodegenerative processes. Quantitative neuropsychological testing and the tuberous sclerosis-associated neuropsychiatric disorders checklist, potentially supplemented by cerebral spinal fluid and imaging biomarkers, could be used to screen and prognosticate for risk of a neurodegenerative process in adult patients with tuberous sclerosis complex.
- Published
- 2020
76. Distinct tau PET patterns in atrophy‐defined subtypes of Alzheimer's disease
- Author
-
Ossenkoppele, Rik, Lyoo, Chul Hyoung, Sudre, Carole H, van Westen, Danielle, Cho, Hanna, Ryu, Young Hoon, Choi, Jae Yong, Smith, Ruben, Strandberg, Olof, Palmqvist, Sebastian, Westman, Eric, Tsai, Richard, Kramer, Joel, Boxer, Adam L, Gorno‐Tempini, Maria L, La Joie, Renaud, Miller, Bruce L, Rabinovici, Gil D, and Hansson, Oskar
- Subjects
Biological Psychology ,Psychology ,Dementia ,Biomedical Imaging ,Neurosciences ,Acquired Cognitive Impairment ,Neurodegenerative ,Alzheimer's Disease ,Bioengineering ,Clinical Research ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Aging ,Brain Disorders ,4.1 Discovery and preclinical testing of markers and technologies ,Aetiology ,2.1 Biological and endogenous factors ,Detection ,screening and diagnosis ,Neurological ,Aged ,Alzheimer Disease ,Atrophy ,Carbolines ,Cognitive Dysfunction ,Female ,Hippocampus ,Humans ,Image Processing ,Computer-Assisted ,Magnetic Resonance Imaging ,Middle Aged ,Positron-Emission Tomography ,White Matter ,tau Proteins ,Alzheimer's disease ,Cognition ,Subtypes ,Tau ,Thickness ,Clinical Sciences ,Geriatrics ,Clinical sciences ,Biological psychology - Abstract
IntroductionDifferential patterns of brain atrophy on structural magnetic resonance imaging (MRI) revealed four reproducible subtypes of Alzheimer's disease (AD): (1) "typical", (2) "limbic-predominant", (3) "hippocampal-sparing", and (4) "mild atrophy". We examined the neurobiological characteristics and clinical progression of these atrophy-defined subtypes.MethodsThe four subtypes were replicated using a clustering method on MRI data in 260 amyloid-β-positive patients with mild cognitive impairment or AD dementia, and we subsequently tested whether the subtypes differed on [18 F]flortaucipir (tau) positron emission tomography, white matter hyperintensity burden, and rate of global cognitive decline.ResultsVoxel-wise and region-of-interest analyses revealed the greatest neocortical tau load in hippocampal-sparing (frontoparietal-predominant) and typical (temporal-predominant) patients, while limbic-predominant patients showed particularly high entorhinal tau. Typical patients with AD had the most pronounced white matter hyperintensity load, and hippocampal-sparing patients showed the most rapid global cognitive decline.DiscussionOur data suggest that structural MRI can be used to identify biologically and clinically meaningful subtypes of AD.
- Published
- 2020
77. Age at symptom onset and death and disease duration in genetic frontotemporal dementia: an international retrospective cohort study.
- Author
-
Moore, Katrina M, Nicholas, Jennifer, Grossman, Murray, McMillan, Corey T, Irwin, David J, Massimo, Lauren, Van Deerlin, Vivianna M, Warren, Jason D, Fox, Nick C, Rossor, Martin N, Mead, Simon, Bocchetta, Martina, Boeve, Bradley F, Knopman, David S, Graff-Radford, Neill R, Forsberg, Leah K, Rademakers, Rosa, Wszolek, Zbigniew K, van Swieten, John C, Jiskoot, Lize C, Meeter, Lieke H, Dopper, Elise Gp, Papma, Janne M, Snowden, Julie S, Saxon, Jennifer, Jones, Matthew, Pickering-Brown, Stuart, Le Ber, Isabelle, Camuzat, Agnès, Brice, Alexis, Caroppo, Paola, Ghidoni, Roberta, Pievani, Michela, Benussi, Luisa, Binetti, Giuliano, Dickerson, Bradford C, Lucente, Diane, Krivensky, Samantha, Graff, Caroline, Öijerstedt, Linn, Fallström, Marie, Thonberg, Håkan, Ghoshal, Nupur, Morris, John C, Borroni, Barbara, Benussi, Alberto, Padovani, Alessandro, Galimberti, Daniela, Scarpini, Elio, Fumagalli, Giorgio G, Mackenzie, Ian R, Hsiung, Ging-Yuek R, Sengdy, Pheth, Boxer, Adam L, Rosen, Howie, Taylor, Joanne B, Synofzik, Matthis, Wilke, Carlo, Sulzer, Patricia, Hodges, John R, Halliday, Glenda, Kwok, John, Sanchez-Valle, Raquel, Lladó, Albert, Borrego-Ecija, Sergi, Santana, Isabel, Almeida, Maria Rosário, Tábuas-Pereira, Miguel, Moreno, Fermin, Barandiaran, Myriam, Indakoetxea, Begoña, Levin, Johannes, Danek, Adrian, Rowe, James B, Cope, Thomas E, Otto, Markus, Anderl-Straub, Sarah, de Mendonça, Alexandre, Maruta, Carolina, Masellis, Mario, Black, Sandra E, Couratier, Philippe, Lautrette, Geraldine, Huey, Edward D, Sorbi, Sandro, Nacmias, Benedetta, Laforce, Robert, Tremblay, Marie-Pier L, Vandenberghe, Rik, Damme, Philip Van, Rogalski, Emily J, Weintraub, Sandra, Gerhard, Alexander, Onyike, Chiadi U, Ducharme, Simon, Papageorgiou, Sokratis G, Ng, Adeline Su Lyn, Brodtmann, Amy, Finger, Elizabeth, and Guerreiro, Rita
- Subjects
FTD Prevention Initiative ,Humans ,Disease Progression ,tau Proteins ,Retrospective Studies ,Cohort Studies ,Family ,Age of Onset ,Phenotype ,Mutation ,Adult ,Aged ,Aged ,80 and over ,Middle Aged ,Female ,Male ,Frontotemporal Dementia ,C9orf72 Protein ,Progranulins ,Clinical Research ,Rare Diseases ,Dementia ,Aging ,Brain Disorders ,Genetic Testing ,Neurodegenerative ,Neurosciences ,Alzheimer's Disease Related Dementias (ADRD) ,Prevention ,Genetics ,Acquired Cognitive Impairment ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,2.1 Biological and endogenous factors ,Neurological ,Neurology & Neurosurgery ,Clinical Sciences - Abstract
BackgroundFrontotemporal dementia is a heterogenous neurodegenerative disorder, with about a third of cases being genetic. Most of this genetic component is accounted for by mutations in GRN, MAPT, and C9orf72. In this study, we aimed to complement previous phenotypic studies by doing an international study of age at symptom onset, age at death, and disease duration in individuals with mutations in GRN, MAPT, and C9orf72.MethodsIn this international, retrospective cohort study, we collected data on age at symptom onset, age at death, and disease duration for patients with pathogenic mutations in the GRN and MAPT genes and pathological expansions in the C9orf72 gene through the Frontotemporal Dementia Prevention Initiative and from published papers. We used mixed effects models to explore differences in age at onset, age at death, and disease duration between genetic groups and individual mutations. We also assessed correlations between the age at onset and at death of each individual and the age at onset and at death of their parents and the mean age at onset and at death of their family members. Lastly, we used mixed effects models to investigate the extent to which variability in age at onset and at death could be accounted for by family membership and the specific mutation carried.FindingsData were available from 3403 individuals from 1492 families: 1433 with C9orf72 expansions (755 families), 1179 with GRN mutations (483 families, 130 different mutations), and 791 with MAPT mutations (254 families, 67 different mutations). Mean age at symptom onset and at death was 49·5 years (SD 10·0; onset) and 58·5 years (11·3; death) in the MAPT group, 58·2 years (9·8; onset) and 65·3 years (10·9; death) in the C9orf72 group, and 61·3 years (8·8; onset) and 68·8 years (9·7; death) in the GRN group. Mean disease duration was 6·4 years (SD 4·9) in the C9orf72 group, 7·1 years (3·9) in the GRN group, and 9·3 years (6·4) in the MAPT group. Individual age at onset and at death was significantly correlated with both parental age at onset and at death and with mean family age at onset and at death in all three groups, with a stronger correlation observed in the MAPT group (r=0·45 between individual and parental age at onset, r=0·63 between individual and mean family age at onset, r=0·58 between individual and parental age at death, and r=0·69 between individual and mean family age at death) than in either the C9orf72 group (r=0·32 individual and parental age at onset, r=0·36 individual and mean family age at onset, r=0·38 individual and parental age at death, and r=0·40 individual and mean family age at death) or the GRN group (r=0·22 individual and parental age at onset, r=0·18 individual and mean family age at onset, r=0·22 individual and parental age at death, and r=0·32 individual and mean family age at death). Modelling showed that the variability in age at onset and at death in the MAPT group was explained partly by the specific mutation (48%, 95% CI 35-62, for age at onset; 61%, 47-73, for age at death), and even more by family membership (66%, 56-75, for age at onset; 74%, 65-82, for age at death). In the GRN group, only 2% (0-10) of the variability of age at onset and 9% (3-21) of that of age of death was explained by the specific mutation, whereas 14% (9-22) of the variability of age at onset and 20% (12-30) of that of age at death was explained by family membership. In the C9orf72 group, family membership explained 17% (11-26) of the variability of age at onset and 19% (12-29) of that of age at death.InterpretationOur study showed that age at symptom onset and at death of people with genetic frontotemporal dementia is influenced by genetic group and, particularly for MAPT mutations, by the specific mutation carried and by family membership. Although estimation of age at onset will be an important factor in future pre-symptomatic therapeutic trials for all three genetic groups, our study suggests that data from other members of the family will be particularly helpful only for individuals with MAPT mutations. Further work in identifying both genetic and environmental factors that modify phenotype in all groups will be important to improve such estimates.FundingUK Medical Research Council, National Institute for Health Research, and Alzheimer's Society.
- Published
- 2020
78. New directions in clinical trials for frontotemporal lobar degeneration: Methods and outcome measures.
- Author
-
Boxer, Adam L, Gold, Michael, Feldman, Howard, Boeve, Bradley F, Dickinson, Susan L-J, Fillit, Howard, Ho, Carole, Paul, Robert, Pearlman, Rodney, Sutherland, Margaret, Verma, Ajay, Arneric, Stephen P, Alexander, Brian M, Dickerson, Bradford C, Dorsey, Earl Ray, Grossman, Murray, Huey, Edward D, Irizarry, Michael C, Marks, William J, Masellis, Mario, McFarland, Frances, Niehoff, Debra, Onyike, Chiadi U, Paganoni, Sabrina, Panzara, Michael A, Rockwood, Kenneth, Rohrer, Jonathan D, Rosen, Howard, Schuck, Robert N, Soares, Holly D, and Tatton, Nadine
- Subjects
Humans ,Atrophy ,Magnetic Resonance Imaging ,Clinical Trials as Topic ,Congresses as Topic ,Frontotemporal Lobar Degeneration ,Biomarkers ,ARTFL ,Biomarker ,C9orf72 ,Clinical trial ,FTD ,FTLD ,Frontotemporal dementia ,Frontotemporal lobar degeneration ,GRN ,LEFFTDS ,MAPT ,Primary progressive aphasia ,Progressive supranuclear palsy ,Brain Disorders ,Genetics ,Acquired Cognitive Impairment ,Dementia ,Clinical Trials and Supportive Activities ,Alzheimer's Disease Related Dementias (ADRD) ,Frontotemporal Dementia (FTD) ,Rare Diseases ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Clinical Research ,Neurodegenerative ,Geriatrics ,Clinical Sciences ,Neurosciences - Abstract
IntroductionFrontotemporal lobar degeneration (FTLD) is the most common form of dementia for those under 60 years of age. Increasing numbers of therapeutics targeting FTLD syndromes are being developed.MethodsIn March 2018, the Association for Frontotemporal Degeneration convened the Frontotemporal Degeneration Study Group meeting in Washington, DC, to discuss advances in the clinical science of FTLD.ResultsChallenges exist for conducting clinical trials in FTLD. Two of the greatest challenges are (1) the heterogeneity of FTLD syndromes leading to difficulties in efficiently measuring treatment effects and (2) the rarity of FTLD disorders leading to recruitment challenges.DiscussionNew personalized endpoints that are clinically meaningful to individuals and their families should be developed. Personalized approaches to analyzing MRI data, development of new fluid biomarkers and wearable technologies will help to improve the power to detect treatment effects in FTLD clinical trials and enable new, clinical trial designs, possibly leveraged from the experience of oncology trials. A computational visualization and analysis platform that can support novel analyses of combined clinical, genetic, imaging, biomarker data with other novel modalities will be critical to the success of these endeavors.
- Published
- 2020
79. Clinical and volumetric changes with increasing functional impairment in familial frontotemporal lobar degeneration.
- Author
-
Olney, Nicholas T, Ong, Elise, Goh, Sheng-Yang M, Bajorek, Lynn, Dever, Reilly, Staffaroni, Adam M, Cobigo, Yann, Bock, Meredith, Chiang, Kevin, Ljubenkov, Peter, Kornak, John, Heuer, Hilary W, Wang, Ping, Rascovsky, Katya, Wolf, Amelia, Appleby, Brian, Bove, Jessica, Bordelon, Yvette, Brannelly, Patrick, Brushaber, Danielle, Caso, Christine, Coppola, Giovanni, Dickerson, Bradford C, Dickinson, Susan, Domoto-Reilly, Kimiko, Faber, Kelly, Ferrall, Jessica, Fields, Julie, Fishman, Ann, Fong, Jamie, Foroud, Tatiana, Forsberg, Leah K, Gearhart, Debra J, Ghazanfari, Behnaz, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Jonathan, Graff-Radford, Neill R, Grant, Ian, Grossman, Murray, Haley, Dana, Hsiung, Gingyuek, Huey, Edward D, Irwin, David J, Jones, David T, Kantarci, Kejal, Karydas, Anna M, Kaufer, Daniel, Kerwin, Diana, Knopman, David S, Kramer, Joel H, Kraft, Ruth, Kremers, Walter, Kukull, Walter, Lapid, Maria I, Litvan, Irene, Mackenzie, Ian R, Maldonado, Miranda, Manoochehri, Masood, McGinnis, Scott M, McKinley, Emily C, Mendez, Mario F, Miller, Bruce L, Onyike, Chiadi, Pantelyat, Alex, Pearlman, Rodney, Petrucelli, Len, Potter, Madeleine, Rademakers, Rosa, Ramos, Eliana M, Rankin, Katherine P, Roberson, Erik D, Rogalski, Emily, Sengdy, Pheth, Shaw, Leslie M, Syrjanen, Jeremy, Tartaglia, M Carmela, Tatton, Nadine, Taylor, Joanne, Toga, Arthur, Trojanowski, John Q, Weintraub, Sandra, Wong, Bonnie, Wszolek, Zbigniew, Boxer, Adam L, Boeve, Brad F, Rosen, Howard J, and ARTFL and LEFFTDS consortia
- Subjects
ARTFL and LEFFTDS consortia ,Temporal Lobe ,Humans ,Atrophy ,Genetic Predisposition to Disease ,tau Proteins ,Magnetic Resonance Imaging ,Longitudinal Studies ,Neuropsychological Tests ,Image Processing ,Computer-Assisted ,Middle Aged ,Female ,Male ,Frontotemporal Lobar Degeneration ,C9orf72 Protein ,Progranulins ,C9ORF72 ,Familial ,Frontotemporal lobar degeneration ,GRN ,Genetic ,MAPT ,Frontotemporalobar degeneration ,Neurodegenerative ,Behavioral and Social Science ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Alzheimer's Disease Related Dementias (ADRD) ,Biomedical Imaging ,Aging ,Alzheimer's Disease ,Clinical Trials and Supportive Activities ,Acquired Cognitive Impairment ,Dementia ,Clinical Research ,Brain Disorders ,Neurosciences ,Rare Diseases ,Frontotemporal Dementia (FTD) ,2.1 Biological and endogenous factors ,Neurological ,Geriatrics ,Clinical Sciences - Abstract
IntroductionThe Advancing Research and Treatment in Frontotemporal Lobar Degeneration and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects longitudinal studies were designed to describe the natural history of familial-frontotemporal lobar degeneration due to autosomal dominant mutations.MethodsWe examined cognitive performance, behavioral ratings, and brain volumes from the first time point in 320 MAPT, GRN, and C9orf72 family members, including 102 non-mutation carriers, 103 asymptomatic carriers, 43 mildly/questionably symptomatic carriers, and 72 carriers with dementia.ResultsAsymptomatic carriers showed similar scores on all clinical measures compared with noncarriers but reduced frontal and temporal volumes. Those with mild/questionable impairment showed decreased verbal recall, fluency, and Trail Making Test performance and impaired mood and self-monitoring. Dementia was associated with impairment in all measures. All MAPT carriers with dementia showed temporal atrophy, but otherwise, there was no single cognitive test or brain region that was abnormal in all subjects.DiscussionImaging changes appear to precede clinical changes in familial-frontotemporal lobar degeneration, but specific early clinical and imaging changes vary across individuals.
- Published
- 2020
80. Individualized atrophy scores predict dementia onset in familial frontotemporal lobar degeneration.
- Author
-
Staffaroni, Adam M, Cobigo, Yann, Goh, Sheng-Yang M, Kornak, John, Bajorek, Lynn, Chiang, Kevin, Appleby, Brian, Bove, Jessica, Bordelon, Yvette, Brannelly, Patrick, Brushaber, Danielle, Caso, Christina, Coppola, Giovanni, Dever, Reilly, Dheel, Christina, Dickerson, Bradford C, Dickinson, Susan, Dominguez, Sophia, Domoto-Reilly, Kimiko, Faber, Kelly, Ferrall, Jessica, Fields, Julie A, Fishman, Ann, Fong, Jamie, Foroud, Tatiana, Forsberg, Leah K, Gavrilova, Ralitza, Gearhart, Debra, Ghazanfari, Behnaz, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Jonathan, Graff-Radford, Neill, Grant, Ian, Grossman, Murray, Haley, Dana, Heuer, Hilary W, Hsiung, Ging-Yuek, Huey, Edward D, Irwin, David J, Jones, David T, Jones, Lynne, Kantarci, Kejal, Karydas, Anna, Kaufer, Daniel I, Kerwin, Diana R, Knopman, David S, Kraft, Ruth, Kramer, Joel H, Kremers, Walter K, Kukull, Walter A, Litvan, Irene, Ljubenkov, Peter A, Lucente, Diane, Lungu, Codrin, Mackenzie, Ian R, Maldonado, Miranda, Manoochehri, Masood, McGinnis, Scott M, McKinley, Emily, Mendez, Mario F, Miller, Bruce L, Multani, Namita, Onyike, Chiadi, Padmanabhan, Jaya, Pantelyat, Alex, Pearlman, Rodney, Petrucelli, Len, Potter, Madeline, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine P, Rascovsky, Katya, Roberson, Erik D, Rogalski, Emily, Sengdy, Pheth, Shaw, Leslie M, Syrjanen, Jeremy, Tartaglia, M Carmela, Tatton, Nadine, Taylor, Joanne, Toga, Arthur, Trojanowski, John Q, Weintraub, Sandra, Wang, Ping, Wong, Bonnie, Wszolek, Zbigniew, Boxer, Adam L, Boeve, Brad F, Rosen, Howard J, and ARTFL/LEFFTDS consortium
- Subjects
ARTFL/LEFFTDS consortium ,Brain ,Humans ,Atrophy ,Genetic Predisposition to Disease ,tau Proteins ,Magnetic Resonance Imaging ,Neuropsychological Tests ,Mutation ,Image Processing ,Computer-Assisted ,Middle Aged ,Female ,Male ,Frontotemporal Dementia ,C9orf72 Protein ,Progranulins ,Frontotemporal dementia ,Genetics ,Magnetic resonance imaging ,TDP-43 ,Tau ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Frontotemporal Dementia (FTD) ,Dementia ,Brain Disorders ,Neurosciences ,Acquired Cognitive Impairment ,Prevention ,Alzheimer's Disease ,Rare Diseases ,Aging ,Neurodegenerative ,Neurological ,Geriatrics ,Clinical Sciences - Abstract
IntroductionSome models of therapy for neurodegenerative diseases envision starting treatment before symptoms develop. Demonstrating that such treatments are effective requires accurate knowledge of when symptoms would have started without treatment. Familial frontotemporal lobar degeneration offers a unique opportunity to develop predictors of symptom onset.MethodsWe created dementia risk scores in 268 familial frontotemporal lobar degeneration family members by entering covariate-adjusted standardized estimates of brain atrophy into a logistic regression to classify asymptomatic versus demented participants. The score's predictive value was tested in a separate group who were followed up longitudinally (stable vs. converted to dementia) using Cox proportional regressions with dementia risk score as the predictor.ResultsCross-validated logistic regression achieved good separation of asymptomatic versus demented (accuracy = 90%, SE = 0.06). Atrophy scores predicted conversion from asymptomatic or mildly/questionably symptomatic to dementia (HR = 1.51, 95% CI: [1.16,1.98]).DiscussionIndividualized quantification of baseline brain atrophy is a promising predictor of progression in asymptomatic familial frontotemporal lobar degeneration mutation carriers.
- Published
- 2020
81. Tracking disease progression in familial and sporadic frontotemporal lobar degeneration: Recent findings from ARTFL and LEFFTDS
- Author
-
Rosen, Howard J, Boeve, Bradley F, and Boxer, Adam L
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Dementia ,Frontotemporal Dementia (FTD) ,Neurosciences ,Neurodegenerative ,Acquired Cognitive Impairment ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Brain Disorders ,Biomarkers ,Disease Progression ,Frontotemporal Dementia ,Humans ,Mutation ,C9orf72 ,familial ,frontotemporal lobar degeneration ,genetic ,GRN ,MAPT ,Geriatrics ,Clinical sciences ,Biological psychology - Abstract
IntroductionFamilial frontotemporal lobar degeneration (f-FTLD) due to autosomal dominant mutations is an important entity for developing treatments for FTLD. The Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) longitudinal studies were designed to describe the natural history of f-FTLD.MethodsWe summarized recent publications from the ARTFL and LEFFTDS studies, along with other recent publications describing the natural history of f-FTLD.ResultsPublished and emerging studies are producing data on all phases of f-FTLD, including the asymptomatic and symptomatic phases of disease, as well as the transitional phase when symptoms are just beginning to develop. These data indicate that rates of change increase along with disease severity, which is consistent with commonly cited models of neurodegeneration, and that measurement of biomarkers may predict onset of symptoms.DiscussionData from large multisite studies are producing important data on the natural history of f-FTLD that will be critical for planning intervention trials.
- Published
- 2020
82. Evidence of corticofugal tau spreading in patients with frontotemporal dementia
- Author
-
Kim, Eun-Joo, Hwang, Ji-Hye L, Gaus, Stephanie E, Nana, Alissa L, Deng, Jersey, Brown, Jesse A, Spina, Salvatore, Lee, Myung Jun, Ramos, Eliana Marisa, Grinberg, Lea T, Kramer, Joel H, Boxer, Adam L, Gorno-Tempini, Maria Luisa, Rosen, Howard J, Miller, Bruce L, and Seeley, William W
- Subjects
Biomedical and Clinical Sciences ,Neurosciences ,Rare Diseases ,Dementia ,Frontotemporal Dementia (FTD) ,Neurodegenerative ,Alzheimer's Disease Related Dementias (ADRD) ,Aging ,Clinical Research ,Alzheimer's Disease ,Brain Disorders ,Acquired Cognitive Impairment ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Aged ,Atrophy ,Brain ,Female ,Frontotemporal Dementia ,Humans ,Male ,Middle Aged ,Neural Pathways ,Pyramidal Tracts ,tau Proteins ,Tau ,Transneuronal ,Frontotemporal dementia ,Frontotemporal lobar degeneration ,Pick's disease ,Corticobasal degeneration ,MAPT ,Pick’s disease ,Clinical Sciences ,Neurology & Neurosurgery - Abstract
Common neurodegenerative diseases feature progressive accumulation of disease-specific protein aggregates in selectively vulnerable brain regions. Increasing experimental evidence suggests that misfolded disease proteins exhibit prion-like properties, including the ability to seed corruptive templating and self-propagation along axons. Direct evidence for transneuronal spread in patients, however, remains limited. To test predictions made by the transneuronal spread hypothesis in human tissues, we asked whether tau deposition within axons of the corticospinal and corticopontine pathways can be predicted based on clinical syndromes and cortical atrophy patterns seen in frontotemporal lobar degeneration (FTLD). Sixteen patients with Pick's disease, 21 with corticobasal degeneration, and 3 with FTLD-MAPT were included, spanning a range of clinical syndromes across the frontotemporal dementia (FTD) spectrum. Cortical involvement was measured using a neurodegeneration score, a tau score, and a composite score based on semiquantitative ratings and complemented by an MRI-based cortical atrophy W-map based on antemortem imaging. Midbrain cerebral peduncle and pontine base descending fibers were divided into three subregions, representing prefrontopontine, corticospinal, and parieto-temporo-occipital fiber pathways. Tau area fraction was calculated in each subregion and related to clinical syndrome and cortical measures. Within each clinical syndrome, there were predicted relationships between cortical atrophy patterns and axonal tau deposition in midbrain cerebral peduncle and pontine base. Between syndromes, contrasting and predictable patterns of brainstem axonal tau deposition emerged, with, for example, greater tau in prefrontopontine fibers in behavioral variant FTD and in corticospinal fibers in corticobasal syndrome. Finally, semiquantitative and quantitative cortical degeneration scores predicted brainstem axonal tau deposition based on anatomical principles. Taken together, these findings provide important human evidence in support of axonal tau spreading in patients with specific forms of tau-related neurodegeneration.
- Published
- 2020
83. Plasma Glial Fibrillary Acidic Protein Levels Differ Along the Spectra of Amyloid Burden and Clinical Disease Stage.
- Author
-
Asken, Breton M, Elahi, Fanny M, La Joie, Renaud, Strom, Amelia, Staffaroni, Adam M, Lindbergh, Cutter A, Apple, Alexandra C, You, Michelle, Weiner-Light, Sophia, Brathaban, Nivetha, Fernandes, Nicole, Karydas, Anna, Wang, Paul, Rojas, Julio C, Boxer, Adam L, Miller, Bruce L, Rabinovici, Gil D, Kramer, Joel H, and Casaletto, Kaitlin B
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Acquired Cognitive Impairment ,Brain Disorders ,Dementia ,Neurodegenerative ,Alzheimer's Disease ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurosciences ,Aging ,Neurological ,Aged ,Aged ,80 and over ,Alzheimer Disease ,Amyloid beta-Peptides ,Amyloidogenic Proteins ,Amyloidosis ,Aniline Compounds ,Brain ,Cognitive Dysfunction ,Cohort Studies ,Cross-Sectional Studies ,Ethylene Glycols ,Female ,Glial Fibrillary Acidic Protein ,Humans ,Male ,Positron-Emission Tomography ,Radiopharmaceuticals ,Thiazoles ,tau Proteins ,Alzheimer's disease ,amyloid ,astrocyte ,biomarker ,glial fibrillary acidic protein ,plasma ,Alzheimer’s disease ,Cognitive Sciences ,Neurology & Neurosurgery ,Clinical sciences ,Biological psychology - Abstract
BackgroundMeasuring plasma glial fibrillary acidic protein (GFAP) alongside cortical amyloid-β (Aβ) may shed light on astrocytic changes in aging and Alzheimer's disease (AD).ObjectiveTo examine associations between plasma GFAP and cortical Aβ deposition in older adults across the typical aging-to-AD dementia spectrum.MethodsWe studied two independent samples from UCSF (Cohort 1, N = 50; Cohort 2, N = 37) covering the spectra of clinical severity (CDR Sum of Boxes; CDR-SB) and Aβ-PET burden. Aβ-PET was completed with either florbetapir or Pittsburgh Compound B and standardized uptake value ratios were converted to the Centiloid (CL) scale for analyses. All participants with CDR-SB > 0 were Aβ-PET positive, while clinically normal participants (CDR-SB = 0) were a mix of Aβ-PET positive and negative. Regression analyses evaluated main effect and interaction associations between plasma GFAP, Aβ-PET, and clinical severity.ResultsIn both cohorts, plasma GFAP increased linearly with Aβ-PET CLs in clinically normal older adults. In Cohort 2, which included participants with more severe clinical dysfunction and Aβ-PET burden, the association between Aβ and GFAP became curvilinear (inverted U-shape; quadratic model R2 change = 0.165, p = 0.009), and Aβ-PET interacted with CDR-SB (R2 change = 0.164, p = 0.007): older adults with intermediate functional impairment (CDR-SB = 0.5-4.0) showed a weak (negative) association between Aβ-PET CLs and plasma GFAP, while older adults with dementia (CDR-SB > 4.0) showed a strong, negative association of higher Aβ-PET CLs with lower plasma GFAP.ConclusionThe relationship between astrocytic integrity and cortical Aβ may be highly dynamic, with linear, positive associations early in disease that diverge in more severe disease stages.
- Published
- 2020
84. Associations Between Amantadine Usage, Gait, and Cognition in PSP: A post-hoc Analysis of the Davunetide Trial
- Author
-
Dale, Marian L, Brumbach, Barbara H, Boxer, Adam L, and Hiller, Amie L
- Subjects
Clinical Research ,Basic Behavioral and Social Science ,Behavioral and Social Science ,progressive supranuclear palsy ,amantadine ,gait ,balance ,cognition ,Clinical Sciences ,Neurosciences ,Psychology - Abstract
Introduction: Amantadine anecdotally improves gait in progressive supranuclear palsy (PSP) but definitive data is lacking. We investigated associations between amantadine usage, gait, cognition, and activities of daily living in 310 subjects with PSP using data from the davunetide trial. Method: We compared baseline demographics, PSP Rating Scale (PSPRS), Repeat Battery for the Assessment of Neuropsychological Status (RBANS), and Schwab and England Activities of Daily Living (SEADL) scores between subjects taking vs. not taking amantadine using chi-square tests for categorical variables and independent sample t-tests for continuous variables. Using the general linear model (GLM), we tested whether group status predicted total PSPRS, PSPRS-gait and midline, total RBANS, RBANS-attention, and SEADL before and after the 52-weeks follow-up. Results: Subjects taking vs. not taking amantadine were similar at baseline, except subjects taking amantadine had a higher Clinical Global Impression (CGI) Score (p = 0.01). However, the CGI change score did not differ between groups at week 52 (p = 0.10). Using GLM models (controlling for covariates), we found that subjects taking vs. not taking amantadine did not significantly predict total PSPRS, PSPRS-gait and midline, total RBANS, RBANS-attention, or SEADL at baseline, week 52, or the change score between baseline and week 52. Discussion: This post-hoc analysis of the davunetide trial did not find an association between amantadine and gait or cognitive measures in PSP, but was not powered to find such a difference. Future studies should still examine amantadine for symptomatic benefit in multiple PSP subtypes.
- Published
- 2020
85. Symptomatic amyloid‐related imaging abnormalities in an APOE ε4/ε4 patient treated with aducanumab
- Author
-
VandeVrede, Lawren, Gibbs, Daniel M, Koestler, Mary, La Joie, Renaud, Ljubenkov, Peter A, Provost, Karine, Soleimani‐Meigooni, David, Strom, Amelia, Tsoy, Elena, Rabinovici, Gil D, and Boxer, Adam L
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Dementia ,Biomedical Imaging ,Neurosciences ,Acquired Cognitive Impairment ,Neurodegenerative ,Alzheimer's Disease ,Clinical Research ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Aging ,Brain Disorders ,aducanumab ,Alzheimer's disease ,amyloid-related imaging abnormalities ,apolipoprotein E ,flortaucipir ,FTP ,Pittsburgh compound B ,amyloid‐related imaging abnormalities ,Genetics ,Biological psychology - Abstract
IntroductionAmyloid-related imaging abnormalities (ARIA) are a common, dose-dependent effect of amyloid-targeting antibodies, strongly associated with the apolipoprotein E (APOE) ε4 allele.MethodsWe describe the clinical course and management of a 66-year-old white male (APOE ε4/ε4) enrolled in an observational study that included amyloid and tau positron emission tomography (PET), who received aducanumab through the ENGAGE clinical trial.ResultsAcute symptoms included headache and encephalopathy, and magnetic resonance imaging revealed ARIA-E and ARIA-H. Malignant hypertension and epileptiform activity were treated with nicardipine and levetiracetam. Subsequent clinical/imaging worsening prompted a course of methylprednisolone. Symptoms and ARIA-E resolved over 6 months, while ARIA-H persisted. Quantitative analysis of interval amyloid PET showed reduced signal in pre-existing areas but increased signal posteriorly; while tau PET showed increased signal overall.DiscussionIn an APOE ε4/ε4 patient, ARIA symptoms were accompanied by malignant hypertension and epileptiform activity, and pulsed steroids reversed edema. Studies from larger cohorts may clarify the optimal treatment and pathophysiology of ARIA.
- Published
- 2020
86. Assessment of executive function declines in presymptomatic and mildly symptomatic familial frontotemporal dementia: NIH-EXAMINER as a potential clinical trial endpoint.
- Author
-
Staffaroni, Adam M, Bajorek, Lynn, Casaletto, Kaitlin B, Cobigo, Yann, Goh, Sheng-Yang M, Wolf, Amy, Heuer, Hilary W, Elahi, Fanny M, Ljubenkov, Peter A, Dever, Reilly, Kornak, John, Appleby, Brian, Bove, Jessica, Bordelon, Yvette, Brannelly, Patrick, Brushaber, Danielle, Caso, Christina, Coppola, Giovanni, Dheel, Christina, Dickerson, Bradford C, Dickinson, Susan, Dominguez, Sophia, Domoto-Reilly, Kimiko, Faber, Kelly, Ferrall, Jessica, Fields, Julie A, Fishman, Ann, Fong, Jamie, Foroud, Tatiana, Forsberg, Leah K, Gavrilova, Ralitza, Gearhart, Debra, Ghazanfari, Behnaz, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Jonathan, Graff-Radford, Neill, Grant, Ian, Grossman, Murray, Haley, Dana, Hsiung, Ging-Yuek, Huey, Edward D, Irwin, David J, Jones, David T, Jones, Lynne, Kantarci, Kejal, Karydas, Anna, Kaufer, Daniel I, Kerwin, Diana R, Knopman, David S, Kraft, Ruth, Kremers, Walter K, Kukull, Walter A, Litvan, Irene, Lucente, Diane, Lungu, Codrin, Mackenzie, Ian R, Maldonado, Miranda, Manoochehri, Masood, McGinnis, Scott M, McKinley, Emily, Mendez, Mario F, Miller, Bruce L, Multani, Namita, Onyike, Chiadi, Padmanabhan, Jaya, Pantelyat, Alex, Pearlman, Rodney, Petrucelli, Len, Potter, Madeline, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine P, Rascovsky, Katya, Roberson, Erik D, Rogalski, Emily, Sengdy, Pheth, Shaw, Leslie M, Syrjanen, Jeremy, Tartaglia, M Carmela, Tatton, Nadine, Taylor, Joanne, Toga, Arthur, Trojanowski, John Q, Weintraub, Sandra, Wang, Ping, Wong, Bonnie, Wszolek, Zbigniew, Boxer, Adam L, Boeve, Brad F, Kramer, Joel H, Rosen, Howard J, and ARTFL/LEFFTDS consortium
- Subjects
ARTFL/LEFFTDS consortium ,Humans ,Disease Progression ,Magnetic Resonance Imaging ,Longitudinal Studies ,Neuropsychological Tests ,Mutation ,Middle Aged ,Female ,Male ,Executive Function ,Frontotemporal Dementia ,Biomarkers ,C9orf72 Protein ,Behavioral variant ,Cognition ,Corticobasal syndrome ,Fluency ,Genetic ,Inhibition ,Neuropsychology ,Nonfluent variant ,Primary progressive aphasia ,Progranulin ,Progressive supranuclear palsy ,Semantic variant ,Set-shifting ,Tau ,Working memory ,Clinical Sciences ,Neurosciences ,Geriatrics - Abstract
IntroductionIdentifying clinical measures that track disease in the earliest stages of frontotemporal lobar degeneration (FTLD) is important for clinical trials. Familial FTLD provides a unique paradigm to study early FTLD. Executive dysfunction is a clinically relevant hallmark of FTLD and may be a marker of disease progression.MethodsNinety-three mutation carriers with no symptoms or minimal/questionable symptoms (MAPT, n = 31; GRN, n = 28; C9orf72, n = 34; Clinical Dementia Rating scale plus NACC FTLD Module < 1) and 78 noncarriers enrolled through Advancing Research and Treatment in Frontotemporal Lobar Degeneration/Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects studies completed the Executive Abilities: Measures and Instruments for Neurobehavioral Evaluation and Research (NIH-EXAMINER) and the UDS neuropsychological battery. Linear mixed-effects models were used to identify group differences in cognition at baseline and longitudinally. We examined associations between cognition, clinical functioning, and magnetic resonance imaging volumes.ResultsNIH-EXAMINER scores detected baseline and differences in slopes between carriers and noncarriers, even in carriers with a baseline Clinical Dementia Rating scale plus NACC FTLD Module = 0. NIH-EXAMINER declines were associated with worsening clinical symptoms and brain volume loss.DiscussionThe NIH-EXAMINER is sensitive to cognitive changes in presymptomatic familial FTLD and is a promising surrogate endpoint.
- Published
- 2020
87. Genetic screening of a large series of North American sporadic and familial frontotemporal dementia cases
- Author
-
Ramos, Eliana Marisa, Dokuru, Deepika Reddy, Van Berlo, Victoria, Wojta, Kevin, Wang, Qing, Huang, Alden Y, Deverasetty, Sandeep, Qin, Yue, van Blitterswijk, Marka, Jackson, Jazmyne, Appleby, Brian, Bordelon, Yvette, Brannelly, Patrick, Brushaber, Danielle E, Dickerson, Bradford, Dickinson, Susan, Domoto‐Reilly, Kimiko, Faber, Kelley, Fields, Julie, Fong, Jamie, Foroud, Tatiana, Forsberg, Leah K, Gavrilova, Ralitza, Ghoshal, Nupur, Goldman, Jill, Graff‐Radford, Jonathan, Graff‐Radford, Neill, Grant, Ian, Grossman, Murray, Heuer, Hilary W, Hsiung, Ging‐Yuek R, Huey, Edward, Irwin, David, Kantarci, Kejal, Karydas, Anna, Kaufer, Daniel, Kerwin, Diana, Knopman, David, Kornak, John, Kramer, Joel H, Kremers, Walter, Kukull, Walter, Litvan, Irene, Ljubenkov, Peter, Lungu, Codrin, Mackenzie, Ian, Mendez, Mario F, Miller, Bruce L, Onyike, Chiadi, Pantelyat, Alexander, Pearlman, Rodney, Petrucelli, Len, Potter, Madeline, Rankin, Katherine P, Rascovsky, Katya, Roberson, Erik D, Rogalski, Emily, Shaw, Leslie, Syrjanen, Jeremy, Tartaglia, Maria Carmela, Tatton, Nadine, Taylor, Joanne, Toga, Arthur, Trojanowski, John Q, Weintraub, Sandra, Wong, Bonnie, Wszolek, Zbigniew, Rademakers, Rosa, Boeve, Brad F, Rosen, Howard J, Boxer, Adam L, consortium, on behalf of the ARTFL LEFFTDS, and Coppola, Giovanni
- Subjects
Biomedical and Clinical Sciences ,Biological Psychology ,Clinical Sciences ,Neurosciences ,Psychology ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Dementia ,Neurodegenerative ,Frontotemporal Dementia (FTD) ,Genetics ,Alzheimer's Disease ,Human Genome ,Prevention ,Rare Diseases ,Aging ,Brain Disorders ,Clinical Research ,Acquired Cognitive Impairment ,Genetic Testing ,Alzheimer's Disease Related Dementias (ADRD) ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,C9orf72 Protein ,Female ,Frontotemporal Dementia ,Genetic Predisposition to Disease ,Humans ,Male ,Middle Aged ,Progranulins ,tau Proteins ,C9orf72 ,familial ,frontotemporal dementia ,GRN ,MAPT ,sporadic ,ARTFL/LEFFTDS consortium ,Geriatrics ,Clinical sciences ,Biological psychology - Abstract
IntroductionThe Advancing Research and Treatment for Frontotemporal Lobar Degeneration (ARTFL) and Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) consortia are two closely connected studies, involving multiple North American centers that evaluate both sporadic and familial frontotemporal dementia (FTD) participants and study longitudinal changes.MethodsWe screened the major dementia-associated genes in 302 sporadic and 390 familial (symptomatic or at-risk) participants enrolled in these studies.ResultsAmong the sporadic patients, 16 (5.3%) carried chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and progranulin (GRN) pathogenic variants, whereas in the familial series we identified 207 carriers from 146 families. Of interest, one patient was found to carry a homozygous C9orf72 expansion, while another carried both a C9orf72 expansion and a GRN pathogenic variant. We also identified likely pathogenic variants in the TAR DNA binding protein (TARDBP), presenilin 1 (PSEN1), and valosin containing protein (VCP) genes, and a subset of variants of unknown significance in other rare FTD genes.DiscussionOur study reports the genetic characterization of a large FTD series and supports an unbiased sequencing screen, irrespective of clinical presentation or family history.
- Published
- 2020
88. 18F-flortaucipir (AV-1451) tau PET in frontotemporal dementia syndromes
- Author
-
Tsai, Richard M, Bejanin, Alexandre, Lesman-Segev, Orit, LaJoie, Renaud, Visani, Adrienne, Bourakova, Viktoriya, O’Neil, James P, Janabi, Mustafa, Baker, Suzanne, Lee, Suzee E, Perry, David C, Bajorek, Lynn, Karydas, Anna, Spina, Salvatore, Grinberg, Lea T, Seeley, William W, Ramos, Eliana M, Coppola, Giovanni, Gorno-Tempini, Maria Luisa, Miller, Bruce L, Rosen, Howard J, Jagust, William, Boxer, Adam L, and Rabinovici, Gil D
- Subjects
Biomedical and Clinical Sciences ,Health Sciences ,Brain Disorders ,Neurosciences ,Alzheimer's Disease ,Alzheimer's Disease Related Dementias (ADRD) ,Acquired Cognitive Impairment ,Frontotemporal Dementia (FTD) ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Dementia ,Aging ,Neurodegenerative ,Clinical Research ,Biomedical Imaging ,Rare Diseases ,Detection ,screening and diagnosis ,Aetiology ,2.1 Biological and endogenous factors ,4.2 Evaluation of markers and technologies ,Neurological ,Adult ,Aged ,Aged ,80 and over ,Carbolines ,Cohort Studies ,Contrast Media ,Female ,Frontotemporal Dementia ,Humans ,Male ,Middle Aged ,Positron-Emission Tomography ,Young Adult ,tau Proteins ,Biomarkers ,Frontotemporal dementia ,Tau imaging ,Neuropathology ,Tau ,Medical and Health Sciences ,Biomedical and clinical sciences ,Health sciences - Abstract
BackgroundThe tau positron emission tomography (PET) ligand 18F-flortaucipir binds to paired helical filaments of tau in aging and Alzheimer's disease (AD), but its utility in detecting tau aggregates in frontotemporal dementia (FTD) is uncertain.MethodsWe performed 18F-flortaucipir imaging in patients with the FTD syndromes (n = 45): nonfluent variant primary progressive aphasia (nfvPPA) (n = 11), corticobasal syndrome (CBS) (n = 10), behavioral variant frontotemporal dementia (bvFTD) (n = 10), semantic variant primary progressive aphasia (svPPA) (n = 2) and FTD associated pathogenic genetic mutations microtubule-associated protein tau (MAPT) (n = 6), chromosome 9 open reading frame 72 (C9ORF72) (n = 5), and progranulin (GRN) (n = 1). All patients underwent MRI and β-amyloid biomarker testing via 11C-PiB or cerebrospinal fluid. 18F-flortaucipir uptake in patients was compared to 53 β-amyloid negative normal controls using voxelwise and pre-specified region of interest approaches.ResultsOn qualitative assessment, patients with nfvPPA showed elevated 18F-flortacupir binding in the left greater than right inferior frontal gyrus. Patients with CBS showed elevated binding in frontal white matter, with higher cortical gray matter uptake in a subset of β-amyloid-positive patients. Five of ten patients with sporadic bvFTD demonstrated increased frontotemporal binding. MAPT mutation carriers had elevated 18F-flortaucipir retention primarily, but not exclusively, in mutations with Alzheimer's-like neurofibrillary tangles. However, tracer retention was also seen in patients with svPPA, and the mutations C9ORF72, GRN predicted to have TDP-43 pathology. Quantitative region-of-interest differences between patients and controls were seen only in inferior frontal gyrus in nfvPPA and left insula and bilateral temporal poles in MAPT carriers. No significant regional differences were found in CBS or sporadic bvFTD. Two patients underwent postmortem neuropathological examination. A patient with C9ORF72, TDP-43-type B pathology, and incidental co-pathology of scattered neurofibrillary tangles in the middle frontal, inferior temporal gyrus showed corresponding mild 18F-flortaucipir retention without additional uptake matching the widespread TDP-43 type B pathology. A patient with sporadic bvFTD demonstrated punctate inferior temporal and hippocampus tracer retention, corresponding to the area of severe argyrophilic grain disease pathology.Conclusions18F-flortaucipir in patients with FTD and predicted tauopathy or TDP-43 pathology demonstrated limited sensitivity and specificity. Further postmortem pathological confirmation and development of FTD tau-specific ligands are needed.
- Published
- 2019
89. Tracking white matter degeneration in asymptomatic and symptomatic MAPT mutation carriers
- Author
-
Chen, Qin, Boeve, Bradley F, Schwarz, Christopher G, Reid, Robert, Tosakulwong, Nirubol, Lesnick, Timothy G, Bove, Jessica, Brannelly, Patrick, Brushaber, Danielle, Coppola, Giovanni, Dheel, Christina, Dickerson, Bradford C, Dickinson, Susan, Faber, Kelley, Fields, Julie, Fong, Jamie, Foroud, Tatiana, Forsberg, Leah, Gavrilova, Ralitza H, Gearhart, Debra, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Jonathan, Graff-Radford, Neill R, Grossman, Murray, Haley, Dana, Heuer, Hilary W, Hsiung, Ging-Yuek R, Huey, Edward, Irwin, David J, Jack, Clifford R, Jones, David T, Jones, Lynne, Karydas, Anna M, Knopman, David S, Kornak, John, Kramer, Joel, Kremers, Walter, Kukull, Walter A, Lapid, Maria, Lucente, Diane, Lungu, Codrin, Mackenzie, Ian RA, Manoochehri, Masood, McGinnis, Scott, Miller, Bruce L, Pearlman, Rodney, Petrucelli, Leonard, Potter, Madeline, Rademakers, Rosa, Ramos, Eliana M, Rankin, Katherine P, Rascovsky, Katya, Sengdy, Pheth, Shaw, Leslie, Syrjanen, Jeremy, Tatton, Nadine, Taylor, Joanne, Toga, Arthur W, Trojanowski, John, Weintraub, Sandra, Wong, Bonnie, Boxer, Adam L, Rosen, Howie, Wszolek, Zbigniew, Kantarci, Kejal, and Consortium, LEFFTDS
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Dementia ,Neurodegenerative ,Aging ,Acquired Cognitive Impairment ,Biomedical Imaging ,Neurosciences ,Clinical Trials and Supportive Activities ,Clinical Research ,Brain Disorders ,2.1 Biological and endogenous factors ,Adult ,Aged ,Diffusion Magnetic Resonance Imaging ,Diffusion Tensor Imaging ,Disease Progression ,Female ,Frontotemporal Dementia ,Gray Matter ,Heterozygote ,Humans ,Male ,Middle Aged ,Mutation ,Neurodegenerative Diseases ,Neuropsychological Tests ,White Matter ,tau Proteins ,Diffusion tensor image ,MAPT ,Asymptomatic ,Frontotemporal dementia ,Longitudinal ,LEFFTDS Consortium ,Neurology & Neurosurgery ,Biological psychology - Abstract
Our aim was to investigate the patterns and trajectories of white matter (WM) diffusion abnormalities in microtubule-associated protein tau (MAPT) mutations carriers. We studied 22 MAPT mutation carriers (12 asymptomatic, 10 symptomatic) and 20 noncarriers from 8 families, who underwent diffusion tensor imaging (DTI) and a subset (10 asymptomatic, 6 symptomatic MAPT mutation carriers, and 10 noncarriers) were followed annually (median = 4 years). Cross-sectional and longitudinal changes in mean diffusivity (MD) and fractional anisotropy were analyzed. Asymptomatic MAPT mutation carriers had higher MD in entorhinal WM, which propagated to the limbic tracts and frontotemporal projections in the symptomatic stage compared with noncarriers. Reduced fractional anisotropy and increased MD in the entorhinal WM were associated with the proximity to estimated and actual age of symptom onset. The annualized change of entorhinal MD on serial DTI was accelerated in MAPT mutation carriers compared with noncarriers. Entorhinal WM diffusion abnormalities precede the symptom onset and track with disease progression in MAPT mutation carriers. Our cross-sectional and longitudinal data showed a potential clinical utility for DTI to track neurodegenerative disease progression for MAPT mutation carriers in clinical trials.
- Published
- 2019
90. Temporal order of clinical and biomarker changes in familial frontotemporal dementia
- Author
-
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., and Boxer, Adam. L.
- Published
- 2022
- Full Text
- View/download PDF
91. The presence of preoperative neurodegeneration biofluid markers in patients with postoperative delirium
- Author
-
Leung, Jacqueline M., Rojas, Julio C., Tang, Christopher, Chan, Brandon, Lario-Lago, Argentina, Boxer, Adam L., Do, Quyen, Kramer, Joel H., Du, Zhiyuan, Du, Pang, and Sands, Laura P.
- Published
- 2023
- Full Text
- View/download PDF
92. Frequency of the TREM2 R47H Variant in Various Neurodegenerative Disorders
- Author
-
Ayer, Ariane H, Wojta, Kevin, Ramos, Eliana Marisa, Dokuru, Deepika, Chen, Jason A, Karydas, Anna M, Papatriantafyllou, John D, Agiomyrgiannakis, Dimitrios, Kamtsadeli, Vasiliki, Tsinia, Niki, Sali, Dimitra, Gylys, Karen H, Agosta, Federica, Filippi, Massimo, Small, Gary W, Bennett, David A, Gearing, Marla, Juncos, Jorge L, Kramer, Joel, Lee, Suzee E, Yokoyama, Jennifer S, Mendez, Mario F, Chui, Helena, Zarow, Chris, Ringman, John M, Kilic, Ulkan, Babacan-Yildiz, Gülsen, Levey, Allan, DeCarli, Charles S, Cotman, Carl W, Boxer, Adam L, Miller, Bruce L, and Coppola, Giovanni
- Subjects
Biomedical and Clinical Sciences ,Biological Psychology ,Clinical Sciences ,Neurosciences ,Psychology ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Alzheimer's Disease Related Dementias (ADRD) ,Neurodegenerative ,Brain Disorders ,Alzheimer's Disease ,Acquired Cognitive Impairment ,Dementia ,Rare Diseases ,Frontotemporal Dementia (FTD) ,Aging ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Aged ,Alzheimer Disease ,Amyotrophic Lateral Sclerosis ,Cognitive Dysfunction ,Cohort Studies ,Female ,Frontotemporal Dementia ,Genetic Predisposition to Disease ,Genetic Variation ,Genotype ,Humans ,Internationality ,Male ,Membrane Glycoproteins ,Neurodegenerative Diseases ,Receptors ,Immunologic ,Alzheimer disease ,frontotemporal dementia ,genetics ,TREM2 ,progressive supranuclear palsy ,mild cognitive impairment ,corticobasal syndrome ,amyotrophic lateral sclerosis ,association study ,Cognitive Sciences ,Geriatrics ,Clinical sciences ,Biological psychology - Abstract
ObjectiveA rare variant in TREM2 (p.R47H, rs75932628) has been consistently reported to increase the risk for Alzheimer disease (AD), while mixed evidence has been reported for association of the variant with other neurodegenerative diseases. Here, we investigated the frequency of the R47H variant in a diverse and well-characterized multicenter neurodegenerative disease cohort.MethodsWe examined the frequency of the R47H variant in a diverse neurodegenerative disease cohort, including a total of 3058 patients clinically diagnosed with AD, frontotemporal dementia spectrum syndromes, mild cognitive impairment, progressive supranuclear palsy syndrome, corticobasal syndrome, or amyotrophic lateral sclerosis and 5089 control subjects.ResultsWe observed a significant association between the R47H variant and AD, while no association was observed with any other neurodegenerative disease included in this study.ConclusionsOur results support the consensus that the R47H variant is significantly associated with AD. However, we did not find evidence for association of the R47H variant with other neurodegenerative diseases.
- Published
- 2019
93. Brain MR Spectroscopy Changes Precede Frontotemporal Lobar Degeneration Phenoconversion in Mapt Mutation Carriers
- Author
-
Chen, Qin, Boeve, Bradley F, Tosakulwong, Nirubol, Lesnick, Timothy, Brushaber, Danielle, Dheel, Christina, Fields, Julie, Forsberg, Leah, Gavrilova, Ralitza, Gearhart, Debra, Haley, Dana, Gunter, Jeffrey L, Graff‐Radford, Jonathan, Jones, David, Knopman, David, Graff‐Radford, Neill, Kraft, Ruth, Lapid, Maria, Rademakers, Rosa, Wszolek, Zbigniew K, Rosen, Howie, Boxer, Adam L, and Kantarci, Kejal
- Subjects
Biomedical and Clinical Sciences ,Clinical Sciences ,Biomedical Imaging ,Aging ,Neurodegenerative ,Prevention ,Clinical Research ,Neurosciences ,2.1 Biological and endogenous factors ,Aetiology ,Good Health and Well Being ,Adult ,Biomarkers ,Brain ,Disease Progression ,Female ,Frontotemporal Lobar Degeneration ,Heterozygote ,Humans ,Longitudinal Studies ,Magnetic Resonance Spectroscopy ,Male ,Middle Aged ,Mutation ,tau Proteins ,converter ,frontotemporal lobar degeneration ,longitudinal ,MAPT ,MRS ,Neurology & Neurosurgery ,Clinical sciences ,Biological psychology - Abstract
Background and purposeThe objective of this study was to longitudinally investigate the trajectory of change in 1 H MRS measurements in asymptomatic MAPT mutation carriers who became symptomatic during follow-up, and to determine the time at which the neurochemical alterations accelerated during disease progression.MethodsWe identified eight MAPT mutations carriers who transitioned from asymptomatic to symptomatic disease during follow-up. All participants were longitudinally followed with an average of 7.75 years (range 4-11 years) and underwent two or more single voxel 1 H MRS examinations from the posterior cingulate voxel, with a total of 60 examinations. The rate of longitudinal change for each metabolite was estimated using linear mixed models. A flex point model was used to estimate the flex time point of the change in slope.ResultsThe decrease in the NAA/mI ratio accelerated 2.09 years prior to symptom onset, and continued to decline. A similar trajectory was observed in the presumed glial marker mI/Cr ratio accelerating 1.86 years prior to symptom onset.ConclusionsOur findings support the potential use of longitudinal 1 H MRS for monitoring the neurodegenerative progression in MAPT mutation carriers starting from the asymptomatic stage.
- Published
- 2019
94. Clinical value of cerebrospinal fluid neurofilament light chain in semantic dementia.
- Author
-
Meeter, Lieke HH, Steketee, Rebecca ME, Salkovic, Dina, Vos, Maartje E, Grossman, Murray, McMillan, Corey T, Irwin, David J, Boxer, Adam L, Rojas, Julio C, Olney, Nicholas T, Karydas, Anna, Miller, Bruce L, Pijnenburg, Yolande AL, Barkhof, Frederik, Sánchez-Valle, Raquel, Lladó, Albert, Borrego-Ecija, Sergi, Diehl-Schmid, Janine, Grimmer, Timo, Goldhardt, Oliver, Santillo, Alexander F, Hansson, Oskar, Vestberg, Susanne, Borroni, Barbara, Padovani, Alessandro, Galimberti, Daniela, Scarpini, Elio, Rohrer, Jonathan D, Woollacott, Ione OC, Synofzik, Matthis, Wilke, Carlo, de Mendonca, Alexandre, Vandenberghe, Rik, Benussi, Luisa, Ghidoni, Roberta, Binetti, Giuliano, Niessen, Wiro J, Papma, Janne M, Seelaar, Harro, Jiskoot, Lize C, de Jong, Frank Jan, Donker Kaat, Laura, Del Campo, Marta, Teunissen, Charlotte E, Bron, Esther E, Van den Berg, Esther, and Van Swieten, John C
- Subjects
Humans ,Neurofilament Proteins ,Magnetic Resonance Imaging ,Proportional Hazards Models ,Case-Control Studies ,Retrospective Studies ,Cross-Sectional Studies ,Neuropsychological Tests ,Aged ,Middle Aged ,Female ,Male ,Frontotemporal Dementia ,Neuroimaging ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery - Abstract
BackgroundSemantic dementia (SD) is a neurodegenerative disorder characterised by progressive language problems falling within the clinicopathological spectrum of frontotemporal lobar degeneration (FTLD). The development of disease-modifying agents may be facilitated by the relative clinical and pathological homogeneity of SD, but we need robust monitoring biomarkers to measure their efficacy. In different FTLD subtypes, neurofilament light chain (NfL) is a promising marker, therefore we investigated the utility of cerebrospinal fluid (CSF) NfL in SD.MethodsThis large retrospective multicentre study compared cross-sectional CSF NfL levels of 162 patients with SD with 65 controls. CSF NfL levels of patients were correlated with clinical parameters (including survival), neuropsychological test scores and regional grey matter atrophy (including longitudinal data in a subset).ResultsCSF NfL levels were significantly higher in patients with SD (median: 2326 pg/mL, IQR: 1628-3593) than in controls (577 (446-766), p
- Published
- 2019
95. Frontal lobe 1H MR spectroscopy in asymptomatic and symptomatic MAPT mutation carriers.
- Author
-
Chen, Qin, Boeve, Bradley F, Tosakulwong, Nirubol, Lesnick, Timothy, Brushaber, Danielle, Dheel, Christina, Fields, Julie, Forsberg, Leah, Gavrilova, Ralitza, Gearhart, Debra, Haley, Dana, Gunter, Jeffrey L, Graff-Radford, Jonathan, Jones, David, Knopman, David, Graff-Radford, Neill, Kraft, Ruth, Lapid, Maria, Rademakers, Rosa, Syrjanen, Jeremy, Wszolek, Zbigniew K, Rosen, Howie, Boxer, Adam L, and Kantarci, Kejal
- Subjects
Neurodegenerative ,Prevention ,Neurosciences ,Dementia ,Brain Disorders ,Clinical Research ,Acquired Cognitive Impairment ,Biomedical Imaging ,Frontotemporal Dementia (FTD) ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Adult ,Aspartic Acid ,Asymptomatic Diseases ,Biomarkers ,Case-Control Studies ,Creatine ,Female ,Frontal Lobe ,Frontotemporal Lobar Degeneration ,Heterozygote ,Humans ,Inositol ,Male ,Middle Aged ,Mutation ,Proton Magnetic Resonance Spectroscopy ,Young Adult ,tau Proteins ,Clinical Sciences ,Cognitive Sciences ,Neurology & Neurosurgery - Abstract
ObjectiveTo determine the frontal lobe proton magnetic resonance spectroscopy (1H MRS) abnormalities in asymptomatic and symptomatic carriers of microtubule-associated protein tau (MAPT) mutations.MethodsWe recruited patients with MAPT mutations from 5 individual families, who underwent single voxel 1H MRS from the medial frontal lobe at 3T (n = 19) from the Longitudinal Evaluation of Familial Frontotemporal Dementia Subjects (LEFFTDS) Study at the Mayo Clinic site. Asymptomatic MAPT mutation carriers (n = 9) had Frontotemporal Lobar Degeneration Clinical Dementia Rating Sum of Boxes (FTLD-CDR SOB) score of zero, and symptomatic MAPT mutation carriers (n = 10) had a median FTLD-CDR SOB score of 5. Noncarriers from healthy first-degree relatives of the patients were recruited as controls (n = 25). The demographic aspects and 1H MRS metabolite ratios were compared by use of the Fisher exact test for sex and linear mixed models to account for within-family correlations. We used Tukey contrasts for pair-wise comparisons.ResultsAsymptomatic MAPT mutation carriers had lower neuronal marker N-acetylaspartate (NAA)/creatine (Cr) (p = 0.001) and lower NAA/myo-inositol (mI) (p = 0.026) than noncarriers after adjustment for age. Symptomatic MAPT mutation carriers had lower NAA/Cr (p = 0.01) and NAA/mI (p = 0.01) and higher mI/Cr (p = 0.02) compared to noncarriers after adjustment for age. Furthermore, NAA/Cr (p = 0.006) and NAA/mI (p < 0.001) ratios decreased, accompanied by an increase in mI/Cr ratio (p = 0.001), as the ages of carriers approached and passed the age at symptom onset.ConclusionFrontal lobe neurochemical alterations measured with 1H MRS precede the symptom onset in MAPT mutation carriers. Frontal lobe 1H MRS is a potential biomarker for early neurodegenerative processes in MAPT mutation carriers.
- Published
- 2019
96. Neuropathological correlates of structural and functional imaging biomarkers in 4-repeat tauopathies
- Author
-
Spina, Salvatore, Brown, Jesse A, Deng, Jersey, Gardner, Raquel C, Nana, Alissa L, Hwang, Ji-Hye L, Gaus, Stephanie E, Huang, Eric J, Kramer, Joel H, Rosen, Howie J, Kornak, John, Neuhaus, John, Miller, Bruce L, Grinberg, Lea T, Boxer, Adam L, and Seeley, William W
- Subjects
Biomedical and Clinical Sciences ,Health Sciences ,Psychology ,Dementia ,Frontotemporal Dementia (FTD) ,Alzheimer's Disease ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Neurodegenerative ,Biomedical Imaging ,Aging ,Neurosciences ,Brain Disorders ,Acquired Cognitive Impairment ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Aged ,Atrophy ,Basal Ganglia ,Biomarkers ,Cerebral Cortex ,Female ,Humans ,Magnetic Resonance Imaging ,Male ,Nerve Degeneration ,Neural Pathways ,Neuroimaging ,Supranuclear Palsy ,Progressive ,Tauopathies ,tau Proteins ,tau ,neuropathology ,biomarkers of neurodegeneration ,progressive supranuclear palsy ,corticobasal degeneration ,Medical and Health Sciences ,Psychology and Cognitive Sciences ,Neurology & Neurosurgery ,Biomedical and clinical sciences ,Health sciences - Abstract
Neurodegenerative dementia syndromes are characterized by spreading of pathological protein deposition along syndrome-specific neural networks. Structural and functional MRI measures can assess the integrity of these networks and have been proposed as biomarkers of disease progression for clinical trials. The relationship between in vivo imaging measures and pathological features, at the single subject level, remains largely unknown. Patient-specific maps of atrophy and seed-based intrinsic connectivity disruption, as compared to normal controls, were obtained for 27 patients subsequently diagnosed with progressive supranuclear palsy (n = 16, seven males, age at death 68.9 ± 6.0 years, imaging-to-pathology interval = 670.2 ± 425.1 days) or corticobasal degeneration (n = 11, two males, age at death 66.7 ± 5.4 years, imaging-to-pathology interval = 696.2 ± 482.2 days). A linear mixed effect model with crossed random effects was used to test regional and single-subject level associations between post-mortem regional measures of neurodegeneration and tau inclusion burden, on the one hand, and regional volume loss and seed-based intrinsic connectivity reduction, on the other. A significant association was found between tau inclusion burden and in vivo volume loss, at the regional level and independent of neurodegeneration severity, in both progressive supranuclear palsy [n = 340 regions; beta 0.036; 95% confidence interval (CI): 0.001, 0.072; P = 0.046] and corticobasal degeneration (n = 215 regions; beta 0.044; 95% CI: 0.009, 0.079; P = 0.013). We also found a significant association between post-mortem neurodegeneration and in vivo volume loss in both progressive supranuclear palsy (n = 340 regions; beta 0.155; 95% CI: 0.061, 0.248; P = 0.001) and corticobasal degeneration (n = 215 regions; beta 0.277; 95% CI: 0.104, 0.450; P = 0.002). We found a significant association between regional neurodegeneration and intrinsic connectivity dysfunction in corticobasal degeneration (n = 215 regions; beta 0.074; 95% CI: 0.005, 0.143; P = 0.035), but no other associations between post-mortem measures of tauopathy and intrinsic connectivity dysfunction reached statistical significance. Our data suggest that in vivo structural imaging measures reflect independent contributions from neurodegeneration and tau burden in progressive supranuclear palsy and corticobasal degeneration. Seed-based measures of intrinsic connectivity dysfunction showed less reliable predictive value when used as in vivo biomarkers of tauopathy. The findings provide important guidance for the use of imaging biomarkers as indirect in vivo assays of microscopic pathology.
- Published
- 2019
97. PARTICIPANT BASELINE CHARACTERISTICS IN PASSPORT, A PHASE 2 STUDY OF THE EFFICACY AND SAFETY OF BIIB092 FOR PROGRESSIVE SUPRANUCLEAR PALSY
- Author
-
Dam, Tien, Boxer, Adam L, Golbe, Lawrence I, Höglinger, Günter, Morris, Huw R, Litvan, Irene, Corvol, Jean-Christophe, Lang, Anthony, Grundman, Michael, Yang, Lili, O'Gorman, John, Olsson, Tina, and Haeberlein, Samantha Budd
- Subjects
Geriatrics ,Clinical Sciences ,Neurosciences - Published
- 2019
98. P2‐314: THE MULTIDOMAIN IMPAIRMENT RATING (MIR) SCALE: INITIAL RELIABILITY DATA ON A MULTIDIMENSIONAL SCALE DESIGNED FOR FTLD SPECTRUM DISORDERS
- Author
-
Forsberg, Leah K, Boeve, Bradley F, Boxer, Adam L, Rosen, Howard J, Kornak, John, Heuer, Hilary W, Fields, Julie A, Brushaber, Danielle, Machulda, Mary M, Sturm, Virginia, Staffaroni, Adam M, Ljubenkov, Peter A, Denver, Reilly, Ong, Elise, Appleby, Brian, Bordelon, Yvette M, Brannelly, Patrick, Coppola, Giovanni, Dickerson, Brad C, Dickinson, Susan, Kimiko, Domoto-Reilly, Faber, Kelley, Fong, Jamie, Foroud, Tatiana M, Gavrilova, Ralitza H, Gearhart, Debra, Ghoshal, Nupur, Goldman, Jill, Graff-Radford, Jonathan, Graff-Radford, Neil R, Grossman, Murray, Hsiung, Ging-Yuek Robin, Huey, Edward D, Irwin, David, Jones, David T, Kantarci, Kejal, Karydas, Anna M, Kaufer, Daniel, Kerwin, Diana R, Knopman, David S, Kraft, Ruth A, Kramer, Joel H, Kremers, Walter K, Kukull, Walter A, Litvan, Irene, Lucente, Diane E, Lungu, Codrin, Mackenzie, Ian R, McGinnis, Scott M, Mendez, Mario F, Miller, Bruce L, Onyike, Chiadi U, Pantelyat, Alex, Pearlman, Rodney, Petrucelli, Leonard, Potter, Madeline, Rademakers, Rosa, Ramos, Eliana Marisa, Rankin, Katherine, Rascovsky, Katya, Roberson, Erik D, Rogalski, Emily J, Shaw, Leslie M, Sutherland, Marg, Syrjanen, Jeremy, Tartaglia, Carmela, Tatton, Nadine, Taylor, Joanne, Toga, Arthur W, Trojanowski, John Q, Weintraub, Sandra, Wong, Bonnie, and Wszolek, Zbigniew
- Subjects
Clinical Sciences ,Neurosciences ,Geriatrics - Published
- 2019
99. P1‐051: PARTICIPANT BASELINE CHARACTERISTICS IN PASSPORT, A PHASE 2 STUDY OF THE EFFICACY AND SAFETY OF BIIB092 FOR PROGRESSIVE SUPRANUCLEAR PALSY
- Author
-
Dam, Tien, Boxer, Adam L, Golbe, Lawrence I, Höglinger, Günter, Morris, Huw R, Litvan, Irene, Corvol, Jean-Christophe, Lang, Anthony, Grundman, Michael, Yang, Lili, O'Gorman, John, Olsson, Tina, and Haeberlein, Samantha Budd
- Subjects
Clinical Sciences ,Neurosciences ,Geriatrics - Published
- 2019
100. Cognitive deficits in progressive supranuclear palsy on the Repeatable Battery for the Assessment of Neuropsychological Status
- Author
-
Duff, Kevin, McDermott, Dana, Luong, Dan, Randolph, Christopher, and Boxer, Adam L
- Subjects
Psychology ,Clinical and Health Psychology ,Applied and Developmental Psychology ,Clinical Research ,Rare Diseases ,Neurosciences ,Brain Disorders ,Behavioral and Social Science ,Mental Health ,Neurological ,Mental health ,Aged ,Attention ,Cognition ,Cognition Disorders ,Female ,Humans ,Male ,Middle Aged ,Neuropsychological Tests ,Supranuclear Palsy ,Progressive ,dementia ,neurological disease ,progressive supranuclear palsy ,Repeatable Battery for the Assessment of Neuropsychological Status ,Cognitive Sciences ,Experimental Psychology ,Biological psychology ,Clinical and health psychology ,Cognitive and computational psychology - Abstract
Progressive supranuclear palsy (PSP) is associated with a variety of cognitive deficits, as well as motor and psychiatric disturbances. As clinical trials for PSP evolve, briefer screening instruments will be needed to determine cognitive effects of interventions. The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) may fill this gap. Three hundred four participants diagnosed with Richardson's syndrome of PSP were evaluated with the RBANS, as well as other scales typically used in PSP. RBANS performances for these participants fell significantly below expectations for the Total Scale score and all five Indexes. Cognitive scores on the RBANS were also significantly related to other markers of PSP (e.g., motor and functional abilities, depression, global cognition). Compared to other clinical conditions from the literature, patients with PSP show impairment on tests of visuospatial perception and construction and attention. Although additional research is needed, the current study supports the clinical applicability of the RBANS in patients with PSP, as well as its potential for future clinical trials.
- Published
- 2019
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.