Association of Cognitive and Behavioral Features Between Adults With Tuberous Sclerosis and Frontotemporal Dementia | Congenital Defects | JAMA Neurology | JAMA Network
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Figure.  Graphic Comparison of 4 Cerebrospinal Fluid (CSF) Biomarkers in All 3 Cohorts
Graphic Comparison of 4 Cerebrospinal Fluid (CSF) Biomarkers in All 3 Cohorts

A, Phosphorylated tau181 (P-tau) was significantly elevated in the tuberous sclerosis complex (TSC) cohort when compared with the control and frontotemporal dementia (FTD) cohorts. B and C, No difference in the total tau (T-tau) or amyloid-β 42 (Aβ42) levels were appreciated when TSC was compared with the other cohorts. D, The mean neurofilament light chain (NfL) level was elevated when TSC was compared with healthy control individuals.

Table 1.  Demographic Information of All Cohorts
Demographic Information of All Cohorts
Table 2.  TAND Checklist Severity Scores From All 3 Cohortsa
TAND Checklist Severity Scores From All 3 Cohortsa
Table 3.  Comparison of the Neuropsychologic Profiles in All Cohortsa
Comparison of the Neuropsychologic Profiles in All Cohortsa
Table 4.  Statistical Analysis of All 3 Cohorts With Corresponding Biomarkersa
Statistical Analysis of All 3 Cohorts With Corresponding Biomarkersa
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    Original Investigation
    December 20, 2019

    Association of Cognitive and Behavioral Features Between Adults With Tuberous Sclerosis and Frontotemporal Dementia

    Author Affiliations
    • 1Memory and Aging Center, University of California, San Francisco
    • 2Providence Health & Services, Portland, Oregon
    • 3Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles
    • 4Associate Editor, JAMA Neurology
    JAMA Neurol. 2020;77(3):358-366. doi:10.1001/jamaneurol.2019.4284
    Key Points

    Question  Do individuals with tuberous sclerosis–associated neuropsychiatric disorders meet criteria for the neurodegenerative disease frontotemporal dementia (FTD)?

    Findings  In this case-control study, quantitative clinical measurements showed that adults with tuberous sclerosis–associated neuropsychiatric disorders exhibit behavioral and cognitive difficulties similar to those seen in FTD. Compared with FTD, significant overlap in cerebrospinal fluid biomarkers was seen in patients with tuberous sclerosis complex, and similarly, a subset of these subjects demonstrated punctate focal retention of the tau PET ligand fluorine 1B–labeled flortaucipir.

    Meaning  Additional longitudinal studies should be performed on adults affected with tuberous sclerosis complex to assess risk for developing a neurodegenerative disease such as FTD.

    Abstract

    Importance  Individuals 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.

    Objective  To investigate the potential association between tuberous sclerosis–associated neuropsychiatric disorders and frontotemporal dementia.

    Design, Setting, and Participants  Case-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 Measures  Tuberous 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.

    Results  Eighteen 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 Relevance  Adults 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.

    Introduction

    Tuberous sclerosis complex (TSC) is a childhood-onset disorder with characteristic dermatological findings, tumors, epilepsy, and developmental delay owing to pathogenic genetic variants in the TSC1 (hamartin) or TSC2 (tuberin) genes.1-10 Many patients with TSC also experience progressive cognitive, behavioral and psychiatric symptoms.2,4 In 2015, de Vries et al11,12 coined the term tuberous sclerosis–associated neuropsychiatric disorders (TAND) to describe this syndrome and developed the TAND checklist to standardize documentation of the constellation of these neuropsychiatric symptoms.11,12 Tuberous sclerosis–associated neuropsychiatric disorders have been reported in the pediatric and adult TSC populations.13,14 In children, TAND has been associated with regression or loss of cognitive skills.13 In adults, features of TAND include abnormalities of comportment, social cognition, language, and executive function, all of which are hallmarks of frontotemporal dementia (FTD).15

    Frontotemporal dementia serves as a clinical term for a group of early-onset neurodegenerative disease disorders characterized by behavioral, executive, and sometimes language disorders associated with atrophy of the frontal and temporal lobes.16-18 There are 3 primary clinical subtypes: behavioral-variant FTD, semantic variant primary progressive aphasia, and nonfluent variant primary progressive aphasia. Frontotemporal dementia is caused by frontotemporal lobar degeneration (FTLD), which features abnormal aggregation of the microtubule associated protein consisting of tau (FTLD-tau) or the transactivating DNA-binding protein 43.16,18-20 In 2017,21 we described a novel genetic variant in the TSC1 gene that represents a potential cause of FTLD-tau, and a deregulation in hamartin, the protein product of TSC1, which is an important upstream modifier of mammalian target of rapamycin (mTOR) activity. Subsequently, TSC1 genetic variant carriers present with mTOR overactivity. Interestingly, an overactivation of other mTOR pathway proteins are also linked to tau pathology.22,23

    The TAND checklist and FTD clinical criteria16-18 both include progressive changes in behavior (obsessive-compulsive symptoms and altered eating habits), attentional deficits, poor executive function (eg, decreased impulse inhibition and error monitoring), and deficits in language.19,21 Nevertheless, to our knowledge, a systematic comparison of neuropsychiatric symptoms in TSC and FTD has not been previously reported. The long-term clinical outcome, especially of mildly affected adult patients with TSC, remains unclear.13 Here, we analyze the clinical overlap between TAND and FTD in a longitudinal observational cohort, leveraging deep phenotyping of patients with TSC and FTD, including neuropsychological testing, neuroimaging, and biofluid markers.

    Methods
    Patient Selection and Study Design

    Patients with a clinical or genetic diagnosis of TSC1 who were older than 18 years and were functionally independent were screened for inclusion (eTable 4 in the Supplement). Recruitment of patients with TSC was achieved in collaboration with the Tuberous Sclerosis Alliance from 2017 through June 2019. Patients with a diagnosis of probable behavioral-variant FTD, semantic variant primary progressive,16-18 were recruited from the program project on FTD at University of California, San Francisco. Many patients with TSC were found to have a genetic variant (eTable 5 in the Supplement). Healthy control (HC) individuals were recruited through the Hillblom Aging Network at University of California, San Francisco. Institutional review board approval was obtained from the University of California Human Research Protection Program, and written informed consent was obtained from all study participants or their surrogates.

    Clinical Evaluation

    A comprehensive clinical evaluation included a neurological examination by a behavioral neurologist, neuropsychological testing by a neuropsychologist,24 genetic counseling, and a caregiver interview, as previously described.18 All patients completed the TAND checklist.11 A severity score was obtained by summing the total number of yes responses to questions on the TAND checklist.11 We evaluated 4 cognitive composites (ie, episodic memory, executive functions, language, and visuospatial) on neuropsychologic testing in all 3 cohorts by calculating z scores for individual tests and then averaging across subtests for each cognitive domain, similar to previously published methods.25 An episodic memory composite score was created using a measure of visual memory, Benson Figure Recall,24 and the California Verbal Learning Test, second edition, short-form (CVLT-II26) subscores: immediate recall total, long (20-minute) delay free recall total, and recognition discriminability (d′). The executive functions composite included Stroop interference,27 modified Trail Making Test,24 phonemic fluency (number of D words per minute,24 Digit Span Backward,28 and design fluency).29 Because the 18 HCs included in this study were not administered the same version of the California Verbal Learning Test, the episodic memory composite was not created in this group. The language composite combined an abbreviated, 15-item version of the Boston Naming Test and animal fluency. Finally, a spatial composite included the copy subtask of the Benson Figure task and number location of the Visual Object and Space Perception Battery. Composite scores were created based on the available data for each patient even if some data were missing. An executive composite was created for a patient if they had at least 3 of 5 measures. An episodic memory composite was created if a patient had at least 2 of 4 measures. A language composite was created if patients had at least 1 of 2 measures. A spatial composite was created if subjects had at least 1 of 2 measures. A subset of patients were administered the Wechsler Abbreviated Intelligence Scale28 to quantify general intelligence. All patients with TSC received a brain magnetic resonance imaging (MRI). A lumbar puncture, carbon 11–labeled Pittsburgh compound B (PiB) and fluorine 1B–labeled [18F] flortaucipir (FTP) positron emission tomography (PET) scans were performed on a subset of patients with TSC.15,24

    Genetic Testing and Cerebrospinal Fluid Biomarker Investigations

    In the TSC cohort, blood-derived DNA was used to sequence the TSC1 and TSC2 genes. Samples were screened using either whole-exome or targeted sequencing as previously described.21,30 Coding and exon-intron boundary regions of TSC1 and TSC2 genes were screened for known or novel pathogenic variants classified as previously described.31 Sanger sequencing was used to confirm pathogenic variants. Confirmed genetic test results were conveyed to the patient with TSC and family members by a licensed genetic counselor and the behavioral neurologist.

    The lumbar puncture was performed by the behavioral neurologist. Cerebrospinal fluid (CSF) was stored at –80°C until analysis. The CSF biomarker analysis was performed in collaboration with Anne Fagan’s laboratory at Washington University in St Louis, Missouri. Cerebrospinal fluid was analyzed using the INNO-BIA AlzBio3 (Fujirebio Europe), a multiplexed, fluorimetric bead immunoassay, for the simultaneous quantification of phosphorylated tau181 (P-tau), total tau (T-tau), and amyloid-β 42 (Aβ42). Neurofilament light chain (NfL) was measured with NF-light enzyme-linked immunosorbent assay (UmanDiagnostics AB). Samples underwent a single freeze-thaw cycle prior to assay. Samples were thawed at 4°C for approximately 3 hours prior to analysis, and all were run in duplicate. For all assays, values had to pass quality control criteria, including coefficients of variation (calculated as standard deviation × 100/mean) 25% or less, kit controls within the expected range as defined by the manufacturer (where applicable), and measurement consistency of 2 common pooled CSF samples that were included on each plate.

    The CSF biomarker levels reported in the FTD and HC cohorts overlapped with the data reported by Ljubenkov et al32 in 2018. Neurofilament light chain was chosen because in 2014 several groups reported that high CSF NfL levels were associated with more severe cognitive impairment and shorter survival time in patients with FTD.32,33 It is also well established that elevated NfL levels in the CSF implicate a neuronal damage.34 An NfL result greater than 4170 pg/mL was considered abnormal.32 Phosphorylated tau181 and T-tau values greater than 23 pg/mL and 93 pg/mL, respectively, were considered abnormal.35 Sato et al36 report that in the human central nervous system, P-tau exhibits a faster turnover rate, which likely explains the elevated CSF level of this protein in various neurodegenerative conditions. An Aβ42 value less than 350 pg/mL was considered abnormal.35

    Neuroimaging Biomarker Investigation

    T1-weighted magnetization–prepared rapid gradient echo MRI sequences were acquired at University of California, San Francisco, either on a 3-T Siemens Tim Trio or a 3-T Siemens Prisma Fit scanner. Both scanners had similar acquisition parameters (sagittal slice orientation; slice thickness = 1.0 mm; 160 slices; in-plane resolution = 1 × 1 mm; matrix = 240 × 256; repetition time = 2.300 ms; inversion time = 900 milliseconds; flip angle = 9°), although echo time slightly differed (Trio: 2.98 milliseconds; Prisma: 2.9 milliseconds).

    Positron emission tomography scans were acquired from a subset of patients with TSC on a Siemens Biograph PET/computed tomography (CT) scanner at the Lawrence Berkeley National Laboratory. 11C-Pittsburgh compound B and FTP were also synthesized and radiolabeled at the Lawrence Berkeley National Laboratory. A low-dose CT scan was performed for attenuation correction prior to PET acquisition, and PET data were reconstructed using an ordered subset expectation maximization algorithm with weighted attenuation and smoothed with a 4-mm gaussian kernel with scatter correction (calculated image resolution 6.5 × 6.5 × 7.25 mm based on Hoffman phantom). Further details of the MRI and PET data acquisition and preprocessing are available in previous publications.35,37-3911C-Pittsburgh compound B–PET standardized uptake value ratio images were read as positive or negative for cortical binding39 and a global neocortical standardized uptake value ratio value was extracted and compared with previously published thresholds.40

    Statistical Analyses

    Linear regression models covarying for age, sex, and genotype determined group differences in the neuropsychologic composite scores. Overall variations were determined by the Omnibus model or χ2 test. Nonparametric analysis was used to analyze the CSF results. Statistical analyses were performed using Stata, version 15 software (StataCorp). All tests were 2-sided, and P values less than .05 were considered statistically significant.

    Results
    Follow-up Case Report

    We previously published a case report of an individual diagnosed as having FTD who was found to have a novel genetic variant loss of function in the TSC1 gene.21 A 3-year follow up MRI scan of this individual revealed progressive atrophy involving the bilateral temporal lobes and orbitofrontal cortices (eFigure 1A and 1B the Supplement). The fluid-attenuated inversion recovery sequence from 2015 showed a hyperintense signal in the left superior temporal lobe typically referred to as a radial band, which is commonly seen in patients with TSC (eFigure 1C and 1D in the Supplement). No significant progression of the hyperintense signal in the radial band was seen during the 3-year period. This individual met criteria for both FTD and TAND in both 2015 and 2018. To assess whether TAND and FTD are overlapping clinical entities in other patients with TSC, we recruited a group of mildly affected adult individuals with TSC, confirmed their genetic variant in TSC1 or TSC2, and performed a comprehensive clinical phenotyping for both TAND and FTD.

    Clinical Phenotyping

    Eighteen individuals with TSC, 16 with FTD, and 18 HCs were included. Basic demographic information from all groups include age, sex, mean years of education, and measures of general intelligence are shown in eTable 1 in the Supplement. Most adult patients with TSC held college and postgraduate degrees. Most had mild cognitive issues. The TSC cohort’s age ranged from 27 to 66 years, with a mean age of 48 years. Seventy-two percent of the TSC cohort were women. The mean age of the TSC cohort was approximately 12 years and 15 years younger than the FTD and HC cohorts, respectively. Other basic demographic information for individual patients in all 3 cohorts is shown in Table 1. Ten of 18 patients with TSC had genetic information available, with an equal number of TSC1 and TSC2 genetic variants (eTable 5 in the Supplement). Notably, patients 9 and 10 have a genetic variant in TSC2 of unknown significance or evidence for pathogenicity at this time (eTable 5 in the Supplement). Two TSC study participants displayed skin findings consistent with TSC and had a child with TSC, but whole-exome sequencing of the enrolled participant showed no genetic variants in their TSC1 or TSC2 genes. These individuals may have had a moderate-sized to large insertion or deletion that could not be detected or were mosaic for a mutation. The 6 remaining TSC genetic results were still pending or their DNA was not collected.

    The TAND checklist serves as a clinical screening tool to assess neuropsychiatric difficulties that include the behavioral, cognitive and psychiatric domains.11 Development of the TAND checklist was necessary because 90% of patients with TSC endorsed neuropsychiatric symptoms, yet only 20% received treatment.11 We collected the TAND checklist from 16 patients with TSC, 15 patients with FTD, and 16 HC individuals (Table 2) and calculated a severity score for each neuropsychiatric domain on all cohorts. The TAND checklist severity score for the TSC and FTD cohorts was not significantly different in the behavioral and cognitive categories (eTable 2 in the Supplement). Both TSC and FTD severity scores in these domains were significantly higher when compared with HC individuals (Table 2). When the total severity score was compared, the TSC group occupied an intermediate space between FTD and HC cohorts, although it was not significantly different from either group (eTable 2 in the Supplement).

    As part of the diagnostic criteria, patients with FTD completed a standardized set of neuropsychological tests that assessed each cognitive domain. Test scores were compared with norms for age (results were considered abnormal if >1 SD from norm). We also performed standardized cognitive testing on the TSC and HC cohorts. The TSC and FTD cohorts performed similarly in tests of executive function, language, and visuospatial function (Table 3). In contrast, both TSC and FTD performed significantly worse than HC individuals in the executive and language domains (Table 3). The TSC and FTD cohorts were significantly different in memory testing (Table 3). The memory composite in the TSC and FTD cohorts could not be compared with the HC owing to differences in the test battery.

    Investigational Tau-PET Imaging Biomarker

    We and others have previously demonstrated a link between TSC and abnormal tau metabolism.21,41 In fact, TSC is considered 1 of a group of juvenile tauopathies.22 Therefore, in addition to comprehensive clinical assessments, we performed tau-PET imaging with the tau tracer FTP.35 Tau-PET neuroimaging was completed in 3 patients with TSC, 2 who were in their mid to late 40s and 1 who was in their late 50s, respectively. All 3 patients demonstrated small foci of FTP uptake predominantly in the frontal and temporal lobes. In 2 of 3 patients, the anatomical location of FTP uptake corresponded with structural changes seen on T1 and fluid attenuation inversion recovery sequences of the brain MRI (eFigure 2-8 in the Supplement). This pattern of distribution has not been reported in the past. The tracer FTP exhibits strong binding to neurofibrillary tangles in Alzheimer disease but also demonstrates low-level uptake to off-target (ie, non–tau-related) lesions such as hemorrhagic foci, calcifications, neuromelanin, and non–tau-related neurodegeneration.42-45 Therefore, we reviewed susceptibility-weighted imaging sequences in 1 patient and the low-dose CT in the 2 other patients who received tau-PET imaging, depending on availability. These sequences showed no evidence of calcifications in the tubers or other cortical malformations; thus, binding to calcifications appears to be less likely. However, the low-dose CT scans are of low quality, and therefore, our sensitivity to capture calcification in two-thirds of the cases was low. All 3 patients with TSC who had tau-PET scans also underwent PiB-PET scans for amyloid β deposition, which were negative (data not shown).

    Cerebrospinal Fluid Biomarkers

    Cerebrospinal fluid was available for biomarker analyses in 7 patients with TSC, 90 with FTD, and 49 HC individuals. The CSF results from the FTD and HC cohorts overlapped with the data used by Ljubenkov et al.32 It was reported that elevated levels of CSF P-tau, with a mean level of 31 pg/mL, is seen in FTD owing to a genetic variant in the MAPT gene,46 which produces the protein product tau. Intriguingly, the mean P-tau level in the TSC cohort was 32 pg/mL. No difference was seen in the CSF P-tau level when the TSC and FTD cohorts were compared (Table 4). In contrast, the P-tau level in the TSC cohort showed a significant difference when compared with HC individuals (Table 4). Ljubenkov et al32 report that the T-tau and Aβ42 levels in patients with FTD are similar to patients with normal cognition. These results were also seen in the TSC cohort (Figure; Table 4), with the exception of TSC patient 2 (eTable 3 in the Supplement). Additionally, Ljubenkov et al32 showed that patients with FTD typically have elevated CSF levels of NfL when compared with control individuals. Comparison of the CSF NfL levels between TSC and HC individuals was underpowered to show a significant difference between the 2 cohorts (Table 4).

    Discussion

    It is well established that patients with TSC can experience TAND symptoms, particularly in those more mildly affected. Nevertheless, these symptoms are not well characterized in older adults with TSC. This is important because medical and surgical advancements in TSC during the past decade have allowed affected individuals to live beyond age 50 years.47-49 The focus of this study was to characterize the clinical phenotype of adult patients with TSC with quantitative neuropsychologic measurements and biomarkers to evaluate its association with the neurodegenerative disorder FTD. The TSC group illustrated a pattern of impairment predominantly involving the cognitive and behavioral domains that closely mirrored what is seen in patients with FTD.

    The patients with TSC described cognitive and psychiatric symptoms that included executive and memory dysfunction, agitation, and aggressive behavior that are all seen in patients with FTD as well. Significant overlap in both the TAND checklist severity score and neuropsychologic testing19,50,51 was appreciated when the patients with TSC and FTD were compared (Table 2 and 3). P-tau is elevated in FTD owing to a genetic variant in MAPT, which was also elevated in the patients with TSC when compared with the HC cohort (Table 4B). The importance of this is highlighted by the fact that elevated CSF NfL and P-tau levels have a greater predictive value in patients with tau pathology.32 Together, the data establish a striking clinical overlap between TAND and FTD that has major implications for care and treatment of the aging TSC population.

    Whether TSC ultimately predisposes to a neurodegenerative disorder, such as FTD, requires further investigation. It can be difficult to perform these types of studies in those with significant intellectual disability from childhood, and therefore our cohort selection was limited to older individuals with normal IQs. An additional limitation of this study is that to achieve an adequate study group for comparison to the patients with TSC, we used different patients with FTD for cognitive testing and CSF biomarker analysis. Nonetheless, our results support future work in which populations of adults with TSC are followed longitudinally with neuropsychologic testing, neuroimaging, and fluid biomarker collection. These types of studies will be key to determining whether TAND symptoms represent a clinical continuum with FTD and for developing targeted interventions and therapeutics.

    Limitations

    Inclusion criteria for this study required that the patients with TSC be able to complete neuropsychological testing. Subsequently, the results from this study may not be generalizable to all patients with TSC. There is a higher risk of a type 1 error owing to the small sample size. A larger sample size will allow for a more precise clinical phenotyping. Longitudinal clinical and biomarker characterization will also further clarify the clinical trajectory of adult patients with TSC. Additionally, the FTP PET ligand is not specific for tau pathology and can show elevated binding unrelated to tau in normal individuals and in patients with non–tau-related neueodegeneration.42 Therefore, neuropathologic correlation is needed in patients with TSC who receive FTP tau-PET scans to determine whether the FTP is binding to a pathological form of tau. Lastly, the patients with FTD and HC participants who provided CSF results were not the same patients with FTD and HC participants who completed clinical measurements.

    Conclusions

    Our data suggest a clinical overlap and therefore potential association between TAND and the neurodegenerative disease FTD, in particular, where the latter is associated with the accumulation of pathological tau. This study provides a template by which to screen and prognosticate regarding cognitive difficulties and behavioral changes in the aging TSC population.

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    Article Information

    Corresponding Author: Aimee W. Kao, MD, PhD, Department of Neurology, University of California, San Francisco Weill Institute for Neurosciences, 675 Nelson Rising Lane, San Francisco, CA 94158 (aimee.kao@ucsf.edu).

    Accepted for Publication: October 17, 2019.

    Published Online: December 20, 2019. doi:10.1001/jamaneurol.2019.4284

    Author Contributions: Dr Kao had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Liu, Staffaroni, Kao.

    Acquisition, analysis, or interpretation of data: Liu, Staffaroni, Rojas, Olney, Alquezar, Ljubenkov, La Joie, Fong, Taylor, Karydas, Ramos, Coppola, Boxer, Rabinovici, Miller.

    Drafting of the manuscript: Liu, Staffaroni, La Joie, Karydas, Kao.

    Critical revision of the manuscript for important intellectual content: Liu, Staffaroni, Rojas, Olney, Alquezar, Ljubenkov, La Joie, Fong, Taylor, Ramos, Coppola, Boxer, Rabinovici, Miller, Kao.

    Statistical analysis: Liu, Staffaroni, Ljubenkov, La Joie, Miller.

    Obtained funding: Olney, Coppola, Boxer, Rabinovici, Miller, Kao.

    Administrative, technical, or material support: Liu, Olney, Fong, Karydas, Boxer, Miller.

    Supervision: Liu, Olney, Coppola, Kao.

    Conflict of Interest Disclosures: Dr Rojas-Martinez is a site Principal Investigator for clinical trials supported by Eli Lilly and receives support from the National Institutes of Health. Dr Liu reported a grant from Tau Consortium that covered travel expenses for the study participants during the conduct of the study. Dr Staffaroni reported grants from National Institute on Aging–National Institutes of Health and Larry L. Hillblom Foundation during the conduct of the study. Dr Olney reported other support from Avanir Pharmaceuticals outside the submitted work. Dr Coppola reported grants from the National Institutes of Health and private foundations during the conduct of the study and is currently an employee of Regeneron Pharmaceuticals. Dr Boxer reported other support from Alector; personal fees from Asceneuron, AGTC, Avexis, Arkuda, Arvinas, Eisai, AbbVie, Ionis, Novartis, Lundbeck, Pinteon, UCB, Toyama, Merck, Amgen, Delani, and Third Rock; grants from Biogen, BMS, Forum, Genentech, and Roche; and grants and nonfinancial support from Cortice outside the submitted work. Dr Rabinovici reported grants from Tau Consortium during the conduct of the study and grants from the National Institutes of Health, American College of Radiology, Alzheimer's Association, Eli Lilly, Tau Consortium, Avid Radiopharmaceuticals, Axon Neurosciences, and Life Molecular Imaging; grants and personal fees from GE Healthcare; and personal fees from Merck, Eisai, Merck, and Roche outside the submitted work. Dr Kao reported grants from Rainwater Tau Consortium during the conduct of the study. No other disclosures were reported.

    Funding/Support: This work is supported by the Rainwater Tau Consortium and grants P50AG023501, P01AG019724, T32AG023481-11S1, P50 AG1657303 and K23AG061253 from the National Institutes of Health/National Institute on Aging. Additional funding is from the Glenn Foundation for Aging Research (Dr Kao) and Larry H. Hillblom Foundation (Dr Staffaroni).

    Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    Disclaimer: Dr Rabinovici is Associate Editor of JAMA Neurology, but he was not involved in any of the decisions regarding review of the manuscript or its acceptance.

    Additional Contributions: We thank the Tau Consortium for providing support for this study. We thank Jo Anne Nakagawa, BS, and others from the Tuberous Sclerosis Alliance in helping us recruit participants to the study; Kyra Neylan, BS, the University of California, San Francisco, research coordinator for the tuberous sclerosis complex trial, who coordinated the tuberous sclerosis complex participants’ visits; Joel Kramer, PhD, and the research coordinators of the University of California, San Francisco, Hillblom Aging Network for recruiting healthy control patients into the study; and Gina Jerome, BS, of the Fagan laboratory for processing the cerebrospinal fluid samples, Amelia Storm, BS, for processing the FTP images, Brenda Porter, MD, PhD, of Stanford Children’s Hospital, Dr Stephen Ruoss of Stanford Hospital, and Rachel Kuperman, MD, and Carrie Krupitsky RN, FNP, of Oakland Children’s Hospital for clinical insights into patients with tuberous sclerosis complex. We thank contributors who collected samples used in this study, as well as patients and their families, whose help and participation made this work possible. We also thank Avid Radiopharmaceuticals who enabled use of the FTP tracer by providing precursor but did not provide direct funding and was not involved in data analysis or interpretation.

    Additional Information: Samples from the National Centralized Repository for Alzheimer Disease and Related Dementias, which receives government support under a cooperative agreement grant (U24 AG21886) awarded by the National Institute on Aging, were used in this study.

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