LEONEL TADAO TAKADA

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Instituto Central, Hospital das Clínicas, Faculdade de Medicina - Médico
LIM/45 - Laboratório de Fisiopatologia Neurocirúrgica, Hospital das Clínicas, Faculdade de Medicina

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  • article 24 Citação(ões) na Scopus
    Classification of Alzheimer's disease and frontotemporal dementia using routine clinical and cognitive measures across multicentric underrepresented samples: A cross sectional observational study
    (2023) MAITO, Marcelo Adrian; SANTAMARIA-GARCIA, Hernando; MOGUILNER, Sebastian; POSSIN, Katherine L.; GODOY, Maria E.; AVILA-FUNES, Jose Alberto; I, Maria Behrens; BRUSCO, Ignacio L.; BRUNO, Martin A.; CARDONA, Juan F.; CUSTODIO, Nilton; GARCIA, Adolfo M.; JAVANDEL, Shireen; LOPERA, Francisco; MATALLANA, Diana L.; MILLER, Bruce; OLIVEIRA, Maira Okada de; PINA-ESCUDERO, Stefanie D.; SLACHEVSKY, Andrea; ORTIZ, Ana L. Sosa; TAKADA, Leonel T.; TAGLIAZUCHI, Enzo; VALCOUR, Victor; YOKOYAMA, Jennifer S.; IBANEZ, Agustin
    Background Global brain health initiatives call for improving methods for the diagnosis of Alzheimer & rsquo;s disease (AD) and frontotemporal dementia (FTD) in underrepresented populations. However, diagnostic procedures in upper -middle-income countries (UMICs) and lower-middle income countries (LMICs), such as Latin American countries (LAC), face multiple challenges. These include the heterogeneity in diagnostic methods, lack of clinical harmonisation, and limited access to biomarkers. Methods This cross-sectional observational study aimed to identify the best combination of predictors to discriminate between AD and FTD using demographic, clinical and cognitive data among 1794 participants [904 diagnosed with AD, 282 diagnosed with FTD, and 606 healthy controls (HCs)] collected in 11 clinical centres across five LAC (ReDLat cohort). Findings A fully automated computational approach included classical statistical methods, support vector machine procedures, and machine learning techniques (random forest and sequential feature selection procedures). Results demonstrated an accurate classification of patients with AD and FTD and HCs. A machine learning model produced the best values to differentiate AD from FTD patients with an accuracy = 0.91. The top features included social cognition, neuropsychiatric symptoms, executive functioning performance, and cognitive screening; with secondary contributions from age, educational attainment, and sex. Interpretation Results demonstrate that data-driven techniques applied in archival clinical datasets could enhance diagnostic procedures in regions with limited resources. These results also suggest specific fine-grained cognitive and behavioural measures may aid in the diagnosis of AD and FTD in LAC. Moreover, our results highlight an opportunity for harmonisation of clinical tools for dementia diagnosis in the region.
  • article 75 Citação(ões) na Scopus
    Genetic PrP Prion Diseases
    (2018) KIM, Mee-Ohk; TAKADA, Leonel T.; WONG, Katherine; FORNER, Sven A.; GESCHWIND, Michael D.
    Genetic prion diseases (gPrDs) caused by mutations in the prion protein gene (PRNF, have been classified as genetic Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker disease, or fatal familial insomnia. Mutations in PRNP can be missense, nonsense, and/or octapeptide repeat insertions or, possibly, deletions. These mutations can produce diverse clinical features. They may also show varying ancillary testing results and neuropathological findings. Although the majority of gPrDs have a rapid progression with a short survival time of a few months, many also present as ataxic or parkinsonian disorders, which have a slower decline over a few to several years. A few very rare mutations manifest as neuropsychiatric disorders, with systemic symptoms that include gastrointestinal disorders and neuropathy; these forms can progress over years to decades. In this review, we classify gPrDs as rapid, slow, or mixed types based on their typical rate of progression and duration, and we review the broad spectrum of phenotypes manifested by these diseases.
  • article 174 Citação(ões) na Scopus
    Atypical, slowly progressive behavioural variant frontotemporal dementia associated with C9ORF72 hexanucleotide expansion
    (2012) KHAN, Baber K.; YOKOYAMA, Jennifer S.; TAKADA, Leonel T.; SHA, Sharon J.; RUTHERFORD, Nicola J.; FONG, Jamie C.; KARYDAS, Anna M.; WU, Teresa; KETELLE, Robin S.; BAKER, Matthew C.; HERNANDEZ, Mariely-Dejesus; COPPOLA, Giovanni; GESCHWIND, Daniel H.; RADEMAKERS, Rosa; LEE, Suzee E.; ROSEN, Howard J.; RABINOVICI, Gil D.; SEELEY, William W.; RANKIN, Katherine P.; BOXER, Adam L.; MILLER, Bruce L.
    Background Some patients meeting behavioural variant frontotemporal dementia (bvFTD) diagnostic criteria progress slowly and plateau at mild symptom severity. Such patients have mild neuropsychological and functional impairments, lack characteristic bvFTD brain atrophy and have thus been referred to as bvFTD 'phenocopies' or slowly progressive (bvFTD-SP). The few patients with bvFTD-SP that have been studied at autopsy have demonstrated no evidence of FTD pathology, suggesting that bvFTD-SP is neuropathologically distinct from other forms of FTD. Here, two patients with bvFTD-SP with chromosome 9 open reading frame 72 (C9ORF72) hexanucleotide expansions are described. Methods 384 patients with an FTD clinical spectrum and Alzheimer's disease diagnoses were screened for C9ORF72 expansion. Two bvFTD-SP mutation carriers were identified. Neuropsychological and functional data, as well as brain atrophy patterns, assessed using voxel based morphometry (VBM), were compared with 44 patients with sporadic bvFTD and 85 healthy controls. Results Both patients were aged 48 years at baseline and met possible bvFTD criteria. In the first patient, VBM revealed thalamic and posterior insula atrophy. Over 7 years, his neuropsychological performance and brain atrophy remained stable. In the second patient, VBM revealed cortical atrophy with subtle frontal and insular volume loss. Over 2 years, her neuropsychological and functional scores as well as brain atrophy remained stable. Conclusions C9ORF72 mutations can present with a bvFTD-SP phenotype. Some bvFTD-SP patients may have neurodegenerative pathology, and C9ORF72 mutations should be considered in patients with bvFTD-SP and a family history of dementia or motor neuron disease.
  • article 11 Citação(ões) na Scopus
    Systematic Review: Genetic, Neuroimaging, and Fluids Biomarkers for Frontotemporal Dementia Across Latin America Countries
    (2021) DURAN-ANIOTZ, Claudia; ORELLANA, Paulina; RODRIGUEZ, Tomas Leon; HENRIQUEZ, Fernando; CABELLO, Victoria; AGUIRRE-PINTO, Maria F.; ESCOBEDO, Tamara; TAKADA, Leonel T.; PINA-ESCUDERO, Stefanie D.; LOPEZ, Oscar; YOKOYAMA, Jennifer S.; IBANEZ, Agustin; PARRA, Mario A.; SLACHEVSKY, Andrea
    Frontotemporal dementia (FTD) includes a group of clinically, genetically, and pathologically heterogeneous neurodegenerative disorders, affecting the fronto-insular-temporal regions of the brain. Clinically, FTD is characterized by progressive deficits in behavior, executive function, and language and its diagnosis relies mainly on the clinical expertise of the physician/consensus group and the use of neuropsychological tests and/or structural/functional neuroimaging, depending on local availability. The modest correlation between clinical findings and FTD neuropathology makes the diagnosis difficult using clinical criteria and often leads to underdiagnosis or misdiagnosis, primarily due to lack of recognition or awareness of FTD as a disease and symptom overlap with psychiatric disorders. Despite advances in understanding the underlying neuropathology of FTD, accurate and sensitive diagnosis for this disease is still lacking. One of the major challenges is to improve diagnosis in FTD patients as early as possible. In this context, biomarkers have emerged as useful methods to provide and/or complement clinical diagnosis for this complex syndrome, although more evidence is needed to incorporate most of them into clinical practice. However, most biomarker studies have been performed using North American or European populations, with little representation of the Latin American and the Caribbean (LAC) region. In the LAC region, there are additional challenges, particularly the lack of awareness and knowledge about FTD, even in specialists. Also, LAC genetic heritage and cultures are complex, and both likely influence clinical presentations and may modify baseline biomarker levels. Even more, due to diagnostic delay, the clinical presentation might be further complicated by both neurological and psychiatric comorbidity, such as vascular brain damage, substance abuse, mood disorders, among others. This systematic review provides a brief update and an overview of the current knowledge on genetic, neuroimaging, and fluid biomarkers for FTD in LAC countries. Our review highlights the need for extensive research on biomarkers in FTD in LAC to contribute to a more comprehensive understanding of the disease and its associated biomarkers. Dementia research is certainly reduced in the LAC region, highlighting an urgent need for harmonized, innovative, and cross-regional studies with a global perspective across multiple areas of dementia knowledge.
  • article 14 Citação(ões) na Scopus
    Dominantly inherited Alzheimer's disease in Latin America: Genetic heterogeneity and clinical phenotypes
    (2021) LLIBRE-GUERRA, Jorge J.; LI, Yan; ALLEGRI, Ricardo F.; MENDEZ, Patricio Chrem; SURACE, Ezequiel I.; LLIBRE-RODRIGUEZ, Juan J.; SOSA, Ana Luisa; ALAEZ-VERSON, Carmen; LONGORIA, Erika-Mariana; TELLEZ, Alberto; CARRILLO-SANCHEZ, Karol; FLORES-LAGUNES, Luis Leonardo; SANCHEZ, Victor; TAKADA, Leonel Tadao; NITRINI, Ricardo; FERREIRA-FROTA, Norberto Anizio; BENEVIDES-LIMA, Joyce; LOPERA, Francisco; RAMIREZ, Laura; JIMENEZ-VELAZQUEZ, Ivonne; SCHENK, Christian; ACOSTA, Daisy; BEHRENS, Maria Isabel; DOERING, Michelle; ZIEGEMEIER, Ellen; MORRIS, John C.; MCDADE, Eric; BATEMAN, Randall J.
    Introduction A growing number of dominantly inherited Alzheimer's disease (DIAD) cases have become known in Latin American (LatAm) in recent years. However, questions regarding mutation distribution and frequency by country remain open. Methods A literature review was completed aimed to provide estimates for DIAD pathogenic variants in the LatAm population. The search strategies were established using a combination of standardized terms for DIAD and LatAm. Results Twenty-four DIAD pathogenic variants have been reported in LatAm countries. Our combined dataset included 3583 individuals at risk; countries with highest DIAD frequencies were Colombia (n = 1905), Puerto Rico (n = 672), and Mexico (n = 463), usually attributable to founder effects. We found relatively few reports with extensive documentation on biomarker profiles and disease progression. Discussion Future DIAD studies will be required in LatAm, albeit with a more systematic approach to include fluid biomarker and imaging studies. Regional efforts are under way to extend the DIAD observational studies and clinical trials to Latin America.
  • article 70 Citação(ões) na Scopus
    Genetic prion disease: Experience of a rapidly progressive dementia center in the United States and a review of the literature
    (2017) TAKADA, Leonel T.; KIM, Mee-Ohk; CLEVELAND, Ross W.; WONG, Katherine; FORNER, Sven A.; GALA, Ignacio Illan; FONG, Jamie C.; GESCHWIND, Michael D.
    Although prion diseases are generally thought to present as rapidly progressive dementias with survival of only a few months, the phenotypic spectrum for genetic prion diseases (gPrDs) is much broader. The majority have a rapid decline with short survival, but many patients with gPrDs present as slowly progressive ataxic or parkinsonian disorders with progression over a few to several years. A few very rare mutations even present as neuropsychiatric disorders, sometimes with systemic symptoms such as gastrointestinal disorders and neuropathy, progressing over years to decades. gPrDs are caused by mutations in the prion protein gene (PRNP), and have been historically classified based on their clinicopathological features as genetic Jakob-Creutzfeldt disease (gJCD), Gerstmann-Straussler-Scheinker (GSS), or Fatal Familial Insomnia (FFI). Mutations in PRNP can be missense, nonsense, and octapeptide repeat insertions or a deletion, and present with diverse clinical features, sensitivities of ancillary testing, and neuropathological findings. We present the UCSF gPrD cohort, including 129 symptomatic patients referred to and/or seen at UCSF between 2001 and 2016, and compare the clinical features of the gPrDs from 22 mutations identified in our cohort with data from the literature, as well as perform a literature review on most other mutations not represented in our cohort. E200K is the most common mutation worldwide, is associated with gJCD, and was the most common in the UCSF cohort. Among the GSS-associated mutations, P102L is the most commonly reported and was also the most common at UCSF. We also had several octapeptide repeat insertions (OPRI), a rare nonsense mutation (Q160X), and three novel mutations (K194E, E200G, and A224V) in our UCSF cohort. (c) 2016 Wiley Periodicals, Inc.
  • article 127 Citação(ões) na Scopus
    Altered network connectivity in frontotemporal dementia with C9orf72 hexanucleotide repeat expansion
    (2014) LEE, Suzee E.; KHAZENZON, Anna M.; TRUJILLO, Andrew J.; GUO, Christine C.; YOKOYAMA, Jennifer S.; SHA, Sharon J.; TAKADA, Leonel T.; KARYDAS, Anna M.; BLOCK, Nikolas R.; COPPOLA, Giovanni; PRIBADI, Mochtar; GESCHWIND, Daniel H.; RADEMAKERS, Rosa; FONG, Jamie C.; WEINER, Michael W.; BOXER, Adam L.; KRAMER, Joel H.; ROSEN, Howard J.; MILLER, Bruce L.; SEELEY, William W.
    Hexanucleotide repeat expansion in C9orf72 represents the most common genetic cause of familial and sporadic behavioural variant frontotemporal dementia. Previous studies show that some C9orf72 carriers with behavioural variant frontotemporal dementia exhibit distinctive atrophy patterns whereas others show mild or undetectable atrophy despite severe behavioural impairment. To explore this observation, we examined intrinsic connectivity network integrity in patients with or without the C9orf72 expansion. We studied 28 patients with behavioural variant frontotemporal dementia, including 14 C9orf72 mutation carriers (age 58.3 +/- 7.7 years, four females) and 14 non-carriers (age 60.8 +/- 6.9 years, four females), and 14 age- and sex-matched healthy controls. Both patient groups included five patients with comorbid motor neuron disease. Neuropsychological data, structural brain magnetic resonance imaging, and task-free functional magnetic resonance imaging were obtained. Voxel-based morphometry delineated atrophy patterns, and seed-based intrinsic connectivity analyses enabled group comparisons of the salience, sensorimotor, and default mode networks. Single-patient analyses were used to explore network imaging as a potential biomarker. Despite contrasting atrophy patterns in C9orf72 carriers versus non-carriers, patient groups showed topo-graphically similar connectivity reductions in the salience and sensorimotor networks. Patients without C9orf72 expansions exhibited increases in default mode network connectivity compared to controls and mutation carriers. Across all patients, behavioural symptom severity correlated with diminished salience network connectivity and heightened default mode network connectivity. In C9orf72 carriers, salience network connectivity reduction correlated with atrophy in the left medial pulvinar thalamic nucleus, and this region further showed diminished connectivity with key salience network hubs. Single-patient analyses revealed salience network disruption and default mode network connectivity enhancement in C9orf72 carriers with earlystage or slowly progressive symptoms. The findings suggest that patients with behavioural variant frontotemporal dementia with or without the C9orf72 expansion show convergent large-scale network breakdowns despite distinctive atrophy patterns. Medial pulvinar degeneration may contribute to the behavioural variant frontotemporal dementia syndrome in C9orf72 carriers by disrupting salience network connectivity. Task-free functional magnetic resonance imaging shows promise in detecting earlystage disease in C9orf72 carriers and may provide a unifying biomarker across diverse anatomical variants.
  • article 2 Citação(ões) na Scopus
    Discovery and validation of dominantly inherited Alzheimer's disease mutations in populations from Latin America
    (2022) TAKADA, Leonel Tadao; ALAEZ-VERSON, Carmen; BURGUTE, Bhagyashri D.; NITRINI, Ricardo; SOSA, Ana Luisa; CASTILHOS, Raphael Machado; CHAVES, Marcia Fagundes; LONGORIA, Erika-Mariana; CARRILLO-SANCHEZ, Karol; BRUCKI, Sonia Maria Dozzi; FLORES-LAGUNES, Luis Leonardo; MOLINA, Carolina; OLIVARES, Marcos Jimenez; ZIEGEMEIER, Ellen; PETRANEK, Jennifer; GOATE, Alison M.; CRUCHAGA, Carlos; RENTON, Alan E.; FERNANDEZ, Maria Victoria; DAY, Gregory S.; MCDADE, Eric; BATEMAN, Randall J.; KARCH, Celeste M.; LLIBRE-GUERRA, Jorge J.
    Background In fewer than 1% of patients, AD is caused by autosomal dominant mutations in either the presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP) genes. The full extent of familial AD and frequency of these variants remains understudied in Latin American (LatAm) countries. Due to the rare nature of these variants, determining the pathogenicity of a novel variant in these genes can be challenging. Here, we use a systematic approach to assign the likelihood of pathogenicity in variants from densely affected families in Latin American populations. Methods Clinical data was collected from LatAm families at risk for DIAD. Symptomatic family members were identified and assessed by local clinicians and referred for genetic counseling and testing. To determine the likelihood of pathogenicity among variants of unknown significance from LatAm populations, we report pedigree information, frequency in control populations, in silico predictions, and cell-based models of amyloid-beta ratios. Results We identified five novel variants in the presenilin1 (PSEN1) gene from Brazilian and Mexican families. The mean age at onset in newly identified families was 43.5 years (range 36-54). PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, p.Ala275Thr, and p.Ile414Thr variants have not been reported in PubMed, ClinVar, and have not been reported in dominantly inherited AD (DIAD) families. We found that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr produce A beta profiles consistent with known AD pathogenic mutations. PSEN1 p.Ile414Thr did not alter A beta in a manner consistent with a known pathogenic mutation. Conclusions Our study provides further insights into the genetics of AD in LatAm. Based on our findings, including clinical presentation, imaging, genetic, segregations studies, and cell-based analysis, we propose that PSEN1 p.Val103_Ser104delinsGly, p.Lys395Ile, p.Pro264Se, and p.Ala275Thr are likely pathogenic variants resulting in DIAD, whereas PSEN1 p.Ile414Thr is likely a risk factor. This report is a step forward to improving the inclusion/engagement of LatAm families in research. Family discovery is of great relevance for the region, as new initiatives are underway to extend clinical trials and observational studies to families living with DIAD.
  • article 59 Citação(ões) na Scopus
    Prion Diseases
    (2013) TAKADA, Leonel T.; GESCHWIND, Michael D.
    Prion diseases are a group of diseases caused by abnormally conformed infectious proteins, called prions. They can be sporadic (Jakob-Creutzfeldt disease [JCD]), genetic (genetic JCD, Gerstmann-Straussler-Scheinker, and familial fatal insomnia), or acquired (kuru, variant JCD, and iatrogenic JCD). The clinical features associated with each form of prion disease, the neuroimaging findings, cerebrospinal fluid markers, and neuropathological findings are reviewed. Sporadic JCD is the most common form of human prion disease, and will be discussed in detail. Genetic prion diseases are caused by mutations in the prion-related protein gene (PRNP), and they are classified based on the mutation, clinical phenotype, and neuropathological features. Acquired prion diseases fortunately are becoming rarer, as awareness of transmission risk has led to implementation of measures to prevent such occurrences, but continued surveillance is necessary to prevent future cases. Treatment and management issues are also discussed.
  • article 67 Citação(ões) na Scopus
    Dementia in Latin America: Paving the way toward a regional action plan
    (2021) PARRA, Mario Alfredo; BAEZ, Sandra; SEDENO, Lucas; CAMPO, Cecilia Gonzalez; SANTAMARIA-GARCIA, Hernando; APRAHAMIAN, Ivan; BERTOLUCCI, Paulo H. F.; BUSTIN, Julian; BICALHO, Maria Aparecida Camargos; CANO-GUTIERREZ, Carlos; CARAMELLI, Paulo; CHAVES, Marcia L. F.; COGRAM, Patricia; BEBER, Barbara Costa; COURT, Felipe A.; SOUZA, Leonardo Cruz de; CUSTODIO, Nilton; DAMIAN, Andres; CRUZ, Myriam de la; RODRIGUEZ, Roberta Diehl; BRUCKI, Sonia Maria Dozzi; FAJERSZTAJN, Lais; FARIAS, Gonzalo A.; FELICE, Fernanda G. De; FERRARI, Raffaele; OLIVEIRA, Fabricio Ferreira de; FERREIRA, Sergio T.; FERRETTI, Ceres; BALTHAZAR, Marcio Luiz Figueredo; FROTA, Norberto Anizio Ferreira; FUENTES, Patricio; GARCIA, Adolfo M.; GARCIA, Patricia J.; PORTO, Fabio Henrique de Gobbi; PENAILILLO, Lissette Duque; ENGLER, Henry Willy; MAIER, Irene; MATA, Ignacio F.; GONZALEZ-BILLAULT, Christian; LOPEZ, Oscar L.; MORELLI, Laura; NITRINI, Ricardo; QUIROZ, Yakeel T.; BARRAGAN, Alejandra Guerrero; HUEPE, David; PIO, Fabricio Joao; SUEMOTO, Claudia Kimie; KOCHHANN, Renata; KOCHEN, Silvia; KUMFOR, Fiona; LANATA, Serggio; MILLER, Bruce; MANSUR, Leticia Lessa; HOSOGI, Mirna Lie; LILLO, Patricia; GUERRA, Jorge Llibre; LIRA, David; LOPERA, Francisco; COMAS, Adelina; AVILA-FUNES, Jose Alberto; SOSA, Ana Luisa; RAMOS, Claudia; RESENDE, Elisa de Paula Franca; SNYDER, Heather M.; TARNANAS, Ioannis; YOKOYAMA, Jenifer; LLIBRE, Juan; CARDONA, Juan Felipe; POSSIN, Kate; KOSIK, Kenneth S.; MONTESINOS, Rosa; MOGUILNER, Sebastian; SOLIS, Patricia Cristina Lourdes; FERRETTI-REBUSTINI, Renata Eloah de Lucena; RAMIREZ, Jeronimo Martin; MATALLANA, Diana; MBAKILE-MAHLANZA, Lingani; TON, Alyne Mendonca Marques; TAVARES, Ronnielly Melo; MIOTTO, Eliane C.; MUNIZ-TERRERA, Graciela; MUNOZ-NEVAREZ, Luis Arnoldo; OROZCO, David; OLIVEIRA, Maira Okada de; PIGUET, Olivier; CAIPA, Maritza Pintado; ESCUDERO, Stefanie Danielle Pina; SCHILLING, Lucas Porcello; PALMEIRA, Andre Luiz Rodrigues; YASSUDA, Monica Sanches; SANTACRUZ-ESCUDERO, Jose Manuel; SERAFIM, Rodrigo Bernardo; SMID, Jerusa; SLACHEVSKY, Andrea; SERRANO, Cecilia; SOTO-ANARI, Marcio; TAKADA, Leonel Tadao; GRINBERG, Lea Tenenholz; TEIXEIRA, Antonio Lucio; BARBOSA, Maira Tonidandel; TREPEL, Dominic; IBANEZ, Agustin
    Across Latin American and Caribbean countries (LACs), the fight against dementia faces pressing challenges, such as heterogeneity, diversity, political instability, and socioeconomic disparities. These can be addressed more effectively in a collaborative setting that fosters open exchange of knowledge. In this work, the Latin American and Caribbean Consortium on Dementia (LAC-CD) proposes an agenda for integration to deliver a Knowledge to Action Framework (KtAF). First, we summarize evidence-based strategies (epidemiology, genetics, biomarkers, clinical trials, nonpharmacological interventions, networking, and translational research) and align them to current global strategies to translate regional knowledge into transformative actions. Then we characterize key sources of complexity (genetic isolates, admixture in populations, environmental factors, and barriers to effective interventions), map them to the above challenges, and provide the basic mosaics of knowledge toward a KtAF. Finally, we describe strategies supporting the knowledge creation stage that underpins the translational impact of KtAF.