Challenges and opportunities in quantitative brain PET imaging

Een van de voornaamste voordelen voor de beeldvorming van Positron Emissie Tomografie (PET) is het verkrijgen van kwantitatieve informatie omtrent fysiologische processen. Helaas vereisen de wiskundige modellen voor het kwantificeren over het algemeen lange acquisitieprotocollen en potentiele invasieve procedures, welke zorgen voor uitdagingen in termen van patiënt comfort en de bezetting van de gezondheidszorg. Als gevolg, de kwantitatieve kwaliteiten van PET komen niet terecht in de klinische toepassing en veel preklinische studies (kleine dierlijke studies) onderzoeken de potentie van kwantificatiemodellen niet volledig. In deze context onderzoekt deze thesis een aantal kansen om 1) het gat te overbruggen tussen het kwantitatieve potentieel en de noodzaak van simpele methodes voor klinische toepassing en 2) het optimaliseren van kwantitatieve methodologieën voor de preklinische omgeving. Ten eerste zijn er twee nieuwe gesimplificeerde methodes ontwikkeld en gevalideerd. Deze methodes pasten wiskundige benaderingen toe om modellen vast te stellen en waren succesvol in het significant reduceren van PET-scan tijd zonder nadelig te zijn voor de kwantitatieve accuraatheid. Als consequentie is het mogelijk volledige kwantitatieve informatie te verkrijgen door middel van korte, simpele, patiëntvriendelijke scans. Vervolgens richtte het onderzoek zich op het optimaliseren van kwantitatieve methodologie voor PET-beeldvorming van het rattenbrein. Hier werd een gevestigde tracer uit menselijk onderzoek geëvalueerd op specifieke toepassing in de preklinische omgeving en optimale kwantitatieve methodes vastgesteld. De bevindingen van dit werk lieten zien dat het niet mogelijk is de methodologie van mensen direct toe te passen op onderzoek bij ratten. Het markeerde het belang van model validatie, ook in het geval van radiotracers welke vastgesteld zijn voor een ander soort

Uso dos Mapas Conceituais na dinâmica da sala de aula: relato de experiência na disciplina Sociedade, Meio Ambiente e Cidadania (EACH-USP)

Este relato versa sobre a experiência da utilização dos mapas conceituais como ferramenta de participação ativa dos alunos no processo de aprendizagem durante a disciplina Sociedade, Meio Ambiente e Cidadania no ciclo básico da Escola de Artes, Ciências e Humanidades da Universidade de São Paulo. O campo de conhecimento articulado nessa disciplina exige métodos de ensino-aprendizagem que incentivem a aquisição e a articulação de conhecimentos de forma interdisciplinar e complexa, o que foi propiciado pelo uso dos mapas conceituais. As atividades com os mapas foram realizadas ao longo da disciplina em três etapas: anteriormente à aula, construíam-se mapas conceituais individualmente, com base nos conceitos da leitura indicada, e coletivamente pelo grupo responsável pela elaboração do seminário temático; durante a aula, a partir das provocações despertadas pelo seminário, os alunos eram convidados a discutir e reelaborar seus mapas em grupos; após a aula, os mapas coletivos eram alocados no ambiente virtual de apoio à graduação (e-disciplina), permitindo o registro e o compartilhamento do conhecimento gerado. O uso dos mapas conceituais resultou em protagonismo dos alunos na construção ativa do conhecimento, em compreensão aprofundada e sistêmica da bibliografia, em maior interesse e engajamento com os conteúdos estudados e em boa avaliação da técnica de ensino-aprendizagem utilizada por parte dos alunos.This paper reports the experience of using conceptual maps as a tool for active participation of students in the learning process during the module Society, Environment and Citizenship of the School of Arts, Sciences and Humanities of the University of São Paulo. The knowledge articulated in this module requires teaching-learning methods that encourage the acquisition and articulation of knowledge in an interdisciplinary and complex way, which was facilitated by the use of conceptual maps. The activities with the maps were carried out along the model in three stages: before a class, students prepared an individual conceptual map, based on the concepts of the recommended reading, and collectively one was elaborated by the group responsible for a thematic seminar. During class, from the inquiries aroused by the seminar, students were invited to discuss and re-elaborate their maps in small groups; after class, the collective maps were posted on the virtual learning environment, registering and sharing the generated knowledge. The use of conceptual maps resulted in the students’ leading role in building knowledge, in-depth and systemic understanding of the bibliography, greater interest and engagement with the studied content and a good evaluation by the students of the teaching-learning technique used

Avaliação do perfil de portadores de HIV do município de Araraquara, SP

A Síndrome da Imunodeficiência Adquirida (AIDS) é uma doença retroviral causada pelo vírus da imunodeficiência humana (HIV), caracterizada por infecção e depleção dos linfócitos T CD4+ e imunossupressão acentuada, causando infecções oportunistas que podem levar ao óbito. Nos últimos anos, embora tenham ocorrido avanços científicos e aumento do acesso à informação acerca do assunto, a média de incidência de pessoas vivendo com HIV/AIDS se manteve alta e muitos pacientes ainda não têm usufruído totalmente das vantagens do tratamento. Este resultado, em grande parte, é decorrente da dificuldade da adesão correta do tratamento devido à visão restrita acerca da doença e complexidade dos regimes terapêuticos e seus efeitos colaterais, o que leva a uma má adesão ou o abandono do mesmo e consequente aumento da disseminação da doença. Assim, por meio da análise de dados, busca-se traçar o perfil de pacientes para que seja viável o planejamento de ações sociais específicas voltadas à conscientização desse público a respeito da importância da manutenção do tratamento. Para que este trabalho seja realizado, foram coletados dados de pacientes que fazem acompanhamento e tratamento no SESA-USP (Serviço Especial de Saúde de Araraquara), fornecidos pelos funcionários da instituição através de tabelas do Excel, sem qualquer tipo de identificação, que contém informações em relação ao sexo, idade, grau de escolaridade e frequência da retirada de medicamentos

A data-driven study of Alzheimer's disease related amyloid and tau pathology progression

Amyloid-beta is thought to facilitate the spread of tau throughout the neocortex in Alzheimer's disease, though how this occurs is not well understood. This is because of the spatial discordance between amyloid-beta, which accumulates in the neocortex, and tau, which accumulates in the medial temporal lobe during aging. There is evidence that in some cases amyloid-beta-independent tau spreads beyond the medial temporal lobe where it may interact with neocortical amyloid-beta. This suggests that there may be multiple distinct spatiotemporal subtypes of Alzheimer's-related protein aggregation, with potentially different demographic and genetic risk profiles. We investigated this hypothesis, applying data-driven disease progression subtyping models to post-mortem neuropathology and in vivo PET based measures from two large observational studies: the Alzheimer's Disease Neuroimaging Initiative and the Religious Orders Study and Rush Memory and Aging Project. We consistently identified 'amyloid-first' and 'tau-first' subtypes using cross-sectional information from both studies. In the amyloid-first subtype, extensive neocortical amyloid-beta precedes the spread of tau beyond the medial temporal lobe, while in the tau-first subtype mild tau accumulates in medial temporal and neocortical areas prior to interacting with amyloid-beta. As expected, we found a higher prevalence of the amyloid-first subtype among apolipoprotein E (APOE) ε4 allele carriers while the tau-first subtype was more common among APOE ε4 non-carriers. Within tau-first APOE ε4 carriers, we found an increased rate of amyloid-beta accumulation (via longitudinal amyloid PET), suggesting that this rare group may belong within the Alzheimer's disease continuum. We also found that tau-first APOE ε4 carriers had several fewer years of education than other groups, suggesting a role for modifiable risk factors in facilitating amyloid-beta-independent tau. Tau-first APOE ε4 non-carriers, in contrast, recapitulated many of the features of Primary Age-related Tauopathy. The rate of longitudinal amyloid-beta and tau accumulation (both measured via PET) within this group did not differ from normal aging, supporting the distinction of Primary Age-related Tauopathy from Alzheimer's disease. We also found reduced longitudinal subtype consistency within tau-first APOE ε4 non-carriers, suggesting additional heterogeneity within this group. Our findings support the idea that amyloid-beta and tau may begin as independent processes in spatially disconnected regions, with widespread neocortical tau resulting from the local interaction of amyloid-beta and tau. The site of this interaction may be subtype-dependent: medial temporal lobe in amyloid-first, neocortex in tau-first. These insights into the dynamics of amyloid-beta and tau may inform research and clinical trials that target these pathologies

Pharmacokinetic modeling of [C-11]flumazenil kinetics in the rat brain

BACKGROUND: Preferred models for the pharmacokinetic analysis of [11C]flumazenil human studies have been previously established. However, direct translation of these models and settings to animal studies might be sub-optimal. Therefore, this study evaluates pharmacokinetic models for the quantification of [11C]flumazenil binding in the rat brain. Dynamic (60 min) [11C]flumazenil brain PET scans were performed in two groups of male Wistar rats (tracer dose (TD), n = 10 and pre-saturated (PS), n = 2). Time-activity curves from five regions were analyzed, including the pons (pseudo-reference region). Distribution volume (VT) was calculated using one- and two-tissue compartment models (1TCM and 2TCM) and spectral analysis (SA). Binding potential (BPND) was determined from full and simplified reference tissue models with one or two compartments for the reference tissue (FRTM, SRTM, and SRTM-2C). Model preference was determined by Akaike information criterion (AIC), while parameter agreement was assessed by linear regression, repeated measurements ANOVA and Bland-Altman plots. RESULTS: 1TCM and 2TCM fits of regions with high specific binding showed similar AIC, a preference for the 1TCM, and good VT agreement (0.1% difference). In contrast, the 2TCM was markedly preferred and necessary for fitting low specific-binding regions, where a worse VT agreement (17.6% difference) and significant VT differences between the models (p < 0.005) were seen. The PS group displayed results similar to those of low specific-binding regions. All reference models (FRTM, SRTM, and SRTM-2C) resulted in at least 13% underestimation of BPND. CONCLUSIONS: Although the 1TCM was sufficient for the quantification of high specific-binding regions, the 2TCM was found to be the most adequate for the quantification of [11C]flumazenil in the rat brain based on (1) higher fit quality, (2) lower AIC values, and (3) ability to provide reliable fits for all regions. Reference models resulted in negatively biased BPND and were affected by specific binding in the pons of the rat

Quantification of amyloid PET for future clinical use: a state-of-the-art review

Amyloid-β (Aβ) pathology is one of the earliest detectable brain changes in Alzheimer's disease (AD) pathogenesis. The overall load and spatial distribution of brain Aβ can be determined in vivo using positron emission tomography (PET), for which three fluorine-18 labelled radiotracers have been approved for clinical use. In clinical practice, trained readers will categorise scans as either Aβ positive or negative, based on visual inspection. Diagnostic decisions are often based on these reads and patient selection for clinical trials is increasingly guided by amyloid status. However, tracer deposition in the grey matter as a function of amyloid load is an inherently continuous process, which is not sufficiently appreciated through binary cut-offs alone. State-of-the-art methods for amyloid PET quantification can generate tracer-independent measures of Aβ burden. Recent research has shown the ability of these quantitative measures to highlight pathological changes at the earliest stages of the AD continuum and generate more sensitive thresholds, as well as improving diagnostic confidence around established binary cut-offs. With the recent FDA approval of aducanumab and more candidate drugs on the horizon, early identification of amyloid burden using quantitative measures is critical for enrolling appropriate subjects to help establish the optimal window for therapeutic intervention and secondary prevention. In addition, quantitative amyloid measurements are used for treatment response monitoring in clinical trials. In clinical settings, large multi-centre studies have shown that amyloid PET results change both diagnosis and patient management and that quantification can accurately predict rates of cognitive decline. Whether these changes in management reflect an improvement in clinical outcomes is yet to be determined and further validation work is required to establish the utility of quantification for supporting treatment endpoint decisions. In this state-of-the-art review, several tools and measures available for amyloid PET quantification are summarised and discussed. Use of these methods is growing both clinically and in the research domain. Concurrently, there is a duty of care to the wider dementia community to increase visibility and understanding of these methods

Quantification of amyloid PET for future clinical use: a state-of-the-art review

Amyloid-β (Aβ) pathology is one of the earliest detectable brain changes in Alzheimer's disease (AD) pathogenesis. The overall load and spatial distribution of brain Aβ can be determined in vivo using positron emission tomography (PET), for which three fluorine-18 labelled radiotracers have been approved for clinical use. In clinical practice, trained readers will categorise scans as either Aβ positive or negative, based on visual inspection. Diagnostic decisions are often based on these reads and patient selection for clinical trials is increasingly guided by amyloid status. However, tracer deposition in the grey matter as a function of amyloid load is an inherently continuous process, which is not sufficiently appreciated through binary cut-offs alone. State-of-the-art methods for amyloid PET quantification can generate tracer-independent measures of Aβ burden. Recent research has shown the ability of these quantitative measures to highlight pathological changes at the earliest stages of the AD continuum and generate more sensitive thresholds, as well as improving diagnostic confidence around established binary cut-offs. With the recent FDA approval of aducanumab and more candidate drugs on the horizon, early identification of amyloid burden using quantitative measures is critical for enrolling appropriate subjects to help establish the optimal window for therapeutic intervention and secondary prevention. In addition, quantitative amyloid measurements are used for treatment response monitoring in clinical trials. In clinical settings, large multi-centre studies have shown that amyloid PET results change both diagnosis and patient management and that quantification can accurately predict rates of cognitive decline. Whether these changes in management reflect an improvement in clinical outcomes is yet to be determined and further validation work is required to establish the utility of quantification for supporting treatment endpoint decisions. In this state-of-the-art review, several tools and measures available for amyloid PET quantification are summarised and discussed. Use of these methods is growing both clinically and in the research domain. Concurrently, there is a duty of care to the wider dementia community to increase visibility and understanding of these methods

Impact of cerebral blood flow and amyloid load on SUVR bias

BACKGROUND: Despite its widespread use, the semi-quantitative standardized uptake value ratio (SUVR) may be biased compared with the distribution volume ratio (DVR). This bias may be partially explained by changes in cerebral blood flow (CBF) and is likely to be also dependent on the extent of the underlying amyloid-β (Aβ) burden. This study aimed to compare SUVR with DVR and to evaluate the effects of underlying Aβ burden and CBF on bias in SUVR in mainly cognitively unimpaired participants. Participants were scanned according to a dual-time window protocol, with either [18F]flutemetamol (N = 90) or [18F]florbetaben (N = 31). The validated basisfunction-based implementation of the two-step simplified reference tissue model was used to derive DVR and R1 parametric images, and SUVR was calculated from 90 to 110 min post-injection, all with the cerebellar grey matter as reference tissue. First, linear regression and Bland-Altman analyses were used to compare (regional) SUVR with DVR. Then, generalized linear models were applied to evaluate whether (bias in) SUVR relative to DVR could be explained by R1 for the global cortical average (GCA), precuneus, posterior cingulate, and orbitofrontal region. RESULTS: Despite high correlations (GCA: R2 ≥ 0.85), large overestimation and proportional bias of SUVR relative to DVR was observed. Negative associations were observed between both SUVR or SUVRbias and R1, albeit non-significant. CONCLUSION: The present findings demonstrate that bias in SUVR relative to DVR is strongly related to underlying Aβ burden. Furthermore, in a cohort consisting mainly of cognitively unimpaired individuals, the effect of relative CBF on bias in SUVR appears limited. EudraCT Number: 2018-002277-22, registered on: 25-06-2018