RESUMO
Based on "reducing amyloid plaques in the brain", the U.S. Food and Drug Administration has granted accelerated and full approval for two monoclonal anti-Alzheimer's antibodies, aducanumab and lecanemab, respectively. Approval of a third antibody, donanemab, is pending. Moreover, lecanemab and donanemab are claimed to cause delay in the cognitive decline that characterizes the disease. We believe that these findings are subject to misinterpretation and statistical bias. Donanemab is claimed to cause removal of up to 86â¯% of cerebral amyloid and 36â¯% delay in cognitive decline compared to placebo. In reality, these are very small changes on an absolute scale and arguably less than what can be achieved with cholinesterase inhibitor/memantine therapy. Moreover, the "removal" of amyloid, based on the reduced accumulation of amyloid-PET tracer, most likely also reflects therapy-related tissue damage. This would also correlate with the minimal clinical effect, the increased frequency of amyloid-related imaging abnormalities, and the accelerated loss of brain volume in treated compared to placebo patients observed with these antibodies. We recommend halting approvals of anti-AD antibodies until these issues are fully understood to ensure that antibody treatment does not cause more harm than benefit to patients.
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The amyloid cascade hypothesis for Alzheimer's disease is still alive, although heavily challenged. Effective anti-amyloid immunotherapy would confirm the hypothesis' claim that the protein amyloid-beta is the cause of the disease. Two antibodies, aducanumab and lecanemab, have been approved by the U.S. Food and Drug Administration, while a third, donanemab, is under review. The main argument for the FDA approvals is a presumed therapy-induced removal of cerebral amyloid deposits. Lecanemab and donanemab are also thought to cause some statistical delay in the determination of cognitive decline. However, clinical efficacy that is less than with conventional treatment, selection of amyloid-positive trial patients with non-specific amyloid-PET imaging, and uncertain therapy-induced removal of cerebral amyloids in clinical trials cast doubt on this anti-Alzheimer's antibody therapy and hence on the amyloid hypothesis, calling for a more thorough investigation of the negative impact of this type of therapy on the brain.
Assuntos
Doença de Alzheimer , Anticorpos Monoclonais Humanizados , Estados Unidos , Humanos , Doença de Alzheimer/terapia , Camada de Gelo , Proteínas Amiloidogênicas , RadioimunoterapiaRESUMO
ABSTRACT: Calcific tendinopathy is a common condition of the shoulder caused by the inflammation and deposition of hydroxyapatite crystals in the rotator cuff tendons. PET tracers capturing the molecular changes associated with the crystal deposition of calcific tendinopathy remain underinvestigated. In this report, we present calcified tendinopathy of the infraspinatus tendon demonstrating both 18 F-NaF and 18 F-FDG focal uptake in a 61-year-old woman.
Assuntos
Manguito Rotador , Tendinopatia , Feminino , Humanos , Pessoa de Meia-Idade , Manguito Rotador/diagnóstico por imagem , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Ombro , Tendinopatia/diagnóstico por imagem , Tendinopatia/complicações , Fluoreto de SódioRESUMO
The recently announced revision of the Alzheimer's disease (AD) diagnostic ATN classification adds to an already existing disregard for clinical assessment the rejection of image-based in vivo assessment of the brain's condition. The revision suggests that the diagnosis of AD should be based solely on the presence of cerebral amyloid-beta and tau, indicated by the "A" and "T". The "N", which stands for neurodegeneration - detected by imaging - should no longer be given importance, except that A+ ± T + = AD with amyloid PET being the main method for demonstrating A+ . We believe this is an artificial and misleading suggestion. It is artificial because it relies on biomarkers whose significance remains obscure and where the detection of "A" is based on a never-validated PET method using a tracer that marks much more than amyloid-beta. It is misleading because many patients without dementia will be falsely classified as having AD, but nonetheless candidates for passive immunotherapy, which may be more harmful than beneficial, and sometimes fatal.
Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Humanos , Doença de Alzheimer/diagnóstico por imagem , Proteínas tau , Peptídeos beta-Amiloides , Amiloide , Biomarcadores , Tomografia por Emissão de PósitronsRESUMO
ABSTRACT: Calcification and formation of calculi in the genitourinary system such as the bladder, kidney, and prostate are common processes of aging. Despite being in different parts of the body, these calculi can share risk factors; for instance, bladder and prostate calculi are seen in older men with benign prostatic hyperplasia. There have been increasing reports of detection of calculi using PET tracers such as 18 F-NaF and 18 F-FDG, suggesting their role for detection of extraosseous calcification. In this report, we present simultaneous detection of bladder and prostate calculi with both 18 F-NaF and 18 F-FDG avidity in a 74-year-old man with multiple myeloma.
Assuntos
Calcinose , Cálculos , Doenças Prostáticas , Masculino , Humanos , Idoso , Fluordesoxiglucose F18 , Bexiga Urinária , Tomografia por Emissão de Pósitrons , Próstata , Fluoreto de SódioRESUMO
The US Food and Drug Administration (FDA)'s recent accelerated approval of two anti-amyloid antibodies for treatment of Alzheimer's disease (AD), aducanumab and lecanemab, has caused substantial debate. To inform this debate, we reviewed the literature on randomized clinical trials conducted with eight such antibodies focusing on clinical efficacy, cerebral amyloid removal, amyloid-related imaging abnormalities (ARIAs) and cerebral volumes to the extent such measurements have been reported. Two antibodies, donanemab and lecanemab, have demonstrated clinical efficacy, but these results remain uncertain. We further argue that the decreased amyloid PET signal in these trials is unlikely to be a one-to-one reflection of amyloid removal, but rather a reflection of increased therapy-related brain damage, as supported by the increased incidence of ARIAs and reported loss of brain volume. Due to these uncertainties of benefit and risk, we recommend that the FDA pauses existing approvals and approval of new antibodies until results of phase 4 studies with these drugs are available to inform on these risk-benefit uncertainties. We recommend that the FDA prioritize FDG PET and detection of ARIAs and accelerated brain volume loss with MRI in all trial patients, and neuropathological examination of all patients who die in these phase 4 trials.
Assuntos
Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico , Anticorpos Monoclonais , Imageamento por Ressonância Magnética , Proteínas Amiloidogênicas , Amiloide , Imunoterapia/métodos , Peptídeos beta-AmiloidesRESUMO
In June 2021, the US Federal Drug and Food Administration (FDA) granted accelerated approval for the antibody aducanumab and, in January 2023, also for the antibody lecanemab, based on a perceived drug-induced removal of cerebral amyloid-beta as assessed by amyloid-PET and, in the case of lecanemab, also a presumption of limited clinical efficacy. Approval of the antibody donanemab is awaiting further data. However, published trial data indicate few, small and uncertain clinical benefits, below what is considered "clinically meaningful" and similar to the effect of conventional medication. Furthermore, a therapy-related decrease in the amyloid-PET signal may also reflect increased cell damage rather than simply "amyloid removal". This interpretation is more consistent with increased rates of amyloid-related imaging abnormalities and brain volume loss in treated patients, relative to placebo. We also challenge the current diagnostic criteria for AD based on amyloid-PET imaging biomarkers and recommend that future anti-AD therapy trials apply: (1) diagnosis of AD based on the co-occurrence of cognitive decline and decreased cerebral metabolism assessed by FDA-approved FDG-PET, (2) therapy efficacy determined by favorable effect on cognitive ability, cerebral metabolism by FDG-PET, and brain volumes by MRI, and (3) neuropathologic examination of all deaths occurring in these trials.
RESUMO
After the CLARITY-AD clinical trial results of lecanemab were interpreted as positive, and supporting the amyloid hypothesis, the drug received accelerated Food and Drug Administration approval. However, we argue that benefits of lecanemab treatment are uncertain and may yield net harm for some patients, and that the data do not support the amyloid hypothesis. We note potential biases from inclusion, unblinding, dropouts, and other issues. Given substantial adverse effects and subgroup heterogeneity, we conclude that lecanemab's efficacy is not clinically meaningful, consistent with numerous analyses suggesting that amyloid-ß and its derivatives are not the main causative agents of Alzheimer's disease dementia.
Assuntos
Doença de Alzheimer , Proteínas Amiloidogênicas , Estados Unidos , Humanos , Peptídeos beta-Amiloides , Anticorpos Monoclonais/uso terapêuticoRESUMO
ABSTRACT: Passive immunotherapy for Alzheimer disease has been tried for over 10 years without success. However, in 2021 and most recently in January 2023, the US Food and Drug Administration granted accelerated approval of 2 antibodies for this purpose, aducanumab and lecanemab. In both cases, the approval was based on a presumed therapy-related removal of amyloid deposits from the brain and, in the case of lecanemab, also some delay in cognitive decline. We question the validity of the evidence for the removal of amyloid in particular as assessed by amyloid PET imaging, believing that what is observed is more likely a large nonspecific amyloid PET signal in the white matter that diminishes during immunotherapy-in line with dose-dependent increases in amyloid-related imaging abnormalities and increased loss of cerebral volume in treated compared with placebo patients. To investigate this further, we recommend repeat FDG PET and MRI in all future immunotherapy trials.
Assuntos
Doença de Alzheimer , Estados Unidos , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/terapia , Fluordesoxiglucose F18 , Imageamento por Ressonância Magnética , Tomografia por Emissão de Pósitrons , Amiloide , Imunoterapia , Peptídeos beta-AmiloidesRESUMO
Results from recent clinical trials of antibodies that target amyloid-ß (Aß) for Alzheimer's disease have created excitement and have been heralded as corroboration of the amyloid cascade hypothesis. However, while Aß may contribute to disease, genetic, clinical, imaging and biochemical data suggest a more complex aetiology. Here we review the history and weaknesses of the amyloid cascade hypothesis in view of the new evidence obtained from clinical trials of anti-amyloid antibodies. These trials indicate that the treatments have either no or uncertain clinical effect on cognition. Despite the importance of amyloid in the definition of Alzheimer's disease, we argue that the data point to Aß playing a minor aetiological role. We also discuss data suggesting that the concerted activity of many pathogenic factors contribute to Alzheimer's disease and propose that evolving multi-factor disease models will better underpin the search for more effective strategies to treat the disease.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides , Amiloide , Cognição , AnticorposRESUMO
The method of 18F-sodium fluoride (NaF) positron emission tomography/computed tomography (PET/CT) of atherosclerosis was introduced 12 years ago. This approach is particularly interesting because it demonstrates microcalcification as an incipient sign of atherosclerosis before the development of arterial wall macrocalcification detectable by CT. However, this method has not yet found its place in the clinical routine. The more exact association between NaF uptake and future arterial calcification is not fully understood, and it remains unclear to what extent NaF-PET may replace or significantly improve clinical cardiovascular risk scoring. The first 10 years of publications in the field were characterized by heterogeneity at multiple levels, and it is not clear how the method may contribute to triage and management of patients with atherosclerosis, including monitoring effects of anti-atherosclerosis intervention. The present review summarizes findings from the recent 2¾ years including the ability of NaF-PET imaging to assess disease progress and evaluate response to treatment. Despite valuable new information, pertinent questions remain unanswered, not least due to a pronounced lack of standardization within the field and of well-designed long-term studies illuminating the natural history of atherosclerosis and effects of intervention.
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ABSTRACT: Uterine leiomyomas (fibroids) are common and benign hormone-dependent tumors of the uterus, often coinciding with atypical menstrual bleeding, urinary incontinence, and lower abdominal pain. The PET tracer 18 F-NaF has been used to study metastatic and benign bone disorders, but its potential use in investigating the molecular alterations of extraosseous tissues and tumors has not been fully investigated. In this report, we present a calcifying uterine leiomyoma incidentally detected on 18 F-NaF PET/CT scans in a postmenopausal 61-year-old woman and follow-up image 2 years after, highlighting the potential of 18 F-NaF in monitoring both the molecular and structural progression of uterine leiomyomas.
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Leiomioma , Neoplasias Uterinas , Feminino , Humanos , Pessoa de Meia-Idade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Leiomioma/diagnóstico por imagem , Compostos Radiofarmacêuticos , Útero , Neoplasias Uterinas/diagnóstico por imagemRESUMO
Using amyloid PET imaging as a single primary surrogate efficacy measure in Alzheimer's disease immunotherapy trials, as happened when the FDA granted accelerated approval of aducanumab, is unjustified. In vivo evidence indicates that PET quantification of amyloid deposition is distorted and misrepresents effects of anti-amyloid treatments due to lack of specificity of the PET imaging probe, effects of amyloid-related imaging abnormalities, spill-over from high white matter signals, and questionable quantification models. Before granting approval to other immunotherapy candidates, the FDA should require rigorous evidence of all imaging claims and irrefutable documentation that proposed treatments are clinically effective and harmless to patients.
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Doença de Alzheimer , Humanos , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/terapia , Peptídeos beta-Amiloides , Proteínas Amiloidogênicas , Imunoterapia/métodos , Tomografia por Emissão de PósitronsRESUMO
Arteriosclerosis and its sequelae are the most common cause of death in diabetic patients and one of the reasons why diabetes has entered the top 10 causes of death worldwide, fatalities having doubled since 2000. The literature in the field claims almost unanimously that arteriosclerosis is more frequent or develops more rapidly in diabetic than non-diabetic subjects, and that the disease is caused by arterial inflammation, the control of which should therefore be the goal of therapeutic efforts. These views are mostly based on indirect methodologies, including studies of artery wall thickness or stiffness, or on conventional CT-based imaging used to demonstrate tissue changes occurring late in the disease process. In contrast, imaging with positron emission tomography and computed tomography (PET/CT) applying the tracers 18F-fluorodeoxyglucose (FDG) or 18F-sodium fluoride (NaF) mirrors arterial wall inflammation and microcalcification, respectively, early in the course of the disease, potentially enabling in vivo insight into molecular processes. The present review provides an overview of the literature from the more than 20 and 10 years, respectively, that these two tracers have been used for the study of atherosclerosis, with emphasis on what new information they have provided in relation to diabetes and which questions remain insufficiently elucidated.
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Aterosclerose , Diabetes Mellitus , Aterosclerose/diagnóstico por imagem , Diabetes Mellitus/diagnóstico por imagem , Fluordesoxiglucose F18 , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos , Fluoreto de SódioRESUMO
Cancer stem cells (CSCs) are resistant to conventional therapy and present a major clinical challenge since they are responsible for the relapse of many cancers, including non-small cell lung cancer (NSCLC). Hence, future successful therapy should also eradicate CSCs. Auger electrons have demonstrated promising therapeutic potential and can induce DNA damage while sparing surrounding cells. Here, we sort primary patient-derived NSCLC cells based on their expression of the CSC-marker CD44 and investigate the effects of cisplatin and a thymidine analog (deoxyuridine) labeled with an Auger electron emitter (125I). We show that the CD44+ populations are more resistant to cisplatin than the CD44- populations. Interestingly, incubation with the thymidine analog 5-[125I]iodo-2'-deoxyuridine ([125I]I-UdR) induces equal DNA damage, G2/M cell cycle arrest, and apoptosis in the CD44- and CD44+ populations. Our results suggest that Auger electron emitters can also eradicate resistant lung cancer CD44+ populations.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Carcinoma Pulmonar de Células não Pequenas/genética , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Desoxiuridina , Elétrons , Humanos , Receptores de Hialuronatos/metabolismo , Neoplasias Pulmonares/metabolismo , Recidiva Local de Neoplasia/tratamento farmacológico , Células-Tronco Neoplásicas/metabolismo , Timidina/farmacologiaRESUMO
Three decades with the amyloid hypothesis, nearly two with amyloid-PET imaging, and one with testing of anti-amyloid therapy have not yielded benefits to patients with Alzheimer's disease (AD). It is time to focus on more promising options, e.g., infection, low dose radiation, and atherosclerosis. The relevance of the latter in managing AD has fluctuated from being significant to insignificant. Current methodologies for detecting cerebral atherosclerosis reflect advanced changes in only major arteries. In contrast, 18F-sodium fluoride PET imaging assessing early-stage cerebral atherosclerosis regionally or in the entire vascular bed may provide new insight in this age-related process in dementia.
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Doença de Alzheimer , Amiloidose , Aterosclerose , Arteriosclerose Intracraniana , Doença de Alzheimer/diagnóstico por imagem , Amiloide , Peptídeos beta-Amiloides , Proteínas Amiloidogênicas , Aterosclerose/diagnóstico por imagem , Humanos , Tomografia por Emissão de Pósitrons/métodosRESUMO
ABSTRACT: Prostatic calculi are common and usually asymptomatic calcified stones frequently found incidentally in imaging or during the evaluation of benign prostatic hyperplasia. Those associated with chronic prostatitis can lead to bacterial colonization, inflammation, and blockage of secretory ducts, resulting in pelvic pain and lower urinary tract symptoms. Although PET tracers such as 18 F-NaF and 18 F-FDG have been used to assess metastatic and benign bone disorders, their comparative avidity in the domain of extraosseous and prostate calcification remains to be fully explored. We present incidentally detected bilateral prostatic calcification in an asymptomatic 42-year-old man exhibiting coavidity of 18 F-NaF and 18 F-FDG, highlighting the molecular coupling of inflammation and microcalcification in the pathogenesis of prostate calculi.
Assuntos
Calcinose , Cálculos , Doenças Prostáticas , Adulto , Calcinose/complicações , Calcinose/diagnóstico por imagem , Cálculos/diagnóstico por imagem , Fluordesoxiglucose F18 , Humanos , Inflamação/diagnóstico por imagem , Masculino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Próstata/diagnóstico por imagem , Doenças Prostáticas/diagnóstico por imagem , Compostos Radiofarmacêuticos , Fluoreto de SódioRESUMO
ABSTRACT: When the FDA granted accelerated approval of Biogen's Alzheimer disease drug, aducanumab (marketed as Aduhelm), it deviated from its mission of guaranteeing drug safety and efficacy because the approval was based exclusively on a perceived dose-dependent reduction in brain amyloid deposits and not upon a proven clinical effect. We believe that the amyloid-PET scans, perceived as showing decreasing amyloid deposits, are an expression of increased cerebral cell death due to aducanumab treatment, so that with time one should instead expect a worsening and not an improvement in the treated patients' condition.
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Doença de Alzheimer , Amiloidose , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Amiloide/metabolismo , Peptídeos beta-Amiloides/metabolismo , Amiloidose/tratamento farmacológico , Anticorpos Monoclonais Humanizados/efeitos adversos , Humanos , Placa AmiloideRESUMO
The high recurrence rate of lung cancer is a major clinical challenge associated with therapyresistant cancer stem cells (CSCs), which are rare subpopulations. Future successful treatment is required to also eradicate these subpopulations. Furthermore, the majority of anticancer treatments are being tested in adherent monolayer cultures with the limitations this entails in the translation of results into clinical practice. The present study aimed to establish and characterize patientderived longterm primary lung cancer tumorspheres enriched in CSCs and evaluate the effects of Auger electrons on them. These electrons are emitted from radionuclides that decay by electron capture or internal conversion and have demonstrated promising therapeutic potential. Their low energy (<1 keV) is sufficiently potent to induce DNA doublestrand breaks and eventually cell death while minimizing irradiation of nontargeted surrounding cells. Labeling a thymidine analog (deoxyuridine) with the Auger electronemitting radionuclide [125I], which is exclusively incorporated into the DNA of proliferating cells during the Sphase, ensures a close distance to the DNA. Primary cell cultures grown as tumorspheres were established and characterized. The tumorspheres were morphologically distinct and differed concerning their proliferation rate and fraction of CSCs. Surface markers associated with CSCs were upregulated and 5[125I]iodo2'deoxyuridine was incorporated in the tumorspheres. The Auger electrons induced DNA doublestrand breaks, G2/M arrest and apoptosis in the tumorspheres; however, the tumorspheres derived from different patients exhibited heterogeneities in their sensitivity to Auger electron irradiation.