Alzheimer's Amyloid Hypothesis and Antibody Therapy: Melting Glaciers?

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.

Central nervous system manifestations following vaccination against COVID-19.

Coronavirus disease 2019 (COVID-19) vaccination has become the most effective countermeasure in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. However, vaccination is associated with side effects. This narrative review focuses on central nervous system (CNS) manifestations following COVID-19 vaccination and provides a summary of the potential underlying mechanisms and methods of diagnosis and management of the vaccination-related CNS manifestations. Headache, myalgia, optic neuritis, seizure, multiple sclerosis, acute disseminated encephalomyelitis and encephalitis, delirium, acute transverse myelitis, and stroke have been reported after COVID-19 vaccination. Constant headache and myalgia are common manifestations that may necessitate further clinical investigation for stroke. To limit consequences, it is imperative to follow standard treatment protocols for each neurological disorder following COVID-19 vaccination. Immunosuppressive medication can be helpful in the treatment of seizures following vaccination since the immune response is involved in their etiology. Clinicians should be aware of the manifestations after COVID-19 vaccination to respond promptly and effectively. Clinical guidelines for the management of CNS manifestations following COVID-19 vaccination are in high demand and would be useful in each new SARS-CoV-2 variant pandemic.

PET Imaging in Chimeric Antigen Receptor T-Cell Trafficking.

The evolving field of chimeric antigen receptor (CAR) T-cell therapy, though promising, necessitates more comprehensive imaging methods to enhance therapeutic effectiveness and track cell trafficking in patients and ex vivo. This review examines the application of PET imaging in CAR T-cell trafficking and optimizing their therapeutic impact. The application of PET imaging using various radiotracers is promising in providing evaluation of CAR T-cell interaction within the host, thereby facilitating strategies for improved patient outcomes. As this technology progresses, further innovative strategies to streamline assessments of immunotherapeutic effectiveness are anticipated.

Role of PET/CT in diagnosing and monitoring disease activity in rheumatoid arthritis: a review.

Rheumatoid Arthritis (RA) is a systemic inflammatory disorder that commonly presents with polyarthritis but can have multisystemic involvement and complications, leading to increased morbidity and mortality. The diagnosis of RA continues to be challenging due to its varied clinical presentations. In this review article, we aim to determine the potential of PET/CT to assist in the diagnosis of RA and its complications, evaluate the therapeutic response to treatment, and predict RA remission. PET/CT has increasingly been used in the last decade to diagnose, monitor treatment response, predict remissions, and diagnose subclinical complications in RA. PET imaging with [18F]-fluorodeoxyglucose ([18F]-FDG) is the most commonly applied radiotracer in RA, but other tracers are also being studied. PET/CT with [18F]-FDG, [18F]-NaF, and other tracers might lead to early identification of RA and timely evidence-based clinical management, decreasing morbidity and mortality. Although PET/CT has been evolving as a promising tool for evaluating and managing RA, more evidence is required before incorporating PET/CT in the standard clinical management of RA.

Current uses and understanding of PET imaging in cardiac sarcoidosis.

Sarcoidosis is a systemic disease with unclear etiology characterized by the accumulation of noncaseating, immune granulomas in affected tissues. In cardiac sarcoidosis (CS), white blood cells build up within the heart muscles, causing cardiac abnormalities. Accurate and early diagnosis of CS proves challenging. However, usage of positron emission tomography (PET) imaging, namely 18F-FDG-PET, has proven successful in diagnosing inflammatory cardiomyopathy. This review seeks to examine the role of PET in managing ventricular tachycardia in cardiac sarcoidosis. PET, in conjunction with cardiac magnetic resonance imaging (CMR) is also endorsed as the premier method for diagnosis and management of arrhythmias associated with CS by The Heart Rhythm Society. After a CS diagnosis, risk stratification of ventricular arrhythmias is a necessity given the potential for sudden cardiac death. 18F-FDG-PET has been successful in monitoring disease advancement and treatment responses in CS patients. Early stages of CS are often treated with immunosuppression drugs if there are additional signs of VT. Currently, corticosteroid and anti-arrhythmia compounds: methotrexate, cyclophosphamide, infliximab, amiodarone, and azathioprine are used to suppress inflammation. 18F-FDG-PET has certainly proven to be an incredibly useful and accurate diagnostic tool of CS. While late gadolinium enhancement by CMR is efficient in detecting myocardial necrosis and/or advanced fibrosis scarring, 18F-FDG portrays the increased uptake level of glucose metabolism. In combination PET/MRI has proven to be more successful in improving the efficacy of both scans, addressing their drawbacks, and highlighting their advantages. Managing CS patients is highly involved in detecting inflammatory regions of the heart. Early recognition prevents cardiac abnormality, mainly VT and VF in CS patients, and extends lifespan.

The utility of PET imaging in depression.

This educational review article aims to discuss growing evidence from PET studies in the diagnosis and treatment of depression. PET has been used in depression to explore the neurotransmitters involved, the alterations in neuroreceptors, non-neuroreceptor targets (e.g., microglia and astrocytes), the severity and duration of the disease, the pharmacodynamics of various antidepressants, and neurobiological mechanisms of non-pharmacological therapies like psychotherapy, electroconvulsive therapy, and deep brain stimulation therapy, by showing changes in brain metabolism and receptor and non-receptor targets. Studies have revealed alterations in neurotransmitter systems such as serotonin, dopamine, GABA, and glutamate, which are linked to the pathophysiology of depression. Overall, PET imaging has furthered the neurobiological understanding of depression. Despite these advancements, PET findings have not yet led to significant changes in evidence-based practices. Addressing the reasons behind inconsistencies in PET imaging results, conducting large sample size studies with a more standardized methodological approach, and investigating further the genetic and neurobiological aspects of depression may better leverage PET imaging in future studies.

FDG-PET in the diagnosis of primary progressive aphasia: a systematic review.

Primary progressive aphasia (PPA) is a disease known to affect the frontal and temporal regions of the left hemisphere. PPA is often an indication of future development of dementia, specifically semantic dementia (SD) for frontotemporal dementia (FTD) and logopenic progressive aphasia (LPA) as an atypical presentation of Alzheimer's disease (AD). The purpose of this review is to clarify the value of 2-deoxy-2-[18F]fluoro-D-glucose (FDG)-positron emission tomography (PET) in the detection and diagnosis of PPA. A comprehensive review of literature was conducted using Web of Science, PubMed, and Google Scholar. The three PPA subtypes show distinct regions of hypometabolism in FDG-PET imaging with SD in the anterior temporal lobes, LPA in the left temporo-parietal junction, and nonfluent/agrammatic Variant PPA (nfvPPA) in the left inferior frontal gyrus and insula. Despite the distinct patterns, overlapping hypometabolic areas can complicate differential diagnosis, especially in patients with SD who are frequently diagnosed with AD. Integration with other diagnostic tools could refine the diagnostic process and lead to improved patient outcomes. Future research should focus on validating these findings in larger populations and exploring the therapeutic implications of early, accurate PPA diagnosis with more targeted therapeutic interventions.

Comprehensive considerations for dermatologists: the application of FDG-PET in evaluating cutaneous lesions in pediatric Langerhans cell histiocytosis.

Langerhans cell histiocytosis (LCH) is a complex disorder characterized by the clonal proliferation of Langerhans cells, primarily affecting children and adolescents. This condition exhibits a wide spectrum of clinical presentations, necessitating a multidisciplinary approach for diagnosis, treatment, and follow-up. Cutaneous manifestations of LCH are significant, mimicking common dermatoses and posing diagnostic challenges. [18F]Fluorodeoxyglucose-Positron Emission Tomography (FDG-PET) has emerged as an important tool in the evaluation of pediatric LCH, offering insights into disease activity, extent, and therapeutic response. Moreover, FDG-PET provides a non-invasive means to distinguish between active LCH skin lesions and other dermatological conditions with similar clinical appearances, enhancing diagnostic accuracy and aiding in disease monitoring. This educational review summarizes the utility of nuclear imaging techniques, with a focus on PET scans, in the diagnosis and management of cutaneous pediatric LCH. A comprehensive literature search identified seven relevant articles, including retrospective studies and case reports. These studies highlight the efficacy of FDG-PET in localizing active LCH skin lesions, monitoring disease activity, and guiding treatment decisions. FDG-PET represents a valuable imaging modality for dermatologists, oncologists, and pediatricians managing pediatric LCH patients with cutaneous involvement. This non-invasive technique contributes to improved diagnostic accuracy and facilitates early intervention, ultimately enhancing patient care and outcomes.

[18F]FDG PET/CT for identifying the causes of fever of unknown origin (FUO).

Fever of unknown origin (FUO) continues to be a challenging diagnosis in clinical medicine. It has more than 200 known causes, including infections, autoimmune diseases, neoplasia, and other miscellaneous disorders. Despite the development of a wide range of diagnostic tools, a specific diagnostic algorithm for FUO is not yet available. However, [18F]FDG PET/CT, which yields information on cellular metabolism, in addition to details of organ anatomy, has been shown to be successful in the FUO investigation. This study highlights the uses of [18F]FDG PET/CT in diagnosing various causes of FUO. [18F]FDG PET/CT has been increasingly used to detect septic infections, sterile inflammatory processes, and malignancies, occupying a significant portion of the known causes of FUO. It has led to a more definitive identification of the etiology of FUO and accurate clinical management. However, more in-depth studies are crucial to understanding if [18F]FDG PET/CT can be used in the work-up of FUO.

Revision of Alzheimer's diagnostic criteria or relocation of the Potemkin village.

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.

Donanemab, another anti-Alzheimer's drug with risk and uncertain benefit.

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 86 % of cerebral amyloid and 36 % 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.

Multimodality Imaging Approaches in Alzheimer's disease. Part II: 1H MR spectroscopy, FDG PET and Amyloid PET / Abordagem e multimodalidade de imagem em doença de Alzheimer. Parte II: espectroscopia, FDG-PET, e imagem Amilóide

ABSTRACT. In this Part II review, as a complement to the Part I published in this supplement, the authors cover the imaging techniques that evaluates the Alzheimer's disease according to the different metabolic and molecular profiles. In this section MR spectroscopy, FDG-PET and amyloid PET are deeply discussed.

RESUMO Nesta revisão Parte II, como complemento da revisão Parte I publicada nesta edição, os autores descrevem as técnicas de imagem que avaliam a doença de Alzheimer de acordo com os diferentes perfis metabólicos e moleculares que caracterizam esta doença. Nesta seção são discutidos em profundidade a espectroscopia por ressonância magnética, FDG-PET and imagem com marcadores de peptide beta amilóide.

Multimodality Imaging Approach in Alzheimer disease. Part I: Structural MRI, Functional MRI, Diffusion Tensor Imaging and Magnetization Transfer Imaging / Abordagem e multimodalidade de imagem em doença de Alzheimer. Parte I: RM estrutural, RMI funcional, tensor de difusão e transferência de magnetização de imagens

ABSTRACT The authors make a complete review of the potential clinical applications of traditional and novel magnetic resonance imaging (MRI) techniques in the evaluation of patients with Alzheimer's disease, including structural MRI, functional MRI, diffusion tension imaging and magnetization transfer imaging.

RESUMO Os autores fazem uma revisão complete das potenciais aplicações clínicas de técnicas tradicional e inovadoras de ressonância magnética na avaliação de pacientes com doença de Alzheimer, incluindo ressonância magnética estrutural, técnicas funcionais de ressonância magnética, técnica de "diffusion tensor imaging" e imagem de transferência magnética.

Hipometabolismo cerebral em pacientes com esclerose mesial temporal demonstrado pelo FDG-PET / Brain hypometabolism in patients with mesial-temporal sclerosis demonstrated by FDG-PET

O objetivo deste estudo foi avaliar a extensao do hipometabolismo cerebral em pacientes com esclerose mesial temporal (EMT). MÉTODO: Este estudo retrospectivo incluiu 21 pacientes que apresentavam epilepsia parcial complexa refrataria à terapia e que foram selecionados para cirurgia após análise extensa que incluía: EEG de superfície e estudos de neuroimagem (PET, SPECT e ressonância magnética). Todos os pacientes foram submetidos a intervençao cirúrgica e tiveram confirmaçao histológica de EMT. Uma análise semi-quantitativa foi realizada, utilizando regioes de interesse (ROIs) nas seguintes estruturas: lobos frontais, parietais e occipitais, gânglios da base, tálamos, cerebelo e três diferentes regioes nos lobos temporais, que compreendiam o córtex medial, inferior e lateral. Um índice de assimetria (IA) foi calculado, comparando as contagens por pixel nas estruturas homólogas em ambos os hemisférios cerebrais. Os IAs das diferentes estruturas foram entao correlacionados. RESULTADOS: Uma correlaçao significativa foi demonstrada entre os IAs do córtex medial dos lobos temporais e aqueles dos lobos frontais, dos lobos parietais, dos gânglios da base e dos tálamos (r = 0,72, 0,62, 0,47 e 0,47 respectivamente com p < 0,05 ). Foi demonstrada correlaçao altamente significativa dos IAs das 3 regioes do lobo temporal entre si (chegando a 0,86 entre os IAs das regioes mediais do lobo temporal e os IAs das regioes inferiores). CONCLUSAO: Esses dados indicam que o hipometabolismo se estende além do foco epiléptico no lobo temporal em pacientes com epilepsia parcial complexa relacionada a EMT. O metabolismo na porçao medial do lobo temporal é mais correlacionado com o metabolismo no lobo frontal do que com aquele de outras estruturas cerebrais externas aos lobos temporais. Os mecanismos fisiopatológicos envolvidos no hipometabolismo continuam controversos

Qual o valor da análise semi-quantitativa dos exames de FDG-PET no diagnóstico da esclerose mesial temporal? / Does semi-quantitative analysis of FDG-PET have any additional value in the diagnosis of mesial temporal sclerosis?

O objetivo deste estudo foi comparar a análise visual dos exames de FDG-PET com uma análise semi-quantitativa no diagnóstico da esclerose mesial temporal (EMT). MÉTODOS: Este estudo incluiu 21 pacientes com confirmaçäo histopatológica de EMT. Os dados referentes à análise visual foram obtidos dos relatórios dos exames. As imagens de FDG-PET foram analisadas de forma semi-quantitativa utilizando-se regiöes de interesse (ROIs) desenhadas em 19 cortes tomográficos perpendiculares ao maior eixo do lobo temporal. Estas ROIs dividiram cada um dos lobos temporais em três regiöes (lateral, inferior e medial). Um índice de assimetria foi calculado para cada regiäo. RESULTADOS: A análise visual dos exames de FDG-PET demonstrou assimetria no metabolismo em todos os pacientes. Todos, menos 1 dos pacientes foram submetidos a lobectomia temporal do tipo standard do lado descrito como hipometabólico pelo exame de FDG-PET. Utilizando como critério um índice de assimetria maior ou igual a 9 por cento em ao menos uma das regiöes, a análise semi-quantitativa demonstrou assimetria considerada significativa em 18 pacientes. Esta assimetria coincidiu com o lado da cirurgia e foi confirmada como correspondente à área de eslerose em todos menos um dos pacientes (o mesmo paciente citado acima). CONCLUSÄO: A análise semi-quantitativa näo forneceu qualquer informaçäo adicional em relaçäo à interpretaçäo visual das imagens nesta série de pacientes

F 18-FDG heart uptake in oncologic pet studies

Background: PET scanning with F-18 FDG is a useful technique to detect malignant lesions. The goal of this work to analyze the frequency of increased heart uptake in routine PET oncologic studies and to correlate F-18 FDG Standardized Uptake Values (SUV) to blood glucose level (BGL)