Prostate-Specific Membrane Antigen Radioligand Therapy in Non-Prostate Cancers: Where Do We Stand?

INTRODUCTION: The term theragnostic refers to the combination of a predictive imaging biomarker with a therapeutic agent. The promising application of prostate-specific membrane antigen (PSMA)-based radiopharmaceuticals in the imaging and treatment of prostate cancer (PCa) patients opens the way to investigate a possible role of PSMA-based radiopharmaceuticals in cancers beyond the prostate. Therefore, the aim of this review was to evaluate the role of 177Lu-PSMA radioligand therapy (RLT) in malignancies other than prostate cancer by evaluating preclinical, clinical studies, and ongoing clinical trials. METHODS: An extensive literature search was performed in three different databases using different combinations of the following terms: "Lu-PSMA", "177Lu-PSMA", "preclinical", "mouse", "salivary gland cancer", "breast cancer", "glioblastoma", "solid tumour", "renal cell carcinoma", "HCC", "thyroid", "salivary", "radioligand therapy", and "lutetium-177". The search had no beginning date limit and was updated to April 2024. Only articles written in English were included in this review. RESULTS: A total of four preclinical studies were selected (breast cancer model n = 3/4). PSMA-RLT significantly reduced cell viability and had anti-angiogenic effects, especially under hypoxic conditions, which increase PSMA binding and uptake. Considering the clinical studies (n = 8), the complexity of evaluating PSMA-RLT in cancers other than prostate cancer was clearly revealed, since in most of the presented cases a sufficient tumour radiation dose was not achieved. However, encouraging results can be found in some types of diseases, such as thyroid cancer. Some clinical trials are still ongoing, and results from prospective larger cohorts of patients are awaited. CONCLUSIONS: The need for larger patient cohorts and more RLT cycles administered underscores the need for further comprehensive studies. Given the very preliminary results of both preclinical and clinical studies, ongoing clinical trials in the near future may provide stronger evidence of both the safety and therapeutic efficacy of PSMA-RLT in malignancies other than prostate cancer.

FAPi-Based Agents in Thyroid Cancer: A New Step towards Diagnosis and Therapy? A Systematic Review of the Literature.

(1) Background: Thyroid cancer (TC) is often treated with surgery followed by iodine-131. Up to 50% of the instances of TC lose their avidity to 131I, becoming more aggressive. In this scenario, [18F]FDG PET/CT imaging is used for evaluating the widespread nature of the disease, despite its low sensitivity and a false negative rate of 8-21.1%. A novel class of PET agents targeting the fibroblast activation protein inhibitor (FAPi) has emerged, studied particularly for their potential application to theranostics. (2) Methods: A search of the literature was performed by two independent authors (P.G. and L.E.) using the PubMed, Scopus, Web of Science, Cochrane Library, and EMBASE databases. The following terms were used: "FAP" or "FAPi" or "Fibroblast activating protein" and "thyroid" or "thyroid cancer", in different combinations. The included papers were original articles, clinical studies, and case reports in the English language. No time limits were used. Editorials, conference papers, reviews, and preclinical studies were excluded. (3) Results: There were 31 papers that were selected. Some studies reported a low or absent FAPi uptake in TC lesions; others reported promising findings for the detection of metastases. (4) Conclusions: The preliminary results are encouraging. FAPI agents are an alternative to [18F]FDG and a promising theranostic tool. However, further studies with a larger population are needed.

Extraosseous distribution of 99mTc-diphosphonates during bone scintigraphy: review of the literature with case series presentation.

PURPOSE: Technetium-99m (99mTc)-diphosphonates represent the most common radiopharmaceutical used for bone scintigraphy. Even if the uptake in bone tissue has been widely explored, atypical uptake could be seen in soft tissue malignancies during bone scintigraphy. Increased vascularization and endothelium permeability represent front-row players in the biodistribution of the tracer, albeit other causes have been identified such as trauma, necrosis, the presence of calcification in metastasis, the pH of the tissue and consequently the type of ion concentration. CONCLUSION: The aim of this paper is to summarize the state of art of atypical soft tissue uptake seen in cancer tissues. The research was conducted on PubMed. The analysis of the literature suggests that calcium metabolism and ionic saturation have a pivotal role in the biodistribution of bone tracers. This phenomenon ranks in a complex scenario that includes carcinogenesis and cancer environment aspects. We also report two cases in our Institution in which atypical uptake in cancer tissues was observed.

Head-to-Head Comparison of FDG and Radiolabeled FAPI PET: A Systematic Review of the Literature.

FAPI-based radiopharmaceuticals are a novel class of tracers, mainly used for PET imaging, which have demonstrated several advantages over [18F]FDG, especially in the case of low-grade or well-differentiated tumors. We conducted this systematic review to evaluate all the studies where a head-to-head comparison had been performed to explore the potential utility of FAPI tracers in clinical practice. FAPI-based radiopharmaceuticals have shown promising results globally, in particular in detecting peritoneal carcinomatosis, but studies with wider populations are needed to better understand all the advantages of these new radiopharmaceuticals.

Radio-Guided Lung Surgery: A Feasible Approach for a Cancer Precision Medicine.

BACKGROUND: Radio-guided surgery is a reliable approach used for localizing ground-glass opacities, lung nodules, and metastatic lymph nodes. Lung nodules, lymph node metastatic involvement, and ground-glass opacities often represent a challenge for surgical management and clinical work-up. METHODS: PubMed research was conducted from January 1997 to June 2023 using the keywords "radioguided surgery and lung cancer". RESULTS: Different studies were conducted with different tracers: technetium-99m-albumin macroaggregates, cyanoacrylate combined to technetium-99m-sulfur colloid, indium-111-pentetreotide, and fluorine-18-deoxyglucose. A study proposed naphthalocyanine radio-labeled with copper-64. Radio-guided surgery has been demonstrated to be a reliable approach in localizing a lesion, and has a low radiological burden for personnel exposure and low morbidity. The lack of necessity to conduct radio-guided surgery under fluoroscopy or echography makes this radio-guided surgery an easy way of performing precise surgical procedures. CONCLUSIONS: Radio-guided surgery is a feasible approach useful for the intraoperative localization of ground-glass opacities, lung nodules, and metastatic lymph nodes. It is a valid alternative to the existing approaches due to its low cost, associated low morbidity, the possibility to perform the procedure after several hours, the low radiation dose applied, and the small amount of time that is required to perform it.

Sex differences in 123I-mIBG scintigraphy imaging techniques in patients with heart failure.

BACKGROUND: 123I-mIBG-scintigraphy could be a useful stratifying tool for patients with heart failure (HF). The purpose of this retrospective study is to evaluate whether there are differences between men and women with HF in terms of the prediction of cardiac arrhythmic events (AE). RESEARCH AND METHODS: A total of 306 patients, before implantable-cardioverter-defibrillator (ICD) implantation, were evaluated. They underwent 123I-mIBG-scintigraphy and an evaluation of the results was performed after 85 months of follow-up. Early and late planar and SPECT cardiac images were acquired. Heart-to-mediastinum ratio (HM) for planar images and the sum of the segmental scores (SS) for SPECT were calculated. RESULTS: In the general population, age, early SS (ESS), late SS (LSS), and ejection fraction (EF) were statistically significant for the prediction of AE at Cox regression, while early and late HM (eHM,lHM) were not significative for the prediction of AE. Population was divided into females and males and univariate analysis was conducted separately for the two cohorts: no significant variables for prediction of AE were found in females. For males, ESS, LSS, EF, and late HM were statistically significant predictors of AE. The overall survival was similar in males and females, but the risk of AE is lower in males than in females. CONCLUSIONS: 123I-mIBG represents a more effective tool for the prediction of AE in male patients than in women.

Medication and ECG Patterns That May Hinder SPECT Myocardial Perfusion Scans.

Coronary artery disease (CAD) is the leading cause of death followed by cancer, in men and women. With risk factors being endemic and the increasing costs of healthcare for management and treatment, myocardial perfusion imaging (MPI) finds a central role in risk stratification and prognosis for CAD patients, but it comes with its limitations in that the referring clinician and managing team must be aware of and use at their advantage. This narrative review examines the utility of myocardial perfusion scans in the diagnosis and management of patients with ECG alterations such as atrioventricular block (AVB), and medications including calcium channel blockers (CCB), beta blockers (BB), and nitroglycerin which may impact the interpretation of the exam. The review analyzes the current evidence and provides insights into the limitations, delving into the reasons behind some of the contraindications to MPI.

Novel Theranostic Approaches Targeting CCR4-Receptor, Current Status and Translational Prospectives: A Systematic Review.

BACKGROUND: With the high mortality rate of malignant tumors, there is a need to find novel theranostic approaches to provide an early diagnosis and targeted therapy. The chemokine receptor 4 (CCR4) is highly expressed in various tumors and plays an important role in tumor pathogenesis. This systematic review aims to provide a complete overview on clinical and preclinical applications of the CCR4 receptor as a target for theranostics, using a systematic approach to classify and assemble published studies performed on humans and animals, sorted by field of application and specific tumor. METHODS: A systematic literature search of articles suiting the inclusion criteria was conducted on Pubmed, Scopus, Central, and Web of Science databases, including papers published from January 2006 to November 2022. Eligible studies had to be performed on humans and/or in vivo/in vitro studying CCR4 expression in tumors. The methodological quality was assessed through the Critical Appraisal Skills Programme (CASP) assessing only the studies performed on humans. RESULTS: A total of 17 articles were screened. The articles were assessed for eligibility with the exclusion of 4 articles. Ultimately, 13 articles were selected for the qualitative analysis, and six articles were selected for the critical appraisal skills program. CONCLUSIONS: The development of new radionuclides and radiopharmaceuticals targeting CCR4 show promising results in the theranostics of CCR4 sensible tumors. Although to widen its use in clinical practice, further translation of preclinical to clinical data is needed.

Imaging of Tauopathies with PET Ligands: State of the Art and Future Outlook.

(1) Background: Tauopathies are a group of diseases characterized by the deposition of abnormal tau protein. They are distinguished into 3R, 4R, and 3R/4R tauopathies and also include Alzheimer's disease (AD) and chronic traumatic encephalopathy (CTE). Positron emission tomography (PET) imaging represents a pivotal instrument to guide clinicians. This systematic review aims to summarize the current and novel PET tracers. (2) Methods: Literature research was conducted on Pubmed, Scopus, Medline, Central, and the Web of Science using the query "pet ligands" and "tauopathies". Articles published from January 2018 to 9 February, 2023, were searched. Only studies on the development of novel PET radiotracers for imaging in tauopathies or comparative studies between existing PET tracers were included. (3) Results: A total of 126 articles were found, as follows: 96 were identified from PubMed, 27 from Scopus, one on Central, two on Medline, and zero on the Web of Science. Twenty-four duplicated works were excluded, and 63 articles did not satisfy the inclusion criteria. The remaining 40 articles were included for quality assessment. (4) Conclusions: PET imaging represents a valid instrument capable of helping clinicians in diagnosis, but it is not always perfect in differential diagnosis, even if further investigations on humans for novel promising ligands are needed.

A Systematic Review on Dementia and Translocator Protein (TSPO): When Nuclear Medicine Highlights an Underlying Expression.

BACKGROUND: Translocator protein (TSPO) is a neuroinflammation hallmark. Different TSPO affinity compounds have been produced and over time, the techniques of radiolabeling have been refined. The aim of this systematic review is to summarize the development of new radiotracers for dementia and neuroinflammation imaging. METHODS: An online search of the literature was conducted in the PubMed, Scopus, Medline, Cochrane Library, and Web of Science databases, selecting published studies from January 2004 to December 2022. The accepted studies considered the synthesis of TSPO tracers for nuclear medicine imaging in dementia and neuroinflammation. RESULTS: A total of 50 articles was identified. Twelve papers were selected from the included studies' bibliographies and 34 were excluded. Thus, 28 articles were ultimately selected for quality assessment. CONCLUSION: Huge efforts in developing specific and stable tracers for PET/SPECT imaging have been made. The long half-life of 18F makes this isotope a preferable choice to 11C. An emerging limitation to this however is that neuroinflammation involves all of the brain which inhibits the possibility of detecting a slight inflammation status change in patients. A partial solution to this is using the cerebellum as a reference region and developing higher TSPO affinity tracers. Moreover, it is necessary to consider the presence of distomers and racemic compounds interfering with pharmacological tracers' effects and increasing the noise ratio in images.

Abscopal Effect on Bone Metastases from Solid Tumors: A Systematic Review and Retrospective Analysis of Challenge within a Challenge.

BACKGROUND: Abscopal effect (AE) describes the ability of radiotherapy (RT) to induce immune-mediated responses in nonirradiated distant metastasis. Bone represents the third most frequent site of metastasis and an immunologically favorable environment for the proliferation of cancer cells. We revised the literature, searching documented cases of AE involving bone metastases (BMs) and evaluated the incidence of AE involving BMs in patients requiring palliative RT on BMs or non-BMs treated at our department. METHODS: Articles published in the PubMed/MEDLINE database were selected using the following search criteria: ((abscopal effect)) AND ((metastases)). Patients with BMs, who underwent performed bone scintigraphy before and at least 2-3 months after RT, were selected and screened between January 2015 and July 2022. AE was defined as an objective response according to the scan bone index for at least one nonirradiated metastasis at a distance > 10 cm from the irradiated lesion. The primary endpoint was the rate of AE on BMs. RESULTS: Ten cases experiencing AE of BMs were identified from the literature and eight among our patients. CONCLUSIONS: The analysis performed here suggests the use of hypofractionated radiotherapy as the only triggering factor for AE of BMs through the activation of the immune response.

Role of Exendin-4 Functional Imaging in Diagnosis of Insulinoma: A Systematic Review.

BACKGROUND: Insulinomas are the most common neuroendocrine neoplasms of the pancreas. Diagnosis is made through patient clinical presentation with hypoglycemia symptoms and imaging, such as EUS, CT, MRI, and functional imaging. Exendin-4 PET/CT (and SPECT/CT) is a new prominent radiotracer developed to image insulinomas. The aim of the study is to evaluate whether exendin-4 imaging is a useful tool in imaging for insulinoma patients when other imaging methods do not reach them. METHODS: MEDLINE research conducted on PubMed, Scopus, and Web of Science gathered a total of 501 papers. Studies that evaluated exendin-4 SPECT and PET in insulinoma patients were screened and assessed through QUADAS-2 for risk of bias and applicability concerns' assessment. Sensitivity, specificity, and accuracy were reported when available. RESULTS: A total of 13 studies were deemed eligible for a QUADAS 2 review. Studies included ranged from 2009 to 2022. The most-used tracer was 68Ga-DOTA-exendin-4 in PET and 111In-DTPA-exendin-4 in SPECT. Exendin-4 labeled with 99mTc was also reported. The QUADAS-2 risk of bias assessment was overall low, with some unclear reports in the reference and index domains. Only two domains were at high risk of bias because of an explicated non-blind imaging review. Applicability concerns for bias were low in all domains. Reported sensitivities ranged from 95% to 100% and specificities from 20% to 100%. CONCLUSIONS: exendin-4 imaging is a sensitive functional imaging tracer in both SPECT and PET applications, especially in suspicion of benign insulinomas located where endoscopic ultrasound cannot reach, being more sensitive than morfostructural imaging.

PET Imaging of Neuro-Inflammation with Tracers Targeting the Translocator Protein (TSPO), a Systematic Review: From Bench to Bedside.

Parkinson's disease is the second most common neurodegenerative disorder, affecting 2-3% of the population of patients >65 years. Although the standard diagnosis of PD is clinical, neuroimaging plays a key role in the evaluation of patients who present symptoms related to neurodegenerative disorders. MRI, DAT-SPECT, and PET with [18F]-FDG are routinely used in the diagnosis and focus on the investigation of morphological changes, nigrostriatal degeneration or shifts in glucose metabolism in patients with parkinsonian syndromes. The aim of this study is to review the current PET radiotracers targeting TSPO, a transmembrane protein that is overexpressed by microglia in another pathophysiological process associated with neurodegenerative disorders known as neuroinflammation. To the best of our knowledge, neuroinflammation is present not only in PD but in many other neurodegenerative disorders, including AD, DLB, and MSA, as well as atypical parkinsonian syndromes. Therefore, in this study, specific patterns of microglial activation in PD and the differences in distribution volumes of these radiotracers in patients with PD as compared to other neurodegenerative disorders are reviewed.

Radiolabeled Dendrimer Coated Nanoparticles for Radionuclide Imaging and Therapy: A Systematic Review.

BACKGROUND: Dendrimers are nanoscale-size polymers with a globular structure. They are composed of an internal core and branching dendrons with surface active groups which can be functionalized for medical applications. Different complexes have been developed for imaging and therapeutic purposes. This systematic review aims to summarize the development of newer dendrimers for oncological applications in nuclear medicine. METHODS: An online literature search was conducted on Pubmed, Scopus, Medline, Cochrane Library, and Web Of Science databases selecting published studies from January 1999 to December 2022. The accepted studies considered the synthesis of dendrimer complexes for oncological nuclear medicine imaging and therapy. RESULTS: 111 articles were identified; 69 articles were excluded because they did not satisfy the selection criteria. Thus, nine duplicate records were removed. The remaining 33 articles were included and selected for quality assessment. CONCLUSION: Nanomedicine has led researchers to create novel nanocarriers with high affinity for the target. Dendrimers represent feasible imaging probes and therapeutic agents since, through the functionalization of external chemical groups and thanks to the possibility to carry pharmaceuticals, it can be possible to exploit different therapeutic strategies and develop a useful weapon for oncological treatments.

Fibroblast Activation Protein Inhibitor (FAPI)-Based Theranostics-Where We Are at and Where We Are Heading: A Systematic Review.

Cancer is the leading cause of death around the globe, followed by heart disease and stroke, with the highest mortality to this day. We have reached great levels of understanding of how these various types of cancer operate at a cellular level and this has brought us to what we call "precision medicine" where every diagnostic examination and the therapeutic procedure is tailored to the patient. FAPI is among the new tracers that can be used to assess and treat many types of cancer. The aim of this review was to gather all the known literature on FAPI theranostics. A MEDLINE search was conducted on four web libraries, PUBMED, Cochrane, Scopus, and Web of Sciences. All of the available articles that included both diagnoses and therapy with FAPI tracers were collected and put through the CASP (Critical Appraisal Skills Programme) questionnaire for systematic reviewing. A total of 8 records were deemed suitable for CASP review, ranging from 2018 to November 2022. These studies were put through the CASP diagnostic checklist, in order to assess the goal of the study, diagnostic and reference tests, results, descriptions of the patient sample, and future applications. Sample sizes were heterogeneous, both for size as well as for tumor type. Only one author studied a single type of cancer with FAPI tracers. Progression of disease was the most common outcome, and no relevant collateral effects were noted. Although FAPI theranostics is still in its infancy and lacks solid grounds to be brought into clinical practice, it does not show any collateral effects that prohibit administration to patients, thus far, and has good tolerability profiles.

18F-fluorodeoxyglucose (18F-FDG) Functionalized Gold Nanoparticles (GNPs) for Plasmonic Photothermal Ablation of Cancer: A Review.

The meeting and merging between innovative nanotechnological systems, such as nanoparticles, and the persistent need to outperform diagnostic-therapeutic approaches to fighting cancer are revolutionizing the medical research scenario, leading us into the world of nanomedicine. Photothermal therapy (PTT) is a non-invasive thermo-ablative treatment in which cellular hyperthermia is generated through the interaction of near-infrared light with light-to-heat converter entities, such as gold nanoparticles (GNPs). GNPs have great potential to improve recovery time, cure complexity, and time spent on the treatment of specific types of cancer. The development of gold nanostructures for photothermal efficacy and target selectivity ensures effective and deep tissue-penetrating PTT with fewer worries about adverse effects from nonspecific distributions. Regardless of the thriving research recorded in the last decade regarding the multiple biomedical applications of nanoparticles and, in particular, their conjugation with drugs, few works have been completed regarding the possibility of combining GNPs with the cancer-targeted pharmaceutical fluorodeoxyglucose (FDG). This review aims to provide an actual scenario on the application of functionalized GNP-mediated PTT for cancer ablation purposes, regarding the opportunity given by the 18F-fluorodeoxyglucose (18F-FDG) functionalization.

Breast-Specific Gamma Imaging: An Added Value in the Diagnosis of Breast Cancer, a Systematic Review.

PURPOSE: Breast cancer is the most common solid tumor and the second highest cause of death in the United States. Detection and diagnosis of breast tumors includes various imaging modalities, such as mammography (MMG), ultrasound (US), and contrast-enhancement MRI. Breast-specific gamma imaging (BSGI) is an emerging tool, whereas morphological imaging has the disadvantage of a higher absorbed dose. Our aim was to assess if this imaging method is a more valuable choice in detecting breast malignant lesions compared to morphological counterparts. METHODS: research on Medline from 1995 to June 2022 was conducted. Studies that compared at least one anatomical imaging modality with BSGI were screened and assessed through QUADAS2 for risk of bias and applicability concerns assessment. Sensitivity, specificity, positive and negative predictive value (PPV and NPV) were reported. RESULTS: A total of 15 studies compared BSGI with MMG, US, and MRI. BSGI sensitivity was similar to MRI, but specificity was higher. Specificity was always higher than MMG and US. BSGI had higher PPV and NPV. When used for the evaluation of a suspected breast lesion, the overall sensitivity was better than the examined overall sensitivity when BSGI was excluded. Risk of bias and applicability concerns domain showed mainly low risk of bias. CONCLUSION: BSGI is a valuable imaging modality with similar sensitivity to MRI but higher specificity, although at the cost of higher radiation burden.

Personalized Dosimetry in the Context of Radioiodine Therapy for Differentiated Thyroid Cancer.

The most frequent thyroid cancer is Differentiated Thyroid Cancer (DTC) representing more than 95% of cases. A suitable choice for the treatment of DTC is the systemic administration of 131-sodium or potassium iodide. It is an effective tool used for the irradiation of thyroid remnants, microscopic DTC, other nonresectable or incompletely resectable DTC, or all the cited purposes. Dosimetry represents a valid tool that permits a tailored therapy to be obtained, sparing healthy tissue and so minimizing potential damages to at-risk organs. Absorbed dose represents a reliable indicator of biological response due to its correlation to tissue irradiation effects. The present paper aims to focus attention on iodine therapy for DTC treatment and has developed due to the urgent need for standardization in procedures, since no unique approaches are available. This review aims to summarize new proposals for a dosimetry-based therapy and so explore new alternatives that could provide the possibility to achieve more tailored therapies, minimizing the possible side effects of radioiodine therapy for Differentiated Thyroid Cancer.

The prognostic value of 123I-mIBG SPECT cardiac imaging in heart failure patients: a systematic review.

This systematic review aimed to evaluate the prognostic value of Iodine123 Metaiodobenzylguanidine (123I-mIBG) SPECT myocardial imaging in patients with heart failure (HF) and to assess whether semi-quantitative SPECT scores can be useful for accurate risk stratification concerning arrhythmic event (AE) and sudden cardiac death (SCD) in this cohort. A systematic literature search of studies published until November 2020 regarding the application of 123I-mIBG SPECT in HF patients was performed, in Pubmed, Scopus, Medline, Central (Cochrane Library) and Web Of Science databases, including the words "MIBG", "metaiodobenzylguanidine", "heart", "spect", and "tomographic". The included studies had to correlate 123I-mIBG SPECT scores with endpoints such as overall survival and prevention of AE and SCD in HF patients. According to the sixteen studies included, the analysis showed that 123I-mIBG SPECT scores, such as summed defect score (SDS), regional wash-out (rWO), and regional myocardial tracer uptake, could have a reliable prognostic value in patients with HF. An increased SDS or rWO, as well as a reduced 123I-mIBG myocardial uptake, have proven to be effective in predicting AE- and SCD-specific risk in HF patients. Despite achieved results being promising, a more reproducible standardized method for semi-quantitative analysis and further studies with larger cohort are needed for 123I-mIBG SPECT myocardial imaging to be as reliable and, thus, accepted as the conventional 123I-mIBG planar myocardial imaging.

Hybrid Imaging of Vascular Cognitive Impairment.

Cerebrovascular disease is a significant cause of cognitive impairment leading to a reduction or loss of functioning, including social and occupational. The connection cause-effect between cerebrovascular disease and cerebral infarction was originally theorized by the studies from Newcastle-Upon-Tyne, England, in the 1960s, where vascular dementia (VaD) was defined as a disease originated from several infarctions that overcome a determined threshold. It differs from Alzheimer's disease (AD), although there are various overlaps in risk factors, symptomatology, the similarity of vascular lesions, and treatment benefits. Nevertheless, AD is one-half of all cases of dementia. Cognitive impairment and dementia (VCID) has recently been proposed to include different entities such as VaD, Vascular cognitive impairment, subcortical (ischemic) VaD, and vascular cognitive disorders. VaD is the most common cause of dementia after AD. Neuroimaging is an essential part of the workup of patients with cognitive decline and in those with suspected VCID it should be used to assess the extent, location, and type of vascular lesions. Computed tomography (CT) or structural magnetic resonance imaging (MRI) are usually used for the diagnosis of vascular diseases of the brain. However, images obtained from new hybrid devices could help the neurologist in the differential diagnosis between various neuropathological entities related to VCID. Single-photon emission computed tomography (SPECT) combined with CT or MRI and positron emission tomography (PET) combined with CT or MRI represent the future of neuroimaging tools as morphological and functional data can be provided simultaneously. New prospects have been developed such as hybrid PET/SPECT/CT, a high-performance prototype able to produce high-quality images but for now suitable only for small animals. Nowadays, PET/CT and PET/MRI are good performance and high-quality instruments, even if the magnetic field of MRI represents a limitation that affects the PET electronics and positron detection ability. SPECT/MRI delineates as a potential and tempting device. It could give us both functional and anatomical details, with the advantage of lack of extra ionizing radiation and high soft-tissue contrast, important features, and considerable auxiliary for differential diagnosis in the variegate word of vascular cognitive impairment. The aim of this review is to summarize the newest viewpoints in hybrid imaging in the diagnosis of VaD and to highlight pros and cons of each methodic.