Significance: Human cerebral small vessel disease (SVD) comprises age-associated intracerebral hemorrhages and global cognitive impairment, including vascular dementia. Human SVD presents in either familial or sporadic manifestation, involving either monogenic Mendelian defects or multitrait genetic variants. To better characterize the genetic and molecular mechanisms underlying SVD, appropriate animal models are needed. The Srf ^iECKO mouse model presented here resembles human SVD pathology with regard to intracerebral hemorrhage formation and vascular dementia, including variability in onset and progression of cerebral symptoms. The Serum Response Factor (SRF)/Myocardin Related Transcription Factor (MRTF) are shown to regulate the expression of genes, which are essential for the maintenance of blood–brain barrier function and cerebral microvessel integrity. These findings suggest impairment of SRF/MRTF-mediated gene control as a molecular mechanism contributing to human SVD.

Positron emission tomography (PET) is a non-invasive imaging technology employed to describe metabolic, physiological, and biochemical processes in vivo. These include receptor availability, metabolic changes, neurotransmitter release, and alterations of gene expression in the brain. Since the introduction of dedicated small-animal PET systems along with the development of many novel PET imaging probes, the number of PET studies using rats and mice in basic biomedical research tremendously increased over the last decade. This article reviews challenges and advances of quantitative rodent brain imaging to make the readers aware of its physical limitations, as well as to inspire them for its potential applications in preclinical research. In the first section, we briefly discuss the limitations of small-animal PET systems in terms of spatial resolution and sensitivity and point to possible improvements in detector development. In addition, different acquisition and post-processing methods used in rodent PET studies are summarized. We further discuss factors influencing the test-retest variability in small-animal PET studies, e.g., different receptor quantification methodologies which have been mainly translated from human to rodent receptor studies to determine the binding potential and changes of receptor availability and radioligand affinity. We further review different kinetic modeling approaches to obtain quantitative binding data in rodents and PET studies focusing on the quantification of endogenous neurotransmitter release using pharmacological interventions. While several studies have focused on the dopamine system due to the availability of several PET tracers which are sensitive to dopamine release, other neurotransmitter systems have become more and more into focus and are described in this review, as well. We further provide an overview of latest genome engineering technologies, including the CRISPR/Cas9 and DREADD systems that may advance our understanding of brain disorders and function and how imaging has been successfully applied to animal models of human brain disorders. Finally, we review the strengths and opportunities of simultaneous PET/magnetic resonance imaging systems to study drug-receptor interactions and challenges for the translation of PET results from bench to bedside.

Multiparametric PET-MRI with the amino-acid analog ¹⁸F-FET enables the simultaneous assessment of molecular, morphologic, and functional brain tumor characteristics. Although it is considered the most accurate non-invasive approach in brain tumors, its relevance for patient management is still under debate. Here we report the diagnostic performance of ¹⁸F-FET PET/MR and its impact on clinical management in a retrospective patient cohort. Methods: We retrospectively analyzed brain tumor patients who underwent ¹⁸F-FET PET/MR between 2017 and 2018. ¹⁸F-FET PET/MR examinations were indicated clinically due to equivocal standard imaging or clinical course. Histological confirmation or clinical and standard imaging follow-up served as the reference standard. We evaluated ¹⁸F-FET PET/MR accuracy in identifying malignancy in untreated suspect lesions (category new diagnosis) and true progression during adjuvant treatment (category detection of progression) in a clinical setting. Using multiple regression, we also estimated the contribution of single modalities to produce an optimal PET/MRI outcome. We assessed the recommended and applied therapies before and after ¹⁸F-FET PET/MR and noted if the treatment changed based on the ¹⁸F-FET PET/MR outcome. Results: We included 189 cases in the study. ¹⁸F-FET PET/MR allowed the identification of malignancy at new diagnosis with an accuracy of 85% and identified true progression with an accuracy of 93%. Contrast enhancement, ¹⁸F-FET PET uptake, and tracer kinetics were the major contributors to an optimal PET/MR outcome. In the previously equivocal patients, ¹⁸F-FET PET/MR changed the clinical management in 33% of the untreated lesions and 53% of the tumor progressions. Conclusion: Our results suggest that ¹⁸F-FET PET/MR helps clarify equivocal conditions and profoundly supports brain tumor patients9 clinical management. The optimal modality setting of ¹⁸F-FET PET/MR and the clinical value of a simultaneous examination need further exploration. At a new diagnosis, multiparametric ¹⁸F-FET PET/MR might help prevent unnecessary invasive procedures by ruling out malignancy; however, adding static ¹⁸F-FET PET to an already existing MR examination seems to be of equal value. At detection of progression, multiparametric ¹⁸F-FET PET/MR may increase therapy effectiveness by distinguishing between tumor progression and therapy-related imaging alterations.