Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are essential molecular imaging tools for the in vivo investigation of neurotransmission. Traditionally, PET and SPECT images are analysed in a univariate manner, testing for changes in radiotracer binding in regions or voxels of interest independently of each other. Over the past decade, there has been an increasing interest in the so-calledmolecular connectivityapproach that captures relationships of molecular imaging measures in different brain regions. Targeting these inter-regional interactions within a neuroreceptor system may allow to better understand complex brain functions. In this article, we provide a comprehensive review of molecular connectivity studies in the field of neurotransmission. We examine the expanding use of molecular connectivity approaches, highlighting their applications, advantages over traditional methods, and contributions to advancing neuroscientific knowledge. A systematic search in three bibliographic databases MEDLINE, EMBASE, and Scopus on July 14, 2023 was conducted. A second search was rerun on April 4, 2024. Molecular imaging studies examining functional interactions across brain regions were included based on predefined inclusion and exclusion criteria. Thirty-nine studies were included in the scoping review. Studies were categorised based on the primary neurotransmitter system being targeted: dopamine, serotonin, opioid, muscarinic, glutamate, and synaptic density. The most investigated system was the dopaminergic and the most investigated disease was Parkinson's disease (PD). This review highlighted the diverse applications and methodologies in molecular connectivity research, particularly for neurodegenerative diseases and psychiatric disorders. Molecular connectivity research offers significant advantages over traditional methods, providing deeper insights into brain function and disease mechanisms. As the field continues to evolve, embracing these advanced methodologies will be essential to understand the complexities of the human brain and improve the robustness and applicability of research findings in clinical settings.

AbstractPatients with Alzheimer’s disease (AD) and clinically overlapping neurodegenerative diseases are classified molecularly using the A/T/N classification system. Apart from fluid biomarkers and structural MRI, the three-dimensional A/T/N system incorporates characteristic features from β-amyloid-PET (A), tau-PET (T), and FDG-PET (N). We evaluated if dynamic features of tau-PET with [18F]PI-2620 allow assessment of A/T/N in individual patients using a single imaging session. Cortical tissue clearance (K2a) of [18F]PI-2620 was validated as a surrogate of the β-amyloid status against β-amyloid-PET and cerebrospinal fluid (CSF) Aβ42/40ratio, demonstrating remarkable positive (91.5%) and negative (95.1%) predictive values at an AUC of 0.99 (P<0.0001). K2a outperformed cortical tau burden as a surrogate for β-amyloid status in 47 participants with a clinical diagnosis of probable AD (3/4-repeat(R)-tauopathy) and 82 β-amyloid-negative patients with primary 4R-tauopathies. Perfusion-like [18F]PI-2620 images (R1) were validated as a surrogate marker for neuronal injury, exhibiting strong quantitative and visual correlations with FDG-PET and early-phase β-amyloid-PET, as well as with volumetric MRI and CSF total tau levels. Composite quantitative A/T/N indices facilitated personalized staging along temporal disease trajectories. Our results suggest that [18F]PI-2620 imaging has the potential to facilitate the assessment of region and stage dependent PET-based A/T/N during a single dynamic PET session.Graphical Abstract

While the implication of a dysfunctional dopaminergic system in Tourette syndrome (TS) is well established, the underlying pathophysiological mechanisms remain unclear. Apart from neurotransmitters, disturbed iron homeostasis and iron regulatory mechanisms are also suspected. Iron is a trace element of fundamental biological importance and is involved in the synthesis and metabolism of dopamine and its receptors and transporters. The goal of the current pre-registered, multi-modal, cross-sectional study was to investigate the relationship between potential iron homeostasis imbalances and dopaminergic system disturbances in patients with TS. Susceptibility-sensitive MRI at 7 Tesla was used to obtain surrogate measures for local brain iron in 25 patients with TS (age 30 ± 9 years, 6 female) and 40 matched control subjects. Additionally, dopamine D1 receptor availability was investigated with [11C]SCH23390 PET in a subgroup of 20 patients and 20 controls. Significantly reduced sub-cortical magnetic susceptibility, indicating reduced iron levels, was observed in TS patients in the caudate, pallidum, sub-thalamic nucleus, thalamus, red nucleus and substantia nigra. These reductions were accompanied by significant reductions of the [11C]SCH23390 binding potential indicating reduced availability of D1 receptors in the dorsal striatum. The D1 receptor abnormality correlated with tic severity. These results point to alterations of intra-synaptic dopamine release and reduced striatal D1 receptor binding, supporting the notion of disruption in multiple functional elements of the dopaminergic system. Such dopaminergic abnormalities appear to be associated with disturbances in iron homeostasis.

White matter hyperintensities (WMHs) are commonly observed in aging and neurodegenerative diseases, but their impact on the α4β2 nicotinic acetylcholine receptor (α4β2-nAChR) system remains unclear. This study investigates the relationship between WMHs and gray matter nicotinic signaling, aiming to elucidate potential pathways contributing to neurodegeneration. Multimodal imaging data using PET and MR imaging from 39 participants, including 19 healthy controls and 20 patients with Alzheimer’s disease dementia (AD), were analyzed. WMHs were identified on T1-weighted MPRAGE and T2-weighted TSE MR images using advanced segmentation algorithms. Probabilistic fiber tracking was applied to determine WMH-connected gray matter. PET-based total distribution volume (VT) values of the α4β2-nAChR tracer (-)-[18F]Flubatine were compared between WMH-affected and unaffected gray matter regions. WMH volumes were significantly correlated with age, Fazekas and MMSE scores, but no differences in absolute or relative WMH volumes were observed between healthy controls and patients with AD. PET-based VT values in WMH-connected gray matter showed no significant difference from contralateral unaffected regions, regardless of disease status or WMH burden. However, intra-individual differences in VT values correlated with Fazekas scores, presumably driven by patients with AD. Pathway-based analyses revealed decreased VT values in the medial cholinergic pathway of patients with AD but no significant differences in lateral pathways. This study shows that WMHs do not significantly alter gray matter nicotinic signaling in directly connected regions. However, the results suggest subtle associations between WMH severity and specific cholinergic pathways, particularly in AD.

Ziel/Aim Sowohl bei der Alzheimer-Erkrankung als auch bei endogener Depression können, insbesondere in Frühstadien, kognitive und depressive Symptome parallel auftreten [1]. Eine akkurate Differenzialdiagnose ist klinisch schwierig, jedoch wichtig für das therapeutische Management. Die vorliegende Arbeit untersucht, ob die b-Amyloid-PET-Bildgebung in der Lage ist, eine solche Differenzialdiagnose zu unterstützen.

Ziel/Aim F-18-PI-2620 is a second-generation tau PET tracer which showed promising results in imaging 3R/4R tau in Alzheimer’s disease as well as in 4R tau imaging of PSP/CBD. 3R Pick tau aggregates occur, to different degrees, in certain types of FTLD. So far, no 3R tau-specific PET imaging tracer is available. It was, thus, the aim of this present study to investigate the potential of F-18-PI-2620 to fill this gap.

Introduction Cachexia has considerable impact on quality of life and survival in lung cancer (LC) patients. We aimed to find out whether glucose metabolism in distinct cerebral regions was associated with anorexia, weight loss, and cachexia in LC patients.

Tau aggregates accumulate in the Alzheimer’s disease (AD) brain according to the established Braak staging scheme and spread from transentorhinal over limbic regions to the neocortex. To impact the management of AD patients, an in vivo tool for tau Braak staging is needed. First-generation tau tracers have limited performance in detecting early stages of tau. Therefore, we tested the corresponding capability of the next-generation tau tracer, 18F-PI-2620. We analyzed 18F-PI-2620 multicenter PET data from 37 beta-amyloid-positive AD dementia patients and those from 26 healthy controls. We applied kinetic modeling of the 0–60 min p.i. PET data using MRTM2 with the lower cerebellum as the reference region to extract Braak stage-dependent distribution volume ratios, whereas controls were used to define Braak stage PET positivity thresholds. Stage-dependent PET positivity widely followed the Braak scheme (except Braak stage III) presenting descending frequency of PET positivity from Braak I (43%), II (38%), III (49%), IV (35%), V (30%) to VI (14%). A strictly hierarchical model was met by 64% of AD dementia cases. Nineteen percent showed a hippocampal sparing tauopathy pattern. Thus, we could assign 87% to the six-stage hierarchical Braak model including tauopathy variants. 18F-PI-2620 PET appears to be able to perform Braak tau staging of AD in vivo.

Tau pathology is the main driver of neuronal dysfunction in 4-repeat tauopathies, including cortico-basal degeneration and progressive supranuclear palsy. Tau is assumed to spread prion-like across connected neurons, but the mechanisms of tau propagation are largely elusive in 4-repeat tauopathies, characterized not only by neuronal but also by astroglial and oligodendroglial tau accumulation. Here, we assess whether connectivity is associated with 4R-tau deposition patterns by combining resting-state fMRI connectomics with both 2 nd generation 18 F-PI-2620 tau-PET in 46 patients with clinically diagnosed 4-repeat tauopathies and post-mortem cell-type-specific regional tau assessments from two independent progressive supranuclear palsy patient samples ( n = 97 and n = 96). We find that inter-regional connectivity is associated with higher inter-regional correlation of both tau-PET and post-mortem tau levels in 4-repeat tauopathies. In regional cell-type specific post-mortem tau assessments, this association is stronger for neuronal than for astroglial or oligodendroglial tau, suggesting that connectivity is primarily associated with neuronal tau accumulation. Using tau-PET we find further that patient-level tau patterns are associated with the connectivity of subcortical tau epicenters. Together, the current study provides combined in vivo tau-PET and histopathological evidence that brain connectivity is associated with tau deposition patterns in 4-repeat tauopathies.

Ziel/Aim Progressive supranuclear palsy (PSP) is primary tauopathy with different phenotypic manifestations. The Richardson’s syndrome (PSP-RS) is the most common phenotype, followed by PSPs with predominant parkinsonian (PSP-P) and frontal presentations (PSP-F). Although the pallido-nigro-luysian axis is commonly affected in all PSP, neuropathological studies indicate variations of tau pathology between subtypes. The next-generation tau PET tracer [18F]PI-2620 seems to enable in vivo mapping of tau pathology in PSP. This study aimed to assess tau network topology in PSP-RS and non-RS individuals using graph theory analysis.