Dynamic properties in functional connectivity changes and striatal dopamine deficiency in Parkinson's disease.

Recent studies in Parkinson's disease (PD) patients reported disruptions in dynamic functional connectivity (dFC, i.e., a characterization of spontaneous fluctuations in functional connectivity over time). Here, we assessed whether the integrity of striatal dopamine terminals directly modulates dFC metrics in two separate PD cohorts, indexing dopamine-related changes in large-scale brain network dynamics and its implications in clinical features. We pooled data from two disease-control cohorts reflecting early PD. From the Parkinson's Progression Marker Initiative (PPMI) cohort, resting-state functional magnetic resonance imaging (rsfMRI) and dopamine transporter (DaT) single-photon emission computed tomography (SPECT) were available for 63 PD patients and 16 age- and sex-matched healthy controls. From the clinical research group 219 (KFO) cohort, rsfMRI imaging was available for 52 PD patients and 17 age- and sex-matched healthy controls. A subset of 41 PD patients and 13 healthy control subjects additionally underwent 18F-DOPA-positron emission tomography (PET) imaging. The striatal synthesis capacity of 18F-DOPA PET and dopamine terminal quantity of DaT SPECT images were extracted for the putamen and the caudate. After rsfMRI pre-processing, an independent component analysis was performed on both cohorts simultaneously. Based on the derived components, an individual sliding window approach (44 s window) and a subsequent k-means clustering were conducted separately for each cohort to derive dFC states (reemerging intra- and interindividual connectivity patterns). From these states, we derived temporal metrics, such as average dwell time per state, state attendance, and number of transitions and compared them between groups and cohorts. Further, we correlated these with the respective measures for local dopaminergic impairment and clinical severity. The cohorts did not differ regarding age and sex. Between cohorts, PD groups differed regarding disease duration, education, cognitive scores and L-dopa equivalent daily dose. In both cohorts, the dFC analysis resulted in three distinct states, varying in connectivity patterns and strength. In the PPMI cohort, PD patients showed a lower state attendance for the globally integrated (GI) state and a lower number of transitions than controls. Significantly, worse motor scores (Unified Parkinson's Disease Rating Scale Part III) and dopaminergic impairment in the putamen and the caudate were associated with low average dwell time in the GI state and a low total number of transitions. These results were not observed in the KFO cohort: No group differences in dFC measures or associations between dFC variables and dopamine synthesis capacity were observed. Notably, worse motor performance was associated with a low number of bidirectional transitions between the GI and the lesser connected (LC) state across the PD groups of both cohorts. Hence, in early PD, relative preservation of motor performance may be linked to a more dynamic engagement of an interconnected brain state. Specifically, those large-scale network dynamics seem to relate to striatal dopamine availability. Notably, most of these results were obtained only for one cohort, suggesting that dFC is impacted by certain cohort features like educational level, or disease severity. As we could not pinpoint these features with the data at hand, we suspect that other, in our case untracked, demographical features drive connectivity dynamics in PD. PRACTITIONER POINTS: Exploring dopamine's role in brain network dynamics in two Parkinson's disease (PD) cohorts, we unraveled PD-specific changes in dynamic functional connectivity. Results in the Parkinson's Progression Marker Initiative (PPMI) and the KFO cohort suggest motor performance may be linked to a more dynamic engagement and disengagement of an interconnected brain state. Results only in the PPMI cohort suggest striatal dopamine availability influences large-scale network dynamics that are relevant in motor control.

Dual-tracer PET/CT protocol with [18F]FDG and [68Ga]Ga-FAPI-46 outperforms single-tracer PET/CT with [18F]FDG in different cancer types, resulting in larger functional and gross tumor volume.

PURPOSE: Fibroblast activation protein (FAP) detected by positron-emission tomography (PET) using fibroblast activation protein inhibitor (FAPI) appears to be a promising target for cancer imaging, staging, and therapy, providing added value and strength as a complement to [18F]fluorodeoxyglucose (FDG) in cancer imaging. We recently introduced a combined single-session/dual-tracer protocol with [18F]FDG and [68Ga]Ga-FAPI for cancer imaging and staging. Malignant tissue visualization and target-to-background uptake ratios (TBRs) as well as functional tumor volume (FTV) and gross tumor volume (GTV) were assessed in the present study with single-tracer [18F]FDG PET/computed tomography (CT) and with dual-tracer [18F]FDG&[68Ga]Ga-FAPI-46 PET/CT. METHODS: A total of 19 patients with head and neck and gastrointestinal cancers received initial [18F]FDG-PET/CT followed by dual-tracer PET/CT after additional injection of [68Ga]Ga-FAPI-46 during the same medical appointment (on average 13.9 ± 12.3 min after injection of [18F]FDG). Two readers visually compared detection rate of malignant tissue, TBR, FTV, and GTV for tumor and metastatic tissue in single- and dual-tracer PET/CT. RESULTS: The diagnostic performance of dual-tracer compared to single-tracer PET/CT was equal in 13 patients and superior in 6 patients. The mean TBRs of tumors and metastases in dual-tracer PET/CTs were mostly higher compared to single-tracer PET/CT using maximal count rates (CRmax). GTV and FTV were significantly larger when measured on dual-tracer compared to single-tracer PET/CT. CONCLUSION: Dual-tracer PET/CT with [18F]FDG and [68Ga]Ga-FAPI-46 showed better visualization due to a generally higher TBR and larger FTV and GTV compared to [18F]FDG-PET/CT in several tumor entities, suggesting that [68Ga]Ga-FAPI-46 provides added value in pretherapeutic staging.

Multicenter development of a PET-based risk assessment tool for product-specific outcome prediction in large B-cell lymphoma patients undergoing CAR T-cell therapy.

PURPOSE: The emergence of chimeric antigen receptor (CAR) T-cell therapy fundamentally changed the management of individuals with relapsed and refractory large B-cell lymphoma (LBCL). However, real-world data have shown divergent outcomes for the approved products. The present study therefore set out to evaluate potential risk factors in a larger cohort. METHODS: Our analysis set included 88 patients, treated in four German university hospitals and one Italian center, who had undergone 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography (PET) before CAR T-cell therapy with tisagenlecleucel or axicabtagene ciloleucel. We first determined the predictive value of conventional risk factors, treatment lines, and response to bridging therapy for progression-free survival (PFS) through forward selection based on Cox regression. In a second step, the additive potential of two common PET parameters was assessed. Their optimal dichotomizing thresholds were calculated individually for each CAR T-cell product. RESULTS: Extra-nodal involvement emerged as the most relevant of the conventional tumor and patient characteristics. Moreover, we found that inclusion of metabolic tumor volume (MTV) further improves outcome prediction. The hazard ratio for a PFS event was 1.68 per unit increase of our proposed risk score (95% confidence interval [1.20, 2.35], P = 0.003), which comprised both extra-nodal disease and lymphoma burden. While the most suitable MTV cut-off among patients receiving tisagenlecleucel was 11 mL, a markedly higher threshold of 259 mL showed optimal predictive performance in those undergoing axicabtagene ciloleucel treatment. CONCLUSION: Our analysis demonstrates that the presence of more than one extra-nodal lesion and higher MTV in LBCL are associated with inferior outcome after CAR T-cell treatment. Based on an assessment tool including these two factors, patients can be assigned to one of three risk groups. Importantly, as shown by our study, metabolic tumor burden might facilitate CAR T-cell product selection and reflect the individual need for bridging therapy.

Investigating reliable amyloid accumulation in Centiloids: Results from the AMYPAD Prognostic and Natural History Study.

INTRODUCTION: To support clinical trial designs focused on early interventions, our study determined reliable early amyloid-ß (Aß) accumulation based on Centiloids (CL) in pre-dementia populations. METHODS: A total of 1032 participants from the Amyloid Imaging to Prevent Alzheimer's Disease-Prognostic and Natural History Study (AMYPAD-PNHS) and Insight46 who underwent [18F]flutemetamol, [18F]florbetaben or [18F]florbetapir amyloid-PET were included. A normative strategy was used to define reliable accumulation by estimating the 95th percentile of longitudinal measurements in sub-populations (NPNHS = 101/750, NInsight46 = 35/382) expected to remain stable over time. The baseline CL threshold that optimally predicts future accumulation was investigated using precision-recall analyses. Accumulation rates were examined using linear mixed-effect models. RESULTS: Reliable accumulation in the PNHS was estimated to occur at >3.0 CL/year. Baseline CL of 16 [12,19] best predicted future Aß-accumulators. Rates of amyloid accumulation were tracer-independent, lower for APOE ε4 non-carriers, and for subjects with higher levels of education. DISCUSSION: Our results support a 12-20 CL window for inclusion into early secondary prevention studies. Reliable accumulation definition warrants further investigations.

Clear-headed into old age: Resilience and resistance against brain aging-A PET imaging perspective.

With the advances in modern medicine and the adaptation towards healthier lifestyles, the average life expectancy has doubled since the 1930s, with individuals born in the millennium years now carrying an estimated life expectancy of around 100 years. And even though many individuals around the globe manage to age successfully, the prevalence of aging-associated neurodegenerative diseases such as sporadic Alzheimer's disease has never been as high as nowadays. The prevalence of Alzheimer's disease is anticipated to triple by 2050, increasing the societal and economic burden tremendously. Despite all efforts, there is still no available treatment defeating the accelerated aging process as seen in this disease. Yet, given the advances in neuroimaging techniques that are discussed in the current Review article, such as in positron emission tomography (PET) or magnetic resonance imaging (MRI), pivotal insights into the heterogenous effects of aging-associated processes and the contribution of distinct lifestyle and risk factors already have and are still being gathered. In particular, the concepts of resilience (i.e. coping with brain pathology) and resistance (i.e. avoiding brain pathology) have more recently been discussed as they relate to mechanisms that are associated with the prolongation and/or even stop of the progressive brain aging process. Better understanding of the underlying mechanisms of resilience and resistance may one day, hopefully, support the identification of defeating mechanism against accelerating aging.

Importance of magnetic resonance imaging and prostate-specific membrane antigen PET-CT in patients treated with salvage radical prostatectomy for radiorecurrent prostate cancer.

BACKGROUND: Accurate staging and identification of optimal candidates for local salvage therapy, such as salvage radical prostatectomy (SRP), is necessary to ensure optimal care in patients with radiorecurrent prostate cancer (PCa). We aimed to analyze performance of magnetic resonance imaging (MRI) and prostate-specific membrane antigen (PSMA)-positron emission tomography (PET)/computed tomography (CT) for predicting pathologic nonorgan confined disease (pT3) and lymph node involvement (pN+) in patients treated with SRP for radiorecurrent PCa. METHODS: We retrospectively reviewed the institutional database to identify patients who underwent MRI or 68 Ga-PSMA-PET/CT before SRP for radiorecurrent PCa. The diagnostic estimates of MRI and PSMA-PET/CT for pT3 and pN+, were calculated. RESULTS: We identified 113 patients with radiorecurrent PCa who underwent preoperative MRI followed by SRP; 53 had preoperative 68 Ga-PSMA-PET/CT. For the detection of pT3 disease, the overall accuracy of MRI was 70% (95% confidence interval [CI] 61-78), sensitivity 40% (95% CI 26-55) and specificity 94% (95% CI 85-98); PSMA-PET/CT had slightly higher accuracy of 77% (95% CI 64-88), and higher sensitivity of 90% (95% CI 68-99), but lower specificity of 70% (95% CI 51-84). For pN+ disease, MRI had poor sensitivity of 14% (95% CI 3-36), specificity of 50 (95% CI 39-61) and total accuracy of 43% (95% CI 34-53); PSMA-PET/CT had an accuracy of 85% (95% CI 72-93), sensitivity of 27% (95% CI 6-61), and specificity of 100% (95% CI 92-100). CONCLUSION: In patients with radiorecurrent PCa, both, MRI, and 68 Ga-PSMA PET/CT are valuable tools for the pre-SRP staging and should be integrated into the standard workup. For lymph node metastases, 68 Ga-PSMA PET/CT is a strong rule-in test with nearly perfect specificity; in contrast MRI had a low accuracy for lymph node metastases.

Additive value of [18F]PI-2620 perfusion imaging in progressive supranuclear palsy and corticobasal syndrome.

PURPOSE: Early after [18F]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [18F]PI-2620 tau-PET is able to discriminate the 4-repeat tauopathies progressive supranuclear palsy and corticobasal syndrome (4RTs) from disease controls and healthy controls. Here, we investigated whether early-phase [18F]PI-2620 PET has an additive value for biomarker based evaluation of 4RTs. METHODS: Seventy-eight patients with 4RTs (71 ± 7 years, 39 female), 79 patients with other neurodegenerative diseases (67 ± 12 years, 35 female) and twelve age-matched controls (69 ± 8 years, 8 female) underwent dynamic (0-60 min) [18F]PI-2620 PET imaging. Regional perfusion (0.5-2.5 min p.i.) and tau load (20-40 min p.i.) were measured in 246 predefined brain regions [standardized-uptake-value ratios (SUVr), cerebellar reference]. Regional SUVr were compared between 4RTs and controls by an ANOVA including false-discovery-rate (FDR, p < 0.01) correction. Hypoperfusion in resulting 4RT target regions was evaluated at the patient level in all patients (mean value - 2SD threshold). Additionally, perfusion and tau pattern expression levels were explored regarding their potential discriminatory value of 4RTs against other neurodegenerative disorders, including validation in an independent external dataset (n = 37), and correlated with clinical severity in 4RTs (PSP rating scale, MoCA, activities of daily living). RESULTS: Patients with 4RTs had significant hypoperfusion in 21/246 brain regions, most dominant in thalamus, caudate nucleus, and anterior cingulate cortex, fitting to the topology of the 4RT disease spectrum. However, single region hypoperfusion was not specific regarding the discrimination of patients with 4RTs against patients with other neurodegenerative diseases. In contrast, perfusion pattern expression showed promise for discrimination of patients with 4RTs from other neurodegenerative diseases (AUC: 0.850). Discrimination by the combined perfusion-tau pattern expression (AUC: 0.903) exceeded that of the sole tau pattern expression (AUC: 0.864) and the discriminatory power of the combined perfusion-tau pattern expression was replicated in the external dataset (AUC: 0.917). Perfusion but not tau pattern expression was associated with PSP rating scale (R = 0.402; p = 0.0012) and activities of daily living (R = - 0.431; p = 0.0005). CONCLUSION: [18F]PI-2620 perfusion imaging mirrors known topology of regional hypoperfusion in 4RTs. Single region hypoperfusion is not specific for 4RTs, but perfusion pattern expression may provide an additive value for the discrimination of 4RTs from other neurodegenerative diseases and correlates closer with clinical severity than tau pattern expression.

Impaired self-awareness of cognitive deficits in Parkinson's disease relates to cingulate cortex dysfunction.

BACKGROUND: Impaired self-awareness of cognitive deficits (ISAcog) has rarely been investigated in Parkinson's disease (PD). ISAcog is associated with poorer long-term outcome in other diseases. This study examines ISAcog in PD with and without mild cognitive impairment (PD-MCI), compared to healthy controls, and its clinical-behavioral and neuroimaging correlates. METHODS: We examined 63 PD patients and 30 age- and education-matched healthy controls. Cognitive state was examined following the Movement Disorder Society Level II criteria. ISAcog was determined by subtracting z-scores (based on controls' scores) of objective tests and subjective questionnaires. Neural correlates were assessed by structural magnetic resonance imaging (MRI) and 2-[fluorine-18]fluoro-2-deoxy-d-glucose-positron emission tomography (FDG-PET) in 47 patients (43 with MRI) and 11 controls. We analyzed whole-brain glucose metabolism and cortical thickness in regions where FDG-uptake correlated with ISAcog. RESULTS: PD-MCI patients (N = 23) showed significantly more ISAcog than controls and patients without MCI (N = 40). When all patients who underwent FDG-PET were examined, metabolism in the bilateral superior medial frontal gyrus, anterior and midcingulate cortex negatively correlated with ISAcog (FWE-corrected p < 0.001). In PD-MCI, ISAcog was related to decreased metabolism in the right superior temporal lobe and insula (N = 13; FWE-corrected p = 0.023) as well as the midcingulate cortex (FWE-corrected p = 0.002). Cortical thickness was not associated with ISAcog in these regions. No significant correlations were found between ISAcog and glucose metabolism in controls and patients without MCI. CONCLUSIONS: Similar to Alzheimer's disease, the cingulate cortex seems to be relevant in ISAcog in PD. In PD-MCI patients, ISAcog might result from a disrupted network that regulates awareness of cognition and error processes.

Synthesis and evaluation of radioiodinated estrogens for diagnosis and therapy of male urogenital tumours.

The preparation of 24 estrogens, their estrogen receptor (ER) affinity and studies of radioiodinated estrogen binding to ER-positive male bladder tumor cells (HTB9) are described. The estrogens with the highest affinity were selected using fluorescence anisotropy assays. A 2,2,2-trifluoroethyl group at the 11ß-position caused particularly promising affinity. (Radio)iodination was performed on the 17α-vinyl group. Binding studies on HTB9 cells revealed picomolar affinities of radioconjugates 19 and 31, indicating promising ability for targeting of urogenital tumors.

Altered limbic functional connectivity in individuals with subjective cognitive decline: Converging and diverging findings across Chinese and German cohorts.

INTRODUCTION: It remains unclear whether functional brain networks are consistently altered in individuals with subjective cognitive decline (SCD) of diverse ethnic and cultural backgrounds and whether the network alterations are associated with an amyloid burden. METHODS: Cross-sectional resting-state functional magnetic resonance imaging connectivity (FC) and amyloid-positron emission tomography (PET) data from the Chinese Sino Longitudinal Study on Cognitive Decline and German DZNE Longitudinal Cognitive Impairment and Dementia cohorts were analyzed. RESULTS: Limbic FC, particularly hippocampal connectivity with right insula, was consistently higher in SCD than in controls, and correlated with SCD-plus features. Smaller SCD subcohorts with PET showed inconsistent amyloid positivity rates and FC-amyloid associations across cohorts. DISCUSSION: Our results suggest an early adaptation of the limbic network in SCD, which may reflect increased awareness of cognitive decline, irrespective of amyloid pathology. Different amyloid positivity rates may indicate a heterogeneous underlying etiology in Eastern and Western SCD cohorts when applying current research criteria. Future studies should identify culture-specific features to enrich preclinical Alzheimer's disease in non-Western populations. HIGHLIGHTS: Common limbic hyperconnectivity across Chinese and German subjective cognitive decline (SCD) cohorts was observed. Limbic hyperconnectivity may reflect awareness of cognition, irrespective of amyloid load. Further cross-cultural harmonization of SCD regarding Alzheimer's disease pathology is required.

Reversal of Tau-Dependent Cognitive Decay by Blocking Adenosine A1 Receptors: Comparison of Transgenic Mouse Models with Different Levels of Tauopathy.

The accumulation of tau is a hallmark of several neurodegenerative diseases and is associated with neuronal hypoactivity and presynaptic dysfunction. Oral administration of the adenosine A1 receptor antagonist rolofylline (KW-3902) has previously been shown to reverse spatial memory deficits and to normalize the basic synaptic transmission in a mouse line expressing full-length pro-aggregant tau (TauΔK) at low levels, with late onset of disease. However, the efficacy of treatment remained to be explored for cases of more aggressive tauopathy. Using a combination of behavioral assays, imaging with several PET-tracers, and analysis of brain tissue, we compared the curative reversal of tau pathology by blocking adenosine A1 receptors in three mouse models expressing different types and levels of tau and tau mutants. We show through positron emission tomography using the tracer [18F]CPFPX (a selective A1 receptor ligand) that intravenous injection of rolofylline effectively blocks A1 receptors in the brain. Moreover, when administered to TauΔK mice, rolofylline can reverse tau pathology and synaptic decay. The beneficial effects are also observed in a line with more aggressive tau pathology, expressing the amyloidogenic repeat domain of tau (TauRDΔK) with higher aggregation propensity. Both models develop a progressive tau pathology with missorting, phosphorylation, accumulation of tau, loss of synapses, and cognitive decline. TauRDΔK causes pronounced neurofibrillary tangle assembly concomitant with neuronal death, whereas TauΔK accumulates only to tau pretangles without overt neuronal loss. A third model tested, the rTg4510 line, has a high expression of mutant TauP301L and hence a very aggressive phenotype starting at ~3 months of age. This line failed to reverse pathology upon rolofylline treatment, consistent with a higher accumulation of tau-specific PET tracers and inflammation. In conclusion, blocking adenosine A1 receptors by rolofylline can reverse pathology if the pathological potential of tau remains below a threshold value that depends on concentration and aggregation propensity.

From Bench to Bedside: Patient-Oriented Radiopharmaceutical Development in Nuclear Medicine Based on the Example of [89Zr]Zr-PSMA-DFO.

The interdisciplinary possibilities inherent in nuclear medicine offer an opportunity for the patient-centered development of radioactive pharmaceuticals based on specific research questions. This approach provides radiopharmaceutical manufacturers with a robust scientific foundation on which to navigate the regulatory requirements for drug approval laid down by the law. A vivid illustration of this interdisciplinary cooperation has been the development of a Zr-89-labeled PSMA ligand where reliable results have been obtained across various domains, including chemistry, radiochemistry, biochemistry, and preclinical research. This comprehensive process extended to feasibility studies conducted with carefully selected patients from a single nuclear medicine clinic. The approach demonstrates how far close collaboration between different disciplines within nuclear medicine can further the move towards patient-oriented radiopharmaceutical treatments while simultaneously meeting regulatory demands. With such a strategy, innovative radiopharmaceutical solutions can be brought to the market more swiftly and efficiently, in line with the needs of patients.

Imaging of cerebral tryptophan metabolism using 7-[18F]FTrp-PET in a unilateral Parkinsonian rat model.

Degradation products of the essential amino acid tryptophan (Trp) are important signaling molecules in the mammalian brain. Trp is metabolized either through the kynurenine pathway or enters serotonin and melatonin syntheses. The aim of the present work was to examine the potential of the novel PET tracer 7-[18F]fluorotryptophan ([18F]FTrp) to visualize all three pathways in a unilateral 6-OHDA rat model. [18F]FDOPA-PET scans were performed in nine 6-OHDA-injected and six sham-operated rats to assess unilateral dopamine depletion severity four weeks after lesion placement. Afterwards, 7-[18F]FTrp-PET scans were conducted at different timepoints up to seven months after 6-OHDA injection. In addition, two 6-OHDA-injected rats were examined for neuroinflammation using [18F]DAA1106-PET. 7-[18F]FTrp-PET showed significantly increased tracer uptake at the 6-OHDA injection site which was negatively correlated to time after lesion placement. Accumulation of [18F]DAA1106 at the injection site was increased as well, suggesting that 7-[18F]FTrp uptake in this region may reflect kynurenine pathway activity associated with inflammation. Bilaterally in the dorsal hippocampus, 7-[18F]FTrp uptake was significantly decreased and was inversely correlated to dopamine depletion severity, indicating that it reflects reduced serotonin synthesis. Finally, 7-[18F]FTrp uptake in the pineal gland was significantly increased in relation with dopamine depletion severity, providing evidence that melatonin synthesis is increased in the 6-OHDA rat model. We conclude that 7-[18F]FTrp is able to detect alterations in both serotonin/melatonin and kynurenine metabolic pathways, and can be applied to visualize pathologic changes related to neurodegenerative processes.

Decoupling of regional neural activity and inter-regional functional connectivity in Alzheimer's disease: a simultaneous PET/MR study.

PURPOSE: Alzheimer's disease (AD) and mild cognitive impairment (MCI) are characterized by both aberrant regional neural activity and disrupted inter-regional functional connectivity (FC). However, the effect of AD/MCI on the coupling between regional neural activity (measured by regional fluorodeoxyglucose imaging (rFDG)) and inter-regional FC (measured by resting-state functional magnetic resonance imaging (rs-fMRI)) is poorly understood. METHODS: We scanned 19 patients with MCI, 33 patients with AD, and 26 healthy individuals by simultaneous FDG-PET/rs-fMRI and assessed rFDG and inter-regional FC metrics (i.e., clustering coefficient and degree centrality). Next, we examined the potential moderating effect of disease status (MCI or AD) on the link between rFDG and inter-regional FC metrics using hierarchical moderated multiple regression analysis. We also tested this effect by considering interaction between disease status and inter-regional FC metrics, as well as interaction between disease status and rFDG. RESULTS: Our findings revealed that both rFDG and inter-regional FC metrics were disrupted in MCI and AD. Moreover, AD altered the relationship between rFDG and inter-regional FC metrics. In particular, we found that AD moderated the effect of inter-regional FC metrics of the caudate, parahippocampal gyrus, angular gyrus, supramarginal gyrus, frontal pole, inferior temporal gyrus, middle frontal, lateral occipital, supramarginal gyrus, precuneus, and thalamus on predicting their rFDG. On the other hand, AD moderated the effect of rFDG of the parietal operculum on predicting its inter-regional FC metric. CONCLUSION: Our findings demonstrated that AD decoupled the link between regional neural activity and functional segregation and global connectivity across particular brain regions.

Neural correlates and predictors of subjective cognitive decline in patients with Parkinson's disease.

BACKGROUND: Subjective cognitive decline (SCD) may occur very early in the course of Parkinson's disease (PD) before the onset of objective cognitive decline. Data on neural correlates and determinants of SCD in PD are rare. OBJECTIVE: The aim of the present study was to identify neural correlates as well as sociodemographic, clinical, and neuropsychological predictors of SCD in patients with PD. METHODS: We retrospectively analyzed 30 patients with PD without cognitive impairment (23% female, 66.90 ± 7.20 years, UPDRS-III: 19.83 ± 9.29), of which n = 12 patients were classified as having no SCD (control group, PD-CG) and n = 18 as having SCD (PD-SCD). Neuropsychological testing and 18-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) were conducted. SCD was assessed using a questionnaire covering multiple cognitive domains. RESULTS: SCD subscores differed significantly between PD-CG and PD-SCD and correlated significantly with other scales measuring related concepts. FDG-PET whole-brain voxel-wise regression analysis revealed hypometabolism in middle frontal, middle temporal, and occipital areas, and the angular gyrus as neural correlates of SCD in PD. Next to this hypometabolism, depressive symptoms were an independent significant determinant of SCD in a stepwise regression analysis (adjusted R2 = 50.3%). CONCLUSION: This study strengthens the hypothesis of SCD being an early manifestation of future cognitive decline in PD and, more generally, early pathological changes in PD. The early identification of the vulnerability for future cognitive decline constitutes the basis for successful prevention and delay of this non-motor symptom.

Description of a European memory clinic cohort undergoing amyloid-PET: The AMYPAD Diagnostic and Patient Management Study.

INTRODUCTION: AMYPAD Diagnostic and Patient Management Study (DPMS) aims to investigate the clinical utility and cost-effectiveness of amyloid-PET in Europe. Here we present participants' baseline features and discuss the representativeness of the cohort. METHODS: Participants with subjective cognitive decline plus (SCD+), mild cognitive impairment (MCI), or dementia were recruited in eight European memory clinics from April 16, 2018, to October 30, 2020, and randomized into three arms: ARM1, early amyloid-PET; ARM2, late amyloid-PET; and ARM3, free-choice. RESULTS: A total of 840 participants (244 SCD+, 341 MCI, and 255 dementia) were enrolled. Sociodemographic/clinical features did not differ significantly among recruiting memory clinics or with previously reported cohorts. The randomization assigned 35% of participants to ARM1, 32% to ARM2, and 33% to ARM3; cognitive stages were distributed equally across the arms. DISCUSSION: The features of AMYPAD-DPMS participants are as expected for a memory clinic population. This ensures the generalizability of future study results.

Effective connectivity in the default mode network is distinctively disrupted in Alzheimer's disease-A simultaneous resting-state FDG-PET/fMRI study.

A prominent finding of postmortem and molecular imaging studies on Alzheimer's disease (AD) is the accumulation of neuropathological proteins in brain regions of the default mode network (DMN). Molecular models suggest that the progression of disease proteins depends on the directionality of signaling pathways. At network level, effective connectivity (EC) reflects directionality of signaling pathways. We hypothesized a specific pattern of EC in the DMN of patients with AD, related to cognitive impairment. Metabolic connectivity mapping is a novel measure of EC identifying regions of signaling input based on neuroenergetics. We simultaneously acquired resting-state functional MRI and FDG-PET data from patients with early AD (n = 35) and healthy subjects (n = 18) on an integrated PET/MR scanner. We identified two distinct subnetworks of EC in the DMN of healthy subjects: an anterior part with bidirectional EC between hippocampus and medial prefrontal cortex and a posterior part with predominant input into medial parietal cortex. Patients had reduced input into the medial parietal system and absent input from hippocampus into medial prefrontal cortex (p < 0.05, corrected). In a multiple linear regression with unimodal imaging and EC measures (F4,25 = 5.63, p = 0.002, r2 = 0.47), we found that EC (ß = 0.45, p = 0.012) was stronger associated with cognitive deficits in patients than any of the PET and fMRI measures alone. Our approach indicates specific disruptions of EC in the DMN of patients with AD and might be suitable to test molecular theories about downstream and upstream spreading of neuropathology in AD.

The default mode network and cognition in Parkinson's disease: A multimodal resting-state network approach.

Involvement of the default mode network (DMN) in cognitive symptoms of Parkinson's disease (PD) has been reported by resting-state functional MRI (rsfMRI) studies. However, the relation to metabolic measures obtained by [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) is largely unknown. We applied multimodal resting-state network analysis to clarify the association between intrinsic metabolic and functional connectivity abnormalities within the DMN and their significance for cognitive symptoms in PD. PD patients were classified into normal cognition (n = 36) and mild cognitive impairment (MCI; n = 12). The DMN was identified by applying an independent component analysis to FDG-PET and rsfMRI data of a matched subset (16 controls and 16 PD patients) of the total cohort. Besides metabolic activity, metabolic and functional connectivity within the DMN were compared between the patients' groups and healthy controls (n = 16). Glucose metabolism was significantly reduced in all DMN nodes in both patient groups compared to controls, with the lowest uptake in PD-MCI (p < .05). Increased metabolic and functional connectivity along fronto-parietal connections was identified in PD-MCI patients compared to controls and unimpaired patients. Functional connectivity negatively correlated with cognitive composite z-scores in patients (r = -.43, p = .005). The current study clarifies the commonalities of metabolic and hemodynamic measures of brain network activity and their individual significance for cognitive symptoms in PD, highlighting the added value of multimodal resting-state network approaches for identifying prospective biomarkers.

Indication of retrograde tau spreading along Braak stages and functional connectivity pathways.

PURPOSE: Tau pathology progression in Alzheimer's disease (AD) is explained through the network degeneration hypothesis and the neuropathological Braak stages; however, the compatibility of these models remains unclear. METHODS: We utilized [18F]AV-1451 tau-PET scans of 39 subjects with AD and 39 sex-matched amyloid-negative healthy controls (HC) in the ADNI (Alzheimer's Disease Neuroimaging Initiative) dataset. The peak cluster of tau-tracer uptake was identified in each Braak stage of neuropathological tau deposition and used to create a seed-based functional connectivity network (FCN) using 198 HC subjects, to identify healthy networks unaffected by neurodegeneration. RESULTS: Voxel-wise tau deposition was both significantly higher inside relative to outside FCNs and correlated significantly and positively with levels of healthy functional connectivity. Within many isolated Braak stages and regions, the correlation between tau and intrinsic functional connectivity was significantly stronger than it was across the whole brain. In this way, each peak cluster of tau was related to multiple Braak stages traditionally associated with both earlier and later stages of disease. CONCLUSION: We show specificity of healthy FCN topography for AD-pathological tau as well as positive voxel-by-voxel correlations between pathological tau and healthy functional connectivity. We propose a model of "up- and downstream" functional tau progression, suggesting that tau pathology evolves along functional connectivity networks not only "downstream" (i.e., along the expected sequence of the established Braak stages) but also in part "upstream" or "retrograde" (i.e., against the expected sequence of the established Braak stages), with pathology in earlier Braak stages intensified by its functional relationship to later disease stages.

Clinical validity of increased cortical binding of tau ligands of the THK family and PBB3 on PET as biomarkers for Alzheimer's disease in the context of a structured 5-phase development framework.

PURPOSE: The research community has focused on defining reliable biomarkers for the early detection of the pathological hallmarks of Alzheimer's disease (AD). In 2017, the Geneva AD Biomarker Roadmap initiative adapted the framework for the systematic validation of oncological biomarkers to AD, with the aim to accelerate their development and implementation in clinical practice. The aim of this work was to assess the validation status of tau PET ligands of the THK family and PBB3 as imaging biomarkers for AD, based on the Biomarker Roadmap methodology. METHODS: A panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of clinical validity of tau PET ligands of the THK family and PBB3 was assessed based on the 5-phase development framework before the meeting and discussed during the workshop. RESULTS: PET radioligands of the THK family discriminate well between healthy controls and patients with AD dementia (phase 2; partly achieved) and recent evidence suggests an accurate diagnostic accuracy at the mild cognitive impairment (MCI) stage of the disease (phase 3; partly achieved). The phases 2 and 3 were considered not achieved for PBB3 since no evidence exists about the ligand's diagnostic accuracy. Preliminary evidence exists about the secondary aims of each phase for all ligands. CONCLUSION: Much work remains for completing the aims of phases 2 and 3 and replicating the available evidence. However, it is unlikely that the validation process for these tracers will be completed, given the presence of off-target binding and the development of second-generation tracers with improved binding and pharmacokinetic properties.