We determined brain microstructure alterations in early-stage Parkinson's disease (PD) using diffusion tensor imaging and neurite orientation dispersion and density imaging (NODDI). Additionally, dopamine transporter (DAT) PET in PD was also performed to evaluate whether microstructural changes and dopaminergic losses within the brain contribute independently to PD motor severity. Mean diffusivity was significantly higher in PD in many mid-brain, nigrostriatal, sub-cortical, cortical and white matter regions. However, Viso (NODDI outcome for cerebrospinal-fluid volume fraction) in the motor cortices and parietal lobe were more strongly correlated (r ~ 0.5, p < 0.01) with PD motor severity. Most DAT PET and diffusion MRI measures were uncorrelated and stepwise multiple linear regression analysis determined a combination of DAT availability in the putamen and Viso in the precentral gyrus (motor cortex) as the best predictor of PD motor severity (55% variance explained); inclusion of Viso in precentral gyrus independently accounted for 11% variance in motor severity.

BACKGROUND:Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disorder which pathology is still largely unclear. OBJECTIVES:To perform an in vivo cross-sectional investigation of mitochondrial complex 1 (MC1), synaptic vesicle 2 A (SV2A), and sigma-1 receptor (S1R) expression in ALS patients using the PET radioligands [18F]BCPP-EF, [11C]UCB-J, and [11C]SA4503. METHODS:Sixteen ALS patients (twelve males, mean age: 57.49 ± 12.08 years) and sixteen healthy controls underwent clinical assessment, MRI, and PET imaging with [18F]BCPP-EF, [11C]UCB-J, and [11C]SA4503. Patients were stratified based on disease the Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) progression rate into slow, and moderate/fast progressors. Volume of distribution (VT) of predefined regions of interest, corrected for partial volume effects, was the primary outcome. RESULTS:Across the ALS cohort, [18F]BCPP-EF binding was reduced in the amygdala (-13.9 %, F = 4.938 p = 0.034). Moderate/fast progression ALS patients exhibited [18F]BCPP-EF binding loss in the hippocampus (-20.0 %), amygdala (-21.4 %), cerebellum (-19.5 %), insular cortex (-19.3 %), temporal lobe (-19.0 %), and anterior cingulate (-18.7 %) (all p < 0.05); and [11C]SA4503 binding loss in the caudate (-20.6 %), pallidus (-26.8 %), amygdala (-20.2 %), hippocampus (-17.4 %), insular cortex (-16.9 %), accumbens (-17.0 %), anterior cingulate (-16.4 %) and temporal lobe (-19.8 %) compared to controls (all p < 0.05). In moderate/fast progressors, [18F]BCPP-EF loss in the insular cortex, amygdala, anterior cingulate, and temporal lobe correlated with lower ALSFRS-R scores (p < 0.05). CONCLUSIONS:Our findings reveal loss of MC1 and S1R in ALS, suggesting mitochondrial dysfunction associated with disease progression. This work provides initial insights of mitochondrial and receptor pathology in ALS, potentially guiding future biomarker development and therapeutic interventions.

[F-18]FE-PE2I PET is a promising alternative to single positron emission computed tomography-based dopamine transporter (DAT) imaging in Parkinson's disease. While the excellent discriminative power of [F-18]FE-PE2I PET has been established, so far only one study has reported meaningful associations between motor severity scores and DAT availability. In this study, we use high-resolution (similar to 3 mm isotropic) PET to provide an independent validation for the clinical correlates of [F-18]FE-PE2I imaging in separate cross-sectional (28 participants with Parkinson's disease, Hoehn-Yahr: 2 and 14 healthy individuals) and longitudinal (initial results from 6 participants with Parkinson's disease with 2-year follow-up) cohorts. In the cross-sectional cohort, DAT availability in the putamen and substantia nigra of patients with Parkinson's disease showed a significant negative association with total motor severity (r = -0.59, P = 0.002 for putamen; r = -0.46, P = 0.018 for substantia nigra), but not tremor severity. To our knowledge, this is the first observed association between motor severity in Parkinson's disease and DAT availability in the substantia nigra. The associations with motor severity in most nigrostriatal regions improved if tremor scores were excluded from motor scores. Further, we found significant asymmetry in DAT availability in the putamen (similar to 28% lower DAT availability within the more-affected side of the putamen), and DAT-based asymmetry index for the putamen was correlated with asymmetry in motor severity (r = -0.60, P = 0.001). In the longitudinal study, [F-18]FE-PE2I PET detected significant annual percentage reduction of DAT availability at the individual level in the putamen (9.7 +/- 2.6%), caudate (10.5 +/- 3.8%) and ventral striatum (5.5 +/- 2.7%), but not the substantia nigra. Longitudinal per cent reduction in DAT availability within the putamen was strongly associated with increase in motor severity (r = 0.91, P = 0.011) at follow-up, demonstrating the high sensitivity of [F-18]FE-PE2I PET in tracking longitudinal changes. These results provide further evidence for the utility of [F-18]FE-PE2I as an important in vivo PET biomarker in future clinical trials of Parkinson's disease.

Depression is the most common psychiatric condition seen in PD. Using PET and [11C]UCB-J – a marker for synaptic density, we have previously provided in-vivo evidence for disease-specific synaptic loss in both major depressive disorder (MDD) and Parkinson’s disease (PD). No study to date has investigated synaptic loss in PD with MDD.

Background: FDG PET/CT is a tool for assessing response to therapy in various cancers, and may provide an earlier biomarker of clinical response. We developed a novel semi-automated approach for analyzing FDG PET/ CT images in patients with multiple myeloma (MM) to standardize FDG PET application.Methods: Patients (n = 8) with relapsed/refractory MM from the Phase 2 study (NCT02899052) of venetoclax plus carfilzomib and dexamethasone underwent FDG PET/CT at baseline and up to two timepoints during treatment. Images were processed using an established automated segmentation algorithm, with the modification that a red marrow region in an unaffected lumbar vertebra was used to define background standardized uptake value normalized to lean body mass (SUL) threshold above which uptake was considered disease-specific uptake. This approach was compared to lesion segmentation, and to International Myeloma Working Group (IMWG) response criteria, including minimal residual disease (MRD).Results: The two FDG PET analysis techniques agreed on evaluation of patient-level SULpeak for 67% of scans. In the metabolic response assessment per PET Response Criteria in Solid Tumors (PERCIST), the two techniques agreed in 75% of patients. Differences between techniques occurred in low-uptake lesions due to greater reader sensitivity to lesions with uptake marginally above background. PERCIST outcomes were generally in agreement with IMWC and MRD. Conclusions: This semi-automated analysis was in high agreement with standard approaches for detecting response to MM therapy. This proof-of-concept study suggests that larger studies should be conducted to confirm how FDG PET analysis may aid early response detection in MM.

In vivo characterization of pathologic deposition of tau protein in the human brain by PET imaging is a promising tool in drug development trials of Alzheimer disease (AD). 6-(fluoro-18F)-3-(1H-pyrrolo[2,3-c]pyridin-1-yl)isoquinolin-5-amine (18F-MK-6240) is a radiotracer with high selectivity and subnanomolar affinity for neurofibrillary tangles that shows favorable nonspecific brain penetration and excellent kinetic properties. The purpose of the present investigation was to develop a visual assessment method that provides both an overall assessment of brain tauopathy and regional characterization of abnormal tau deposition. Methods: 18F-MK-6240 scans from 102 participants (including cognitively normal volunteers and patients with AD or other neurodegenerative disorders) were reviewed by an expert nuclear medicine physician masked to each participant's diagnosis to identify common patterns of brain uptake. This initial visual read method was field-tested in a separate, nonoverlapping cohort of 102 participants, with 2 additional naïve readers trained on the method. Visual read outcomes were compared with semiquantitative assessments using volume-of-interest SUV ratio. Results: For the visual read, the readers assessed 8 gray-matter regions per hemisphere as negative (no abnormal uptake) or positive (1%-25% of the region involved, 25%-75% involvement, or >75% involvement) and then characterized the tau binding pattern as positive or negative for evidence of tau and, if positive, whether brain uptake was in an AD pattern. The readers demonstrated agreement 94% of the time for overall positivity or negativity. Concordance on the determination of regional binary outcomes (negative or positive) showed agreement of 74.3% and a Fleiss κ of 0.912. Using clinical diagnosis as the ground truth, the readers demonstrated a sensitivity of 73%-79% and specificity of 91%-93%, with a combined reader-concordance sensitivity of 80% and specificity of 93%. The average SUV ratio in cortical regions showed a robust correlation with visually derived ratings of regional involvement (r = 0.73, P < 0.0001). Conclusion: We developed a visual read algorithm for 18F-MK-6240 PET offering determination of both scan positivity and the regional degree of cortical involvement. These cross-sectional results show strong interreader concordance on both binary and regional assessments of tau deposition, as well as good sensitivity and excellent specificity supporting use as a tool for clinical trials.

Magnetic resonance imaging (MRI) is a sensitive imaging modality for identifying inflammatory and/or demyelinating lesions, which is critical for a clinical diagnosis of MS and evaluating drug responses. There are many unique means of probing brain tissue status, including conventional T1 and T2 weighted imaging (T1WI, T2WI), T2 fluid attenuated inversion recovery (FLAIR), magnetization transfer, myelin water fraction, diffusion tensor imaging (DTI), phase-sensitive inversion recovery and susceptibility weighted imaging (SWI), but no study has combined all of these modalities into a single well-controlled investigation. The goals of this study were to: compare different MRI measures for lesion visualization and quantification; evaluate the repeatability of various imaging methods in healthy controls; compare quantitative susceptibility mapping (QSM) with myelin water fraction; measure short-term longitudinal changes in the white matter of MS patients and map out the tissue properties of the white matter hyperintensities using STAGE (strategically acquired gradient echo imaging). Additionally, the outcomes of this study were anticipated to aid in the choice of an efficient imaging protocol reducing redundancy of information and alleviating patient burden. Of all the sequences used, T2 FLAIR and T2WI showed the most lesions. To differentiate the putative demyelinating lesions from inflammatory lesions, the fusion of SWI and T2 FLAIR was used. Our study suggests that a practical and efficient imaging protocol combining T2 FLAIR, T1WI and STAGE (with SWI and QSM) can be used to rapidly image MS patients to both find lesions and study the demyelinating and inflammatory characteristics of the lesions.

Amyloid and tau are recognized hallmarks of Alzheimer’s disease (AD). Tilavonemab is a monoclonal antibody that binds to the N terminus of human tau and is being developed as a treatment for early AD. The goal of this work is to present the baseline amyloid and tau PET imaging characteristics of patients enrolled in the ongoing phase 2 study of tilavonemab. 453 patients who met the clinical criteria for early AD and had a positive amyloid PET scan (by visual read) at screening were randomized into the study. Amyloid PET was quantified on the standard Centiloid (CL) scale utilizing a processing pipeline developed in-house and validated using recommended procedures [Klunk, et al., 2015]. Tau PET imaging using 18 F-MK6240 was also performed in a subset of patients to assess presence of tau pathology, the target of tilavonemab, and to monitor disease progression and treatment effects. Here we report baseline tau PET data from 59 subjects randomized into the trial (out of 70 scans collected, not including screen fails or out of baseline window scans). Tau PET was quantified in Braak regions I-VI using standardized uptake value ratio (SUVR), extent (percentage of voxels within a region above threshold) and load (extent * mean SUVR of voxels within a region above threshold) metrics. Ventral cerebellar gray matter was used as a reference region for SUVR calculation and to determine the subject-specific threshold needed for the extent and load calculation. Over 99% of subjects (449/453) had amyloid measurements greater than 20CL, a threshold used for positivity [Burnham, et al., 2020], consistent with visual read; mean±s.d. was 99.0±31.1 CL. For the 59 patients with baseline tau PET data 95% (56/59) were considered to have elevated tau pathology in the brain (SUVR ≥1.27 in the entorhinal cortex [Betthauser, et al., 2020]). The tau metrics for Braak regions I-VI are summarized in Table 1. This analysis confirmed the presence of amyloid pathology in the patients randomized into the trial and suggested a high proportion of patients have tau pathology in the brain. Future analyses will examine how tilavonemab effects tau pathology.

Bruton's tyrosine kinase (BTK) is a key component of B cell receptor (BCR) signaling, and as such a critical regulator of cell proliferation and survival. Aberrant BCR signaling is important in the pathogenesis of various B cell malignancies and autoimmune disorders. Here, we describe the development of a novel positron emission tomography (PET) tracer for imaging BTK expression and/or occupancy by small molecule therapeutics. Radiochemistry was carried out by reacting the precursor with [18F]fluoride on a GE FX-FN TracerLab synthesis module to produce [18F]BTK-1 with a 6