Person:

Chonde, Daniel B.

Local prefrontal dopamine signaling supports working memory by tuning pyramidal neurons to task-relevant stimuli. Enabled by simultaneous positron emission tomography–magnetic resonance imaging (PET-MRI), we determined whether neuromodulatory effects of dopamine scale to the level of cortical networks and coordinate their interplay during working memory. Among network territories, mean cortical D1 receptor densities differed substantially but were strongly interrelated, suggesting cross-network regulation. Indeed, mean cortical D1 density predicted working memory–emergent decoupling of the frontoparietal and default networks, which respectively manage task-related and internal stimuli. In contrast, striatal D1 predicted opposing effects within these two networks but no between-network effects. These findings specifically link cortical dopamine signaling to network crosstalk that redirects cognitive resources to working memory, echoing neuromodulatory effects of D1 signaling on the level of cortical microcircuits.

The purpose of this work – the first of its kind – was to evaluate the impact of chronic selective histone deacetylase (HDAC) inhibitor treatment on brain activity using uptake of the radioligand 18F-fluorodeoxyglucose and positron emission tomography (18FDG-PET). HDAC dysfunction and other epigenetic mechanisms are implicated in diverse CNS disorders and animal research suggests HDAC inhibition may provide a lead toward developing improved treatment. To begin to better understand the role of the class I HDAC subtypes HDAC 1, 2 and 3 in modulating brain activity, we utilized two benzamide inhibitors from the literature, compound 60 (Cpd-60) and CI-994 which selectively inhibit HDAC 1 and 2 or HDACs 1, 2 and 3, respectively. One day after the seventh treatment with Cpd-60 (22.5 mg/kg) or CI-994 (5 mg/kg), 18FDG-PET experiments (n = 11–12 rats per treatment group) revealed significant, local changes in brain glucose utilization. These 2–17% changes were represented by increases and decreases in glucose uptake. The pattern of changes was similar but distinct between Cpd-60 and CI-994, supporting that 18FDG-PET is a useful tool to examine the relationship between HDAC subtype activity and brain activity. Further work using additional selective HDAC inhibitors will be needed to clarify these effects as well as to understand how brain activity changes influence behavioral response.

Objective: In this cross-sectional study, we aimed to evaluate brain structural abnormalities in relation to glial activation in the same cohort of participants. Methods: Ten individuals with amyotrophic lateral sclerosis (ALS) and 10 matched healthy controls underwent brain imaging using integrated MR/PET and the radioligand [11C]-PBR28. Diagnosis history and clinical assessments including Upper Motor Neuron Burden Scale (UMNB) were obtained from patients with ALS. Diffusion tensor imaging (DTI) analyses including tract-based spatial statistics and tractography were applied. DTI metrics including fractional anisotropy (FA) and diffusivities (mean, axial, and radial) were measured in regions of interest. Cortical thickness was assessed using surface-based analysis. The locations of structural changes, measured by DTI and the areas of cortical thinning, were compared to regional glial activation measured by relative [11C]-PBR28 uptake. Results: In this cohort of individuals with ALS, reduced FA and cortical thinning colocalized with regions demonstrating higher radioligand binding. [11C]-PBR28 binding in the left motor cortex was correlated with FA (r = −0.68, p < 0.05) and cortical thickness (r = −0.75, p < 0.05). UMNB was correlated with glial activation (r = +0.75, p < 0.05), FA (r = −0.77, p < 0.05), and cortical thickness (r = −0.75, p < 0.05) in the motor cortex. Conclusions: Increased uptake of the glial marker [11C]-PBR28 colocalizes with changes in FA and cortical thinning. This suggests a link between disease mechanisms (gliosis and inflammation) and structural changes (cortical thinning and white and gray matter changes). In this multimodal neuroimaging work, we provide an in vivo model to investigate the pathogenesis of ALS.

Recently, systems that integrate positron emission tomography and magnetic resonance imaging (PET/MR) have become available for clinical use. This new technology, which combines the high spatial resolution and superior soft-tissue contrast of MR with the picomolar sensitivity, quantitative capabilities, and wide array of tracers of PET, has the potential to benefit patients and provide insights that were previously unattainable in standalone systems. Simultaneous measurement of PET and MR parameters provides complementary information, allowing for a more complete assessment of disease, as well as cross validation and calibration of MR and PET measurements and techniques. To take full advantage of such a multi-modal system, accurate quantification of the PET data is necessary. Due to the low spatial resolution of PET – which can be further reduced by external factors like patient motion – and the inherent lack of anatomic detail, accurate quantification can be challenging. The simultaneously acquired MR information provides an opportunity to optimize PET quantification and analysis. In order to fully realize the benefits provided by the simultaneously acquired MR data, the MR data cannot be treated as discrete sequences, but as the continuous flow of information. This is due to differences in the time required for data collection to generate PET and MR images. This work describes the development and optimization of a pipeline for the reconstruction and analysis of PET data in a brain-dedicated prototype PET/MR system, the BrainPET (Siemens Healthcare). First, the performance of the BrainPET system was optimized for neurological imaging. MR-hardware interference and characteristics of the PET camera were quantified and a method for multimodal alignment was developed. To simplify and streamline the reconstruction and quantification process, a platform was designed which utilizes the functionality of a number of specialized brain imaging analysis software packages in an automated fashion. Second, MR-based methods addressing specific challenges to PET quantification were addressed. Simultaneously acquired structural MR data was used to correct the PET data for attenuation and partial volume effects. The use of MR data for motion correction was addressed and a unified algorithm which derives motion estimates from the PET data when MR data is unavailable was presented. Finally, the value of the optimized PET processing for neurological studies was evaluated in three instances: first an upper limit on the physiologic noise introduced by MR imaging on cerebral metabolism was estimated using PET and found to be minimal; next the benefit of MR-based motion correction and partial volume effect correction were estimated in a patient study; and lastly, a method to derive the PET radiotracer input function from the PET data using multiple MR sequences was presented.

Evidence from human post mortem, in vivo and animal model studies implicates the neuroimmune system and activated microglia in the pathology of amyotrophic lateral sclerosis. The study aim was to further evaluate in vivo neuroinflammation in individuals with amyotrophic lateral sclerosis using [11C]-PBR28 positron emission tomography. Ten patients with amyotrophic lateral sclerosis (seven males, three females, 38–68 years) and ten age- and [11C]-PBR28 binding affinity-matched healthy volunteers (six males, four females, 33–65 years) completed a positron emission tomography scan. Standardized uptake values were calculated from 60 to 90 min post-injection and normalized to whole brain mean. Voxel-wise analysis showed increased binding in the motor cortices and corticospinal tracts in patients with amyotrophic lateral sclerosis compared to healthy controls (pFWE < 0.05). Region of interest analysis revealed increased [11C]-PBR28 binding in the precentral gyrus in patients (normalized standardized uptake value = 1.15) compared to controls (1.03, p < 0.05). In patients those values were positively correlated with upper motor neuron burden scores (r = 0.69, p < 0.05), and negatively correlated with the amyotrophic lateral sclerosis functional rating scale (r = –0.66, p < 0.05). Increased in vivo glial activation in motor cortices, that correlates with phenotype, complements previous histopathological reports. Further studies will determine the role of [11C]-PBR28 as a marker of treatments that target neuroinflammation.