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Abstract Background Secondary prevention clinical trials for Alzheimer’s disease (AD) target amyloid accumulation in asymptomatic, amyloid-positive individuals, but it is unclear to what extent other pathophysiological processes, such as small vessel cerebrovascular disease, account for participant performance on the primary cognitive outcomes in those trials. White matter hyperintensities are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) that reflect small vessel cerebrovascular disease. They are associated with cognitive functioning in older adults and with clinical presentation and course of AD, particularly when distributed in posterior brain regions. The purpose of this study was to examine to what degree regional WMH volume is associated with performance on the primary cognitive outcome measure in the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Disease (A4) study, a secondary prevention trial. Methods Data from 1791 participants (59.5% women, mean age (SD) 71.6 (4.74)) in the A4 study and the Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN) companion study at the screening visit were used to quantify WMH volumes on T2-weighted fluid-attenuated inversion recovery (FLAIR) MR images. Cognition was assessed with the preclinical Alzheimer cognitive composite (PACC). We tested the association of total and regional WMH volumes with PACC performance, adjusting for age, education, and amyloid positivity status, with general linear models. We also considered interactions between WMH and amyloid positivity status. Results Increased frontal and parietal lobe WMH volume was associated with poorer performance on the PACC. While amyloid positivity was also associated with lower cognitive test scores, WMH volumes did not interact with amyloid positivity status. Conclusion These results highlight the potential of small vessel cerebrovascular disease to drive AD-related cognitive profiles. Measures of small vessel cerebrovascular disease should be considered when evaluating outcome in trials, both as potential effect modifiers and as a possible target for intervention or prevention.

Objective: To determine the relationship between brain tissue metabolites measured by in vivo magnetic resonance spectroscopy (1H-MRS), and glial activation assessed with [11C]-PBR28 uptake in people with amyotrophic lateral sclerosis (ALS). Methods: Forty ALS participants were evaluated clinically using the revised ALS functional rating scale (ALSFRS-R) and upper motor neuron burden (UMNB). All participants underwent simultaneous brain [11C]-PBR28 PET and MR imaging including diffusion tensor imaging to acquire fractional anisotropy (FA). [11C]-PBR28 uptake was measured as standardized uptake values normalized by whole brain mean (SUVR). 1H-MRS metabolite ratios (myo-inositol/creatine, mI/Cr; N-acetylaspartate/creatine, NAA/Cr) were measured within the precentral gyri and brain stem (regions known to be involved in ALS pathophysiology), and precuneus (which served as a control region). Whole brain voxel-wise correlation analyses were employed to identify brain regions exhibiting an association between metabolites within the VOIs and [11C]-PBR28 uptake. Results: In the precentral gyri, [11C]-PBR28 uptake correlated positively with mI/Cr and negatively with NAA/Cr. The same correlations were not statistically significant in the brain stem, or in the control precuneus region. Whole brain voxel-wise correlation analyses between the estimated brain metabolites within the VOIs and SUVR were highly correlated in the precentral gyri. Decreased FA values in the precentral gyri were correlated with reduced NAA/Cr and elevated mI/Cr. Higher UMNB was correlated with increased [11C]-PBR28 uptake and mI/Cr, and decreased NAA/Cr. ALSFRS-R total score correlated positively with NAA/Cr and negatively with mI/Cr. Conclusion: Integrated PET-MR and 1H-MRS imaging demonstrates associations between markers for neuronal integrity and neuroinflammation and may provide valuable insights into disease mechanisms in ALS. Keywords: 1H-MRS, PET, Glial activation, Amyotrophic lateral sclerosis, [11C]-PBR28, DTI

Background: Glia activation is thought to contribute to neuronal damage in several neurodegenerative diseases based on preclinical and human post-mortem studies, but its role in primary lateral sclerosis (PLS) is unknown. Objectives: To localize and measure glia activation in people with PLS compared to healthy controls (HC). Methods: Ten participants with PLS and ten age-matched HCs underwent simultaneous magnetic resonance (MR) and proton emission tomography (PET). The radiotracer [11C]-PBR28 was used to obtain PET-based measures of 18kDa translocator protein (TSPO) expression, a marker of activated glial cells. MR techniques included a structural sequence to measure cortical thickness and diffusion tensor imaging (DTI) to assess white matter integrity. Results: PET data showed increased [11C]-PBR28 uptake in anatomically-relevant motor regions which co-localized with areas of regional gray matter atrophy and decreased subcortical fractional anisotropy. Conclusions: This study supports a link between glia activation and neuronal degeneration in PLS, and suggests that these disease mechanisms can be measured in vivo in PLS. Future studies are needed to determine the longitudinal changes of these imaging measures and to clarify if MR-PET with [11C]-PBR28 can be used as a biomarker for drug development in the context of clinical trials for PLS. Keywords: Diffusion, PET, TSPO, Primary lateral sclerosis, Amyotrophic lateral sclerosis, [11C]-PBR28

We used established databases in standard ways to systematically characterize gene ontologies, pathways and functional linkages in the large set of genes now associated with autism spectrum disorders (ASDs). These conditions are particularly challenging--they lack clear pathognomonic biological markers, they involve great heterogeneity across multiple levels (genes, systemic biological and brain characteristics, and nuances of behavioral manifestations)-and yet everyone with this diagnosis meets the same defining behavioral criteria. Using the human gene list from Simons Foundation Autism Research Initiative (SFARI) we performed gene set enrichment analysis with the Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Database, and then derived a pathway network from pathway-pathway functional interactions again in reference to KEGG. Through identifying the GO (Gene Ontology) groups in which SFARI genes were enriched, mapping the coherence between pathways and GO groups, and ranking the relative strengths of representation of pathway network components, we 1) identified 10 disease-associated and 30 function-associated pathways 2) revealed calcium signaling pathway and neuroactive ligand-receptor interaction as the most enriched, statistically significant pathways from the enrichment analysis, 3) showed calcium signaling pathways and MAPK signaling pathway to be interactive hubs with other pathways and also to be involved with pervasively present biological processes, 4) found convergent indications that the process "calcium-PRC (protein kinase C)-Ras-Raf-MAPK/ERK" is likely a major contributor to ASD pathophysiology, and 5) noted that perturbations associated with KEGG's category of environmental information processing were common. These findings support the idea that ASD-associated genes may contribute not only to core features of ASD themselves but also to vulnerability to other chronic and systemic problems potentially including cancer, metabolic conditions and heart diseases. ASDs may thus arise, or emerge, from underlying vulnerabilities related to pleiotropic genes associated with pervasively important molecular mechanisms, vulnerability to environmental input and multiple systemic co-morbidities.