Gray matter atrophy, glucose hypometabolism, and ␤-amyloid A␤ deposition are well-described hallmarks of Alzheimer's disease, but their relationships are poorly understood. The present study aims to compare the local levels of these three alterations in humans with Alzheimer's disease. Structural magnetic resonance imaging, 18 F-fluorodeoxyglucose positron emission tomography (PET), and 18 Fflorbetapir PET data from 34 amyloid-negative healthy controls and 20 demented patients with a high probability of Alzheimer's disease etiology (attested using neuroimaging biomarkers as recently recommended) were analyzed. For each patient and imaging modality, age-adjusted Z-score maps were computed, and direct between-modality voxelwise comparison and correlation analyses were performed. Significant differences in the levels of atrophy, hypometabolism, and A␤ deposition were found in most brain areas, but the hierarchy differed across regions. A cluster analysis revealed distinct subsets of regions: (1) in the hippocampus, atrophy exceeded hypometabolism, whereas A␤ load was minimal; (2) in posterior association areas, A␤ deposition was predominant, together with high hypometabolism and lower but still significant atrophy; and (3) in frontal regions, A␤ deposition was maximal, whereas structural and metabolic alterations were low. Atrophy and hypometabolism significantly correlated in the hippocampus and temporo-parietal cortex, whereas A␤ load was not significantly related to either atrophy or hypometabolism. These findings provide direct evidence for regional variations in the hierarchy and relationships between A␤ load, hypometabolism, and atrophy. Altogether, these variations probably reflect the differential involvement of region-specific pathological or protective mechanisms, such as the presence of neurofibrillary tangles, disconnection, as well as compensation processes.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease characterized by an extensive fibroinflammatory stroma, which includes abundant cancer-associated fibroblast (CAF) populations. PDAC CAFs are heterogeneous, but the nature of this heterogeneity is incompletely understood. The Hedgehog pathway functions in PDAC in a paracrine manner, with ligands secreted by cancer cells signaling to stromal cells in the microenvironment. Previous reports investigating the role of Hedgehog signaling in PDAC have been contradictory, with Hedgehog signaling alternately proposed to promote or restrict tumor growth. In light of the newly discovered CAF heterogeneity, we investigated how Hedgehog pathway inhibition reprograms the PDAC microenvironment.Experimental Design: We used a combination of pharmacologic inhibition, gain-and loss-of-function genetic experiments, cyto-metry by time-of-flight, and single-cell RNA sequencing to study the roles of Hedgehog signaling in PDAC.Results: We found that Hedgehog signaling is uniquely activated in fibroblasts and differentially elevated in myofibroblastic CAFs (myCAF) compared with inflammatory CAFs (iCAF). Sonic Hedgehog overexpression promotes tumor growth, while Hedgehog pathway inhibition with the smoothened antagonist, LDE225, impairs tumor growth. Furthermore, Hedgehog pathway inhibition reduces myCAF numbers and increases iCAF numbers, which correlates with a decrease in cytotoxic T cells and an expansion in regulatory T cells, consistent with increased immunosuppression.Conclusions: Hedgehog pathway inhibition alters fibroblast composition and immune infiltration in the pancreatic cancer microenvironment.

Neuroimaging biomarkers, namely hippocampal volume loss, temporoparietal hypometabolism, and neocortical ␤-amyloid (A␤) deposition, are included in the recent research criteria for preclinical Alzheimer's disease (AD). However, how to use these biomarkers is still being debated, especially regarding their sequence. Our aim was to characterize the cognitive and brain profiles of elders classified as positive or negative for each biomarker to further our understanding of their use in the preclinical diagnosis of AD. Fifty-four cognitively normal individuals (age ϭ 65.8 Ϯ 8.3 years) underwent neuropsychological tests (structural MRI, FDG-PET, and Florbetapir-PET) and were dichotomized into positive or negative independently for each neuroimaging biomarker. Demographic, neuropsychological, and neuroimaging data were compared between positive and negative subgroups. The MRI-positive subgroup had lower executive performances and mixed patterns of lower volume and metabolism in AD-characteristic regions and in the prefrontal cortex. The FDG-positive subgroup showed only hypometabolism, predominantly in AD-sensitive areas extending to the whole neocortex, compared with the FDG-negative subgroup. The amyloid-positive subgroup was older and included more APOE 4 carriers compared with the amyloidnegative subgroup. When considering MRI and/or FDG biomarkers together (i.e., the neurodegeneration-positive), there was a trend for an inverse relationship with A␤ deposition such that those with neurodegeneration tended to show less A␤ deposition and the reverse was true as well. Our findings suggest that: (1) MRI and FDG biomarkers provide complementary rather than redundant information and (2) relatively young cognitively normal elders tend to have either neurodegeneration or A␤ deposition, but not both, suggesting additive rather than sequential/causative links between AD neuroimaging biomarkers at this age. Key words: Alzheimer's disease; amyloid; biomarkers; FDG; MRI; PET Significance StatementNeuroimaging biomarkers are included in the recent research criteria for preclinical Alzheimer's disease (AD). However, how to use these biomarkers is still being debated, especially regarding their sequence. Our findings suggest that MRI and FDG-PET biomarkers should be used in combination, offering an additive contribution instead of reflecting the same process of neurodegeneration. Moreover, the present study also challenges the hierarchical use of the neuroimaging biomarkers in preclinical AD because it suggests that the neurodegeneration observed in this population is not due to ␤-amyloid deposition. Rather, our results suggest that ␤-amyloid-and tau-related pathological processes may interact but not necessarily appear in a systematic sequence.

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This radiotracer merits further evaluation to establish its clinical usefulness to image low-grade lymphoma in humans in future clinical investigations.

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 Question: Which brain changes are associated with sleep-disordered breathing (SDB) in aging?  Findings: In this cross-sectional study of 127 cognitively unimpaired communitydwelling older individuals, the presence of SDB was associated with greater amyloid burden, gray matter volume, metabolism, and perfusion in the posterior cingulate cortex and precuneus. There was no association with cognitive performance, selfreported cognitive or sleep difficulties, nor excessive daytime sleepiness.  Meaning: SDB-related changes include amyloid deposition in brain regions typically involved in Alzheimer's disease (AD), which might explain why SDB is associated with an increased risk for developing Alzheimer's clinical syndrome at a younger age.

Semantic memory has been investigated in numerous neuroimaging and clinical studies, most of which have used verbal or visual, but only very seldom, musical material. Clinical studies have suggested that there is a relative neural independence between verbal and musical semantic memory. In the present study, "musical semantic memory" is defined as memory for "well-known" melodies without any knowledge of the spatial or temporal circumstances of learning, while "verbal semantic memory" corresponds to general knowledge about concepts, again without any knowledge of the spatial or temporal circumstances of learning. Our aim was to compare the neural substrates of musical and verbal semantic memory by administering the same type of task in each modality. We used high-resolution PET H(2)O(15) to observe 11 young subjects performing two main tasks: (1) a musical semantic memory task, where the subjects heard the first part of familiar melodies and had to decide whether the second part they heard matched the first, and (2) a verbal semantic memory task with the same design, but where the material consisted of well-known expressions or proverbs. The musical semantic memory condition activated the superior temporal area and inferior and middle frontal areas in the left hemisphere and the inferior frontal area in the right hemisphere. The verbal semantic memory condition activated the middle temporal region in the left hemisphere and the cerebellum in the right hemisphere. We found that the verbal and musical semantic processes activated a common network extending throughout the left temporal neocortex. In addition, there was a material-dependent topographical preference within this network, with predominantly anterior activation during musical tasks and predominantly posterior activation during semantic verbal tasks.