Background: The diffusion tensor imaging analysis along the perivascular space (ALPS)‐index can be used to model the glymphatic system in vivo.Aim: This study explores putative mechanisms between prediction of ALPS‐index and cognitive outcomes in young‐onset Alzheimer's disease (YOAD) and age‐matched controls (CTLs) and analyzes whether the link was mediated by the integrity of ALPS‐index‐anchored cerebral gray matter (GM).Methods: We enrolled 130 patients with YOAD and 137 CTLs. All participants underwent three‐dimensional T₁‐weighted MRI, diffusion tensor imaging and cognitive tests. We constructed GM regions correlated with the ALPS‐index in the YOAD and CTL groups. For the GM regions significantly correlated with the ALPS‐index and cognitive measures, we extracted a 4‐mm radius sphere. In the YOAD and CTL groups, we used mediator analysis to explore the ALPS‐index as predictor, GM partitions as mediators, and significant cognitive test scores as outcomes.Results: Patient group had significantly lower ALPS‐index. The ALPS‐index was associated with GM volume in the cerebellar gray, dorsolateral prefrontal, thalamus, superior frontal, amygdala and hippocampus, and these coherent regions coincided with those showing GM atrophy in the YOAD group. Mediation analysis of the YOAD group suggested that the relationships between the ALPS‐index and cognitive performance were fully mediated by the integrity of ALPS‐index coherent GM areas.Discussion: Reserved GM mediates the link between the glymphatic system and cognition. Our findings suggest that GM integrity rather than the glymphatic system could serve as a direct cognitive test scores predictor in patients with YOAD.

Summary: Endothelial dysfunction leads to worse cognitive performance in Alzheimer’s dementia (AD). While both cerebrovascular risk factors and endothelial dysfunction lead to activation of vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1) and E-selectin, it is not known whether these biomarkers extend the diagnostic repertoire in reflecting intracerebral structural damage or cognitive performance. A total of 110 AD patients and 50 age-matched controls were enrolled. Plasma levels of VCAM-1, ICAM-1 and E-selectin were measured and correlated with the cognitive performance, white matter macro-structural changes, and major tract-specific fractional anisotropy quantification. The AD patients were further stratified by clinical dementia rating score (mild dementia, n=60; moderate-to-severe dementia, n=50). Compared with the controls, plasma levels of VCAM-1 (p< 0.001), ICAM-1 (p=0.028) and E-selectin (p=0.016) were significantly higher in the patients, but only VCAM-1 levels significantly reflected the severity of dementia (p< 0.001). In addition, only VCAM-1 levels showed an association with macro- and micro- white matter changes especially in the superior longitudinal fasciculus (p< 0.001), posterior thalamic radiation (p=0.002), stria terminalis (p=0.002) and corpus callosum (p=0.009), and were independent of, age and cortical volume. These tracts show significant association with MMSE, short term memory and visuospatial function. Meanwhile, while VCAM-1 level correlated significantly with short-term memory (p=0.026) and drawing (p=0.025) scores in the AD patients after adjusting for age and education, the significance disappeared after adjusting for global FA. Endothelial activation, especially VCAM-1, was of clinical significance in AD that reflects macro- and micro-structural changes and poor short term memory and visuospatial function.

Fever of unknown origin (FUO) is a diagnostic challenge. This study aimed to assess the efficacy of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and gallium-67 single-photon emission computed tomography/computed tomography (67Ga SPECT/CT) in diagnosing FUO. A total of 68 patients with FUO underwent 18F-FDG PET/CT and 67Ga SPECT/CT from January 2013 through May 2016. Images were read independently. The imaging results were compared with the final diagnosis and categorized as helpful for diagnosis or non-contributory to diagnosis in the clinical setting. Associations between categorical variables were evaluated with the chi-square test or Fisher's exact test. Ten of the 68 patients were excluded. An infectious underlying disease was found in 23 patients. A malignant disorder was the cause of FUO in 10 patients. Non-infectious inflammatory disease was found in 11 patients. Adrenal insufficiency was the cause of FUO in two patients. The cause of FUO was not found for 12 patients. A high false-positive rate of 44% (7/16) was observed for 18F-FDG PET/CT, while a high false-negative rate of 55% (23/42) was observed for 67Ga SPECT/CT. 18F-FDG PET/CT studies depicted all 67Ga-avid lesions. The sensitivity (79% vs. 45%) and clinical contribution (72% vs. 55%) of 18F-FDG PET/CT in diagnosing FUO were significantly higher than those of 67Ga SPECT/CT (p<0.05). On the basis of this study, the diagnostic performance of 18F-FDG PET/CT is superior to 67Ga SPECT/CT in the work-up of patients with FUO. With its rapid results and superior sensitivity, 18F-FDG PET/CT may replace 67Ga SPECT/CT where this technique is available.