Gut microbiota dysbiosis is linked to Alzheimer’s disease (AD), but our understanding of the molecular and neuropathological bases underlying such association remains fragmentary. Using 16S rDNA amplicon sequencing, untargeted metabolomics, and multi-modal magnetic resonance imaging, we examined group differences in gut microbiome, fecal metabolome, neuroimaging measures, and cognitive variables across 30 patients with AD, 75 individuals with mild cognitive impairment (MCI), and 61 healthy controls (HC). Furthermore, we assessed the associations between these multi-omics changes using correlation and mediation analyses. There were significant group differences in gut microbial composition, which were driven by 8 microbial taxa (e.g., Staphylococcus and Bacillus) exhibiting a progressive increase in relative abundance from HC to MCI to AD, and 2 taxa (e.g., Anaerostipes) showing a gradual decrease. 26 fecal metabolites (e.g., Arachidonic, Adrenic, and Lithocholic acids) exhibited a progressive increase from HC to MCI to AD. We also observed progressive gray matter atrophy in broadly distributed gray matter regions and gradual micro-structural integrity damage in widespread white matter tracts along the AD continuum. Integration of these multi-omics changes revealed significant associations between microbiota, metabolites, neuroimaging, and cognition. More importantly, we identified two potential mediation pathways: (1) microbiota → metabolites → neuroimaging → cognition, and (2) microbiota → metabolites → cognition. Aside from elucidating the underlying mechanism whereby gut microbiota dysbiosis is linked to AD, our findings may contribute to groundwork for future interventions targeting the microbiota-metabolites-brain-cognition pathways as a therapeutic strategy in the AD continuum.

White matter hyperintensities (WMHs) of presumed vascular origin are one of the most important neuroimaging markers of cerebral small vessel disease (CSVD), which are closely associated with cognitive impairment. The aim of this study was to elucidate the pathogenesis of WMHs from the perspective of inflammation and hypoperfusion mechanisms. A total of 65 patients with WMHs and 65 healthy controls were enrolled in this study. Inflammatory markers measurements [hypersensitive C-reactive protein (hsCRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2)], cognitive evaluation, and pseudocontinuous arterial spin labeling (PCASL) MRI scanning were performed in all the subjects. The multivariate logistic regression analysis showed that Lp-PLA2 was an independent risk factor for WMHs. Cerebral blood flow (CBF) in the whole brain, gray matter (GM), white matter (WM), left orbital medial frontal gyrus [MFG.L (orbital part)], left middle temporal gyrus (MTG.L), and right thalamus (Tha.R) in the patients was lower than those in the controls and CBF in the left triangular inferior frontal gyrus [IFG.L (triangular part)] was higher in the patients than in the controls. There was a significant correlation between Lp-PLA2 levels and CBF in the whole brain (R = −0.417, p < 0.001) and GM (R = −0.278, p = 0.025), but not in the WM in the patients. Moreover, CBF in the MFG.L (orbital part) and the Tha.R was, respectively, negatively associated with the trail making test (TMT) and the Stroop color word test (SCWT), suggesting the higher CBF, the better executive function. The CBF in the IFG.L (triangular part) was negatively correlated with attention scores in the Cambridge Cognitive Examination-Chinese Version (CAMCOG-C) subitems (R = −0.288, p = 0.020). Our results revealed the vascular inflammation roles in WMHs, which may through the regulation of CBF in the whole brain and GM. Additionally, CBF changes in different brain regions may imply a potential role in the modulation of cognitive function in different domains.

Patients who survive critical illness commonly suffer cognitive impairments. We aimed to study the effects of cognitive intervention to treat the long-term impairments observed among different populations of intensive care unit (ICU) survivors. The results showed that the intervention significantly suppressed the deterioration of cognitive function in these patients. Medical and neurological ICU survivors were more susceptible than post-anaesthesia ICU patients to severe cognitive damage. In the former, the deterioration of impairments can be slowed by cognitive intervention. In comparison, intervention exerted significantly positive effects on the recovery of the cognitive functions of post-anaesthesia care unit patients. Furthermore, young populations were more likely than older populations to recover from acute cognitive impairments, and the impairment observed among the older population seemed to be multi-factorial and irreversible.

Prior efforts have revealed changes in gut microbiome, circulating metabolome, and multimodal neuroimaging features in cerebral small vessel disease (CSVD). However, there is a paucity of research integrating the multi-omic information to characterize the role of the microbiota-gut-brain axis in CSVD. We collected gut microbiome, fecal and blood metabolome, multimodal magnetic resonance imaging data from 37 CSVD patients with white matter hyperintensities and 46 healthy controls. Between-group comparison was performed to identify the differential gut microbial taxa, followed by performance of multi-stage microbiome-metabolome-neuroimaging-neuropsychology correlation analyses in CSVD patients. Our data showed both depleted and enriched gut microbes in CSVD patients. Among the differential microbes, Haemophilus and Akkermansia were associated with a range of metabolites enriched for Aminoacyl-tRNA biosynthesis pathway. Furthermore, the affected metabolites were associated with neuroimaging measures involving gray matter morphology, spontaneous intrinsic brain activity, white matter integrity, and global structural network topology, which were in turn related to cognition and emotion in CSVD patients. Our findings provide an integrative framework to understand the pathophysiological mechanisms underlying the interplay between gut microbiota dysbiosis and CSVD, highlighting the potential of targeting the microbiota-gut-brain axis as a therapeutic strategy in CSVD patients.

Background: Both Alzheimer's disease (AD) and cerebral small vessel disease (CSVD) manifest in cognitive impairment and gait disorders. The precise similarities and differences in gait characteristics and underlying neuroimaging mechanisms remain unclear.Methods: A total of 399 participants were enrolled: 132 with probable AD, including 98 with mild cognitive impairment due to AD (AD‐MCI) and 34 with AD dementia, and 185 with CSVD and 82 healthy controls. CSVD patients with cognitive impairment, including subcortical vascular mild cognitive impairment (svMCI) and subcortical vascular dementia, were grouped as subcortical vascular cognitive impairment (SVCI). Voxel‐based morphology analysis assessed grey matter volume (GMV), while cerebral blood flow (CBF) was derived from 3D‐arterial spin labelling data. Gait metrics included the timed up and go (TUG) test, dual‐task TUG (DTUG) test, Berg balance scale (BBS), dual‐task cost (DTC), step length, gait speed, cadence and coefficient of variation of gait. The relationships among structural and perfusion variations, gait metrics and cognitive function were examined.Results: SVCI patients exhibited greater gait impairments and variability than those with AD, while AD patients experienced higher DTC (p < 0.05). These differences were most evident in the MCI stage. In AD, gait speed correlated with GMV in the left middle occipital gyrus (F = 6.149), middle temporal gyrus (F = 4.595), right precuneus (F = 5.174) and other regions (all p < 0.025). In SVCI, gait speed was linked to thalamic GMV (F = 6.004, p < 0.025). Altered CBF in the parietal lobe and precuneus was associated with DTUG (F = 5.672), gait speed (F = 4.347) and BBS (F = 4.153) in AD, while cerebellar CBF related to TUG (F = 6.042), DTUG (F = 4.857) and BBS (F = 7.097) in SVCI (all p < 0.025). In AD‐MCI, memory mediated the effect of hippocampal volume on DTC (indirect effect: −2.432, 95% CI [−5.503, −0.438]), while executive function (indirect effect: −2.920, 95% CI [−7.227, −0.695]) and processing speed (indirect effect: −2.286, 95% CI [−5.174, −0.484]) mediated the effect on DTUG. In svMCI, executive function mediated the effect of thalamic volume on step length (indirect effect: 2.309, 95% CI [0.486, 4.685]) and gait speed (indirect effect: 2.029, 95% CI [0.142, 4.588]), while processing speed mediated the effect on step length (indirect effect: 1.777, 95% CI [0.311, 4.021]).Conclusions: Different gait disorder characteristics and mechanisms were observed in AD and CSVD patients. In AD, gait is associated with volume/perfusion in posterior brain regions, whereas in SVCI, it relates to thalamic volume and cerebellar perfusion. Cognitive impairment mediates the effect of hippocampal and thalamic volumes on gait in AD‐MCI and svMCI, respectively.

Objective: While emerging evidence links glymphatic dysfunction to cerebral small vessel disease (CSVD), its clinical relevance remains poorly defined. This study aimed to investigate the relationships among glymphatic function, perivascular space (PVS), and cognitive performance in CSVD. Methods: We enrolled 120 CSVD patients [52 with no cognitive impairment (CSVD-NCI) and 68 with mild cognitive impairment (CSVD-MCI)] and 40 healthy controls (HCs). Glymphatic function was assessed using the left ALPS index derived from diffusion tensor imaging analysis along the perivascular space (DTI-ALPS). Group comparisons in the ALPS index and PVS volume fraction (VF), and correlations among glymphatic function, PVS burden, and cognition were analyzed. Results: Compared to HCs, CSVD patients showed decreased ALPS index and increased PVS VF in basal ganglia (BG), caudate, putamen, and hippocampus, with more pronounced alterations in the left hemisphere. The ALPS index was inversely correlated with PVS VF in the BG ( r = −0.232, p = 0.014), thalamus ( r = −0.213, p = 0.024), caudate ( r = −0.221, p = 0.019), and putamen ( r = −0.210, p = 0.026) in CSVD. Furthermore, a lower ALPS index was associated with poorer performance in global cognition ( r = 0.312, p = 0.001), executive function ( r = 0.242, p = 0.012), processing speed ( r = 0.264, p = 0.006), and visuospatial function ( r = 0.272, p = 0.004). Finally, the ALPS index partially mediated the association between putamen-PVS VF and global cognitive function, especially in the left hemisphere. Conclusion: Our findings demonstrate that impaired glymphatic function was associated with enlarged BG-PVS, especially in the putamen, and worse cognitive performance, highlighting its potential role in disease progression and cognitive decline in CSVD.