Liver transplantation (LT) improves daily function and cognition in patients with cirrhosis, but a subset of patients can remain impaired. Unfavorable microbiota or dysbiosis is observed in patients ...with cirrhosis, but the effect of LT on microbial composition, especially with poor post‐LT cognition, is unclear. The aims were to determine the effect of LT on gut microbiota and to determine whether gut microbiota are associated with cognitive dysfunction after LT. We enrolled outpatient patients with cirrhosis on the LT list and followed them until 6 months after LT. Cognition (Psychometric Hepatic Encephalopathy score PHES), health‐related quality of life (HRQOL), and stool microbiota (multitagged sequencing for diversity and taxa) tests were performed at both visits. Persistent cognitive impairment was defined as a stable/worsening PHES. Both pre‐/post‐LT data were compared with age‐matched healthy controls. We enrolled 45 patients (56 ± 7 years, Model for End‐Stage Liver Disease score 26 ± 8). They received LT 6 ± 3 months after enrollment and were re‐evaluated 7 ± 2 months after LT with a stable course. A significantly improved HRQOL, PHES, with increase in microbial diversity, increase in autochthonous, and decrease in potentially pathogenic taxa were seen after LT compared with baseline. However, there was continued dysbiosis and HRQOL/cognitive impairment after LT compared with controls in 29% who did not improve PHES after LT. In these, Proteobacteria relative abundance was significantly higher and Firmicutes were lower after LT, whereas the reverse occurred in the group that improved. Delta PHES was negatively correlated with delta Proteobacteria and positively with delta Firmicutes. In conclusion, LT improves gut microbiota diversity and dysbiosis compared with pre‐LT baseline but residual dysbiosis remains compared with controls. There is cognitive and HRQOL enhancement in general after LT, but a higher Proteobacteria relative abundance change is associated with posttransplant cognitive impairment. Liver Transplantation 23 907–914 2017 AASLD.
Background & Aims Hyponatraemia in cirrhosis is associated with impaired cognition and poor health-related quality of life (HRQOL). However, the benefit of hyponatraemia correction is unclear. The ...aim of this study was to evaluate the effect of tolvaptan on serum sodium (Na), cognition, HRQOL, companion burden, and brain MRI (volumetrics, spectroscopy, and diffusion tensor imaging) in cirrhotics with hyponatraemia. Methods Cirrhotics with Na <130 mEq/L were included for a four-week trial. At screening, patients underwent cognitive and HRQOL testing, serum/urine chemistries and companion burden assessment. Patients then underwent fluid restriction and diuretic withdrawal for two weeks after which cognitive tests were repeated. If Na was still <130 mEq/L, brain magnetic resonance imaging (MRI) was performed and tolvaptan was initiated for 14 days with frequent clinical/laboratory monitoring. After 14 days of tolvaptan, all tests were repeated. Comparisons were made between screen, pre-and post-drug periods Na, urine/serum laboratories, cognition, HRQOL and companion burden. Results 24 cirrhotics were enrolled; seven normalized Na without tolvaptan with improvement in cognition. The remaining 17 received tolvaptan of which 14 completed the study over 13 ± 2 days (age 58 ± 6 years, MELD 17, 55% HCV, median 26 mg/day of tolvaptan). Serum Na and urine free water clearance increased with tolvaptan without changes in mental status or liver function. Cognitive function, HRQOL and companion burden only improved in these 14 patients after tolvaptan, along with reduced total brain and white matter volume, increase in choline on magnetic resonance spectroscopy, and reduced cytotoxic oedema. Conclusions Short-term tolvaptan therapy is well tolerated in cirrhosis. Hyponatraemia correction is associated with cognitive, HRQOL, brain MRI and companion burden improvement.
Cognitive difficulties manifested by the growing elderly population with cirrhosis could be amnestic (memory-related) or non-amnestic (memory-unrelated). The underlying neuro-biological and gut-brain ...changes are unclear in this population. We aimed to define gut-brain axis alterations in elderly cirrhotics compared to non-cirrhotic individuals based on presence of cirrhosis and on neuropsychological performance. Age-matched outpatients with/without cirrhosis underwent cognitive testing (amnestic/non-amnestic domains), quality of life (HRQOL), multi-modal MRI (fMRI go/no-go task, volumetry and MR spectroscopy), blood (inflammatory cytokines) and stool collection (for microbiota). Groups were studied based on cirrhosis/not and also based on neuropsychological performance (amnestic-type, amnestic/non-amnestic-type and unimpaired). Cirrhotics were impaired on non-amnestic and selected amnestic tests, HRQOL and systemic inflammation compared to non-cirrhotics. Cirrhotics demonstrated significant changes on MR spectroscopy but not on fMRI or volumetry. Correlation networks showed that Lactobacillales members were positively while Enterobacteriaceae and Porphyromonadaceae were negatively linked with cognition. Using the neuropsychological classification amnestic/non-amnestic-type individuals were majority cirrhosis and had worse HRQOL, higher inflammation and decreased autochthonous taxa relative abundance compared to the rest. This classification also predicted fMRI, MR spectroscopy and volumetry changes between groups. We conclude that gut-brain axis alterations may be associated with the type of neurobehavioral decline or inflamm-aging in elderly cirrhotic subjects.
Background & Aims Hyponatremia (HN) and hepatic encephalopathy (HE) together can impair health-related quality of life (HRQOL) and cognition in cirrhosis. We aimed at studying the effect of ...hyponatremia on cognition, HRQOL, and brain MR spectroscopy (MRS) independent of HE. Methods Four cirrhotic groups (no HE/HN, HE alone, HN alone (sodium <130 mEq/L), HE + HN) underwent cognitive testing, HRQOL using Sickness Impact Profile (SIP: higher score is worse; has psychosocial and physical sub-scores) and brain MRS (myoinositol (mI) and glutamate + glutamine (Glx)), which were compared across groups. A subset underwent HRQOL testing before/after diuretic withdrawal. Results 82 cirrhotics (30 no HE/HN, 25 HE, 17 HE + HN, and 10 HN, MELD 12, 63% hepatitis C) were included. Cirrhotics with HN alone and without HE/HN had better cognition compared to HE groups (median abnormal tests no-HE/HN: 3, HN: 3.5, HE: 6.5, HE + HN: 7, p = 0.008). Despite better cognition, HN only patients had worse HRQOL in total and psychosocial SIP while both HN groups (with/without HE) had a significantly worse physical SIP ( p <0.0001, all comparisons). Brain MRS showed the lowest Glx in HN and the highest in HE groups ( p <0.02). mI levels were comparably decreased in the three affected (HE, HE + HN, and HN) groups compared to no HE/HN and were associated with poor HRQOL. Six HE + HN cirrhotics underwent diuretic withdrawal which improved serum sodium and total/psychosocial SIP scores. Conclusions Hyponatremic cirrhotics without HE have poor HRQOL despite better cognition than those with concomitant HE. Glx levels were lowest in HN without HE but mI was similar across affected groups. HRQOL improved after diuretic withdrawal. Hyponatremia has a complex, non-linear relationship with brain Glx and mI, cognition and HRQOL.
Human vestibular processing involves distributed networks of cortical and subcortical regions which perform sensory and multimodal integrative functions. These functional hubs are also interconnected ...with areas subserving cognitive, affective, and body-representative domains. Analysis of these diverse components of the vestibular and vestibular-associated networks, and synthesis of their holistic functioning, is therefore vital to our understanding of the genesis of vestibular dysfunctions and aid treatment development. Novel neuroimaging methodologies, including functional and structural connectivity analyses, have provided important contributions in this area, but often require the use of atlases which are comprised of well-defined a priori regions of interest. Investigating vestibular dysfunction requires a more detailed atlas that encompasses cortical, subcortical, cerebellar, and brainstem regions. The present paper represents an effort to establish a compilation of existing, peer-reviewed brain atlases which collectively afford comprehensive coverage of these regions while explicitly focusing on vestibular substrates. It is expected that this compilation will be iteratively improved with additional contributions from researchers in the field.
Patients with cirrhosis are growing older, which could have an impact on brain dysfunction beyond hepatic encephalopathy. Our aim was to study the effect of concomitant aging and cirrhosis on brain ...inflammation and degeneration using human and animal experiments. For the human study, age‐matched patients with cirrhosis and controls between 65 and 85 years underwent cognitive testing, quality of life (QOL) assessment, and brain magnetic resonance (MR) spectroscopy and resting state functional MR imaging (rs‐fMRI) analysis. Data were compared between groups. For the animal study, young (10‐12 weeks) and old (1.5 years) C57BL/6 mice were given either CCl4 gavage to develop cirrhosis or a vehicle control and were followed for 12 weeks. Cortical messenger RNA (mRNA) expression of inflammatory mediators (interleukin IL‐6, IL‐1β, transforming growth factor β TGF‐β, and monocyte chemoattractant protein 1), sirtuin‐1, and gamma‐aminobutyric acid (GABA)‐ergic synaptic plasticity (neuroligin‐2 NLG2, discs large homolog 4 DLG4, GABA receptor, subunit gamma 1/subunit B1 GABRG1/B1) were analyzed and compared between younger/older control and cirrhotic mice. The human study included 46 subjects (23/group). Patients with cirrhosis had worse QOL and cognition. On MR spectroscopy, patients with cirrhosis had worse changes related to ammonia and lower N‐acetyl aspartate, whereas rs‐fMRI analysis revealed that these patients demonstrated functional connectivity changes in the frontoparietal cortical region compared to controls. Results of the animal study showed that older mice required lower CCl4 to reach cirrhosis. Older mice, especially with cirrhosis, demonstrated higher cortical inflammatory mRNA expression of IL‐6, IL‐1β, and TGF‐β; higher glial and microglial activation; and lower sirtuin‐1 expression compared to younger mice. Older mice also had lower expression of DLG4, an excitatory synaptic organizer, and higher NLG2 and GABRG1/B1 receptor expression, indicating a predominantly inhibitory synaptic organization. Conclusion: Aging modulates brain changes in cirrhosis; this can affect QOL, cognition, and brain connectivity. Cortical inflammation, microglial activation, and altered GABA‐ergic synaptic plasticity could be contributory.
Older age synergizes with cirrhosis to alter brain function and connectivity, which is associated with a poor quality of life. This could be potentially through effects on neuro‐inflammation, microglial activation, synaptic plasticity and GABA receptor expression in the cerebral cortex.
Cirrhosis is associated with brain dysfunction known as hepatic encephalopathy (HE). The mechanisms behind HE are unclear although hyperammonemia and systemic inflammation through gut dysbiosis have ...been proposed. We aimed to define the individual contribution of specific gut bacterial taxa towards astrocytic and neuronal changes in brain function using multi-modal MRI in patients with cirrhosis. 187 subjects (40 controls, 147 cirrhotic; 87 with HE) underwent systemic inflammatory assessment, cognitive testing, stool microbiota analysis and brain MRI analysis. MR spectroscopy (MRS) changes of increased Glutamate/glutamine, reduced myo-inositol and choline are hyperammonemia-associated astrocytic changes, while diffusion tensor imaging (DTI) demonstrates changes in neuronal integrity and edema. Linkages between cognition, MRI parameters and gut microbiota were compared between groups. We found that HE patients had a significantly worse cognitive performance, systemic inflammation, dysbiosis and hyperammonemia compared to controls and cirrhotics without HE. Specific microbial families (autochthonous taxa negatively and Enterobacteriaceae positively) correlated with MR spectroscopy and hyperammonemia-associated astrocytic changes. On the other hand Porphyromonadaceae, were only correlated with neuronal changes on DTI without linkages with ammonia. We conclude that specific gut microbial taxa are related to neuronal and astrocytic consequences of cirrhosis-associated brain dysfunction.
Convergent clinical and neuroimaging evidence suggests that higher vestibular function is subserved by a distributed network including visuospatial, cognitive–affective, proprioceptive, and ...integrative brain regions. Clinical vestibular syndromes may perturb this network, resulting in deficits across a variety of functional domains. Here, we leverage structural and functional neuroimaging to characterize this extended network in healthy control participants and patients with post‐concussive vestibular dysfunction (PCVD). Then, 27 healthy control subjects (15 females) and 18 patients with subacute PCVD (12 female) were selected for participation. Eighty‐two regions of interest (network nodes) were identified based on previous publications, group‐wise differences in BOLD signal amplitude and connectivity, and multivariate pattern analysis on affective tests. Group‐specific “core” networks, as well as a “consensus” network comprised of connections common to all participants, were then generated based on probabilistic tractography and functional connectivity between the 82 nodes and subjected to analyses of node centrality and community structure. Whereas the consensus network was comprised of affective, integrative, and vestibular nodes, PCVD participants exhibited diminished integration and centrality among vestibular and affective nodes and increased centrality of visual, supplementary motor, and frontal and cingulate eye field nodes. Clinical outcomes, derived from dynamic posturography, were associated with approximately 62% of all connections but best predicted by amygdalar, prefrontal, and cingulate connectivity. No group‐wise differences in diffusion metrics or tractography were noted. These findings indicate that cognitive, affective, and proprioceptive substrates contribute to vestibular processing and performance and highlight the need to consider these domains during clinical diagnosis and treatment planning.
Convergent clinical and neuroimaging evidence suggests that higher vestibular function is subserved by a distributed network including visuospatial, cognitive–affective, proprioceptive, and integrative brain regions. In this article, we leverage structural and functional neuroimaging to characterize an extended vestibular‐cognitive network in twenty‐seven healthy control participants and eighteen patients with post‐concussive vestibular dysfunction (PCVD), determine commonalities between control and PCVD patients as a “consensus” network, and describe network differences corresponding to clinical outcomes.
BACKGROUND: Cirrhosis-related cognitive dysfunction can result in car crashes due to impaired navigation skills & slowed reaction times. There is insufficient understanding of the neural basis of ...this impairment. AIM: Determine feasibility of using an MRI-compatible functional MRI (fMRI) driving simulator and differences in performance of cirrhotics vs controls. METHODS: We recruited cirrhotic outpatients and controls between ages 25–70 years, were current drivers, were candidates for MRI & free of alcohol/drug use. Cirrhotics did not have active HE. All subjects underwent an fMRI-compatible task consisting of simulated driving on a single lane highway. The simulation presented 4 blocks of 4 scenarios (1) straight section (SS) (2) Curved highway without oncoming traffic in the opposite lane (No Traffic) (3) Curved highway with oncoming traffic in the opposite lane (Traffic) and (4) Curved highway with oncoming traffic while responding to a ringing cellphone (Traffic+Distractor), Figure 1a,b. Contrast images between curved sections were created. SS was used as a baseline. Group-analysis was performed for each group using these three contrasts via human connectome project guidelines. RESULTS: Seven cirrhotic patients MELD 7 (6, 11), 4 HCV, 2 Alcohol 1 NASH and five controls completed the study. Controls & cirrhotics had statistically similar age 60 ± 15.5 vs 61.8 ± 10, P = 0.08, and gender (men 50% vs 20%, P = 0.3). Patients and controls had similar driving duration of driving 44 (42, 50) vs 45 (24, 51), P = 0.48. On MRI driving simulation- Mean activations: As the driving task complexity increased from No-traffic to Traffic to Traffic+Distractor states, we observed a shift of increased activation from parietal (precuneus, supramarginal and angular gyri) and visual (lingual gyrus, V1 and V2) to frontal (dorsolateral prefrontal cortex, anterior cingulate cortex), and sub-lobar regions (caudate, putamen, pallidum, insula, and thalamus). This pattern reveals a gradual shift from basic visuo-spatial to complex performance brain regions regardless of control or cirrhosis group. Between-group activations: During both Traffic and Traffic+Distractor conditions, cirrhotic patients showed significantly lower activation than controls in brain regions associated with top-down attentional processing (posterior cingulate cortex), error detection and conflict monitoring (anterior cingulate cortex), attentional resource allocation (paracingulate gyrus), visual attention regulation (superior parietal lobule), inhibitory control (left middle frontal gyrus) and regions associated with regulation of voluntary movement (left pallidum, putamen) (Figure 1c). CONCLUSIONS: Using MRI-compatible driving simulation, patients with cirrhosis demonstrated suppressed attention regulation circuits and sensorimotor control compared to controls, which worsened when distractors such as cellphone use were included. This is likely the neural basis for impaired driving skills in cirrhosis.
ABSTRACT
BACKGROUND AND PURPOSE
Vestibular symptoms after concussion are common and associated with protracted recovery. The purpose of this study is to define resting‐state functional MRI (rs‐fMRI) ...brain connectivity alterations in patients with postconcussion vestibular dysfunction (PCVD) and correlations between rs‐fMRI connectivity and symptoms provoked during Vestibular/Ocular‐Motor Screening (VOMS) assessment.
METHODS
Prospective IRB approved study. Study group: 12 subjects with subacute PCVD (2‐10 weeks); control group: 10 age‐matched subjects without history of concussion or vestibular impairment. Both groups underwent clinical vestibular assessment. rs‐fMRI was acquired on 3.0T Siemens Trio with a 12‐channel head coil. rs‐fMRI data analysis included independent component analysis‐based functional connectivity group differences, graph theory analysis, and ROI‐to‐ROI connectivity correlation analysis with VOMS clinical derivatives. Group difference maps between resting‐state networks were calculated using dual regression method and corrected for multiple comparisons. Correlation analysis between ROI‐to‐ROI rs‐fMRI brain activation and VOMS assessment ratings was performed using Pearson correlation coefficient, with a significance threshold of P ≤ .05.
RESULTS
Compared to controls, PCVD group demonstrated significantly increased rs‐fMRI connectivity between the default‐mode network and right middle frontal gyrus and right postcentral gyrus; and between a vestibular‐sensorimotor network and right prefrontal cortex. Significant positive correlations were found between clinical derivative VOMS scores and components of the vestibular, visual networks, and multisensory processing cortical representations.
CONCLUSION
Altered rs‐fMRI brain connectivity with increased connectivity of visual input, multisensory processing, and spatial memory in PCVD is correlative with clinical derivative VOMS scores, suggesting maladaptive brain plasticity underlying vestibular symptomatology.
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