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Movement Disorders Clinical Practice Nov 2023Gait analysis objectively quantifies gait impairment in idiopathic normal pressure hydrocephalus (iNPH), may improve diagnosis and evaluation for surgical candidacy. (Review)
Review
BACKGROUND
Gait analysis objectively quantifies gait impairment in idiopathic normal pressure hydrocephalus (iNPH), may improve diagnosis and evaluation for surgical candidacy.
OBJECTIVES
This meta-analysis aims to understand which objective gait parameters improve after tap-test (TT) and CSF shunt surgery (CSS), also comparing responders (R) with non-responders (NR) and to assess if gait restores within the range of healthy controls after procedures.
METHODS
Studies enrolling iNPH with at least one instrumented gait measure were selected. Three time points of gait assessment were defined: PRE, POST-TT, and POST-CSS. Gait velocity, cadence, step length, stride length, and double limb support time were evaluated. Patients were categorized based on responsiveness to CSF diversion procedures.
RESULTS
Seventeen studies including 527 patients were selected. iNPH improved significantly in almost all gait parameters POST-TT, and to a greater extent POST-CSS. Gait parameters consistently discriminated iNPH from healthy controls. Despite the aforementioned improvements, iNPH's gait did not completely normalize after CSF diversion procedures. Meta-regression analysis also revealed that TT's effect on gait velocity plateaus after 24-48 hr and returns to baseline in 90-100 hr.
CONCLUSIONS
Gait analysis is a reliable quantitative instrument to assess gait impairment in iNPH, demarking a net differentiation from healthy controls, according to the notion that the iNPH CSF dynamic alteration also leads to an irreversible damage. Specific gait parameters improve among TT-R, providing an opportunity to select patients that will respond to CSS. Future studies validating a standardized reporting method including criteria of responsiveness, specific gait parameters, and timeframe of assessment are needed.
PubMed: 38026510
DOI: 10.1002/mdc3.13816 -
World Journal of Gastroenterology Jan 2024This comprehensive review elucidates the complex interplay between gut microbiota and constipation in Parkinson's disease (PD), a prevalent non-motor symptom... (Review)
Review
This comprehensive review elucidates the complex interplay between gut microbiota and constipation in Parkinson's disease (PD), a prevalent non-motor symptom contributing significantly to patients' morbidity. A marked alteration in the gut microbiota, predominantly an increase in the abundance of and , is observed in PD-related constipation. Conventional treatments, although safe, have failed to effectively alleviate symptoms, thereby necessitating the development of novel therapeutic strategies. Microbiological interventions such as prebiotics, probiotics, and fecal microbiota transplantation (FMT) hold therapeutic potential. While prebiotics improve bowel movements, probiotics are effective in enhancing stool consistency and alleviating abdominal discomfort. FMT shows potential for significantly alleviating constipation symptoms by restoring gut microbiota balance in patients with PD. Despite promising developments, the causal relationship between changes in gut microbiota and PD-related constipation remains elusive, highlighting the need for further research in this expanding field.
Topics: Humans; Parkinson Disease; Constipation; Fecal Microbiota Transplantation; Prebiotics; Probiotics
PubMed: 38314132
DOI: 10.3748/wjg.v30.i3.225 -
Molecular Neurodegeneration Jul 2023Previous studies show that antibiotic-mediated (abx) alteration of the gut microbiome (GMB) results in a reduction of amyloid beta (Aβ) plaques and proinflammatory...
BACKGROUND
Previous studies show that antibiotic-mediated (abx) alteration of the gut microbiome (GMB) results in a reduction of amyloid beta (Aβ) plaques and proinflammatory microglial phenotype in male APPPS1-21 mice. However, the effect of GMB perturbation on astrocyte phenotypes and microglial-astrocyte communication in the context of amyloidosis has not been examined.
METHODS
To study whether the GMB modulates astrocyte phenotype in the context of amyloidosis, APPPS1-21 male and female mice were treated with broad-spectrum abx leading to GMB perturbation. GFAP + astrocytes, plaque-associated astrocytes (PAA), PAA morphological parameters, and astrocyte complement component C3 levels were quantified using a combination of immunohistochemistry, immunoblotting, widefield microscopy, and confocal microscopy. Furthermore, these same astrocyte phenotypes were assessed in abx-treated APPPS1-21 male mice that received either fecal matter transplant (FMT) from untreated APPPS1-21 male donors to restore their microbiome or vehicle control. To assess complete absence of the GMB on astrocyte phenotypes, the same astrocyte phenotypes were quantified in APPPS1-21 male mice raised in germ-free (GF) or specific-pathogen free conditions (SPF). Lastly, we assessed whether microglia are necessary for abx-induced astrocyte phenotypes by depleting microglia in APPPS1-21 male mice via treatment with a colony-stimulating factor 1 receptor (CSF1R) inhibitor (PLX5622) and vehicle control or PLX5622 and abx.
RESULTS
Herein, we demonstrate that postnatal treatment of male APPPS1-21 mice with broad-spectrum abx leading to GMB perturbation reduces GFAP + reactive astrocytes and PAAs, suggesting that the GMB plays a role in regulating reactive astrocyte induction and recruitment to Aβ plaques. Additionally, we show that compared to controls, PAAs in abx-treated male APPPS1-21 mice exhibit an altered morphology with increased number and length of processes and reduced astrocytic complement C3, consistent with a homeostatic phenotype. GFAP + astrocyte reduction, PAA reduction, astrocyte morphological changes, and C3 levels are restored when abx-treated mice are subject to FMT from untreated APPPS1-21 male donor mice. Next, we found that APPPS1-21 male mice raised in GF conditions have similar astrocyte phenotypes as abx-treated male APPPS1-21 male mice. Correlational analysis revealed that pathogenic bacteria depleted by abx correlate with GFAP + astrocytosis, PAAs, and astrocyte morphological changes. Finally, we determined that abx-mediated reduction in GFAP + astrocytosis, PAAs, and astrocytic C3 expression is independent of microglia. However, abx-induced astrocyte morphological alterations are dependent on the presence of microglia, suggesting that there is both microglial independent and dependent GMB control of reactive astrocyte phenotypes.
CONCLUSIONS
We show for the first time, in the context of amyloidosis, that the GMB plays an important role in controlling reactive astrocyte induction, morphology, and astrocyte recruitment to Aβ plaques. GMB regulation of these astrocytic phenotypes is both independent and dependent on microglia.
Topics: Mice; Male; Female; Animals; Amyloid beta-Peptides; Alzheimer Disease; Microglia; Astrocytes; Amyloid beta-Protein Precursor; Gastrointestinal Microbiome; Mice, Transgenic; Gliosis; Amyloidosis; Plaque, Amyloid
PubMed: 37415149
DOI: 10.1186/s13024-023-00635-2 -
Frontiers in Immunology 2023Vancomycin is a broad-spectrum antibiotic widely used in cases of suspected sepsis in premature neonates. While appropriate and potentially lifesaving in this setting,...
Vancomycin is a broad-spectrum antibiotic widely used in cases of suspected sepsis in premature neonates. While appropriate and potentially lifesaving in this setting, early-life antibiotic exposure alters the developing microbiome and is associated with an increased risk of deadly complications, including late-onset sepsis (LOS) and necrotizing enterocolitis (NEC). Recent studies show that neonatal vancomycin treatment disrupts postnatal enteric nervous system (ENS) development in mouse pups, which is in part dependent upon neuroimmune interactions. This suggests that early-life antibiotic exposure could disrupt these interactions in the neonatal gut. Notably, a subset of tissue-resident intestinal macrophages, muscularis macrophages, has been identified as important contributors to the development of postnatal ENS. We hypothesized that vancomycin-induced neonatal dysbiosis impacts postnatal ENS development through its effects on macrophages. Using a mouse model, we found that exposure to vancomycin in the first 10 days of life, but not in adult mice, resulted in an expansion of pro-inflammatory colonic macrophages by increasing the recruitment of bone-marrow-derived macrophages. Single-cell RNA sequencing of neonatal colonic macrophages revealed that early-life vancomycin exposure was associated with an increase in immature and inflammatory macrophages, consistent with an influx of circulating monocytes differentiating into macrophages. Lineage tracing confirmed that vancomycin significantly increased the non-yolk-sac-derived macrophage population. Consistent with these results, early-life vancomycin exposure did not expand the colonic macrophage population nor decrease enteric neuron density in CCR2-deficient mice. Collectively, these findings demonstrate that early-life vancomycin exposure alters macrophage number and phenotypes in distinct ways compared with vancomycin exposure in adult mice and results in altered ENS development.
Topics: Mice; Animals; Vancomycin; Dysbiosis; Gastrointestinal Microbiome; Macrophages; Anti-Bacterial Agents; Neurons; Sepsis
PubMed: 37901245
DOI: 10.3389/fimmu.2023.1268909 -
Psychological Medicine Nov 2023Depression is associated with metabolic alterations including lipid dysregulation, whereby associations may vary across individual symptoms. Evaluating these...
BACKGROUND
Depression is associated with metabolic alterations including lipid dysregulation, whereby associations may vary across individual symptoms. Evaluating these associations using a network perspective yields a more complete insight than single outcome-single predictor models.
METHODS
We used data from the Netherlands Study of Depression and Anxiety ( = 2498) and leveraged networks capturing associations between 30 depressive symptoms (Inventory of Depressive Symptomatology) and 46 metabolites. Analyses involved 4 steps: creating a network with Mixed Graphical Models; calculating centrality measures; bootstrapping for stability testing; validating central, stable associations by extra covariate-adjustment; and validation using another data wave collected 6 years later.
RESULTS
The network yielded 28 symptom-metabolite associations. There were 15 highly-central variables (8 symptoms, 7 metabolites), and 3 stable links involving the symptoms Low energy (fatigue), and Hypersomnia. Specifically, fatigue showed consistent associations with higher mean diameter for VLDL particles and lower estimated degree of (fatty acid) unsaturation. These remained present after adjustment for lifestyle and health-related factors and using another data wave.
CONCLUSIONS
The somatic symptoms Fatigue and Hypersomnia and cholesterol and fatty acid measures showed central, stable, and consistent relationships in our network. The present analyses showed how metabolic alterations are more consistently linked to specific symptom profiles.
Topics: Humans; Depression; Anxiety; Fatigue; Disorders of Excessive Somnolence; Fatty Acids
PubMed: 37092859
DOI: 10.1017/S0033291723001009 -
MedRxiv : the Preprint Server For... Nov 2023Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease.
PURPOSE
Gamma delta T-cell receptor-positive acute lymphoblastic leukemia (γδ T-ALL) is a high-risk but poorly characterized disease.
METHODS
We studied clinical features of 200 pediatric γδ T-ALL, and compared the prognosis of 93 cases to 1,067 protocol-matched non-γδ T-ALL. Genomic features were defined by transcriptome and genome sequencing. Experimental modeling was used to examine the mechanistic impacts of genomic alterations. Therapeutic vulnerabilities were identified by high throughput drug screening of cell lines and xenografts.
RESULTS
γδ T-ALL in children under three was extremely high-risk with 5-year event-free survival (33% v. 70% [age 3-<10] and 73% [age ≥10], =9.5 x 10 ) and 5-year overall survival (49% v. 78% [age 3-<10] and 81% [age ≥10], =0.002), differences not observed in non-γδ T-ALL. γδ T-ALL in this age group was enriched for genomic alterations activating activation and inactivating inactivation ( ). Mechanistically, we show that inactivation of STAG2 profoundly perturbs chromatin organization by altering enhancer-promoter looping resulting in deregulation of gene expression associated with T-cell differentiation. Drug screening showed resistance to prednisolone, consistent with clinical slow treatment response, but identified a vulnerability in DNA repair pathways arising from STAG2 inactivation, which was efficaciously targeted by Poly(ADP-ribose) polymerase (PARP) inhibition, with synergism with HDAC inhibitors. Ex-vivo drug screening on PDX cells validated the efficacy of PARP inhibitors as well as other potential targets including nelarabine.
CONCLUSION
γδ T-ALL in children under the age of three is extremely high-risk and enriched for ALL. STAG2 loss perturbs chromatin conformation and differentiation, and ALL is sensitive to PARP inhibition. These data provide a diagnostic and therapeutic framework for pediatric γδ T-ALL.
SUPPORT
The authors are supported by the American and Lebanese Syrian Associated Charities of St Jude Children's Research Hospital, NCI grants R35 CA197695, P50 CA021765 (C.G.M.), the Henry Schueler 41&9 Foundation (C.G.M.), and a St. Baldrick's Foundation Robert J. Arceci Innovation Award (C.G.M.), Gabriella Miller Kids First X01HD100702 (D.T.T and C.G.M.) and R03CA256550 (D.T.T. and C.G.M.), F32 5F32CA254140 (L.M.), and a Garwood Postdoctoral Fellowship of the Hematological Malignancies Program of the St Jude Children's Research Hospital Comprehensive Cancer Center (S.K.). This project was supported by the National Cancer Institute of the National Institutes of Health under the following award numbers: U10CA180820, UG1CA189859, U24CA114766, U10CA180899, U10CA180866 and U24CA196173.
DISCLAIMER
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funding agencies were not directly involved in the design of the study, gathering, analysis and interpretation of the data, writing of the manuscript, or decision to submit the manuscript for publication.
PubMed: 37986997
DOI: 10.1101/2023.11.06.23298028 -
International Journal of Molecular... Feb 2024In this narrative review, we delved into the intricate interplay between alleles (typically associated with Alzheimer's disease-AD) and alpha-synucleinopathies... (Review)
Review
In this narrative review, we delved into the intricate interplay between alleles (typically associated with Alzheimer's disease-AD) and alpha-synucleinopathies (aS-pathies), involving Parkinson's disease (PD), Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA). First, in-vitro, animal, and human-based data on the exacerbating effect of on LB pathology were summarized. We found robust evidence that carriage constitutes a risk factor for PDD-APOE2, and APOE3 may not alter the risk of developing PDD. We confirmed that copies confer an increased hazard towards DLB, as well. Again and appear unrelated to the risk of conversion. Of note, in individuals with DLB , carriage appears to be intermediately prevalent between AD and PDD-PD (AD > DLB > PDD > PD). Less consistency existed when it came to PD; -PD associations tended to be markedly modified by ethnicity. Finally, we failed to establish an association between the gene and MSA. Phenotypic associations (age of disease onset, survival, cognitive-neuropsychiatric- motor-, and sleep-related manifestations) between alleles, and each of the aforementioned conditions were also outlined. Finally, a synopsis of literature gaps was provided followed by suggestions for future research.
Topics: Humans; Alzheimer Disease; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Dementia; Lewy Body Disease; Parkinson Disease; Synucleinopathies
PubMed: 38339074
DOI: 10.3390/ijms25031795 -
Biomolecules Sep 2023Previous studies have suggested that bile acids (BAs) may participate in the development and/or progression of metabolic dysfunction-associated steatotic liver disease... (Meta-Analysis)
Meta-Analysis Review
Previous studies have suggested that bile acids (BAs) may participate in the development and/or progression of metabolic dysfunction-associated steatotic liver disease (MASLD). The present study aimed to define whether specific BA molecular species are selectively associated with MASLD development, disease severity, or geographic region. We comprehensively identified all eligible studies reporting circulating BAs in both MASLD patients and healthy controls through 30 July 2023. The pooled results were expressed as the standard mean difference (SMD) and 95% confidence interval (CI). Subgroup, sensitivity, and meta-regression analyses were performed to address heterogeneity. Nineteen studies with 154,807 individuals were included. Meta-analysis results showed that total BA levels in MASLD patients were higher than those in healthy controls (SMD = 1.03, 95% CI: 0.63-1.42). When total BAs were divided into unconjugated and conjugated BAs or primary and secondary BAs, the pooled results were consistent with the overall estimates except for secondary BAs. Furthermore, we examined each individual BA and found that 9 of the 15 BAs were increased in MASLD patients, especially ursodeoxycholic acids (UDCA), taurococholic acid (TCA), chenodeoxycholic acids (CDCA), taurochenodeoxycholic acids (TCDCA), and glycocholic acids (GCA). Subgroup analysis revealed that different geographic regions or disease severities led to diverse BA profiles. Notably, TCA, taurodeoxycholic acid (TDCA), taurolithocholic acids (TLCA), and glycolithocholic acids (GLCA) showed a potential ability to differentiate metabolic dysfunction-associated steatohepatitis (MASH) (all 0.05). An altered profile of circulating BAs was shown in MASLD patients, providing potential targets for the diagnosis and treatment of MASLD.
Topics: Humans; Bile Acids and Salts; Metabolic Diseases; Ursodeoxycholic Acid; Chenodeoxycholic Acid; Fatty Liver
PubMed: 37759756
DOI: 10.3390/biom13091356 -
Frontiers in Psychiatry 2023Gut inflammation is thought to modify brain activity and behaviour via modulation of the gut-brain axis. However, how relapsing and remitting exposure to peripheral...
Gut inflammation is thought to modify brain activity and behaviour via modulation of the gut-brain axis. However, how relapsing and remitting exposure to peripheral inflammation over the natural history of inflammatory bowel disease (IBD) contributes to altered brain dynamics is poorly understood. Here, we used electroencephalography (EEG) to characterise changes in spontaneous spatiotemporal brain states in Crohn's Disease (CD) ( = 40) and Ulcerative Colitis (UC) ( = 30), compared to healthy individuals ( = 28). We first provide evidence of a significantly perturbed and heterogeneous microbial profile in CD, consistent with previous work showing enduring and long-standing dysbiosis in clinical remission. Results from our brain state assessment show that CD and UC exhibit alterations in the temporal properties of states implicating default-mode network, parietal, and visual regions, reflecting a shift in the predominance from externally to internally-oriented attentional modes. We investigated these dynamics at a finer sub-network resolution, showing a CD-specific and highly selective enhancement of connectivity between the insula and medial prefrontal cortex (mPFC), regions implicated in cognitive-interoceptive appraisal mechanisms. Alongside overall higher anxiety scores in CD, we also provide preliminary support to suggest that the strength of chronic interoceptive hyper-signalling in the brain co-occurs with disease duration. Together, our results demonstrate that a long-standing diagnosis of CD is, in itself, a key factor in determining the risk of developing altered brain network signatures.
PubMed: 38025434
DOI: 10.3389/fpsyt.2023.1250268 -
Science Advances Sep 2023Severe wildfire is altering the natural and the built environment and posing risks to environmental and societal health and well-being, including cascading impacts to... (Review)
Review
Severe wildfire is altering the natural and the built environment and posing risks to environmental and societal health and well-being, including cascading impacts to water systems and built water infrastructure. Research on wildfire-resilient water systems is growing but not keeping pace with the scale and severity of wildfire impacts, despite their intensifying threat. In this study, we evaluate the state of knowledge regarding wildfire-related hazards to water systems. We propose a holistic framework to assess interactions and feedback loops between water quality, quantity, and infrastructure hazards as determinants of post-fire water availability and access. Efforts to address the evolving threat of wildfires to water systems will require more interdisciplinary research on the complex relationships shaping wildfire's threat to water availability and access. To support this, we need reliable long-term data availability, consistent metrics, greater research in shared contexts, more extensive research beyond the burn area, and multistakeholder collaboration on wildfire risks to water systems.
PubMed: 37713490
DOI: 10.1126/sciadv.adf9534