Amyotrophic lateral sclerosis (ALS) is a multifactorial neurodegenerative disease characterised by the loss of upper and lower motor neurons. Increasing evidence indicates that neuroinflammation ...mediated by microglia contributes to ALS pathogenesis. This microglial activation is evident in post-mortem brain tissues and neuroimaging data from patients with ALS. However, the role of microglia in the pathogenesis and progression of amyotrophic lateral sclerosis remains unclear, partly due to the lack of a model system that is able to faithfully recapitulate the clinical pathology of ALS. To address this shortcoming, we describe an approach that generates monocyte-derived microglia-like cells that are capable of expressing molecular markers, and functional characteristics similar to in vivo human brain microglia.
In this study, we have established monocyte-derived microglia-like cells from 30 sporadic patients with ALS, including 15 patients with slow disease progression, 6 with intermediate progression, and 9 with rapid progression, together with 20 non-affected healthy controls.
We demonstrate that patient monocyte-derived microglia-like cells recapitulate canonical pathological features of ALS including non-phosphorylated and phosphorylated-TDP-43-positive inclusions. Moreover, ALS microglia-like cells showed significantly impaired phagocytosis, altered cytokine profiles, and abnormal morphologies consistent with a neuroinflammatory phenotype. Interestingly, all ALS microglia-like cells showed abnormal phagocytosis consistent with the progression of the disease. In-depth analysis of ALS microglia-like cells from the rapid disease progression cohort revealed significantly altered cell-specific variation in phagocytic function. In addition, DNA damage and NOD-leucine rich repeat and pyrin containing protein 3 (NLRP3) inflammasome activity were also elevated in ALS patient monocyte-derived microglia-like cells, indicating a potential new pathway involved in driving disease progression.
Taken together, our work demonstrates that the monocyte-derived microglia-like cell model recapitulates disease-specific hallmarks and characteristics that substantiate patient heterogeneity associated with disease subgroups. Thus, monocyte-derived microglia-like cells are highly applicable to monitor disease progression and can be applied as a functional readout in clinical trials for anti-neuroinflammatory agents, providing a basis for personalised treatment for patients with ALS.
The bidirectional relationship between depression and chronic pain is well-recognized, but their clinical management remains challenging. Here we characterize the shared risk factors and outcomes for ...their comorbidity in the Australian Genetics of Depression cohort study (
= 13,839). Participants completed online questionnaires about chronic pain, psychiatric symptoms, comorbidities, treatment response and general health. Logistic regression models were used to examine the relationship between chronic pain and clinical and demographic factors. Cumulative linked logistic regressions assessed the effect of chronic pain on treatment response for 10 different antidepressants. Chronic pain was associated with an increased risk of depression (OR = 1.86 1.37-2.54), recent suicide attempt (OR = 1.88 1.14-3.09), higher use of tobacco (OR = 1.05 1.02-1.09) and misuse of painkillers (e.g., opioids; OR = 1.31 1.06-1.62). Participants with comorbid chronic pain and depression reported fewer functional benefits from antidepressant use and lower benefits from sertraline (OR = 0.75 0.68-0.83), escitalopram (OR = 0.75 0.67-0.85) and venlafaxine (OR = 0.78 0.68-0.88) when compared to participants without chronic pain. Furthermore, participants taking sertraline (OR = 0.45 0.30-0.67), escitalopram (OR = 0.45 0.27-0.74) and citalopram (OR = 0.32 0.15-0.67) specifically for chronic pain (among other indications) reported lower benefits compared to other participants taking these same medications but not for chronic pain. These findings reveal novel insights into the complex relationship between chronic pain and depression. Treatment response analyses indicate differential effectiveness between particular antidepressants and poorer functional outcomes for these comorbid conditions. Further examination is warranted in targeted interventional clinical trials, which also include neuroimaging genetics and pharmacogenomics protocols. This work will advance the delineation of disease risk indicators and novel aetiological pathways for therapeutic intervention in comorbid pain and depression as well as other psychiatric comorbidities.
•Hippocampal-cortical connectivity gradients change during naturalistic memory tasks.•Familiar cues accentuate the hippocampal anterior-posterior functional transition.•This transition is more ...posterior in the left hippocampus of subjects with MCI or AD.•Gradients of the anterior hippocampus map onto the default mode network.
The functional organization of the hippocampus mirrors that of the cortex, changing smoothly along connectivity gradients and abruptly at inter-areal boundaries. Hippocampal-dependent cognitive processes require flexible integration of these hippocampal gradients into functionally related cortical networks. To understand the cognitive relevance of this functional embedding, we acquired fMRI data while participants viewed brief news clips, either containing or lacking recently familiarized cues. Participants were 188 healthy mid-life adults and 31 adults with mild cognitive impairment (MCI) or Alzheimer's disease (AD). We employed a recently developed technique - connectivity gradientography - to study gradually changing patterns of voxel to whole brain functional connectivity and their sudden transitions. We observed that functional connectivity gradients of the anterior hippocampus map onto connectivity gradients across the default mode network during these naturalistic stimuli. The presence of familiar cues in the news clips accentuates a stepwise transition across the boundary from the anterior to the posterior hippocampus. This functional transition is shifted in the posterior direction in the left hippocampus of individuals with MCI or AD. These findings shed new light on the functional integration of hippocampal connectivity gradients into large-scale cortical networks, how these adapt with memory context and how these change in the presence of neurodegenerative disease.
IMPORTANCE: Physical health and chronic medical comorbidities are underestimated, inadequately treated, and often overlooked in psychiatry. A multiorgan, systemwide characterization of brain and body ...health in neuropsychiatric disorders may enable systematic evaluation of brain-body health status in patients and potentially identify new therapeutic targets. OBJECTIVE: To evaluate the health status of the brain and 7 body systems across common neuropsychiatric disorders. DESIGN, SETTING, AND PARTICIPANTS: Brain imaging phenotypes, physiological measures, and blood- and urine-based markers were harmonized across multiple population-based neuroimaging biobanks in the US, UK, and Australia, including UK Biobank; Australian Schizophrenia Research Bank; Australian Imaging, Biomarkers, and Lifestyle Flagship Study of Ageing; Alzheimer’s Disease Neuroimaging Initiative; Prospective Imaging Study of Ageing; Human Connectome Project–Young Adult; and Human Connectome Project–Aging. Cross-sectional data acquired between March 2006 and December 2020 were used to study organ health. Data were analyzed from October 18, 2021, to July 21, 2022. Adults aged 18 to 95 years with a lifetime diagnosis of 1 or more common neuropsychiatric disorders, including schizophrenia, bipolar disorder, depression, generalized anxiety disorder, and a healthy comparison group were included. MAIN OUTCOMES AND MEASURES: Deviations from normative reference ranges for composite health scores indexing the health and function of the brain and 7 body systems. Secondary outcomes included accuracy of classifying diagnoses (disease vs control) and differentiating between diagnoses (disease vs disease), measured using the area under the receiver operating characteristic curve (AUC). RESULTS: There were 85 748 participants with preselected neuropsychiatric disorders (36 324 male) and 87 420 healthy control individuals (40 560 male) included in this study. Body health, especially scores indexing metabolic, hepatic, and immune health, deviated from normative reference ranges for all 4 neuropsychiatric disorders studied. Poor body health was a more pronounced illness manifestation compared to brain changes in schizophrenia (AUC for body = 0.81 95% CI, 0.79-0.82; AUC for brain = 0.79 95% CI, 0.79-0.79), bipolar disorder (AUC for body = 0.67 95% CI, 0.67-0.68; AUC for brain = 0.58 95% CI, 0.57-0.58), depression (AUC for body = 0.67 95% CI, 0.67-0.68; AUC for brain = 0.58 95% CI, 0.58-0.58), and anxiety (AUC for body = 0.63 95% CI, 0.63-0.63; AUC for brain = 0.57 95% CI, 0.57-0.58). However, brain health enabled more accurate differentiation between distinct neuropsychiatric diagnoses than body health (schizophrenia-other: mean AUC for body = 0.70 95% CI, 0.70-0.71 and mean AUC for brain = 0.79 95% CI, 0.79-0.80; bipolar disorder-other: mean AUC for body = 0.60 95% CI, 0.59-0.60 and mean AUC for brain = 0.65 95% CI, 0.65-0.65; depression-other: mean AUC for body = 0.61 95% CI, 0.60-0.63 and mean AUC for brain = 0.65 95% CI, 0.65-0.66; anxiety-other: mean AUC for body = 0.63 95% CI, 0.62-0.63 and mean AUC for brain = 0.66 95% CI, 0.65-0.66). CONCLUSIONS AND RELEVANCE: In this cross-sectional study, neuropsychiatric disorders shared a substantial and largely overlapping imprint of poor body health. Routinely monitoring body health and integrated physical and mental health care may help reduce the adverse effect of physical comorbidity in people with mental illness.
Acne vulgaris is a highly heritable skin disorder that primarily impacts facial skin. Severely inflamed lesions may leave permanent scars that have been associated with long-term psychosocial ...consequences. Here, we perform a GWAS meta-analysis comprising 20,165 individuals with acne from nine independent European ancestry cohorts. We identify 29 novel genome-wide significant loci and replicate 14 of the 17 previously identified risk loci, bringing the total number of reported acne risk loci to 46. Using fine-mapping and eQTL colocalisation approaches, we identify putative causal genes at several acne susceptibility loci that have previously been implicated in Mendelian hair and skin disorders, including pustular psoriasis. We identify shared genetic aetiology between acne, hormone levels, hormone-sensitive cancers and psychiatric traits. Finally, we show that a polygenic risk score calculated from our results explains up to 5.6% of the variance in acne liability in an independent cohort.
Abstract Introduction The aim of this study was to (1) replicate previous associations between six blood lipids and Alzheimer's disease (AD) (Proitsi et al 2015) and (2) identify novel associations ...between lipids, clinical AD diagnosis, disease progression and brain atrophy (left/right hippocampus/entorhinal cortex). Methods We performed untargeted lipidomic analysis on 148 AD and 152 elderly control plasma samples and used univariate and multivariate analysis methods. Results We replicated our previous lipids associations and reported novel associations between lipids molecules and all phenotypes. A combination of 24 molecules classified AD patients with >70% accuracy in a test and a validation data set, and we identified lipid signatures that predicted disease progression (R2 = 0.10, test data set) and brain atrophy (R2 ≥ 0.14, all test data sets except left entorhinal cortex). We putatively identified a number of metabolic features including cholesteryl esters/triglycerides and phosphatidylcholines. Discussion Blood lipids are promising AD biomarkers that may lead to new treatment strategies.
Lipids such as ceramides and phosphatidylcholines (PC) have been found altered in the plasma of Alzheimer's disease (AD) patients in a number of discovery studies. For this reason, the levels of 6 ...ceramides and 3 PCs, with different fatty acid length and saturation levels, were measured in the plasma from 412 participants (AD n = 205, Control n = 207) using mass spectrometry coupled with ultra-performance liquid chromatography. After this, associations with AD status, brain atrophy, and age-related effects were studied. In the plasma of AD participants, cross-sectional analysis revealed elevated levels of three ceramides (Cer16:0 p < 0.01, Cer18:0 p < 0.01, Cer24:1 p < 0.05). In addition, two PCs in AD plasma (PC36:5 p < 0.05, PC38:6 p < 0.05) were found to be depleted compared to the control group, with PC36:5 also associating with hippocampal atrophy (p < 0.01). Age-specific analysis further revealed that levels of Cer16:0, Cer18:0, and Cer20:0 were associated with hippocampal atrophy only in younger participants (age < 75, p < 0.05), while all 3 PCs did so in the older participants (age > 75, p < 0.05). PC36:5 was associated with AD status in the younger group (p < 0.01), while PC38:6 and 40:6 did so in the older group (p < 0.05). In this study, elevated ceramides and depleted PCs were found in the plasma from 205 AD volunteers. Our findings also suggest that dysregulation in PC and ceramide metabolism could be occurring in different stages of AD progression.
Alzheimer's disease (AD) is an incurable neurodegenerative disorder with a rapidly increasing prevalence worldwide. Current approaches targeting hallmark pathological features of AD have had no ...consistent clinical benefit. Neuroinflammation is a major contributor to neurodegeneration and hence, microglia, the brain's resident immune cells, are an attractive target for potentially more effective therapeutic strategies. However, there is no current in vitro model system that captures AD patient-specific microglial characteristics using physiologically relevant and experimentally flexible culture conditions.
To address this shortcoming, we developed novel 3D Matrigel-based monocyte-derived microglia-like cell (MDMi) mono-cultures and co-cultures with neuro-glial cells (ReNcell VM). We used single-cell RNA sequencing (scRNAseq) analysis to compare the transcriptomic signatures of MDMi between model systems (2D, 3D and 3D co-culture) and against published human microglia datasets. To demonstrate the potential of MDMi for use in personalized pre-clinical strategies, we generated and characterized MDMi models from sixteen AD patients and matched healthy controls, and profiled cytokine responses upon treatment with anti-inflammatory drugs (dasatinib and spiperone).
MDMi in 3D exhibited a more branched morphology and longer survival in culture compared to 2D. scRNAseq uncovered distinct MDMi subpopulations that exhibit higher functional heterogeneity and best resemble human microglia in 3D co-culture. AD MDMi in 3D co-culture showed altered cell-to-cell interactions, growth factor and cytokine secretion profiles and responses to amyloid-β. Drug testing assays revealed patient- and model-specific cytokine responses.
Our study presents a novel, physiologically relevant and AD patient-specific 3D microglia cell model that opens avenues towards improving personalized drug development strategies in AD.
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