Brain Disease Research Articles

Perceptions of substance use disorder in rural areas: how the brain disease model impacts public stigma

BackgroundRural communities are disproportionately affected by substance use disorder (SUD) and public stigma impedes access to and utilization of treatment and support services.MethodsThis study compares data from a 2020 study conducted in rural Ohio (N = 173) with results from a recent study conducted in South Dakota (N = 41) on publicly-held stigmatizing views of SUD. South Dakota participants were recruited at several public events across the state via convenience sampling between August 2022-February 2023 to complete a survey. Data from responses to 19 stigma-related questions were merged with the associated data from the 2020 Ohio study and a comparative analysis was performed using Fisher’s exact and Chi square tests.ResultsThe data shows that respondents in South Dakota, when compared to respondents in Ohio, are more likely to believe addiction is an illness (SD = 86.5%, OH = 48.5%, p < 0.001). The belief in SUD as an illness aligns with reduced stigmatizing beliefs, as indicated by respondents in SD showing lower stigmatizing ideologies and higher support for naloxone and harm reduction services, when compared to Ohio respondents. In both studies, the belief that SUD is an illness was associated with a reduction in other stigmatizing beliefs.ConclusionsThese results can be used to inform more focused anti-stigma efforts. As more people adopt fewer stigmatizing views on SUD in rural areas, more people with SUD may be supported to seek treatment and recovery services.

Lysosome-Targeting Protein Degradation Through Endocytosis Pathway Triggered by Polyvalent Nano-Chimera for AD Therapy.

The excessive up-regulation of receptor for advanced glycation end products (RAGE), a well-known pathological marker, drives the onset and progression of Alzheimer's disease. Although lysosome-targeting protein degradation has emerged as an effective therapeutic modality, the limited lysosome-sorting efficacy greatly hindered the degradation efficiency of target proteins. Herein, a lysosome-shuttle-like nano-chimera (endoTAC) is proposed based on polyvalent receptor binding mode for enhanced RAGE degradation as well as precise drug delivery. The endoTAC shows a high affinity to RAGE and enhances RAGE degradation due to its polyvalent-interaction with RAGE. Additionally, endoTAC features increased accumulation in diseased brain and shows promise as a precise brain delivery system. After loading with simvastatin, the SV@endoTAC proves to successfully reverse pathological features both in vitro and in vivo. The work proposes that the combination of a lysosome-targeting chimera and an effective drug delivery system can be promising in Alzheimer's disease therapy.

MRI Findings in Demyelinating Diseases of the Central Nervous System

Demyelinating diseases of the brain represent a complex group of neurological disorders characterised by the destruction of the myelin sheath surrounding nerve fibres, which disrupts neural transmission and leads to a wide range of neurological deficits1 . This article reviews the pathophysiology, radiologic features, and diagnostic criteria of key demyelinating disorders, including Multiple sclerosis (MS), Neuromyelitis optica, Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), Tumefactive demyelinating lesions, Acute necrotizing encephalopathy, and Krabbe disease. Advanced imaging techniques, particularly Magnetic resonance imaging (MRI), play a crucial role in the identification and differentiation of these diseases. Key MRI findings, such as T2-weighted hyperintense lesions in specific brain regions, contrast enhancement patterns, and lesion evolution, aid in diagnosis and disease monitoring. Radiologists play a vital role in early diagnosis, monitoring treatment response, and detecting complications, thereby guiding clinical management and improving patient outcomes in demyelinating brain diseases.

Orexin in depression: Evidence from basic and clinical research

Orexin &amp;ndash; a neuropeptide &amp;ndash; is extensively distributed in the central nervous system and is involved in the regulation of diverse physiological functions and behaviors. Orexin is strongly associated with the onset and development of depression. The most important function of orexin is to interact with the transport system, mediating arousal, and energy homeostasis. Hypothalamic-ventral tegmental and hypothalamic-ventral thalamic pathways provide clues for understanding the function of orexin and related disorders, such as sleep disorders, eating disorders, and substance abuse. This article summarizes the basic and clinical studies on the role of the orexin system in regulating and treating depression, including the relationship between the expression level of orexin in specific brain areas and diseases, relationship between adolescent depression and orexin, orexin receptor antagonists as a treatment for depression, and narcolepsy, which is closely associated with depression. Research progress on the role of orexin in depression and recent relevant studies are summarized, providing novel directions for developing depression treatment strategies.

Oxidation of CaMKIIα cysteines inhibits autonomous activation induced by phosphorylation.

Ca2+/calmodulin-dependent protein kinase II α (CaMKIIα) "autonomous" activation induced by Thr286 phosphorylation has a crucial role in synaptic plasticity. Previous studies showed that in Alzheimer's disease brain, CaMKIIα autophosphorylation at Thr286 is reduced while the level of cysteine-oxidized CAMKIIα is elevated. We performed tryptic mapping of the oxidized CaMKIIα and discovered the formation of a disulfide between the N-terminal Cys6 and the regulatory domain Cys280. The apparent pKa values of Cys6 and Cys280 are 7.1 and 7.7, respectively, lower than the 8.5 for free Cys. The low apparent pKa of Cys6 facilitates the oxidation of its thiol to the sulfenic acid at physiological pH. The thiolate of Cys280 can then attack the sulfenic acid to form a disulfide. Using an antibody against phosphorylated Thr286, we showed that disulfide formation prevents Thr286 phosphorylation. CaMKIIα autonomous activation induced by disulfide formation is much lower than the autonomous activation induced by phosphorylation. The decreased autonomous activation may contribute to the synaptic impairment of Alzheimer's disease. We also generated a CaMKIIα mutant in which Cys6 was mutated to Ser6. This mutation prevented disulfide formation and restored autonomous activation induced by phosphorylation. Our findings provide insight into the mechanistic details of CaMKIIα autonomous activation induced by disulfide formation that may contribute to the impairment of long-term potentiation in Alzheimer's disease.

RNA isoform diversity in human neurodegenerative diseases.

Single-nucleus RNA-sequencing (snRNA-seq) has revealed new levels of cellular organization and diversity within the human brain. However, full-length mRNA isoforms are not resolved in typical snRNA-seq analyses using short-read sequencing that cannot capture full-length transcripts. Here we combine standard 10X Genomics short-read snRNA-seq with targeted PacBio long-read snRNA-seq to examine isoforms of genes associated with neurological diseases at the single-cell level from prefrontal cortex samples of diseased and non-diseased human brain, assessing over 165,000 cells. Samples from 25 post-mortem donors with Alzheimer's disease (AD), dementia with Lewy bodies (DLB), or Parkinson's disease (PD), along with age-matched controls were compared. Analysis of the short-read libraries identified shared and distinct gene expression changes across the diseases. The same libraries were then assayed using enrichment probes to target 50 disease-related genes followed by long-read PacBio sequencing, enabling linkage between cell type and isoform expression. Vast mRNA isoform diversity was observed in all 50 targeted genes, even those that were not differentially expressed in the short-read data. We also developed an informatics method for detection of isoform structural differences in novel isoforms vs. the reference annotation. These data expand available single-cell datasets of the human prefrontal cortical transcriptome with combined short- and long-read sequencing across AD, DLB, and PD, revealing increased mRNA isoform diversity that may contribute to disease features and could potentially represent therapeutic targets for neurodegenerative diseases.Significance Statement Limited comparisons using single-cell transcriptomics analysis have been conducted amongst common neurodegenerative diseases. Here we identify new cell type and disease relationships involving known and novel mRNA isoforms by profiling single nuclei from human prefrontal cortices of Alzheimer's disease, Parkinson's disease, dementia with Lewy bodies and non-diseased controls. Cell-type-specific RNA isoform diversity across the different diseases was examined using the combination of short-read snRNA-seq and targeted long-read single-nucleus isoform sequencing. We identified myriad novel transcripts that highlight an untapped understanding of RNA isoform diversity that exists within the brain and potentially contribute to human neurodegenerative diseases.

Multiplexing cortical brain organoids for the longitudinal dissection of developmental traits at single-cell resolution.

Dissecting human neurobiology at high resolution and with mechanistic precision requires a major leap in scalability, given the need for experimental designs that include multiple individuals and, prospectively, population cohorts. To lay the foundation for this, we have developed and benchmarked complementary strategies to multiplex brain organoids by pooling cells from different pluripotent stem cell (PSC) lines either during organoid generation (mosaic models) or before single-cell RNA sequencing (scRNA-seq) library preparation (downstream multiplexing). We have also developed a new computational method, SCanSNP, and a consensus call to deconvolve cell identities, overcoming current criticalities in doublets and low-quality cell identification. We validated both multiplexing methods for charting neurodevelopmental trajectories at high resolution, thus linking specific individuals' trajectories to genetic variation. Finally, we modeled their scalability across different multiplexing combinations and showed that mosaic organoids represent an enabling method for high-throughput settings. Together, this multiplexing suite of experimental and computational methods provides a highly scalable resource for brain disease and neurodiversity modeling.

Canine medial retropharyngeal lymph node measurements on T2 spin-echo sequences at 3T

IntroductionThe objective of this study is to estimate reference values for medial retropharyngeal lymph nodes (MRLNs) measured in high-field (3T) MRI studies of the canine head/brain using transverse T2 spin-echo images and to determine if dogs with structural brain disease exhibit medial retropharyngeal lymph nodes that are larger than expected from estimated reference values.MethodsThe study population comprises 142 MRLNs from 71 dogs with no evidence of structural brain disease and normal CSF evaluation and 116 MRLNs from 58 dogs with structural brain disease confirmed by histopathology as of infectious or neoplastic origin, or to represent meningoencephalitis of unknown etiology.ResultsBased on this sample, MRLNs are expected to measure 2.9–12.4 mm in maximum short-axis transverse diameter. Interobserver measurement differences are ~1 mm in 95% of the sampled subjects. Lymph node size is correlated with body weight (R = 0.47–0.52) and age (R = −0.39 – −0.47).DiscussionNo difference was found between the lymph node size of dogs with structural brain disease of any type, or overall, compared to that of dogs without structural brain disease.

Synthetic gene circuits drive disease-fighting T cells.

Immune cells can be programmed to deliver targeted therapies in models of brain and inflammatory disease.

Mapping the microRNA landscape in the older adult brain and its genetic contribution to neuropsychiatric conditions.

MicroRNAs (miRNAs) play a crucial role in regulating gene expression and influence many biological processes. Despite their importance, understanding of how genetic variation affects miRNA expression in the brain and how this relates to brain disorders remains limited. Here we investigated these questions by identifying microRNA expression quantitative trait loci (miR-QTLs), or genetic variants associated with brain miRNA levels, using genome-wide small RNA sequencing profiles from dorsolateral prefrontal cortex samples of 604 older adult donors of European ancestry. Here we show that nearly half (224 of 470) of the analyzed miRNAs have associated miR-QTLs, many of which fall in regulatory regions such as brain promoters and enhancers. We also demonstrate that intragenic miRNAs often have genetic regulation independent from their host genes. Furthermore, by integrating our findings with 16 genome-wide association studies of psychiatric and neurodegenerative disorders, we identified miRNAs that likely contribute to bipolar disorder, depression, schizophrenia and Parkinson's disease. These findings advance understanding of the genetic regulation of miRNAs and their role in brain health and disease.

In vivo dynamic tracking of cerebral chloride regulation using molecularly tailored liquid/liquid interfacial ultramicro iontronics.

Chloride ion, a pivotal cerebral anion involved in neuronal inhibition, is implicated in various neurodegenerative diseases. Conventional direct faradaic detection based on electron transfers at solid electrode/solution interfaces has been proven ineffective due to the electrochemically inactive nature of Cl-. Here, we present an approach involving molecularly tailored liquid/liquid interfacial ultramicro iontronics (L/L-UIs) supported at ultramicropipettes filled with organic gel containing lipophilic bis-thioureas ionophores, which represents the first application of amperometric methodology based on electrochemical facilitated ion transfers reactions at a soft L/L ultramicrointerface to achieve in vivo sensing of electrochemically inactive ions, and dynamically tracking cerebral Cl- in vivo. Furthermore, evidence of dynamic neuronal Cl- regulation via KCC2 modulated through GABAB receptors was provided, further substantiating GABAB receptor-mediated Cl--related neuronal inhibition. The proposed L/L-UIs have notable potential for in situ tracking of other crucial electrochemically inactive ions or ionized biomolecules in vivo, thereby facilitating the study of brain diseases and the diagnosis and treatment of related disorders.

Changes in Cerebral Hemodynamics and Progression of Subclinical Vascular Brain Disease: A Population-Based Cohort Study.

Cerebral hypoperfusion is associated with vascular brain injury and neurodegeneration, but their longitudinal relationship is largely unknown, especially in healthy older adults. We investigated the longitudinal relationship between cerebral hemodynamics and subclinical vascular brain disease in community-dwelling older adults without stroke or dementia at baseline. Participants underwent brain magnetic resonance imaging scans every 3 to 4 years between 2005 and 2016. Cerebral blood flow (CBF) was measured through 2-dimensional phase-contrast magnetic resonance imaging; the cerebrovascular resistance index (CVRi) was defined as the ratio of mean arterial blood pressure to total CBF. Simultaneous progression in subclinical brain disease was evaluated through repeated magnetic resonance imaging assessment of white matter hyperintensities (WMH), cerebral microbleeds, lacune, and brain atrophy. The longitudinal relationship was estimated using generalized estimating equations, with adjustment for age, sex, smoking habits, body mass index, systolic blood pressure (for CBF measures), lipid level, history of diabetes and cardiovascular disease, and the baseline burden of magnetic resonance imaging markers. Among 3623 older adults (mean age, 61.4±9.3 years; 54.6% women), large decreases and increases in CBF and increases in CVRi over time were associated with white matter hyperintensity progression. The risk ratios for white matter hyperintensity progression were 1.36 (95% CI, 1.19-1.55) for large decreases in total CBF (lowest quartile), 1.02 (95% CI, 0.91-1.14) for moderate decreases (second quartile), and 1.28 (95% CI, 1.14-1.45) for large increases (highest quartile), compared with stable CBF (third quartile). The corresponding risk ratios for changes in CVRi were 1.13 (95% CI, 1.00-1.30), 1.25 (95% CI, 1.09-1.43), and 1.33 (95% CI, 1.16-1.52) for the second to fourth (versus lowest) quartiles, respectively, showing a dose-response relationship. The changes in CBF also demonstrate a similar U-shaped association with the progression of brain atrophy and incident microbleeds, whereas increases in CVRi were associated with lower microbleed risk. Longitudinal changes in CBF and CVRi may capture distinct pathophysiologies linking cerebral hemodynamics to subclinical brain disease, extending beyond single-time point measurements.

Mitochondrial pathways of copper neurotoxicity: focus on mitochondrial dynamics and mitophagy

Copper (Cu) is essential for brain development and function, yet its overload induces neuronal damage and contributes to neurodegeneration and other neurological disorders. Multiple studies demonstrated that Cu neurotoxicity is associated with mitochondrial dysfunction, routinely assessed by reduction of mitochondrial membrane potential. Nonetheless, the role of alterations of mitochondrial dynamics in brain mitochondrial dysfunction induced by Cu exposure is still debatable. Therefore, the objective of the present narrative review was to discuss the role of mitochondrial dysfunction in Cu-induced neurotoxicity with special emphasis on its influence on brain mitochondrial fusion and fission, as well as mitochondrial clearance by mitophagy. Existing data demonstrate that, in addition to mitochondrial electron transport chain inhibition, membrane damage, and mitochondrial reactive oxygen species (ROS) overproduction, Cu overexposure inhibits mitochondrial fusion by down-regulation of Opa1, Mfn1, and Mfn2 expression, while promoting mitochondrial fission through up-regulation of Drp1. It has been also demonstrated that Cu exposure induces PINK1/Parkin-dependent mitophagy in brain cells, that is considered a compensatory response to Cu-induced mitochondrial dysfunction. However, long-term high-dose Cu exposure impairs mitophagy, resulting in accumulation of dysfunctional mitochondria. Cu-induced inhibition of mitochondrial biogenesis due to down-regulation of PGC-1α further aggravates mitochondrial dysfunction in brain. Studies from non-brain cells corroborate these findings, also offering additional evidence that dysregulation of mitochondrial dynamics and mitophagy may be involved in Cu-induced damage in brain. Finally, Cu exposure induces cuproptosis in brain cells due mitochondrial proteotoxic stress, that may also contribute to neuronal damage and pathogenesis of certain brain diseases. Based on these findings, it is assumed that development of mitoprotective agents, specifically targeting mechanisms of mitochondrial quality control, would be useful for prevention of neurotoxic effects of Cu overload.

A novel monomeric amyloid β-activated signaling pathway regulates brain development via inhibition of microglia.

Amyloid β (Aβ) forms aggregates in the Alzheimer's disease brain and is well known for its pathological roles. Recent studies show that it also regulates neuronal physiology in the healthy brain. Whether Aβ also regulates glial physiology in the normal brain, however, has remained unclear. In this article, we describe the discovery of a novel signaling pathway activated by the monomeric form of Aβ in vitro that plays essential roles in the regulation of microglial activity and the assembly of neocortex during mouse development in vivo. We find that activation of this pathway depends on the function of amyloid precursor and the heterotrimeric G protein regulator Ric8a in microglia and inhibits microglial immune activation at transcriptional and post-transcriptional levels. Genetic disruption of this pathway during neocortical development results in microglial dysregulation and excessive matrix proteinase activation, leading to basement membrane degradation, neuronal ectopia, and laminar disruption. These results uncover a previously unknown function of Aβ as a negative regulator of brain microglia and substantially elucidate the underlying molecular mechanisms. Considering the prominence of Aβ and neuroinflammation in the pathology of Alzheimer's disease, they also highlight a potentially overlooked role of Aβ monomer depletion in the development of the disease.

The effects of two Alzheimer's disease related genes APOE and MAPT in healthy young adults: An attentional blink study.

Genetic risk factors start to affect the brain and behavior in Alzheimer's disease (AD) before clinical symptoms occur. Although AD is mainly associated with memory deficits, attention and executive dysfunctions can present at the early presymptomatic stages in middle age for those with non-modifiable risks. Here, we investigated whether known risk genes for AD already affected attention in young adulthood. A total of 392 healthy young adults aged around 20 years underwent genetic testing for risks of dementia (APOE and MAPT) and performed a computerized cognitive test for temporal attention called the Attentional Blink (AB) task, in which patients with dementia tested in previous studies often showed reduced performance. Here, the AB task was analyzed using repeated-measurements analysis of variance for the ability of visual perception, attention deployment and temporal memory encoding/binding performance. The results showed that all participants exhibited AB effects. Importantly, genetic risk factors had statistically significant influence on temporal attention depending on sex in healthy young adults. APOE4 status was associated with enhanced attention deployment in males but not females, while MAPT AA carriers had poorer performance in AB but only in females. No genetic effects were found for visual perception and temporal memory binding errors between high and low risk groups. We provided evidence that both APOE and MAPT start to affect attentional function as early as young adulthood. Furthermore, unlike previous findings in older people, these genes had a differential effect for males and females in young adults.

A survey of MRI-based brain tissue segmentation using deep learning

Segmentation of brain tissue from MR images provides detailed quantitative brain analysis for accurate diagnosis, detection, and classification of brain diseases, and plays an important role in neuroimaging research and clinical environments. Recently, a plethora of deep learning-based approaches have been employed to achieve brain tissue segmentation in fetuses, infants, and adults with impressive outcomes. However, owing to the existence of noise, motion artifacts, and edge blurriness in MR images, automatically segmenting brain tissue accurately from MR images is still a very challenging task. This survey examines both deep learning and MRI, providing an overview of the latest advances in fetal, infant, and adult brain tissue segmentation techniques based on deep learning. It includes the performance and quantitative analysis of the state-of-the-art methods. Over 100 scientific papers covering various technical aspects, including network architecture, prior knowledge, and attention mechanisms, were reviewed and analyzed. This article also comprehensively discusses these technologies and their potential applications in the future. Brain tissue segmentation provides detailed quantitative brain analysis for accurate diagnosis, detection, and classification of brain diseases, and plays an important role in neuroimaging research and clinical environments.

Understanding ubiquitination in neurodevelopment by integrating insights across space and time.

Ubiquitination regulates a myriad of eukaryotic signaling cascades by modifying substrate proteins, thereby determining their functions and fates. In this perspective, we discuss current challenges in investigating the ubiquitin system in the developing brain. We foster the concept that ubiquitination pathways are spatiotemporally regulated and tightly intertwined with molecular and cellular transitions during neurogenesis and neural circuit assembly. Focusing on the neurologically highly relevant class of homologous to E6AP C-terminus (HECT) ubiquitin ligases, we propose cross-disciplinary translational approaches bridging state-of-the-art cell biology, proteomics, biochemistry, structural biology and neuroscience to dissect ubiquitination in neurodevelopment and its specific perturbations in brain diseases. We highlight that a comprehensive understanding of ubiquitin signaling in the brain may reveal new horizons in basic neuroscience and clinical applications.

Leucencephalopathy in Patients with Parkinson's Disease and Deep Brain Stimulation.

Leucencephalopathy (LE) is often detected on magnetic resonance imaging in elderly patients. These white matter lesions may interfere with lead trajectories for deep brain stimulation (DBS) in patients with Parkinson's disease (PD) and are associated with complications after DBS surgery. This study was conducted to assess the incidence of LE in PD patients and to evaluate correlations with complications after DBS surgery. A consecutive cohort of PD patients who underwent DBS surgery in the subthalamic nucleus (STN-DBS) was retrospectively analyzed. The presence and extent of LE were quantified using the Fazekas scale. Postoperative complications were extracted from the medical records. DBS efficacy was calculated using the side-specific motor symptom ratio (Unified Parkinson's Disease Rating Scale, Part III, postoperative stimulation ON/medication off divided by preoperative medication off) at 1-year follow-up. A total of 135 PD patients were included in the study. LE was detected in 35.6% (48/135) of the patients. In 87.7% (57/65), LE was mild, in 10.7% (7/65) moderate, and in 1.6% (1/65) severe. A higher incidence of mild to moderate LE did not correlate with postoperative hemorrhage or postoperative infection. There was no correlation of LE with stimulation efficacy (r = -0.05, P = 0.69) or with surgical index (r = -0.10, P = 0.35). Neither was the presence of mild to moderate LE associated with an increased risk for surgical complications, nor did it negatively impact the long-term improvement in motor function after DBS surgery in PD patients. Therefore, mild to moderate LE should not be considered a contraindication for DBS.

The Importance of Stem Cells in the Treatment of Neuropathic Pain.

Many disorders, including heart, bone, cancer, liver, and brain disease, have been treated using stem cell therapy as a viable alternative. The somatosensory system is affected by a lesion, which leads to neuropathic pain (NP), and just a relatively tiny fraction of patients now receive effective care from existing pharmacological medications. There have been studies to show the effectiveness of various stem cells in reducing or treating experimental neurological pain, although these studies are uncommon in number. In this narrative review, we will summarize the preclinical and clinical research that has been conducted on the effectiveness of several stem cell types, such as mesenchymal stem cells, bone-derived stem cells, and neural stem cells, in reducing neurological pain in this study.

Depression Symptoms Do Not Worsen Over Time in a Cohort of CKD Patients: The BRINK Study.

The prevalence of depression is high in the chronic kidney disease (CKD) (20-40%) and dialysis (30-50%) populations. Less is known about how depressive symptoms change over time in patients with CKD. Participants in the Brain in Kidney Disease (BRINK) cohort study completed a depressive symptom questionnaire (PHQ-9) and serum creatinine testing annually. We used linear mixed effects models to examine changes in PHQ-9 scores over time and compared rates of change between participants with different ranges of eGFR impairment and those with normal eGFR. At baseline, 147 participants had normal eGFR, 424 had impaired eGFR without dialysis dependence, and 31% reported a diagnosis of depression, with a mean baseline PHQ-9 score of 4.3. Participants were followed for up to 5 years. After adjustment for factors associated with depression, mean PHQ-9 scores decreased (improved) by 0.25 points per year (95% confidence interval [CI] 0.07, 0.42) among participants with normal eGFR (>60 ml/min/1.73m2) and by 0.35 points (95% CI 0.14, 0.56), 0.30 points (95% CI 0.13,0.46) and 0.42 points (95% CI 0.06, 0.77) among participants with eGFR of 45 to 59 ml/min/1.73m2, 30 to 44 ml/min/1.73m2, and participants who developed dialysis dependence, respectively. PHQ-9 scores among participants with eGFR <30 ml/min/1.73m2 did not change significantly. We did not observe any statistically significant differences in mean change in PHQ-9 score between participants with any degree of eGFR impairment and those with normal eGFR, nor between participants with dialysis-dependence and those with eGFR of ≤15 ml/min/1.73m2. Participants with a PHQ-9 score ≥5 had 80% greater odds of immediate study attrition than participants with a PHQ-9 score of 0-4." The mean PHQ-9 scores of participants were largely stable over time, and we observed no differences in the change in PHQ-9 scores between those with impaired eGFR and those with normal eGFR.