Check out some of the papers that were recently published by DMCBH members:
Daniel Goldowtiz: Identification of an early subset of cerebellar nuclei neurons in mice
Journal: eLife
The cerebellum is a key player in both motor and non-motor functions. Cerebellar nuclei neurons serve as the primary output of the cerebellum and originate from the cerebellar primordium at early stages of development. These neurons integrate information from the cerebellar cortex and relay it to different brain regions. The authors characterized a specific subset of CN neurons that do not originate from the rhombic lip or ventricular zone of the cerebellar primordium. Mice embryos were collected at early stages of development and processed for immunohistochemistry, western blotting, in situ hybridization, embryonic culture, DiI labeling and flow cytometry analysis. Findings indicated that a subset of CN neurons expressing α-synuclein, OTX2, MEIS2 and p75NTR were in the rostroventral region of the nuclear transitory zone (NTZ). CN neurons derived from the rhombic lip are positioned in the caudodorsal area of the NTZ. Using Otx2–GFP and Atoh1-/- mice, authors determined that these cells do not originate from the germinal zone of the cerebellar primordium, suggesting the existence of a novel extrinsic germinal zone, possibly the mesencephalon, where early CN neurons may originate.
Helen Tremlett: The Misclassification of Depression and Anxiety Disorders in the Multiple Sclerosis Prodrome: A Probabilistic Bias Analysis
Journal: Annals of Epidemiology
Several studies suggest that depression/anxiety form part of the multiple sclerosis prodrome. However, these studies may be biased towards the null hypothesis. The authors re-examined this association after correcting for: (i) the misclassification of individuals who were not seeking healthcare, (ii) differential surveillance of depression/anxiety in the healthcare system, and (iii) misclassified person-time from using the date of the first diagnostic claim as a proxy for MS onset. This cohort study applied probabilistic bias analyses to account for misclassification and differential surveillance while time-distribution matching was used for misclassified person-time. It was found that previous conventional analyses led to an underestimation of the association between depression/anxiety and MS in the prod Roman period.
Kiran Soma: Lipopolysaccharide differentially alters systemic and brain glucocorticoid levels in neonatal and adult mice
Journal: Journal of Neuroendocrinology
In response to stressors like infection, the adrenal glands secrete glucocorticoids (GCs). The brain regulates local GC levels through synthesis, regeneration and/or metabolism, though little is known about local GC regulation within discrete brain areas at baseline or after stress. Male and female mice at postnatal day 5 or 90 were treated with lipopolysaccharide (LPS) or placebo and after 4 hours, blood and brain samples were collected. Researchers microdissected the prefrontal cortex, hippocampus, hypothalamus and amygdala. Seven steroids, including corticosterone, were measured using liquid chromatography-tandem mass spectrometry and transcripts for key steroidogenic enzymes were measured. At both day 5 and day 90, LPS increased GC levels in blood and all brain regions with a greater increase at day 90. In the day 5 condition, corticosterone levels were lower in the prefrontal cortex but higher in the amygdala relative to blood. These changes aligned with increased steroidogenic enzyme expression, showing regional heterogeneity. In the day 90 condition, corticosterone levels were lower and homogenous in all brain regions than in blood and steroidogenic enzyme levels were generally unaffected. These data indicated that local GC levels within discrete brain regions were more heterogeneous at postnatal day 5 than postnatal day 90 as a result of increased local GC production and metabolism.
Annie Ciernia, Tao Huan, Kiran Soma: Early-Life gut inflammation drives sex-dependent shifts in the microbiome-endocrine-brain axis
Journal: Brain, Behaviour, and Immunity
It is unclear how gut inflammation affects brain development. It was hypothesized that gut inflammation during early life would negatively affect neurodevelopment by disrupting microbiota communication to the brain. The researchers developed a novel pediatric chemical model of inflammatory bowel disease (IBD), an incurable condition affecting millions worldwide and sometimes diagnosed in childhood. IBD is characterized by chronic intestinal inflammation and associated with anxiety, depression and cognitive impairment. This study investigated the effects of early life gut inflammation included by dextran sulfate sodium (DSS) on a range of microbiota, endocrine and behavioural outcomes. DSS-treated mice showed increased intestinal inflammation and altered microbiota membership. Most behavioural measures were unaffected except for impaired mate-seeking behaviours in males. DSS-treated males also had significantly smaller seminal vesicles, lower circulating androgens and decreased intestinal hormone-activating enzyme activity compared to controls. DSS treatment also led to chronic, sex-specific alterations in microglial morphology. Results suggest that early-life gut inflammation causes changes in gut microbiota composition, affecting short-chain fatty acid producers and glucuronidase activity, correlating with lower androgen levels. This emphasized the developmental sensitivity to inflammation-induced changes in endocrine signalling and the long-lasting effects of juvenile IBD.
Helen Tremlett: Symptoms Prior to Diagnosis of Multiple Sclerosis in Individuals Younger Than 18 Years
Journal: Neurology
A growing body of literature suggests the existence of a prodromal period of symptoms before the onset of multiple sclerosis (MS), nut not much is known about how these are expressed in pediatric patients. This population-based, matched case-control study looked at children and adolescents <18 years of age to systematically assess symptoms observed 5 years before a first MS or central nervous system demyelination’s disease-related diagnostic code. Children and adolescents with MS were found to have diverse metabolic, ocular, musculoskeletal, gastrointestinal, and cardiovascular symptoms within 5 years before their first MS diagnosis. Building on our understanding of early symptoms and/or risk factors may improve early recognition and progression trajectories.
Robin Hsiung, Ian Mackenzie: Clinical Symptoms and Risk Factors in Older Adults with Limbic-Predominant Age-Related TDP-43 Neuropathology in the Context of Mixed Dementia
Journal: Alzheimer’s and Dementia
This study examines the clinical characteristics of individuals with Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC), a pathological process involving TDP-43 deposition in the medial temporal lobes, compared to controls without LATE-NC. Data from 39 autopsy cases with moderate to severe Alzheimer’s or Lewy Body pathology were reviewed. The LATE+ group (n=19) had significantly more years of education (14.9 vs. 13.3) and a higher prevalence of prior head injury (33.3% vs. 5.3%) compared to the LATE- group (n=20). Mood symptoms were more common in the LATE+ group, while psychotic symptoms were less frequent, though neither difference was statistically significant. No significant differences were found in cognitive domains affected, cognitive test scores, or disease progression. The findings suggest head injury and higher education may be risk factors for LATE-NC, but its clinical impact appears small relative to Alzheimer’s or Lewy Body pathology. Further research is needed to clarify its clinical features, particularly in cases with minimal co-existing pathology.
Robin Hsiung, Ian Mackenzie: Functional connectivity associations with markers of disease progression in GRN mutation carriers
Journal: Alzheimer’s & Dementia
Autosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Previous studies showed that presymptomatic GRN carriers exhibit thalamocortical hyper connectivity that increases with age. Using functional magnetic resonance imaging from 49 presymptomatic and 26 symptomatic GRN mutation carriers, functional connectivity was examined. In presymptomatic carriers, hyperconnectivity was associated with elevated plasma neurofilament light chain (NfL) levels and reduced gray matter volume in regions prone to GRN-related degeneration, suggesting it may signal the transition to the neurodegenerative phase. In symptomatic carriers, hyperconnectivity correlated with complement protein levels, while gray matter atrophy was more extensive. OCD symptom severity was linked to hypoconnectivity across all carriers. These findings highlight hyperconnectivity as an early indicator of disease progression.
Joanne Matsubara, Robin Hsiung, Ian Mackenzie: Evidence for impaired clearance leading to amyloid beta (Aβ) accumulation in the Alzheimer’s eye
Journal: Alzheimer’s and Dementia
Retinal wholemount studies offer insights into cell-specific involvement in amyloid beta (Aβ) clearance mechanisms in Alzheimer’s disease (AD). Retinal cross-sections of double transgenic mice (Tg, APP-PS1) at 3 or 9 months and wholemount neuroretinas of human AD samples were analyzed using various antibodies. In the eye cross-sections, there was a significant increase in 6E10, IBA1, GFAP, and AQP4 in older versus younger Tg mice, suggesting Aβ accumulation led to gliosis and AQP4 mislocalization. In contrast, older non-carrier siblings showed a significant reduction in 6E10, indicating more effective Aβ clearance, possibly through microglial and macrophage activity, as well as glymphatic drainage. In wholemount human AD neuroretinas, macroglia degenerations (GFAP, GS, and AQP4) were prominent, suggesting a defective ocular glymphatic system in AD. The microglia phenotype in AD eyes was different from its resting stage, but the complexity of resident microglia and other cell types made it challenging to definitively characterize their phenotype. Interestingly, NIR-E3-positive perivascular macrophages (but negative to 12F4, indicating soluble Aβ clearance) were found within the blood vessels of control donor eyes. This study confirms the presence of impaired Aβ clearance mechanisms in human AD eyes.
Haakon Nygaard: Unravelling the mechanisms of aducanumab on efficacy of Aß clearance by iPSC-derived human microglia in 2D and 3D cell cultures
Journal: Alzheimer’s and Dementia
Antibodies targeting amyloid beta have been developed as promising treatments for Alzheimer‘s Disease (AD). In 2021, Aducanumab received limited FDA approval, offering a new treatment option for patients. This drug clears aggregated amyloid beta in the brain, possibly through microglial phagocytosis, although mechanisms are not yet fully understood. Using iPSC-derived microglial, researchers studied how aducanumab facililates amyloid beta clearance in the brain. Microglia treated with aducanumab had significantly higher levels of phagocytosed amyloid beta and at a faster rate. Additionally, immunostaining showed a decrease in the amount of highly aggregated intracellular amyloid beta. While it did not cause a significant reduction in amyloid beta in the 3D tissue, it prevented the formation of larger aggregates, potentially facilitating microglia mediated clearance. Researchers concluded that Aducanumab acutely increased the ability of iPSC-derived microglia to phagocytoses amyloid beta and may also prevent aggregation.
Haakon Nygaard: Alzheimer’s disease modeling and drug screening through hiPSC 3D bioprinting
Journal: Alzheimer’s and Dementia
Our current understanding of Alzheimer’s Disease (AD) is limited due to the lack of comprehensive models closely resembling human pathology. Human induced pluripotent stem cell (hiPSC) 3D models like brain organoids and neurospheres are emerging as innovative models for neurodegenerative diseases. However, they rely on self-organization, leading to low reproducibility and homogeneity. Moreover, they lack proper extracellular matrix and microglial cells which are heavily involved in AD. Researchers generated a 3D-bio printed brain model suitable for long-lasting culturing of IPSCs-derived cortical neurons and astrocytes from neuronal precursor cells. This technique mimics the human cerebral cortex architecture with greater accuracy. Moreover, using synthetic amyloid beta enriched bio ink and familial AD cell lines, this system might offer the chance to study the nucleation of amyloid beta in real time and mimic plaque formation without animal models.
Haakon Nygaard, Brian MacVicar: Temporal dynamics of microglial neuroprotection during chronic Aß -treatment in human iPSC-derived 3D neurospheres
Journal: Alzheimer’s and Dementia
While mouse models of Alzheimer’s disease (AD) have led to many discoveries about AD pathogenesis, the results are poorly translated to human treatments. IPSC-derived human neuronal cultures offer an alternative model for AD in vitro. Neurospheres were formed from iPSC-derived neuronal progenitor cells, expanded, differentiated and maintained for 60 days. Microglia were added for the last 10 days and oligomeric amyloid beta was added chronically for 3 or 5 weeks. One key hallmark of AD is the presence of insoluble amyloid beta in the brain, and this model allows study of the complex neuron-glia-amyloid beta interaction. Infiltrating microglia displayed high phagocytic activity and reduced extracellular amyloid beta deposits, loss of neuronal activity and oxidative stress when added early in treatment. When they were transferred late during amyloid beta exposure, they reduced neuronal death but failed to recover function or reduce oxidative stress. This human 3D cell culture model allowed the formation of neurospheres and a means to mimic amyloidosis as a novel human AD model.
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Joanne Matsubara: Apolipoprotein E dysfunction in Alzheimer’s disease: a study on miRNA regulation, glial markers, and amyloid pathology
Journal: Frontiers in Aging Neuroscience
Apolipoprotein E (ApoE) is expressed in astrocytes and some microglia within the central nervous system and plays a role in lipid homeostasis. The APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD), but its precise role in pathogenesis is unknown. This study explores ApoE’s role in AD by analyzing brain and retinal samples from mice with ApoE gene knockouts (Apoe-KO), focusing on the identification of potential retinal biomarkers which would improve living diagnosis. Findings indicated that microRNA levels were generally lower in 3-month-old knockout mice but increased in 9-month-old mice across distinct brain regions and eye tissue. A high fat diet further increased microRNA dysregulation and relevant protein markers also showed accumulation in brain tissues and in the retina. The findings of this paper highlighted ApoE’s impact on inflammatory and amyloidogenic microRNA expression, glial homeostasis and amyloid beta peptide clearance. There is potential for miR-146a and miR-15a as a tear-based biomarker for ApoE dysfunction.
Journal: Frontiers in Human Neuroscience
Cognitive deficits are common in psychiatric and mental health disorders; thus, it is important to examine how we assess cognitive function in mental health treatment. Cognitive Function Development Therapy (CFDT) is a new therapeutic modality designed to enhance cognitive function and regulate the autonomic nervous system using targeted exercises and activities. This retrospective observational study analyzed data from 183 children and adults undergoing CFDT. Results indicate that it holds promise for improving cognitive performance, significantly increasing Primary Cognitive function scores. Additionally, age was found to influence the degree of cognitive improvement, emphasizing the importance of early intervention. Overall, the study suggests a positive impact of CFDT on cognitive function.
Teresa Liu-Ambrose: Global consensus on optimal exercise recommendations for enhancing healthy longevity in older adults (ICFSR)
Journal: The Journal of Nutrition, Health and Aging
Aging is a universal process marked by gradual physiological changes that increase vulnerability to diseases and mortality over time. Physical activity (PA) and exercise play a critical role in slowing biological aging, improving health span, and reducing the risk of chronic diseases like cardiometabolic conditions, cancer, musculoskeletal disorders, and neurological issues. Exercise serves as both prevention and therapy, particularly for older adults with frailty, sarcopenia, or chronic illnesses. Tailored exercise programs combining aerobic, resistance, balance, and flexibility training are highly effective for maintaining physical and cognitive function, preventing falls, and enhancing quality of life. Anabolic exercises, such as progressive resistance training (PRT), are particularly crucial for improving strength and mobility in older adults. Despite its proven benefits, PA is underutilized in geriatric care, partly due to gaps in healthcare professionals’ training. Personalized exercise prescriptions, integrated with pharmacotherapy, could reduce medication reliance and optimize outcomes for aging populations. Economic analyses highlight the cost-effectiveness of these interventions, justifying their broader adoption in healthcare. This consensus emphasizes the importance of incorporating exercise into health promotion and disease management strategies for older adults, with detailed recommendations for effective exercise regimens and a call for greater integration of PA into geriatric medicine.
Mypinder Sekhon, Cheryl Wellington: The role of C-reactive protein and ferritin in the diagnosis of HLH, adult-onset still’s disease, and COVID-19 cytokine storm
Journal: Scientific Reports
Cytokine storm syndromes are characterized by elevated inflammatory cytokines and include hemophagocytic lymphohistiocytosis (HLH), Adult-onset Still’s disease (AOSD) and COVID-19 cytokine storm (CCS). However, clinical measurements of serum cytokines is not widely available. This study examined the clinical use of C-reactive protein (CRP) and ferritin, two inexpensive and accessible inflammatory markers for distinguishing different cytokine storm syndromes. The median CRP was significantly lower in HLH than AOSD or CCS and median ferritin was significantly lower in CCS than HLG or AOSD. Results indicate that CRP and ferritin may be clinically useful for identifying different cytokine storm syndromes.
Tamara Vanderwal: Mapping patterns of thought onto brain activity during movie-watching
Journal: eLife
Watching movies offers a valuable way to study how the brain processes everyday cognition. Current theories suggest that understanding events in the moment relies on sensory information processed by auditory and visual areas of the brain, regulated by association cortex systems. However, it has been challenging to map patterns of thought onto brain activity during movie-watching without disrupting the natural experience. Using a novel method, this study tracked thought patterns and brain activity during different moments of a film without interrupting the process. It found that when participants engaged with the film’s multi-sensory elements or experienced episodic thoughts, sensory cortex activity increased, leading to better memory for movie events. In contrast, intrusive distractions arose when activity in the association cortex within the frontoparietal system decreased. These findings highlight the importance of sensory systems in immersive movie-watching and the role of association cortex in minimizing distractions.
Journal: Cannabis
This cross-sectional study examined the relationship between cannabis use, mood disorders, anxiety, and psychosis in an inpatient psychiatric population with severe concurrent mental health and substance use disorders and explored the potential effect of legalizing recreational cannabis in Canada. Cannabis use was associated with higher self-reported depression, anxiety, and psychotic symptoms but was not associated with diagnosis of a mood, anxiety, or psychotic disorder. The age of first use was negatively associated with self-reported psychoticism symptoms and frequency of cannabis use was unrelated to mental health outcomes. Generally, legalization was unrelated to measured outcomes.
Rebecca Todd: Hear it here: Built environments predict ratings and descriptions of ambiguous sounds
Journal: PLoS One
The built environments we spend time in can affect the stimuli we experience. Past research suggests that the layout and lighting of a space may affect how a neutrally valanced sound is perceived whether it be more pleasant or unpleasant. This study investigated whether listening to a series of neutral sounds in an older, darker building leads these sounds to be rated as less pleasant compared to listening to these sounds in a newer building with more natural light. Undergraduate students listened to ten sounds that had previously been rated as ambiguous in valence and then described how they felt about each sound. Participants rated sounds as being more pleasant at the New site compared to the Old site. Results suggest that features of built environments can impact the appraisal of everyday sounds.
Robin Hsiung, Ian Mackenzie: White matter pathology in FTLD caused by GRN mutations
Journal: Acta Neuropathologica
This study explored white matter (WM) changes in frontotemporal lobar degeneration caused by progranulin gene mutations (FTLD-GRN) compared to other subtypes of FTLD with TDP-43 pathology (FTLD-TDP) and healthy controls. Examining brain tissue from 50 cases, researchers found that FTLD-GRN cases showed significantly less myelin in the frontal lobe than controls or other FTLD-TDP subtypes, even after accounting for axonal loss. These cases also had more activated microglia, with a strikingly higher proportion displaying ameboid morphology, and unique pathology involving TMEM106B protein in both the frontal and parietal lobes. Additionally, FTLD-GRN and non-GRN FTLD-TDP type A cases exhibited a distinctive pattern of TDP-43 pathology, with more thread-like features in the frontal lobe. These findings highlight the role of WM damage and inflammation in FTLD-GRN, contributing to its unique disease mechanisms and supporting future biomarker and treatment development.
Miriam Spering, Douglas Wylie, Douglas Altshuler: Hummingbirds use compensatory eye movements to stabilize both rotational and translational visual motion
Journal: Proceedings: Biological Sciences
Hummingbirds stabilize their vision during flight through whole-body movements rather than relying heavily on compensatory eye movements, known as the optokinetic response (OKR). OKR is a reflex that helps animals stabilize vision by making eye movements in response to image slip. In most vertebrates with laterally placed eyes, OKR shows a strong bias favoring backward over forward motion, but hummingbirds were expected to show symmetrical OKR due to their unique whole-body stabilization. Surprisingly, experiments with restrained hummingbirds revealed asymmetrical OKR that varied with visual motion speed. Furthermore, their eyes moved largely independently, enabling disjunctive OKR to forward and backward motion. This unexpected oculomotor behavior suggests that compensatory eye movements may play a more significant role in hummingbird flight than previously thought.
Teresa Liu-Ambrose: Physical activity, cathepsin B, and cognitive health
Journal: Trends in Molecular Medicine
Regular physical activity is beneficial for cognitive health, potentially mediated by cathepsin B (CTSB), which is a protease released by muscle. Physical activity produces metabolic and mechanical stress, increasing plasma CTSB levels. CTSB facilitates neurogenesis and plasticity in brain regions supporting cognitive functions like memory and learning. However, evidence is mixed. This review article identifies key factors that may explain the mixed results and proposes a new model, guiding future research.
Helen Tremlett: Healthcare use is elevated two decades before a first demyelinating event and differs by age and sex
Journal: Annals of Clinical and Translational Neurology
This study analyzed healthcare usage patterns before multiple sclerosis (MS) onset using administrative data from Canada and Sweden, comparing individuals with MS (PwMS) to matched controls. Findings showed that PwMS had higher healthcare use up to 28 years before onset in Ontario and 15 years in Sweden, with a steady increase that sharply escalated 6–7 years pre-onset and peaked in the year before diagnosis. Emergency visits in Ontario and physician visits in Sweden tripled in the year prior to onset, with disproportionately higher rates among males and older individuals. A smaller clinical dataset confirmed similar but more modest trends, with increased physician visits up to five years pre-onset. These results suggest that early signs of MS may be detectable in healthcare records decades before diagnosis, highlighting an opportunity for earlier identification and intervention.
