Check out some of the papers that were recently published by DMCBH members:
Cheryl Wellington: Plasma biomarkers distinguish Boston Criteria 2.0 cerebral amyloid angiopathy from healthy controls
Journal: Alzheimer’s & Dementia: the Journal of the Alzheimer’s Association
When beta-amyloid (Aβ) accumulates in small blood vessels, cerebral amyloid angiopathy (CAA) occurs, leading to stroke and dementia. The present study examined whether plasma Aβ42/40, phosphorylated-tau (p-tau), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) differ in CAA and whether these could be viable biomarkers. These molecules were quantified using a single molecule array (Simoa) and Aβ42/40 was additionally measured using immunoprecipitation liquid chromatography mass spectrometry. Aβ42/40 ratios were significantly lower in CAA than in healthy controls. While p-tau-181 and NfL were elevated in CAA, GFAP was similar. Together, these molecules can discriminate CAA from healthy controls with potential use as plasma biomarkers, offering a more accessible alternative to PET and CSF studies.
Noah Silverberg: Interventions to help adults with concussion return to work: A systematic review
Journal: PM&R: the journal of injury, function, and rehabilitation
Symptoms of concussion can delay return to work (RTW) and impair workplace function. Clinicians would benefit from guidance about how to aid patient transitions back into the workforce. This systemic review summarized the results of various interventions to determine efficacy, examine behaviour change techniques (BCTs), and identify promising BCTs. Psychotherapy, neuropsychological training, vestibular rehabilitation, vision rehabilitation, exercise, compensatory strategies, cognitive training, vocational support, and interpersonal training may be efficacious. Effective BCTs provided instruction on how to perform the behaviour, reduce negative emotions, and action planning; participants were also provided information about health consequences and encouraged to do problem-solving. The identified interventions and BCTs may be useful for aiding RTW in patients.
Terry Snutch: Maturational Stage-Dependent Contributions of the Cav3.2 T-Type Calcium Channel to Dentate Gyrus Granule Cell Excitability
Journal: eNeuro
T-Type calcium channels are important for neuronal excitability, driving burst firing, plasticity and neuronal oscillations influencing circuit activity. Three distinct T-type channel subtypes exist and are differentially expressed in the brain. Type Cav3.2 is expressed in the dentate gyrus (DG) of the hippocampus, and mice lacking this channel are worse at learning and memory tasks. Since neurogenesis occurs in the DG, there are granule cells of different maturity levels. The present study investigated how Cav3.2 channels contributed to granule cell activity at 3 different maturation levels. In immature cells, they likely contribute to low-threshold calcium spikes, while they may increase excitability in intermediate and mature cells. Calcium influx using Cav3.2 may differentially regulate granule cell excitability based on maturity, contributing to the development of DG processes like memory.
Lawrence Ward: Are emotional stimuli prioritised in visual awareness?
Journal: Cognition & Emotion
Although visual stimuli can affect awareness, it’s unclear whether and how much emotional stimuli are prioritized. Researchers conducted three online experiments to assess whether positive and negative emotional photographs would be noticed more than neutral ones. Experiment 1 showed that positive photographs were more noticeable, while experiment 2 showed that this effect was not due to increased memorability. Experiment 3 used a verbal method and was consistent with the results of the first experiment. Images of people are animals were consistently noticed, suggesting potential prioritization.
Mypinder Sekhon, Ryan Hoiland: ABO blood group and COVID-19 severity: Associations with endothelial and adipocyte activation in critically ill patients
Journal: PLoS One
Blood type has been implicated in both susceptibility to and severity of SARS-CoV-2 infection. The present study explored potential associations between ABO blood group and severity of COVID-19 infection in critically ill patients, examining inflammatory cytokines, endothelial injury and adipokines. Patients with type A and AB blood had more frequent ventilation requirements compared to those with type B and O. Additionally, they had higher ICU mortality rates, longer median ICU and hospital stay. There were no associations with blood type and endothelial injury or inflammatory cytokines. This retrospective study showed that type A and AB blood was associated with more severe COVID-19 and higher adipsin levels.
Wilfred Jefferies: A secreted Tapasin isoform impairs cytotoxic T lymphocyte recognition by disrupting exogenous MHC class I antigen presentation
Journal: Frontiers in Neuroimmunology
The MHC-1 peptide-loading complex (PLC) is essential for initiating cytotoxic T cell responses against pathogens and tumours. Tapasin is a key component of the PLC and is produced in multiple forms through alternative splicing. Each form influences the assembly and stability of MHC-1 molecules differently. This study investigated the role of Tapasin isoforms, particularly type 3, in modulating antigen presentation and immune responses. Results show that isoforms 1 and 2 promote optimal antigen presentation while 3 is secreted and acts as a negative regulator. Isoform 3 may play a role in immune regulation by preventing inappropriate T cell activation and cytotoxicity, which could otherwise damage tissue and lead to autoimmune disorders.
Khaled Abdelrahman: Enhancing remyelination in multiple sclerosis via M1 muscarinic acetylcholine receptor
Journal: Molecular Pharmacology
Current treatments for multiple sclerosis are limited to disease management, and there is a need for restorative treatments that can reverse progressive forms of the disease. This review aims to summarize the potential mechanisms by which antagonizing the M1 muscarinic acetylcholine receptor could promote remyelination and elaborate on a collection of promising antimuscarinic drugs, consolidating the knowledge needed to target these mechanisms and develop therapeutics that could reverse the progress of demyelinating diseases like multiple sclerosis.
Journal: Canadian Journal of Psychiatry
Although genetics and psychiatric disorders are interconnected, it is unclear how genes affect the antidepressant response. This study investigated whether polygenic risk scores (PRS) for major psychiatric disorders and neuroticism are associated with antidepressant treatment outcomes. With 148 participants with major depressive disorder from the CAN-BIND-1 cohort, researchers assessed the efficacy of escitalopram, with nonresponders additionally receiving aripiprazole. At week 16, a higher PRS for major depressive disorder was associated with increased remission probability and greater symptom improvement. In contrast, higher PRSs for schizophrenia and attention-deficit hyperactivity disorder were associated with lower symptom improvement. These findings suggest that PRSs may influence treatment outcomes, particularly in ESC monotherapy.
Irene Vavasour: Sensitivity of multi-parametric quantitative magnetic resonance imaging for multiple sclerosis pathology
Journal: PLoS One
In patients with multiple sclerosis (MS), objective MRI-based characterization of subtle changes in lesions, perilesion and normal appearing white and grey matter would revolutionize clinical assessment. The present study investigated the sensitivity of quantitative MRI parameters to focal and diffuse MS pathology with a small sample size. All nine assessed biomarkers for MS were significantly different between lesion, perilesion and normal appearing white matter. While all biomarkers allowed effective characterization of lesions, investigating white matter with myelin water fraction, magnetization transfer saturation and inhomogeneous MT ratio could be most promising.
Miriam Spering: Visual factors that determine sensory uncertainty in rapid interceptive hand movements
Journal: Journal of Vision
Tracking and intercepting a moving object, such as catching a ball, requires predicting its trajectory. This ability depends on the available motion information, including how long an object is shown and how long it is occluded. A simulated flyball was shown briefly on a computer screen and then occluded before it entered a hit zone. Participants tracked the trajectory of the ball with their eyes and intercepted it in the hit zone with a rapid pointing movement. When the ball was shown for a shorter duration, there was a strong center bias in hand movements, while a long occlusion duration only yielded a weak center bias. These findings suggest that sensorimotor decisions under uncertainty might rely more on priors when an object is presented briefly versus when it is occluded for longer periods.
Ann Marie Craig: Targeted splicing approach for alleviation of a neurexin 1 haploinsufficiency model
Journal: Molecular Psychiatry
NRXN1 is a gene encoding the synaptic organization protein neurexin 1 (Nrxn1) and is among the strongest risk genes for autism spectrum disorders as well as other neuropsychiatric disorders. The most common contributing mutation is deletion in one allele. It was found that Nrxn1+/- mice with a deletion affecting all isoforms, α, β and γ, show deficits in excitatory synaptic transmission affecting presynaptic and postsynaptic properties at hippocampal CA3-CA1 synapses, and show increased repetitive behaviors. Researchers additionally tested whether exclusion of the insert at the remaining Nrxn1 splice site 5 could boost synaptic transmission as a potential therapeutic approach. Indeed, it alleviated the deficits, restoring miniature excitatory postsynaptic current frequency, paired pulse ratio, AMPA/NMDA ratio, and repetitive behaviors to wild type levels. This therapy has potential in treating cases of neuropsychiatric disorders involving NRXN1.
Robin Hsiung, Ian Mackenzie: Deciphering distinct genetic risk factors for FTLD-TDP pathological subtypes via whole-genome sequencing
Journal: Nature communications
Frontotemporal lobar degeneration is a group of brain disorders caused by degeneration of the frontal and/or temporal lobes of the brain. With neuronal inclusions of TAR DNA-binding protein 43 (FTLD-TDP), this is a fatal neurodegenerative disorder with a genetic link and limited risk loci identified. This comprehensive genome-wide association study confirmed UNC13A as the strongest FTLD-TDP risk factor and identified TNIP1 as a novel risk factor. Moreover, researchers found genome-wide significant loci corresponding to each of the three main FTLD-TDP pathological subtypes indicating distinct disease etiologies in each one. More novel subtype-specific risk genes were confirmed, highlighting the role of immunity and the notch signaling pathway in FTLD-TDP, with potential diagnostic and therapeutic implications.
Robin Hsiung, Ian Mackenzie: Sex differences in clinical phenotypes of behavioral variant frontotemporal dementia
Journal: Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association
Sporadic behavioural variant frontotemporal dementia (bvTD) is more prevalent in males. With regards to this sex difference, researchers hypothesized that there were phenotypic differences between genetic and sporadic females, leading to underdiagnosis of the sporadic subcategory. Females with sporadic bvFTD showed worse compulsive behaviour and language impairments compared with those with genetic bvFTD. Females with sporadic bvFTD exhibit a distinct clinical phenotype compared to females with genetic bvFTD. This difference may explain the discrepancy in prevalence between genetic and sporadic cases, as some females without genetic mutations may be misdiagnosed due to atypical bvFTD symptom presentation.
Journal: Journal of Huntington’s disease
Synaptic dysfunction underlies early sensorimotor and cognitive deficits in Huntington’s disease (HD) and occurs before the degeneration of striatal spiny projection neurons and cortical pyramidal neurons. Connections between the motor cortex, basal ganglia and thalamus are important for movement selection and motor learning, two processes impaired early in HD. Endocannabinoid-mediated long-term depression (LTD) at corticostriatal synapses is critical for motor learning. JZL184 is an inhibitor of endocannabinoid 2-arachidonoyl glycerol (2-AG) degradation and can correct impaired LTD. Oral administration of JZL184 significantly increased 2-AG levels in striatal tissue and restored motor learning on the rotarod task in HD mouse models. Moreover, high frequency stimulation induced striatal plasticity was normalized to WT levels. Overall, these results suggest a novel target for mitigating early symptoms of HD and support the need for clinical trials of therapies that modulate the endocannabinoid system.
Haakon Nygaard, Brian MacVicar, Freda Miller, David Kaplan, Ian Mackenzie: A 3D human iPSC-derived multi-cell type neurosphere system to model cellular responses to chronic amyloidosis
Journal: Journal of Neuroinflammation
Alzheimer’s disease is characterized by progressive accumulation of amyloid beta (Aβ) in the brain, with eventual widespread neurodegeneration. This study used a human 3D iPSC-derived neurosphere model to explore how resident neurons, microglia and astrocytes as well as their interactions are modified by chronic amyloid protein buildup. Microglia efficiently phagocytosed Aβ inside neurospheres and significantly reduced neurotoxicity, mitigating amyloidosis-induced oxidative stress and neurodegeneration. The presence of microglia was neuroprotective and directly altered the molecular landscape of Alzheimer’s disease. They may be essential for the cellular and transcriptional responses in AD pathogenesis, including in APOE expression. This human 3D neurosphere culture system offers unique opportunities to study the roles of microglia and identify new therapeutic targets.
Ian Mackenzie: Increased TMEM106B levels lead to lysosomal dysfunction which affects synaptic signaling and neuronal health
Journal: Molecular Neurodegeneration
Genetic variation in Transmembrane protein 106B is known to influence the risk and presentation in several neurodegenerative diseases. While human studies suggest that the risk allele is associated with higher levels of TMEM106B, it is unclear how these elevated levels modulate disease risk. Researchers created the first transgenic mouse model that successfully overexpresses TMEM106B in heterozygous and homozygous animals. Increased TMEM106B levels induced lysosomal dysfunction and age-related downregulation of genes associated with neuronal plasticity, learning, and memory. Moreover, it led to altered synaptic signaling in 12-month-old animals, which additionally demonstrated an anxiety-like phenotype. Researchers also observed mild neuronal loss in the hippocampus of 21-month-old animals. TMEM106B may affect brain health by modifying brain aging and impairing the resilience of the brain to pathomechanisms of neurodegenerative disorders.
