230 results on '"Schweizer TA"'
Search Results
2. Between-center and between-country differences in outcome after aneurysmal subarachnoid hemorrhage in the Subarachnoid Hemorrhage International Trialists (SAHIT) repository
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Dijkland, Simone, Jaja, BNR, van der Jagt, Mathieu, Roozenbeek, Bob, Vergouwen, MDI, Suarez, JI, Torner, JC, Todd, M, Bergh, WM, Saposnik, G, Zumofen, DW, Cusimano, MD, Mayer, SA, Lo, BWY, Steyerberg, Ewout, Dippel, Diederik, Schweizer, TA, Macdonald, RLA, Lingsma, Hester, Dijkland, Simone, Jaja, BNR, van der Jagt, Mathieu, Roozenbeek, Bob, Vergouwen, MDI, Suarez, JI, Torner, JC, Todd, M, Bergh, WM, Saposnik, G, Zumofen, DW, Cusimano, MD, Mayer, SA, Lo, BWY, Steyerberg, Ewout, Dippel, Diederik, Schweizer, TA, Macdonald, RLA, and Lingsma, Hester
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- 2019
3. Prioritization and timing of outcomes & endpoints after aneurysmal subarachnoid hemorrhage in clinical trials and observational studies – proposal of a multidisciplinary research group
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Stienen, MN, Visser-Meily, A, Schweizer, TA, Hänggi, D, Macdonald, RL, and Vergouwen, MDI
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ddc: 610 ,cardiovascular diseases ,610 Medical sciences ,Medicine ,nervous system diseases - Abstract
Objective: In studies on aneurysmal subarachnoid hemorrhage (SAH), substantial variability exists in the use and timing of outcomes and endpoints, which complicates interpretation and comparison of results between studies. The aim of the National Institute of Health (NIH) / National Institute of[for full text, please go to the a.m. URL], 69. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Mexikanischen und Kolumbianischen Gesellschaft für Neurochirurgie
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- 2018
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4. Development and validation of outcome prediction models for aneurysmal subarachnoid haemorrhage: the SAHIT multinational cohort study
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Jaja, BNR, Saposnik, G, Lingsma, Hester, Macdonald, E, Thorpe, KE, Mamdani, M, Steyerberg, Ewout, Molyneux, A, Manoel, ALD, Schatlo, B, Hanggi, D, Hasan, D, Wong, GKC, Etminan, N, Fukuda, H, Torner, J, Schaller, KL, Suarez, JI, Stienen, MN, Vergouwen, MDI, Rinkel, GJE, Spears, J, Cusimano, MD, Todd, M, le Roux, P, Kirkpatrick, P, Pickard, J, Bergh, WM, Murray, G, Johnston, SC, Yamagata, S, Mayer, S, Schweizer, TA, Macdonald, RL, Jaja, BNR, Saposnik, G, Lingsma, Hester, Macdonald, E, Thorpe, KE, Mamdani, M, Steyerberg, Ewout, Molyneux, A, Manoel, ALD, Schatlo, B, Hanggi, D, Hasan, D, Wong, GKC, Etminan, N, Fukuda, H, Torner, J, Schaller, KL, Suarez, JI, Stienen, MN, Vergouwen, MDI, Rinkel, GJE, Spears, J, Cusimano, MD, Todd, M, le Roux, P, Kirkpatrick, P, Pickard, J, Bergh, WM, Murray, G, Johnston, SC, Yamagata, S, Mayer, S, Schweizer, TA, and Macdonald, RL
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- 2018
5. 'Blue is music to my ears': Multimodal synesthesias after a thalamic stroke.
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Fornazzari L, Fischer CE, Ringer L, and Schweizer TA
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Acquired synesthesias have been reported in association with deafferentation of the visual system, temporal lobe seizures, and the use of psychedelics. Based on our review of the literature, the appearance of synesthesias after a thalamic stroke has been reported only once. We present the case of a 45-year-old hypertensive male who, 9 months after a hemorrhagic stroke involving the left lateral posterior nucleus of the thalamus developed persistent sound-tactile, sound-color, and grapheme-gustatory synesthesias. Moreover, the patient noted that even thinking about a sensory stimulus could trigger the experience of another sensory modality, a conceptual type of synesthesia. [ABSTRACT FROM AUTHOR]
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- 2012
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6. Functional outcome in delusional Alzheimer disease patients: a systematic review.
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Fischer CE, Verhoeff NPL, Churchill K, and Schweizer TA
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BACKGROUND: In spite of the prevalence of delusions in Alzheimer's disease (AD) and their association with poor outcomes, there has been little study of the impact of delusions on real-world functioning. METHOD: A number of databases, including Psychlit and Medline, were searched using the keywords: delusions, functional outcomes, activities of daily living, dementia, and Alzheimer's disease. Studies were included in the review if they were in English, restricted to patients with AD, and addressed delusions and function. RESULTS: The review yielded a total of 6 studies, 3 of which showed a correlation between delusions and real-world functioning and 3 of which did not. CONCLUSION: A critical analysis of the existing studies suggests that there may be an association between delusions and impaired real-world functioning. We believe that 2 of the 3 negative studies did not show an association due to issues relating to study design and the use of measures insensitive to executive impairment. This review highlights the future need for more scientifically rigorous studies to clarify this association, so as to ultimately improve treatment outcomes for patients. [ABSTRACT FROM AUTHOR]
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- 2009
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7. Fast, but error-prone, responses during acute alcohol intoxication: effects of stimulus-response mapping complexity.
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Schweizer TA, Jolicoeur P, Vogel-Sprott M, and Dixon MJ
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BACKGROUND: Although moderate doses of alcohol can impair performance on tasks that require information processing, little is known about the locus of the alcohol effects within the processing stream. This study used a psychological refractory period paradigm to investigate the effect of alcohol on the central, cognitive stage of information processing when task complexity is manipulated by altering stimulus-response compatibility. METHODS: Thirty-four healthy male social drinkers were assigned to one of two groups (n = 17) that performed two tasks. Each trial consisted of a task 1 stimulus (tone) followed by a task 2 stimulus (letter) that was presented after one of four stimulus onset asynchronies (50, 200, 500, or 1100 msec). A baseline test of performance was obtained before the groups received a beverage containing either 0.0 g/kg (placebo) or 0.65 g/kg alcohol. Both groups were retested when blood alcohol concentration (BAC) was increasing and was decreasing. RESULTS: The alcohol group made significantly more errors in task 1 compared with their drug-free baseline measure during the ascending phase of the BAC curve, and error rates increased to a greater extent for the more complex arbitrary stimulus-response mapping condition. Moreover, this increase in errors continued unabated during the descending phase of the BAC curve. Increasing BACs also slowed performance (longer reaction time), but unlike errors, reaction time returned to drug-free baseline levels when BAC was decreasing. CONCLUSIONS: The results provide evidence that an acute dose of alcohol can impair one aspect of the central, cognitive stages of information processing. The possibility that errors in information processing remain during decreasing BACs even after processing speed has returned to drug-free levels has important practical implications relating to the detrimental consequences of acute alcohol intoxication. [ABSTRACT FROM AUTHOR]
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- 2004
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8. Cognitive and functional outcome after aneurysmal subarachnoid hemorrhage.
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Al-Khindi T, Macdonald RL, Schweizer TA, Al-Khindi, Timour, Macdonald, R Loch, and Schweizer, Tom A
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- 2010
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9. Palatable feeding effects on expression and reinstatement of morphine conditioned place preference in male and female rats.
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Cam Y, Kocum CG, Houska TK, Konrad ER, Schweizer TA, and Will MJ
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While many environmental factors are known to play a factor in the recovery and risk of relapse for individuals with opioid use disorder (OUD), the role of diet has been relatively unexplored. Individuals with OUD demonstrate unhealthy diet choices with an exaggerated craving for palatable "junk food," yet this relationship has not been well characterized. The present study begins to examine this relationship by first determining the influence of palatable food access on the expression of conditioned rewarding properties of acute morphine exposure in male and female rats. Following the establishment of morphine conditioned place preference (CPP) in all rats, morphine CPP expression was assessed following intra-accumbens (Acb) administration of the µ-opioid receptor agonist D-Ala2,NMe-Phe4,Glyol5-enkephalin (DAMGO) + 20 min access to no diet (ND) or high-fat (HF), in counter-balanced order. Next, all rats received 12 sessions of extinction training before CPP expression was first assessed following no treatment, then again following counter-balanced ND and HF treatments. The results showed that both male and female rats expressed similar levels of morphine CPP. Subsequent examination of morphine CPP expression revealed that HF treatment significantly reduced morphine CPP expression in males, but not females, compared to ND treatment. Neither HF or ND treatment produced morphine CPP reinstatement in either males or females following extinction. In summary, the impact of palatable feeding on the expression of conditioned drug seeking may be sex-specific and more sensitive prior to extinction., Competing Interests: Conflict of Interest The authors declare no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)
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- 2024
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10. Sex Differences in Cortical Thickness and Neuropsychiatric Symptom Burden Based on APOE4 Homozygosity in Alzheimer's Disease.
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Khoury MA, Valcic M, Churchill NW, Di Battista A, De Luca V, Fornazzari LR, Munoz DG, Fischer CE, and Schweizer TA
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Sex differences in patterns of cortical thickness and neuropsychiatric symptom (NPS) burden were examined among individuals with Alzheimer's disease (AD) and two copies (homozygote carriers) of the e4 allele of the apolipoprotein gene (APOE). A total of 752 participants with a clinical etiologic diagnosis of AD were selected from the National Alzheimer's Coordinating Center (NACC) database. Bayesian multilevel regression was used to examine both the within- and between-sex differences in gray-matter cortical thickness and total NPS burden associated with APOE homozygosity. Female homozygote carriers displayed a high probability of having reduced cortical thickness primarily in medial-lateral temporal regions and a greater burden of NPS, relative to both non-homozygous females and homozygous males. These findings support the notion that APOE4 status affects cortical thickness and symptom burden in men and women with AD differentially, with females showing more pronounced effects in brain areas known to be vulnerable in early AD. Future investigations should attempt to elucidate the proposed pattern of decline longitudinally., (© 2024 The Author(s). American Journal of Medical Genetics Part B: Neuropsychiatric Genetics published by Wiley Periodicals LLC.)
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- 2024
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11. Incentive motivation for palatable food blocked by intra-accumbens melanin-concentrating hormone (MCH) receptor-1 antagonist in female rats.
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Cam Y, Kocum CG, Konrad ER, Schweizer TA, Houska TK, Sardina CA, Suri SK, and Will MJ
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Melanin-concentrating hormone (MCH) activity in the nucleus accumbens (Acb) has been shown to influence feeding behavior, yet this has not been characterized in terms of homeostatic vs. hedonic feeding processes. Hedonic feeding, driven by palatability rather than energy deficit, can be modeled through intra-Acb administration of the selective μ-opioid receptor agonist d-Ala2, NMe-Phe4, Glyol5-enkephalin (DAMGO), which preferentially increases consumption and incentive motivation to obtain preferred palatable food. Pharmacological activation of MCH 1 receptors (MCHR1) within Acb has been shown to promote general feeding of chow in males, but not females. However, the effects of MCH on the incentive motivation to obtain preferred palatable food have not been explored. Here, we investigated the role of MCHR1 within the Acb in DAMGO-induced incentive motivation to obtain a sucrose pellet reward. Female Sprague Dawley rats were trained and tested for operant responding under a progressive ratio (PR) breakpoint in response to concurrent intra-Acb administration of DAMGO (0 μg and 0.025 μg/.5 μl/side) immediately following intra-Acb administration of the MCHR1 antagonist (N-(3-{1-[4-(3,4-difluoro-phenoxy)-benzyl]-piperdin-4-yl}-4-methyl-phenyl)-isobutyramide (SNAP-94847; 0 μg, 1.5 μg, and 15 μg/.5 μl/side), in a counterbalanced fashion. As expected, DAMGO significantly increased PR breakpoint and overall active lever presses. SNAP-94847 did not influence PR breakpoint by itself, compared to vehicle; however, both 1.5 and 15 μg doses of SNAP-94847 significantly blocked the increased PR breakpoint produced by intra-Acb DAMGO. The results of the study demonstrate that Acb MCHR1 may play a specific role in the hedonically-driven motivation for palatable food in females., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)
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- 2024
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12. Target engagement of the subgenual anterior cingulate cortex with transcranial temporal interference stimulation in major depressive disorder: a protocol for a randomized sham-controlled trial.
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Demchenko I, Rampersad S, Datta A, Horn A, Churchill NW, Kennedy SH, Krishnan S, Rueda A, Schweizer TA, Griffiths JD, Boyden ES, Santarnecchi E, and Bhat V
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Background: Transcranial temporal interference stimulation (tTIS) is a new, emerging neurostimulation technology that utilizes two or more electric fields at specific frequencies to modulate the oscillations of neurons at a desired spatial location in the brain. The physics of tTIS offers the advantage of modulating deep brain structures in a non-invasive fashion and with minimal stimulation of the overlying cortex outside of a selected target. As such, tTIS can be effectively employed in the context of therapeutics for the psychiatric disease of disrupted brain connectivity, such as major depressive disorder (MDD). The subgenual anterior cingulate cortex (sgACC), a key brain center that regulates human emotions and influences negative emotional states, is a plausible target for tTIS in MDD based on reports of its successful neuromodulation with invasive deep brain stimulation., Methods: This pilot, single-site, double-blind, randomized, sham-controlled interventional clinical trial will be conducted at St. Michael's Hospital - Unity Health Toronto in Toronto, ON, Canada. The primary objective is to demonstrate target engagement of the sgACC with 130 Hz tTIS using resting-state magnetic resonance imaging (MRI) techniques. The secondary objective is to estimate the therapeutic potential of tTIS for MDD by evaluating the change in clinical characteristics of participants and electrophysiological outcomes and providing feasibility and tolerability estimates for a large-scale efficacy trial. Thirty participants (18-65 years) with unipolar, non-psychotic MDD will be recruited and randomized to receive 10 sessions of 130 Hz tTIS or sham stimulation ( n = 15 per arm). The trial includes a pre- vs. post-treatment 3T MRI scan of the brain, clinical evaluation, and electroencephalography (EEG) acquisition at rest and during the auditory mismatch negativity (MMN) paradigm., Discussion: This study is one of the first-ever clinical trials among patients with psychiatric disorders examining the therapeutic potential of repetitive tTIS and its neurobiological mechanisms. Data obtained from this trial will be used to optimize the tTIS approach and design a large-scale efficacy trial. Research in this area has the potential to provide a novel treatment option for individuals with MDD and circuitry-related disorders and may contribute to the process of obtaining regulatory approval for therapeutic applications of tTIS., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT05295888., Competing Interests: AD is an employee of Soterix Medical, Inc. AH was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft, 424778381 – TRR 295), Deutsches Zentrum für Luft- und Raumfahrt (DynaSti grant within the EU Joint Programme Neurodegenerative Disease Research, JPND), the National Institutes of Health (R01 13478451, 1R01NS127892-01, 2R01 MH113929, and UM1NS132358) as well as the New Venture Fund (FFOR Seed Grant), and reports lecture fees for Boston Scientific and is a consultant for Functional Neuromodulation Ltd. and Abbott. SHK has received honoraria or research funds from Abbott, Alkermes, Allergan, Boehringer Ingelheim, Brain Canada, Canadian Institutes of Health Research, Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund, Otsuka, Pfizer, Servier, Sunovion, Sun Pharmaceuticals, and holds stock in Field Trip Health. ESB is an inventor on the Temporal Interference (TI) Stimulation patent and a co-founder of TI Solutions, a for-profit company. VB is supported by the Academic Scholar Award from the University of Toronto Department of Psychiatry and has received research support from the Canadian Institutes of Health Research, Brain & Behavior Foundation, Ontario Ministry of Health Innovation Funds, Royal College of Physicians and Surgeons of Canada, Department of National Defence (Government of Canada), New Frontiers in Research Fund, Associated Medical Services Inc. Healthcare, American Foundation for Suicide Prevention, Roche Canada, Novartis, and Eisai. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Demchenko, Rampersad, Datta, Horn, Churchill, Kennedy, Krishnan, Rueda, Schweizer, Griffiths, Boyden, Santarnecchi and Bhat.)
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- 2024
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13. Effects of post-acute COVID-19 syndrome on cerebral white matter and emotional health among non-hospitalized individuals.
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Churchill NW, Roudaia E, Chen JJ, Sekuler A, Gao F, Masellis M, Lam B, Cheng I, Heyn C, Black SE, MacIntosh BJ, Graham SJ, and Schweizer TA
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Introduction: Post-acute COVID syndrome (PACS) is a growing concern, given its impact on mental health and quality of life. However, its effects on cerebral white matter remain poorly understood, particularly in non-hospitalized cohorts. The goals of this cross-sectional, observational study were to examine (1) whether PACS was associated with distinct alterations in white matter microstructure, compared to symptom-matched non-COVID viral infection; and (2) whether microstructural alterations correlated with indices of post-COVID emotional health., Methods: Data were collected for 54 symptomatic individuals who tested positive for COVID-19 (mean age 41 ± 12 yrs., 36 female) and 14 controls who tested negative for COVID-19 (mean age 41 ± 14 yrs., 8 female), with both groups assessed an average of 4-5 months after COVID testing. Diffusion magnetic resonance imaging data were collected, and emotional health was assessed via the NIH emotion toolbox, with summary scores indexing social satisfaction, well-being and negative affect., Results: Despite similar symptoms, the COVID-19 group had reduced mean and axial diffusivity, along with increased mean kurtosis and neurite dispersion, in deep white matter. After adjusting for social satisfaction, higher levels of negative affect in the COVID-19 group were also correlated with increased mean kurtosis and reduced free water in white matter., Discussion: These results provide preliminary evidence that indices of white matter microstructure distinguish PACS from symptomatic non-COVID infection. Moreover, white matter effects seen in PACS correlate with the severity of emotional sequelae, providing novel insights into this highly prevalent disorder., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Churchill, Roudaia, Chen, Sekuler, Gao, Masellis, Lam, Cheng, Heyn, Black, MacIntosh, Graham and Schweizer.)
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- 2024
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14. Voluntary wheel running access produces opposite effects in male and female rats on both palatable diet consumption and associated ventral striatal opioid- and dopamine-related gene expression.
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Kocum CG, Cam Y, Shay DA, Schweizer TA, Konrad ER, Houska TK, Sardina CA, Schachtman TR, Vieira-Potter VJ, and Will MJ
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The relationship between physical activity levels and feeding behaviors has been a focus of preclinical research for decades, yet this interaction has only recently been explored for potential sex differences. The aim of the present study was to isolate sex-dependent effects of voluntary wheel running (RUN) vs. sedentary locked wheel (SED) home cage conditions on palatability-driven feeding behavior using a 2-diet choice task between standard chow and a high-fat diet. The sex-dependent effects of physical activity on feeding behavior were examined following a within-subject novel reversal design of physical activity conditions (i.e., RUN > SED > RUN), to assess temporal sensitivity of the interaction. Following the final 2 weeks of reestablished and sustained RUN vs. SED conditions in separate groups of both males and females, reward-related opioid and dopamine gene expression within the nucleus accumbens (Acb) brain region were analyzed. Results demonstrated that the initial RUN > SED transition led to sex-dependent effects of SED condition, as males increased, and females decreased their high fat consumption, compared to their respective high fat consumption during previous RUN condition phase. Following reintroduction to the RUN condition, males decreased, and females increased their high fat consumption, compared to their separate SED control group. Last, sex-dependent shifts in ventral striatal opioid- and dopamine-related gene expression were observed to parallel the behavioral effects. The major findings of the study reveal that SED and RUN home cage conditions shift palatability-driven feeding in the opposite direction for males and females, these effects are sensitive to reversal, and these sex-dependent feeding behaviors track sex-dependent changes to critical reward-related gene expression patterns in the Acb. Considering the present high rates of sedentary behavior and obesity, furthering our understanding of the interaction between physical activity (or lack thereof) and feeding behavior should be a priority, especially in the context of these divergent sex-dependent outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kocum, Cam, Shay, Schweizer, Konrad, Houska, Sardina, Schachtman, Vieira-Potter and Will.)
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- 2024
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15. Persistent fatigue in post-acute COVID syndrome is associated with altered T1 MRI texture in subcortical structures: a preliminary investigation.
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Churchill NW, Roudaia E, Chen JJ, Sekuler A, Gao F, Masellis M, Lam B, Cheng I, Heyn C, Black SE, MacIntosh BJ, Graham SJ, and Schweizer TA
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- Humans, Male, Female, Middle Aged, Adult, Brain diagnostic imaging, Brain pathology, Thalamus diagnostic imaging, Thalamus pathology, Aged, Putamen diagnostic imaging, Putamen pathology, SARS-CoV-2, Post-Acute COVID-19 Syndrome, COVID-19 complications, COVID-19 diagnostic imaging, Magnetic Resonance Imaging, Fatigue diagnostic imaging, Fatigue etiology, Fatigue pathology, Brain Stem diagnostic imaging, Brain Stem pathology
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Post-acute COVID syndrome (PACS) is a global health concern and is often associated with debilitating symptoms. Post-COVID fatigue is a particularly frequent and troubling issue, and its underlying mechanisms remain incompletely understood. One potential contributor is micropathological injury of subcortical and brainstem structures, as has been identified in other patient populations. Texture-based analysis (TA) may be used to measure such changes in anatomical MRI data. The present study develops a methodology of voxel-wise TA mapping in subcortical and brainstem regions, which is then applied to T1-weighted MRI data from a cohort of 48 individuals who had PACS (32 with and 16 without ongoing fatigue symptoms) and 15 controls who had cold and flu-like symptoms but tested negative for COVID-19. Both groups were assessed an average of 4-5 months post-infection. There were no significant differences between PACS and control groups, but significant differences were observed within the PACS groups, between those with and without fatigue symptoms. This included reduced texture energy and increased entropy, along with reduced texture correlation, cluster shade and profile in the putamen, pallidum, thalamus and brainstem. These findings provide new insights into the neurophysiological mechanisms that underlie PACS, with altered tissue texture as a potential biomarker of this debilitating condition., Competing Interests: Declaration of Competing Interest The authors report no disclosures relevant to the manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)
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- 2024
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16. History of traumatic brain injury is associated with increased grey-matter loss in patients with mild cognitive impairment.
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Khoury MA, Churchill NW, Di Battista A, Graham SJ, Symons S, Troyer AK, Roberts A, Kumar S, Tan B, Arnott SR, Ramirez J, Tartaglia MC, Borrie M, Pollock B, Rajji TK, Pasternak SH, Frank A, Tang-Wai DF, Scott CJM, Haddad SMH, Nanayakkara N, Orange JB, Peltsch A, Fischer CE, Munoz DG, and Schweizer TA
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- Humans, Male, Female, Aged, Middle Aged, Longitudinal Studies, Neuropsychological Tests, Cerebral Cortex diagnostic imaging, Cerebral Cortex pathology, Bayes Theorem, Cognitive Dysfunction etiology, Cognitive Dysfunction pathology, Cognitive Dysfunction diagnostic imaging, Brain Injuries, Traumatic diagnostic imaging, Brain Injuries, Traumatic pathology, Brain Injuries, Traumatic complications, Gray Matter diagnostic imaging, Gray Matter pathology, Magnetic Resonance Imaging
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Objectives: To investigate whether a history of traumatic brain injury (TBI) is associated with greater long-term grey-matter loss in patients with mild cognitive impairment (MCI)., Methods: 85 patients with MCI were identified, including 26 with a previous history of traumatic brain injury (MCI[TBI-]) and 59 without (MCI[TBI+]). Cortical thickness was evaluated by segmenting T1-weighted MRI scans acquired longitudinally over a 2-year period. Bayesian multilevel modelling was used to evaluate group differences in baseline cortical thickness and longitudinal change, as well as group differences in neuropsychological measures of executive function., Results: At baseline, the MCI[TBI+] group had less grey matter within right entorhinal, left medial orbitofrontal and inferior temporal cortex areas bilaterally. Longitudinally, the MCI[TBI+] group also exhibited greater longitudinal declines in left rostral middle frontal, the left caudal middle frontal and left lateral orbitofrontal areas sover the span of 2 years (median = 1-2%, 90%HDI [-0.01%: -0.001%], probability of direction (PD) = 90-99%). The MCI[TBI+] group also displayed greater longitudinal declines in Trail-Making-Test (TMT)-derived ratio (median: 0.737%, 90%HDI: [0.229%: 1.31%], PD = 98.8%) and differences scores (median: 20.6%, 90%HDI: [-5.17%: 43.2%], PD = 91.7%)., Conclusions: Our findings support the notion that patients with MCI and a history of TBI are at risk of accelerated neurodegeneration, displaying greatest evidence for cortical atrophy within the left middle frontal and lateral orbitofrontal frontal cortex. Importantly, these results suggest that long-term TBI-mediated atrophy is more pronounced in areas vulnerable to TBI-related mechanical injury, highlighting their potential relevance for diagnostic forms of intervention in TBI., (© 2024. Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2024
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17. Neuroanatomical correlates of distracted straight driving performance: a driving simulator MRI study across the lifespan.
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Guan DX, Churchill NW, Fischer CE, Graham SJ, and Schweizer TA
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Background: Driving is the preferred mode of transportation for adults across the healthy age span. However, motor vehicle crashes are among the leading causes of injury and death, especially for older adults, and under distracted driving conditions. Understanding the neuroanatomical basis of driving may inform interventions that minimize crashes. This exploratory study examined the neuroanatomical correlates of undistracted and distracted simulated straight driving., Methods: One-hundred-and-thirty-eight participants (40.6% female) aged 17-85 years old (mean and SD = 58.1 ± 19.9 years) performed a simulated driving task involving straight driving and turns at intersections in a city environment using a steering wheel and foot pedals. During some straight driving segments, participants responded to auditory questions to simulate distracted driving. Anatomical T1-weighted MRI was used to quantify grey matter volume and cortical thickness for five brain regions: the middle frontal gyrus (MFG), precentral gyrus (PG), superior temporal cortex (STC), posterior parietal cortex (PPC), and cerebellum. Partial correlations controlling for age and sex were used to explore relationships between neuroanatomical measures and straight driving behavior, including speed, acceleration, lane position, heading angle, and time speeding or off-center. Effects of interest were noted at an unadjusted p -value threshold of 0.05., Results: Distracted driving was associated with changes in most measures of straight driving performance. Greater volume and cortical thickness in the PPC and cerebellum were associated with reduced variability in lane position and heading angle during distracted straight driving. Cortical thickness of the MFG, PG, PPC, and STC were associated with speed and acceleration, often in an age-dependent manner., Conclusion: Posterior regions were correlated with lane maintenance whereas anterior and posterior regions were correlated with speed and acceleration, especially during distracted driving. The regions involved and their role in straight driving may change with age, particularly during distracted driving as observed in older adults. Further studies should investigate the relationship between distracted driving and the aging brain to inform driving interventions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Guan, Churchill, Fischer, Graham and Schweizer.)
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- 2024
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18. Pro-angiogenic and antibacterial copper containing nanoparticles in PLGA/amorphous calcium phosphate bone nanocomposites.
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Näf L, Miescher I, Pfuderer L, Schweizer TA, Brunner D, Dürig J, Gröninger O, Rieber J, Meier-Buergisser G, Spanaus K, Calcagni M, Bosshard PP, Achermann Y, Stark WJ, and Buschmann J
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Large bone defects after trauma demand for adequate bone substitutes. Bone void fillers should be antibacterial and pro-angiogenic. One viable option is the use of composite materials like the combination of PLGA and amorphous calcium phosphate (aCaP). Copper stimulates angiogenesis and has antibacterial qualities. Either copper oxide (CuO) nanoparticles (NPs) were therefore added to PLGA/aCaP/CuO in different concentrations (1, 5 and 10 w/w %) or copper-doped tricalcium phosphate NPs (TCP with 2% of copper) were electrospun into PLGA/CuTCP nanocomposites. Bi-layered nanocomposites of PLGA/aCaP with different copper NPs (CuO or TCP) and a second layer of pristine PLGA were fabricated. Two clinical bacterial isolates ( Staphylococcus aureus and Staphylococcus epidermidis ) were used to assess antibacterial properties of the copper-containing materials. For angiogenesis, the chorioallantoic membrane (CAM) assay of the chicken embryo was performed. The higher the CuO content, the higher were the antibacterial properties, with 10 % CuO reducing bacterial adhesion most effectively. Vessel and cell densities were highest in the 5 % CuO containing scaffolds, while tissue integration was more pronounced at lower CuO content. The PLGA/aCaP/CuO (1 % CuO) behaved similar like PLGA/CuTCP in all angiogenic and antibacterial readouts, based on the same copper fraction. We conclude that CuO NPs or CuTCP NPs are useful components to increase angiogenic properties of nanocomposites and at the same time exhibiting antibacterial characteristics., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Johanna Buschmann reports financial support was provided by 10.13039/501100009396University Hospital Zurich. Johanna Buschmann reports a relationship with University Hospital Zurich that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)
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- 2024
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19. Neuropsychiatric symptoms and brain morphology in patients with mild cognitive impairment, cerebrovascular disease and Parkinson disease: A cross sectional and longitudinal study.
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Rashidi-Ranjbar N, Churchill NW, Black SE, Kumar S, Tartaglia MC, Freedman M, Lang A, Steeves TDL, Swartz RH, Saposnik G, Sahlas D, McLaughlin P, Symons S, Strother S, Pollock BG, Rajji TK, Ozzoude M, Tan B, Arnott SR, Bartha R, Borrie M, Masellis M, Pasternak SH, Frank A, Seitz D, Ismail Z, Tang-Wai DF, Casaubon LK, Mandzia J, Jog M, Scott CJM, Dowlatshahi D, Hassan A, Grimes D, Marras C, Zamyadi M, Munoz DG, Ramirez J, Berezuk C, Holmes M, Fischer CE, and Schweizer TA
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- Humans, Cross-Sectional Studies, Longitudinal Studies, Brain diagnostic imaging, Brain pathology, Neuropsychological Tests, Parkinson Disease psychology, Cognitive Dysfunction psychology, Alzheimer Disease psychology, Cerebrovascular Disorders complications
- Abstract
Objectives: Neuropsychiatric symptoms (NPS) increase risk of developing dementia and are linked to various neurodegenerative conditions, including mild cognitive impairment (MCI due to Alzheimer's disease [AD]), cerebrovascular disease (CVD), and Parkinson's disease (PD). We explored the structural neural correlates of NPS cross-sectionally and longitudinally across various neurodegenerative diagnoses., Methods: The study included individuals with MCI due to AD, (n = 74), CVD (n = 143), and PD (n = 137) at baseline, and at 2-years follow-up (MCI due to AD, n = 37, CVD n = 103, and PD n = 84). We assessed the severity of NPS using the Neuropsychiatric Inventory Questionnaire. For brain structure we included cortical thickness and subcortical volume of predefined regions of interest associated with corticolimbic and frontal-executive circuits., Results: Cross-sectional analysis revealed significant negative correlations between appetite with both circuits in the MCI and CVD groups, while apathy was associated with these circuits in both the MCI and PD groups. Longitudinally, changes in apathy scores in the MCI group were negatively linked to the changes of the frontal-executive circuit. In the CVD group, changes in agitation and nighttime behavior were negatively associated with the corticolimbic and frontal-executive circuits, respectively. In the PD group, changes in disinhibition and apathy were positively associated with the corticolimbic and frontal-executive circuits, respectively., Conclusions: The observed correlations suggest that underlying pathological changes in the brain may contribute to alterations in neural activity associated with MBI. Notably, the difference between cross-sectional and longitudinal results indicates the necessity of conducting longitudinal studies for reproducible findings and drawing robust inferences., (© 2024 John Wiley & Sons Ltd.)
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- 2024
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20. Enzymatic debridement with bromelain and development of bacteremia in burn injuries: A retrospective cohort study.
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Deplazes BC, Hofmaenner DA, Scheier TC, Epprecht J, Mayer M, Schweizer TA, Buehler PK, Frey PM, and Brugger SD
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- Adult, Humans, Middle Aged, Retrospective Studies, Debridement, Bromelains therapeutic use, Burns complications, Bacteremia drug therapy
- Abstract
Background: Debridement is crucial for effective wound management in patients with severe burn injuries, and bromelain, a proteolytic enzyme from pineapple stems, has emerged as a promising alternative for surgery. However, potential links of bromelain use to fever and sepsis have raised some concerns. Given the uncertainty as to whether this was caused by infection or other inflammatory sources, we aimed to investigate if the use of topical bromelain was associated with bacteremia., Methods: This single-centre retrospective cohort study included critically ill adult patients with severe burn injuries hospitalised at the Burn Center of the University Hospital Zurich between January 2017 and December 2021. Data were collected from two in-hospital electronic medical records databases. Our primary outcome, the association between topical bromelain treatment and the development of bacteremia, was investigated using a competing risk regression model, taking into account the competing risk of death. As a secondary outcome, the relationship between bromelain treatment and overall ICU mortality was examined using a Cox proportional hazards model., Results: The study included 269 patients with a median age of 50 years and median burnt total body surface area of 19%. A first bacteremia occurred in 61 patients (23%) after a median time of 6 days. Bromelain treatment was given to 83 (31%) of patients, with 22 (27%) of these developing bacteremia. In the fully adjusted competing risk regression model, no evidence for an association between bromelain treatment and bacteremia was found (SHR 0.79, 95%CI 0.42-1.48, p = 0.47). During hospital stay, 40 (15%) of patients died. There was no significant difference in mortality between patients treated with bromelain and those who were not (HR 0.55, 95%CI 0.26-1.20, p = 0.14). Among the five multidrug-resistant (MDR) pathogens identified, three were found in patients with bromelain treatment., Conclusion: Our study did not confirm an association between topical bromelain and bacteremia in patients with severe burn injuries. This finding can inform evidence-based practices by addressing concerns about potential risks of bromelain use, contributing to the development of more effective and safe burn wound management strategies., Competing Interests: Declaration of Competing Interest All authors declare to have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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21. MEndoB, a chimeric lysin featuring a novel domain architecture and superior activity for the treatment of staphylococcal infections.
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Roehrig C, Huemer M, Lorgé D, Arn F, Heinrich N, Selvakumar L, Gasser L, Hauswirth P, Chang C-C, Schweizer TA, Eichenseher F, Lehmann S, Zinkernagel AS, and Schmelcher M
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- Humans, Animals, Mice, Staphylococcus aureus, Peptidoglycan, Zebrafish, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Staphylococcus, N-Acetylmuramoyl-L-alanine Amidase genetics, N-Acetylmuramoyl-L-alanine Amidase therapeutic use, Methicillin-Resistant Staphylococcus aureus, Staphylococcal Infections drug therapy, Staphylococcal Infections microbiology, Sepsis drug therapy
- Abstract
Bacterial infections are a growing global healthcare concern, as an estimated annual 4.95 million deaths are associated with antimicrobial resistance (AMR). Methicillin-resistant Staphylococcus aureus is one of the deadliest pathogens and a high-priority pathogen according to the World Health Organization. Peptidoglycan hydrolases (PGHs) of phage origin have been postulated as a new class of antimicrobials for the treatment of bacterial infections, with a novel mechanism of action and no known resistances. The modular architecture of PGHs permits the creation of chimeric PGH libraries. In this study, the chimeric enzyme MEndoB was selected from a library of staphylococcal PGHs based on its rapid and sustained activity against staphylococci in human serum. The benefit of the presented screening approach was illustrated by the superiority of MEndoB in a head-to-head comparison with other PGHs intended for use against staphylococcal bacteremia. MEndoB displayed synergy with antibiotics and rapid killing in human whole blood with complete inhibition of re-growth over 24 h at low doses. Successful treatment of S. aureus -infected zebrafish larvae with MEndoB provided evidence for its in vivo effectiveness. This was further confirmed in a lethal systemic mouse infection model in which MEndoB significantly reduced S. aureus loads and tumor necrosis factor alpha levels in blood in a dose-dependent manner, which led to increased survival of the animals. Thus, the thorough lead candidate selection of MEndoB resulted in an outstanding second-generation PGH with in vitro , ex vivo, and in vivo results supporting further development.IMPORTANCEOne of the most pressing challenges of our era is the rising occurrence of bacteria that are resistant to antibiotics. Staphylococci are prominent pathogens in humans, which have developed multiple strategies to evade the effects of antibiotics. Infections caused by these bacteria have resulted in a high burden on the health care system and a significant loss of lives. In this study, we have successfully engineered lytic enzymes that exhibit an extraordinary ability to eradicate staphylococci. Our findings substantiate the importance of meticulous lead candidate selection to identify therapeutically promising peptidoglycan hydrolases with unprecedented activity. Hence, they offer a promising new avenue for treating staphylococcal infections., Competing Interests: C.R. is an employee of Micreos Pharmaceuticals AG. M.H., D.L., F.A., N.H., L.S., F.E., and M.S. are employees of Micreos GmbH. Micreos Pharmaceuticals AG and Micreos GmbH are commercial companies developing bacteriophage-based antimicrobials.
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- 2024
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22. In Vitro Assessment of Bacterial Adhesion and Biofilm Formation on Novel Bioactive, Biodegradable Electrospun Fiber Meshes Intended to Support Tendon Rupture Repair.
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Miescher I, Rieber J, Schweizer TA, Orlietti M, Tarnutzer A, Andreoni F, Meier Buergisser G, Giovanoli P, Calcagni M, Snedeker JG, Zinkernagel AS, and Buschmann J
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- Humans, Bacterial Adhesion, Silver pharmacology, Silver chemistry, Insulin-Like Growth Factor I pharmacology, Anti-Bacterial Agents pharmacology, Biofilms, Tendons, Metal Nanoparticles chemistry, Tendon Injuries surgery
- Abstract
The surgical repair of a ruptured tendon faces two major problems: specifically increased fibrous adhesion to the surrounding tissue and inferior mechanical properties of the scar tissue compared to the native tissue. Bacterial attachment to implant materials is an additional problem as it might lead to severe infections and impaired recovery. To counteract adhesion formation, two novel implant materials were fabricated by electrospinning, namely, a random fiber mesh containing hyaluronic acid (HA) and poly(ethylene oxide) (PEO) in a ratio of 1:1 (HA/PEO 1:1) and 1:4 (HA/PEO 1:4), respectively. Electrospun DegraPol (DP) treated with silver nanoparticles (DP-Ag) was developed to counteract the bacterial attachment. The three novel materials were compared to the previously described DP and DP with incorporated insulin-like growth factor-1 (DP-IGF-1), two implant materials that were also designed to improve tendon repair. To test whether the materials are prone to bacterial adhesion and biofilm formation, we assessed 10 strains of Staphylococcus aureus , Staphylococcus epidermidis , Pseudomonas aeruginosa, and Enterococcus faecalis , known for causing nosocomial infections. Fiber diameter, pore size, and water contact angle, reflecting different degrees of hydrophobicity, were used to characterize all materials. Generally, we observed higher biofilm formation on the more hydrophobic DP as compared to the more hydrophilic DP-IGF-1 and a trend toward reduced biofilm formation for DP treated with silver nanoparticles. For the two HA/PEO implants, a similar biofilm formation was observed. All tested materials were highly prone to bacterial adherence and biofilm formation, pointing toward the need of further material development, including the optimized incorporation of antibacterial agents such as silver nanoparticles or antibiotics.
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- 2024
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23. The Relationship between History of Traumatic Brain Injury and Longitudinal Changes in Cortical Thickness among Patients with Alzheimer's Disease.
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D'Souza GM, Churchill NW, Guan DX, Khoury MA, Graham SJ, Kumar S, Fischer CE, and Schweizer TA
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- Humans, Male, Female, Aged, Longitudinal Studies, Cerebral Cortex pathology, Cerebral Cortex diagnostic imaging, Atrophy, Middle Aged, Brain Cortical Thickness, Aged, 80 and over, Alzheimer Disease pathology, Alzheimer Disease diagnostic imaging, Brain Injuries, Traumatic diagnostic imaging, Brain Injuries, Traumatic complications, Brain Injuries, Traumatic pathology, Magnetic Resonance Imaging
- Abstract
Background: There has been little direct examination of how traumatic brain injury (TBI) affects the rate of neurodegeneration for individuals with Alzheimer's disease (AD)., Methods: The study examined 89 cognitively normal adults (65 with and 24 without prior TBI) and 65 with AD (16 with and 49 without prior TBI). Cortical thickness was quantified from T1-weighted MRI scans at baseline and follow-up (mean interval 33.4 months). Partial least squares analysis was used to evaluate the effects of AD and TBI history on the longitudinal change in cortical thickness., Results: Significant group effects were identified throughout the frontal and temporal cortices. Comparison of the AD groups to their control cohorts showed greater relative atrophy for the AD cohort with prior TBI., Conclusion: These results indicate that a history of TBI exacerbates longitudinal declines in cortical thickness among AD patients, providing new insights into the shared pathomechanisms between these neurological conditions., Competing Interests: On behalf of all authors, the corresponding author states that there is no conflict of interest.
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- 2024
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24. Interaction of Alzheimer Disease and Traumatic Brain Injury on Cortical Thickness.
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D'Souza GM, Churchill NW, Guan DX, Khoury MA, Graham SJ, Kumar S, Fischer CE, and Schweizer TA
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- Humans, Aging pathology, Magnetic Resonance Imaging methods, Alzheimer Disease diagnosis, Brain Injuries, Traumatic complications, Brain Injuries, Traumatic pathology
- Abstract
Introduction: Traumatic brain injury (TBI) is associated with an accelerated course of dementia, although biological relationships are incompletely understood., Methods: The study examined 1124 participants, including 343 with Alzheimer disease (AD), 127 with AD with TBI, 266 cognitively normal adults with TBI, and 388 cognitively normal adults without TBI. Cortical thickness was quantified from T1-weighted magnetic resonance imaging data. Multiple linear regression was used to determine the interaction between AD and TBI on cortical thickness., Results: Among those with AD, TBI was associated with an earlier age of AD onset but, counterintuitively, less cortical thinning in frontotemporal regions relative to non-AD controls., Discussion: AD with TBI represents a distinct group from AD, likely with distinct pathologic contributions beyond gray matter loss. This finding has important implications for the diagnosis and treatment of AD in the presence of TBI and indicates that models of AD, aging, and neural loss should account for TBI history., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)
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- 2024
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25. Persistent post-COVID headache is associated with suppression of scale-free functional brain dynamics in non-hospitalized individuals.
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Churchill NW, Roudaia E, Jean Chen J, Gilboa A, Sekuler A, Ji X, Gao F, Lin Z, Masellis M, Goubran M, Rabin JS, Lam B, Cheng I, Fowler R, Heyn C, Black SE, MacIntosh BJ, Graham SJ, and Schweizer TA
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- Humans, Cross-Sectional Studies, Magnetic Resonance Imaging methods, Brain physiology, Headache diagnostic imaging, Headache etiology, COVID-19 Testing, COVID-19 complications
- Abstract
Introduction: Post-acute coronavirus disease 2019 (COVID-19) syndrome (PACS) is a growing concern, with headache being a particularly debilitating symptom with high prevalence. The long-term effects of COVID-19 and post-COVID headache on brain function remain poorly understood, particularly among non-hospitalized individuals. This study focused on the power-law scaling behavior of functional brain dynamics, indexed by the Hurst exponent (H). This measure is suppressed during physiological and psychological distress and was thus hypothesized to be reduced in individuals with post-COVID syndrome, with greatest reductions among those with persistent headache., Methods: Resting-state blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging data were collected for 57 individuals who had COVID-19 (32 with no headache, 14 with ongoing headache, 11 recovered) and 17 controls who had cold and flu-like symptoms but tested negative for COVID-19. Individuals were assessed an average of 4-5 months after COVID testing, in a cross-sectional, observational study design., Results: No significant differences in H values were found between non-headache COVID-19 and control groups., while those with ongoing headache had significantly reduced H values, and those who had recovered from headache had elevated H values, relative to non-headache groups. Effects were greatest in temporal, sensorimotor, and insular brain regions. Reduced H in these regions was also associated with decreased BOLD activity and local functional connectivity., Conclusions: These findings provide new insights into the neurophysiological mechanisms that underlie persistent post-COVID headache, with reduced BOLD scaling as a potential biomarker that is specific to this debilitating condition., (© 2023 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)
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- 2023
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26. Limited Adaptation of Staphylococcus aureus during Transition from Colonization to Invasive Infection.
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Räz AK, Andreoni F, Boumasmoud M, Bergada-Pijuan J, Schweizer TA, Mairpady Shambat S, Hasse B, Zinkernagel AS, and Brugger SD
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- Humans, Adaptation, Physiological, Nasal Cavity microbiology, Virulence, Staphylococcus aureus, Staphylococcal Infections microbiology
- Abstract
Staphylococcus aureus carriage is a risk factor for invasive infections. Unique genetic elements favoring the transition from colonizing to invasive phenotype have not yet been identified, and phenotypic adaptation traits are understudied. We therefore assessed phenotypic and genotypic profiles of 11 S. aureus isolate pairs sampled from colonized patients simultaneously suffering from invasive S. aureus infections. Ten out of 11 isolate pairs displayed the same spa and multilocus sequence type, suggesting colonization as an origin for the invasive infection. Systematic analysis of colonizing and invasive isolate pairs showed similar adherence, hemolysis, reproductive fitness properties, antibiotic tolerance, and virulence in a Galleria mellonella infection model, as well as minimal genetic differences. Our results provide insights into the similar phenotypes associated with limited adaptation between colonizing and invasive isolates. Disruption of the physical barriers of mucosa or skin was identified in the majority of patients, further emphasizing colonization as a major risk factor for invasive disease. IMPORTANCE S. aureus is a major pathogen of humans, causing a wide range of diseases. The difficulty to develop a vaccine and antibiotic treatment failure warrant the exploration of novel treatment strategies. Asymptomatic colonization of the human nasal passages is a major risk factor for invasive disease, and decolonization procedures have been effective in preventing invasive infections. However, the transition of S. aureus from a benign colonizer of the nasal passages to a major pathogen is not well understood, and both host and bacterial properties have been discussed as being relevant for this behavioral change. We conducted a thorough investigation of patient-derived strain pairs reflecting colonizing and invasive isolates in a given patient. Although we identified limited genetic adaptation in certain strains, as well as slight differences in adherence capacity among colonizing and invasive isolates, our work suggests that barrier breaches are a key event in the disease continuum of S. aureus., Competing Interests: The authors declare no conflict of interest.
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- 2023
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27. Resting-state neural mechanisms of capability for suicide and their interaction with pain - A CAN-BIND-05 Study.
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Wang S, Kennedy SH, Salomons TV, Ceniti AK, McInerney SJ, Bergmans Y, Pizzagalli DA, Farb N, Turecki G, Schweizer TA, Churchill N, Sinyor M, and Rizvi SJ
- Subjects
- Humans, Magnetic Resonance Imaging, Canada, Gyrus Cinguli diagnostic imaging, Pain diagnostic imaging, Depressive Disorder, Major diagnostic imaging
- Abstract
Background: Suicidal ideation is highly prevalent in Major Depressive Disorder (MDD). However, the factors determining who will transition from ideation to attempt are not established. Emerging research points to suicide capability (SC), which reflects fearlessness of death and increased pain tolerance, as a construct mediating this transition. This Canadian Biomarker Integration Network in Depression study (CANBIND-5) aimed to identify the neural basis of SC and its interaction with pain as a marker of suicide attempt., Methods: MDD patients (n = 20) with suicide risk and healthy controls (n = 21) completed a self-report SC scale and a cold pressor task measuring pain threshold, tolerance, endurance, and intensity at threshold and tolerance. All participants underwent a resting-state brain scan and functional connectivity was examined for 4 regions: anterior insula (aIC), posterior insula (pIC), anterior mid-cingulate cortex (aMCC) and subgenual anterior cingulate cortex (sgACC)., Results: In MDD, SC correlated positively with pain endurance and negatively with threshold intensity. Furthermore, SC correlated with the connectivity of aIC to the supramarginal gyrus, pIC to the paracingulate gyrus, aMCC to the paracingulate gyrus, and sgACC to the dorsolateral prefrontal cortex. These correlations were stronger in MDD compared to controls. Only threshold intensity mediated the correlation between SC and connectivity strength., Limitations: Resting-state scans provided an indirect assessment of SC and the pain network., Conclusions: These findings highlight point to a neural network underlying SC that is associated with pain processing. This supports the potential clinical utility of pain response measurement as a method to investigate markers of suicide risk., Competing Interests: Conflict of interest Dr. Sidney H. Kennedy has received research funding or honoraria from Abbott, Alkermes, Allergan, Boehringer Ingelheim, Brain Canada, Canadian Institutes for Health Research (CIHR), Janssen, Lundbeck, Lundbeck Institute, Ontario Brain Institute, Ontario Research Fund (ORF), Otsuka, Pfizer, Servier, Sunovion and Xian-Janssen. He also has received stock options from Field Trip Health. Over the past 3 years, Dr. Shane J. McInerney has received research funding from The National Office of Suicide Prevention (NOSP) in Ireland. Over the past 3 years, Dr. Diego A. Pizzagalli has received consulting fees from BlackThorn Therapeutics, Boehringer Ingelheim, Compass Pathway, Concert Pharmaceuticals, Engrail Therapeutics, Neurocrine Biosciences, Neuroscience Software, Otsuka Pharmaceuticals, and Takeda Pharmaceuticals; one honorarium from Alkermes, and research funding from NIMH, Dana Foundation, Brain and Behavior Research Foundation, Millennium Pharmaceuticals. In addition, he has received stock options from BlackThorn Therapeutics and Compass Pathways. All views expressed are solely those of the authors. All other authors report no financial relationships with commercial interest. DAP was also partially supported by R37 2R37MH068376 and P50 MH119467 from the National Institute of Mental Health. Dr. Mark Sinyor receives funding through Academic Scholar Awards from the Departments of Psychiatry at Sunnybrook Health Sciences Centre and the University of Toronto. Dr. Sakina J. Rizvi has received research funding or honoraria from Pfizer Canada, Quintiles, Janssen, Neurocrine Inc., Allergan, and Takeda. Ms. Shijing Wang, Ms. Amanda K. Ceniti, Dr. Yvonne Bergmans, Dr. Tim V. Salomons, Dr. Gustavo Turecki, Dr. Norman Farb, Dr. Nathan Churchill, and Dr. Tom A. Schweizer declare no conflict of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)
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- 2023
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28. Perfusion Imaging of Traumatic Brain Injury.
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Churchill NW, Graham SJ, and Schweizer TA
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- Humans, Cerebrovascular Circulation physiology, Perfusion Imaging, Magnetic Resonance Imaging, Brain, Brain Injuries, Traumatic diagnostic imaging
- Abstract
The mechanisms for regulating cerebral blood flow (CBF) are highly sensitive to traumatic brain injury (TBI). The perfusion imaging technique may be used to assess CBF and identify perfusion abnormalities following a TBI. Studies have identified CBF disturbances across the injury severity spectrum and correlations with both acute and long-term indices of clinical outcome. Although not yet widely used in the clinical context, this is an important area of ongoing research., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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29. Return to Driving Following Concussion: A Research Priority.
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Dawson J, Johnston S, Marshall S, Schweizer TA, Reed N, Devos H, Schmidt J, Lithopoulos A, and Zemek R
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- Humans, Students, Research, Brain Concussion, Athletic Injuries
- Abstract
Competing Interests: The authors declare no conflicts of interests.
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- 2023
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30. Effects of post-acute COVID-19 syndrome on the functional brain networks of non-hospitalized individuals.
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Churchill NW, Roudaia E, Chen JJ, Gilboa A, Sekuler A, Ji X, Gao F, Lin Z, Jegatheesan A, Masellis M, Goubran M, Rabin JS, Lam B, Cheng I, Fowler R, Heyn C, Black SE, MacIntosh BJ, Graham SJ, and Schweizer TA
- Abstract
Introduction: The long-term impact of COVID-19 on brain function remains poorly understood, despite growing concern surrounding post-acute COVID-19 syndrome (PACS). The goal of this cross-sectional, observational study was to determine whether there are significant alterations in resting brain function among non-hospitalized individuals with PACS, compared to symptomatic individuals with non-COVID infection., Methods: Data were collected for 51 individuals who tested positive for COVID-19 (mean age 41±12 yrs., 34 female) and 15 controls who had cold and flu-like symptoms but tested negative for COVID-19 (mean age 41±14 yrs., 9 female), with both groups assessed an average of 4-5 months after COVID testing. None of the participants had prior neurologic, psychiatric, or cardiovascular illness. Resting brain function was assessed via functional magnetic resonance imaging (fMRI), and self-reported symptoms were recorded., Results: Individuals with COVID-19 had lower temporal and subcortical functional connectivity relative to controls. A greater number of ongoing post-COVID symptoms was also associated with altered functional connectivity between temporal, parietal, occipital and subcortical regions., Discussion: These results provide preliminary evidence that patterns of functional connectivity distinguish PACS from non-COVID infection and correlate with the severity of clinical outcome, providing novel insights into this highly prevalent disorder., Competing Interests: SB reports payments for contract research to her institution from GE Healthcare, Eli Lilly and Company, Biogen, Genentech, Optina Diagnostics, and Roche; consulting fees and payments related to an advisory board from Roche; and payments related to an advisory board, a speaker panel, talks, and an educational session from Biogen. There were peer-reviewed grants to her institution from the Ontario Brain Institute, Canadian Institutes of Health Research, Leducq Foundation, Heart and Stroke Foundation of Canada, National Institutes of Health, Alzheimer’s Drug Discovery Foundation, Brain Canada, Weston Brain Institute, Canadian Partnership for Stroke Recovery, Canadian Foundation for Innovation, Focused Ultrasound Foundation, Alzheimer’s Association US, Department of National Defense, Montreal Medical International Kuwait, Queen’s University, Compute Canada Resources for Research Groups, CANARIE, and Networks of Centres of Excellence of Canada. She has participated on a data safety monitoring board or advisory board for the Conference Board of Canada, World Dementia Council, and University of Rochester. She has contributed to the mission and scientific leadership of the Small Vessel VCID Biomarker Validation Consortium, National Institute of Neurological Disorders and Stroke. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Churchill, Roudaia, Chen, Gilboa, Sekuler, Ji, Gao, Lin, Jegatheesan, Masellis, Goubran, Rabin, Lam, Cheng, Fowler, Heyn, Black, MacIntosh, Graham and Schweizer.)
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- 2023
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31. Cerebello-cerebral Functional Connectivity Networks in Major Depressive Disorder: a CAN-BIND-1 Study Report.
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Anteraper SA, Guell X, Lee YJ, Raya J, Demchenko I, Churchill NW, Frey BN, Hassel S, Lam RW, MacQueen GM, Milev R, Schweizer TA, Strother SC, Whitfield-Gabrieli S, Kennedy SH, and Bhat V
- Subjects
- Humans, Magnetic Resonance Imaging methods, Cerebellum diagnostic imaging, Brain Mapping, Neuroimaging, Neural Pathways diagnostic imaging, Brain diagnostic imaging, Depressive Disorder, Major diagnostic imaging, Depressive Disorder, Major therapy
- Abstract
Neuroimaging studies have demonstrated aberrant structure and function of the "cognitive-affective cerebellum" in major depressive disorder (MDD), although the specific role of the cerebello-cerebral circuitry in this population remains largely uninvestigated. The objective of this study was to delineate the role of cerebellar functional networks in depression. A total of 308 unmedicated participants completed resting-state functional magnetic resonance imaging scans, of which 247 (148 MDD; 99 healthy controls, HC) were suitable for this study. Seed-based resting-state functional connectivity (RsFc) analysis was performed using three cerebellar regions of interest (ROIs): ROI
1 corresponded to default mode network (DMN)/inattentive processing; ROI2 corresponded to attentional networks, including frontoparietal, dorsal attention, and ventral attention; ROI3 corresponded to motor processing. These ROIs were delineated based on prior functional gradient analyses of the cerebellum. A general linear model was used to perform within-group and between-group comparisons. In comparison to HC, participants with MDD displayed increased RsFc within the cerebello-cerebral DMN (ROI1 ) and significantly elevated RsFc between the cerebellar ROI1 and bilateral angular gyrus at a voxel threshold (p < 0.001, two-tailed) and at a cluster level (p < 0.05, FDR-corrected). Group differences were non-significant for ROI2 and ROI3 . These results contribute to the development of a systems neuroscience approach to the diagnosis and treatment of MDD. Specifically, our findings confirm previously reported associations between MDD, DMN, and cerebellum, and highlight the promising role of these functional and anatomical locations for the development of novel imaging-based biomarkers and targets for neuromodulation therapies. ClinicalTrials.gov TRN: NCT01655706; Date of Registration: August 2nd, 2012., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)- Published
- 2023
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32. Altered connectivity of default mode and executive control networks among female patients with persistent post-concussion symptoms.
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Wong JKY, Churchill NW, Graham SJ, Baker AJ, and Schweizer TA
- Subjects
- Humans, Female, Diffusion Tensor Imaging methods, Executive Function, Brain diagnostic imaging, Magnetic Resonance Imaging methods, Post-Concussion Syndrome diagnostic imaging, Brain Concussion
- Abstract
Objective: To examine the roles of the default mode network (DMN) and executive control network (ECN) in prolonged recovery after mild traumatic brain injury (mTBI), and relationships with indices of white matter microstructural injury., Methods: Seventeen mTBI patients with persistent symptoms were imaged an average of 21.5 months post-injury, along with 23 healthy controls. Resting-state functional magnetic resonance imaging (rs-fMRI) was used to evaluate functional connectivity (FC) of the DMN and ECN. Diffusion tensor imaging (DTI) quantified fractional anisotropy, along with mean, axial and radial diffusivity of white matter tracts., Results: Compared to controls, patients with mTBI had increased functional connectivity of the DMN and ECN to brain regions implicated in salience and frontoparietal networks, and increased white matter diffusivity within the cerebrum and brainstem. Among the patients, FC was correlated with better neurocognitive test scores, while diffusivity was correlated with more severe self-reported symptoms. The FC and diffusivity values within abnormal brain regions were not significantly correlated., Conclusion: For female mTBI patients with prolonged symptoms, hyper-connectivity may represent a compensatory response that helps to mitigate the effects of mTBI on cognition. These effects are unrelated to indices of microstructural injury, which are correlated with symptom severity, suggesting that rs-fMRI and DTI may capture distinct aspects of pathophysiology.
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- 2023
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33. Cognitive resilience and severe Alzheimer's disease neuropathology.
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Ahangari N, Fischer CE, Schweizer TA, and Munoz DG
- Abstract
Cognitive resilience in Alzheimer's disease (AD) can be defined as retention of high cognition despite presence of considerable cerebral AD lesions. We sought to identify factors associated with this phenomenon. Data were obtained from National Alzheimer's Coordinating Centre (NACC) dataset. Subjects with severe AD neuropathology, based on National Institute on Aging-Reagan (NIA-Reagan) criteria, no other primary neuropathology, and a ≤ 2-year interval between last follow-up and death were included. Mini-mental status examination score ≥ 24 was used as a proxy for normal cognition. In total, 654 cases were included; 59 (9%) were cognitively resilient. Multivariable logistic regression model showed that resilient participants were more educated, had a lower body mass index (BMI), were more likely to be lifetime/recent smoker or use an anticoagulant/antiplatelet agent, compared with cognitively impaired subjects. In addition to expected protective factors such as higher education and lower BMI, our results showed that smoking (especially recent smoking) and anticoagulant/antiplatelet consumption are associated with resilience to clinical cognitive expression of severe AD pathology. Pharmacological approaches using this information might be explored for clinical AD amelioration., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Inc.)
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- 2023
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34. Antibacterial Neutrophil Effector Response: Ex Vivo Quantification of Regulated Cell Death Associated with Extracellular Trap Release.
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Schweizer TA, Hertegonne S, Vulin C, Zinkernagel AS, and Mairpady Shambat S
- Subjects
- Neutrophils metabolism, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents metabolism, Flow Cytometry methods, Extracellular Traps metabolism, Regulated Cell Death
- Abstract
Regulated cell death (RCD) and the concomitant release of extracellular traps by neutrophils (NETs) constitute an important antibacterial effector response. Usually, the dynamic processes of RCD and NETs release are assessed independently of each other by either unspecific or time-consuming methods. Here, we describe a flow cytometry-based high-throughput analysis method incorporating neutrophil RCD and NETs release with visual live-imaging conformation upon ex vivo bacterial challenge. This combined approach allows to quantify and closely follow the kinetics of the dynamic neutrophil effector response towards bacterial infection., (© 2023. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2023
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35. Correction: Valcic et al. Determining Whether Sex and Zygosity Modulates the Association between APOE4 and Psychosis in a Neuropathologically-Confirmed Alzheimer's Disease Cohort. Brain Sci. 2022, 12 , 1266.
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Valcic M, Khoury MA, Kim J, Fornazzari L, Churchill NW, Ismail Z, De Luca V, Tsuang D, Schweizer TA, Munoz DG, and Fischer CE
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In the original publication [...].
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- 2022
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36. Psychotic Disorders in the Elderly: Diagnosis, Epidemiology, and Treatment.
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Fischer CE, Namasivayam A, Crawford-Holland L, Hakobyan N, Schweizer TA, Munoz DG, and Pollock BG
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- Aged, Humans, Citalopram therapeutic use, Psychotic Disorders diagnosis, Psychotic Disorders drug therapy, Psychotic Disorders epidemiology, Schizophrenia drug therapy, Antipsychotic Agents therapeutic use, Dementia drug therapy
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This review covers the latest advances in our understanding of psychosis in the elderly population with respect to diagnosis, epidemiology, and treatment. Major topics of discussion include late life psychiatric disorders such as schizophrenia, schizoaffective disorder, and delusional disorder as well as dementia-related psychosis. Clinical differences between early-onset and late-onset disorders are reviewed in terms of prevalence, symptomatology, and approach to treatment. Newly revised research and clinical criteria for dementia-related psychosis are referenced. The evidence base for emerging therapies including citalopram and pimavanserin in relation to conventional therapies such as atypical antipsychotics are discussed.., Competing Interests: Disclosure Dr B.G. Pollock holds United States Provisional Patent Nos. 6/490,680, 17/396,030 and Canadian Provisional Patent No. 3,054,093 for a cell-based assay and kits for assessing serum anticholinergic activity. Dr C.E. Fischer receives grant funding from Hoffman La Roche and Vielight Inc., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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37. Determining Whether Sex and Zygosity Modulates the Association between APOE4 and Psychosis in a Neuropathologically-Confirmed Alzheimer's Disease Cohort.
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Valcic M, Khoury MA, Kim J, Fornazzari L, Churchill NW, Ismail Z, De Luca V, Tsuang D, Schweizer TA, Munoz DG, and Fischer CE
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Background: The APOE4 allele is a genetic risk factor for developing late-onset Alzheimer's disease (AD). Previous work by our group revealed that female APOE4 homozygotes with Lewy body (LB) pathology were more likely to experience psychosis compared to female APOE4 non-carriers, whereas in males there was no APOE4 dose-dependent significant effect. The objective of this study was to refine our previous findings by adjusting for covariates and determining the probability of an APOE4 sex-mediated effect on psychosis., Methods: Neuropathologically confirmed AD patients with LB pathology (n = 491) and without LB pathology (n = 716) were extracted from the National Alzheimer's Coordinating Center (NACC). Patients were classified as psychotic if they scored positively for delusions and/or hallucinations on the Neuropsychiatric Inventory. Analysis consisted of a preliminary unadjusted binary logistic regression and a Generalized Additive binary logistic regression Model (GAM) to predict the relationship between APOE4 status and sex on the presence of psychosis in both cohorts, adjusting for age, education and MMSE., Results: In the cohort with LB pathology, female APOE4 homozygotes were significantly more likely to experience psychosis compared to female APOE4 non-carriers (OR = 4.15, 95%CI [1.21, 14.2], p = 0.023). Female heterozygotes were also more likely to experience psychosis compared to female APOE4 non-carriers, but to a lesser extent (OR = 2.37, 95%CI [1.01, 5.59], p = 0.048). There was no significant difference in males with LB pathology or in any sex in the cohort without LB pathology., Conclusions: Sex and zygosity influence the effect of APOE4 on psychosis in neuropathologically confirmed AD patients, with the effect being limited to females with LB pathology.
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- 2022
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38. Intervertebral disc cell chondroptosis elicits neutrophil response in Staphylococcus aureus spondylodiscitis.
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Schweizer TA, Andreoni F, Acevedo C, Scheier TC, Heggli I, Maggio EM, Eberhard N, Brugger SD, Dudli S, and Zinkernagel AS
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- Animals, Cytokines metabolism, Humans, Neutrophils metabolism, Retrospective Studies, Staphylococcus aureus metabolism, Swine, Discitis metabolism, Discitis pathology, Intervertebral Disc metabolism, Staphylococcal Infections metabolism
- Abstract
To understand the pathophysiology of spondylodiscitis due to Staphylococcus aureus , an emerging infectious disease of the intervertebral disc (IVD) and vertebral body with a high complication rate, we combined clinical insights and experimental approaches. Clinical data and histological material of nine patients suffering from S. aureus spondylodiscitis were retrospectively collected at a single center. To mirror the clinical findings experimentally, we developed a novel porcine ex vivo model mimicking acute S. aureus spondylodiscitis and assessed the interaction between S. aureus and IVD cells within their native environment. In addition, the inflammatory features underlying this interaction were assessed in primary human IVD cells. Finally, mirroring the clinical findings, we assessed primary human neutrophils for their ability to respond to secreted inflammatory modulators of IVD cells upon the S. aureus challenge. Acute S. aureus spondylodiscitis in patients was characterized by tissue necrosis and neutrophil infiltration. Additionally, the presence of empty IVD cells' lacunae was observed. This was mirrored in the ex vivo porcine model, where S. aureus induced extensive IVD cell death, leading to empty lacunae. Concomitant engagement of the apoptotic and pyroptotic cell death pathways was observed in primary human IVD cells, resulting in cytokine release. Among the released cytokines, functionally intact neutrophil-priming as well as broad pro- and anti-inflammatory cytokines which are known for their involvement in IVD degeneration were found. In patients as well as ex vivo in a novel porcine model, S. aureus IVD infection caused IVD cell death, resulting in empty lacunae, which was accompanied by the release of inflammatory markers and recruitment of neutrophils. These findings offer valuable insights into the important role of inflammatory IVD cell death during spondylodiscitis and potential future therapeutic approaches., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Schweizer, Andreoni, Acevedo, Scheier, Heggli, Maggio, Eberhard, Brugger, Dudli and Zinkernagel.)
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- 2022
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39. Quantification of within-patient Staphylococcus aureus phenotypic heterogeneity as a proxy for the presence of persisters across clinical presentations.
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Bär J, Boumasmoud M, Mairpady Shambat S, Vulin C, Huemer M, Schweizer TA, Gómez-Mejia A, Eberhard N, Achermann Y, Zingg PO, Mestres CA, Brugger SD, Schuepbach RA, Kouyos RD, Hasse B, and Zinkernagel AS
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- Agar, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Biofilms, Humans, Microbial Sensitivity Tests, Rifampin, Staphylococcal Infections diagnosis, Staphylococcal Infections drug therapy, Staphylococcal Infections microbiology, Staphylococcus aureus genetics
- Abstract
Objectives: Difficult-to-treat infections caused by antibiotic-susceptible strains have been linked to the occurrence of persisters, a subpopulation of dormant bacteria that tolerate antibiotic exposure despite lacking genetic resistance. These persisters can be identified phenotypically by plating on nutrient agar because of their altered growth dynamics, resulting in colony-size heterogeneity. The occurrence of within-patient bacterial phenotypic heterogeneity in various infections and clinical determinants of persister formation remains unknown., Methods: We plated bacteria derived from 132 patient samples of difficult-to-treat infections directly on nutrient-rich agar and monitored colony growth by time-lapse imaging. We retained 36 Staphylococcus aureus monocultures for further analysis. We investigated clinical factors associated with increased colony growth-delay with regression analyses. We corroborated the clinical findings using in vitro grown static biofilms exposed to distinct antibiotics., Results: The extent of phenotypic heterogeneity of patient-derived S. aureus varied substantially between patients (from no delay to a maximum of 57.6 hours). Increased heterogeneity coincided with increased median colony growth-delay. Multivariable regression showed that rifampicin treatment was significantly associated with increased median growth-delay (13.3 hours; 95% CI 7.13-19.6 hours; p < 0.001). S. aureus grown in biofilms and exposed to high concentrations of rifampicin or a combination of rifampicin with clindamycin or levofloxacin exhibited prolonged growth-delay (p < 0.05 for 11 of 12 comparisons), correlating with a strain-dependent increase in antibiotic tolerance., Discussion: Colony-size heterogeneity upon direct sampling of difficult-to-treat S. aureus infections was frequently observed. Hence, future studies are needed to assess the potential benefit of phenotypic heterogeneity quantification for staphylococcal infection prognosis and treatment guidelines., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2022
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40. Comparing cardiovascular risk factors in older persons with mild cognitive impairment and lifetime history of major depressive disorder.
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Karameh WK, Kortebi I, Kumar S, Gallagher D, Golas A, Lanctôt KL, Butters MA, Bowie CR, Flint A, Rajji T, Herrmann N, Pollock BG, Mulsant B, Mah L, Munoz DG, Schweizer TA, and Fischer CE
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- Aged, Aged, 80 and over, Cohort Studies, Heart Disease Risk Factors, Humans, Neuropsychological Tests, Risk Factors, Cardiovascular Diseases complications, Cardiovascular Diseases epidemiology, Cognitive Dysfunction psychology, Depressive Disorder, Major complications, Depressive Disorder, Major epidemiology, Hypertension complications, Hypertension epidemiology, Transcranial Direct Current Stimulation
- Abstract
Objectives: To compare the prevalence of select cardiovascular risk factors (CVRFs) in patients with mild cognitive impairment (MCI) versus lifetime history of major depression disorder (MDD) and a normal comparison group using baseline data from the Prevention of Alzheimer's Dementia with Cognitive Remediation plus Transcranial Direct Current Stimulation (PACt-MD) study., Design: Baseline data from a multi-centered intervention study of older adults with MCI, history of MDD, or combined MCI and history of MDD (PACt-MD) were analyzed., Setting: Community-based multi-centered study based in Toronto across 5 academic sites., Participants: Older adults with MCI, history of MDD, or combined MCI and history of MDD and healthy controls., Measurements: We examined the baseline distribution of smoking, hypertension and diabetes in three groups of participants aged 60+ years in the PACt-MD cohort study: MCI (n = 278), MDD (n = 95), and healthy older controls (n = 81). Generalized linear models were fitted to study the effect of CVRFs on MCI and MDD as well as neuropsychological composite scores., Results: A higher odds of hypertension among the MCI cohort compared to healthy controls (p < .05) was noted in unadjusted analysis. Statistical significance level was lost on adjusting for age, sex and education (p > .05). A history of hypertension was associated with lower performance in composite executive function (p < .05) and overall composite neuropsychological test score (p < .05) among a pooled cohort with MCI or MDD., Conclusions: This study reinforces the importance of treating modifiable CVRFs, specifically hypertension, as a means of mitigating cognitive decline in patients with at-risk cognitive conditions.
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- 2022
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41. Delusional Severity Is Associated with Abnormal Texture in FLAIR MRI.
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Khoury MA, Bahsoun MA, Fadhel A, Shunbuli S, Venkatesh S, Ghazvanchahi A, Mitha S, Chan K, Fornazzari LR, Churchill NW, Ismail Z, Munoz DG, Schweizer TA, Moody AR, Fischer CE, and Khademi A
- Abstract
Background: This study examines the relationship between delusional severity in cognitively impaired adults with automatically computed volume and texture biomarkers from the Normal Appearing Brain Matter (NABM) in FLAIR MRI. Methods: Patients with mild cognitive impairment (MCI, n = 24) and Alzheimer’s Disease (AD, n = 18) with delusions of varying severities based on Neuropsychiatric Inventory-Questionnaire (NPI-Q) (1—mild, 2—moderate, 3—severe) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) were analyzed for this task. The NABM region, which is gray matter (GM) and white matter (WM) combined, was automatically segmented in FLAIR MRI volumes with intensity standardization and thresholding. Three imaging biomarkers were computed from this region, including NABM volume and two texture markers called “Integrity” and “Damage”. Together, these imaging biomarkers quantify structural changes in brain volume, microstructural integrity and tissue damage. Multivariable regression was used to investigate relationships between imaging biomarkers and delusional severities (1, 2 and 3). Sex, age, education, APOE4 and baseline cerebrospinal fluid (CSF) tau were included as co-variates. Results: Biomarkers were extracted from a total of 42 participants with longitudinal time points representing 164 imaging volumes. Significant associations were found for all three NABM biomarkers between delusion level 3 and level 1. Integrity was also sensitive enough to show differences between delusion level 1 and delusion level 2. A significant specified interaction was noted with severe delusions (level 3) and CSF tau for all imaging biomarkers (p < 0.01). APOE4 homozygotes were also significantly related to the biomarkers. Conclusion: Cognitively impaired older adults with more severe delusions have greater global brain disease burden in the WM and GM combined (NABM) as measured using FLAIR MRI. Relative to patients with mild delusions, tissue degeneration in the NABM was more pronounced in subjects with higher delusional symptoms, with a significant association with CSF tau. Future studies are required to establish potential tau-associated mechanisms of increased delusional severity.
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- 2022
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42. Genomic Surveillance of Vancomycin-Resistant Enterococcus faecium Reveals Spread of a Linear Plasmid Conferring a Nutrient Utilization Advantage.
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Boumasmoud M, Dengler Haunreiter V, Schweizer TA, Meyer L, Chakrakodi B, Schreiber PW, Seidl K, Kühnert D, Kouyos RD, and Zinkernagel AS
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- Genomics, Humans, Nutrients, Plasmids genetics, Vancomycin pharmacology, Enterococcus faecium genetics, Gram-Positive Bacterial Infections microbiology, Vancomycin-Resistant Enterococci genetics
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Healthcare-associated outbreaks of vancomycin-resistant Enterococcus faecium (VREfm) are a worldwide problem with increasing prevalence. The genomic plasticity of this hospital-adapted pathogen contributes to its efficient spread despite infection control measures. Here, we aimed to identify the genomic and phenotypic determinants of health care-associated transmission of VREfm. We assessed the VREfm transmission networks at the tertiary-care University Hospital of Zurich (USZ) between October 2014 and February 2018 and investigated microevolutionary dynamics of this pathogen. We performed whole-genome sequencing for the 69 VREfm isolates collected during this time frame and assessed the population structure and variability of the vancomycin resistance transposon. Phylogenomic analysis allowed us to reconstruct transmission networks and to unveil external or wider transmission networks undetectable by routine surveillance. Notably, it unveiled a persistent clone , sampled 31 times over a 29-month period. Exploring the evolutionary dynamics of this clone and characterizing the phenotypic consequences revealed the spread of a variant with decreased daptomycin susceptibility and the acquired ability to utilize N-acetyl-galactosamine (GalNAc), one of the primary constituents of the human gut mucins. This nutrient utilization advantage was conferred by a novel plasmid, termed pELF_USZ, which exhibited a linear topology. This plasmid, which was harbored by two distinct clones, was transferable by conjugation. Overall, this work highlights the potential of combining epidemiological, functional genomic, and evolutionary perspectives to unveil adaptation strategies of VREfm. IMPORTANCE Sequencing microbial pathogens causing outbreaks has become a common practice to characterize transmission networks. In addition to the signal provided by vertical evolution, bacterial genomes harbor mobile genetic elements shared horizontally between clones. While macroevolutionary studies have revealed an important role of plasmids and genes encoding carbohydrate utilization systems in the adaptation of Enterococcus faecium to the hospital environment, mechanisms of dissemination and the specific function of many of these genetic determinants remain to be elucidated. Here, we characterize a plasmid providing a nutrient utilization advantage and show evidence for its clonal and horizontal spread at a local scale. Further studies integrating epidemiological, functional genomics, and evolutionary perspectives will be critical to identify changes shaping the success of this pathogen.
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- 2022
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43. Hyperinflammatory environment drives dysfunctional myeloid cell effector response to bacterial challenge in COVID-19.
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Mairpady Shambat S, Gómez-Mejia A, Schweizer TA, Huemer M, Chang CC, Acevedo C, Bergada-Pijuan J, Vulin C, Hofmaenner DA, Scheier TC, Hertegonne S, Parietti E, Miroshnikova N, Wendel Garcia PD, Hilty MP, Buehler PK, Schuepbach RA, Brugger SD, and Zinkernagel AS
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- COVID-19 virology, Cytokine Release Syndrome microbiology, Cytokine Release Syndrome virology, Humans, Lymphocytes immunology, Lymphocytes microbiology, Lymphocytes virology, Monocytes immunology, Monocytes microbiology, Neutrophils immunology, Neutrophils microbiology, SARS-CoV-2 pathogenicity, COVID-19 microbiology, Cytokine Release Syndrome complications, Cytokines metabolism, Monocytes virology, Neutrophils virology
- Abstract
COVID-19 displays diverse disease severities and symptoms including acute systemic inflammation and hypercytokinemia, with subsequent dysregulation of immune cells. Bacterial superinfections in COVID-19 can further complicate the disease course and are associated with increased mortality. However, there is limited understanding of how SARS-CoV-2 pathogenesis and hypercytokinemia impede the innate immune function against bacterial superinfections. We assessed the influence of COVID-19 plasma hypercytokinemia on the functional responses of myeloid immune cells upon bacterial challenges from acute-phase COVID-19 patients and their corresponding recovery-phase. We show that a severe hypercytokinemia status in COVID-19 patients correlates with the development of bacterial superinfections. Neutrophils and monocytes derived from COVID-19 patients in their acute-phase showed an impaired intracellular microbicidal capacity upon bacterial challenges. The impaired microbicidal capacity was reflected by abrogated MPO and reduced NETs production in neutrophils along with reduced ROS production in both neutrophils and monocytes. Moreover, we observed a distinct pattern of cell surface receptor expression on both neutrophils and monocytes, in line with suppressed autocrine and paracrine cytokine signaling. This phenotype was characterized by a high expression of CD66b, CXCR4 and low expression of CXCR1, CXCR2 and CD15 in neutrophils and low expression of HLA-DR, CD86 and high expression of CD163 and CD11b in monocytes. Furthermore, the impaired antibacterial effector function was mediated by synergistic effect of the cytokines TNF-α, IFN-γ and IL-4. COVID-19 patients receiving dexamethasone showed a significant reduction of overall inflammatory markers in the plasma as well as exhibited an enhanced immune response towards bacterial challenge ex vivo. Finally, broad anti-inflammatory treatment was associated with a reduction in CRP, IL-6 levels as well as length of ICU stay and ventilation-days in critically ill COVID-19 patients. Our data provides insights into the transient functional dysregulation of myeloid immune cells against subsequent bacterial infections in COVID-19 patients and describe a beneficial role for the use of dexamethasone in these patients., Competing Interests: The authors have declared that no competing interests exist.
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- 2022
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44. Sex Modifies the Associations of APOEɛ4 with Neuropsychiatric Symptom Burden in Both At-Risk and Clinical Cohorts of Alzheimer's Disease.
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Dissanayake AS, Tan YB, Bowie CR, Butters MA, Flint AJ, Gallagher D, Golas AC, Herrmann N, Ismail Z, Kennedy JL, Kumar S, Lanctot KL, Mah L, Mulsant BH, Pollock BG, Rajji TK, Tau M, Maraj A, Churchill NW, Tsuang D, Schweizer TA, Munoz DG, and Fischer CE
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- Male, Female, Humans, Neuropsychological Tests, Alzheimer Disease diagnosis, Depressive Disorder, Major genetics, Depressive Disorder, Major complications, Cognitive Dysfunction diagnosis
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Background: Recent work suggests that APOEɛ4/4 females with Alzheimer's disease (AD) are more susceptible to developing neuropsychiatric symptoms (NPS)., Objective: To examine the interaction of sex and APOEɛ4 status on NPS burden using two independent cohorts: 1) patients at risk for AD with mild cognitive impairment and/or major depressive disorder (n = 252) and 2) patients with probable AD (n = 7,261)., Methods: Regression models examined the interactive effects of sex and APOEɛ4 on the number of NPS experienced and NPS Severity. APOEɛ3/4 and APOEɛ4/4 were pooled in the at-risk cohort due to the sample size., Results: In the at-risk cohort, there was a significant sex*APOEɛ4 interaction (p = 0.007) such that the association of APOEɛ4 with NPS was greater in females than in males (incident rate ratio (IRR) = 2.0). APOEɛ4/4 females had the most NPS (mean = 1.9) and the highest severity scores (mean = 3.5) of any subgroup. In the clinical cohort, APOEɛ4/4 females had significantly more NPS (IRR = 1.1, p = 0.001, mean = 3.1) and higher severity scores (b = 0.31, p = 0.015, mean = 3.7) than APOEɛ3/3 females (meanNPS = 2.9, meanSeverity = 3.3). No association was found in males., Conclusion: Our study suggests that sex modifies the association of APOEɛ4 on NPS burden. APOEɛ4/4 females may be particularly susceptible to increased NPS burden among individuals with AD and among individuals at risk for AD. Further investigation into the mechanisms behind these associations are needed.
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- 2022
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45. Neuropsychiatric Inventory-Questionnaire Assessed Nighttime Behaviors in Cognitively Asymptomatic Patients with Pathologically Confirmed Alzheimer's Disease Predict More Rapid Cognitive Deterioration.
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Atayde AL, Fischer CE, Schweizer TA, and Munoz DG
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- Apolipoprotein E4 genetics, Apolipoproteins E genetics, Cognition, Humans, Surveys and Questionnaires, Alzheimer Disease pathology, Cerebral Amyloid Angiopathy pathology, Cognitive Dysfunction genetics, Cognitive Dysfunction psychology
- Abstract
Background: The temporal relationship between sleep, Alzheimer's disease (AD), and cognitive impairment remains to be further elucidated., Objective: First, we aim to determine whether the Neuropsychiatric Inventory-Questionnaire (NPI-Q) assessed nighttime behaviors prior to cognitive decline influence the rate of cognitive deterioration in pathologically confirmed AD, and second, to assess the possible interactions with APOE allele and cerebral amyloid angiopathy (CAA)., Methods: The rate of cognitive decline between cognitively asymptomatic participants from the National Alzheimer Coordinating Center who eventually received a neuropathologic diagnosis of AD with (+NTB) or without (-NTB) nighttime behaviors were compared using independent samples t-test. Participants were stratified by APOE carrier and CAA status. Demographic and patient characteristics were assessed using descriptive statistics, and the independent samples t-test was used for continuous variables and chi-square test for categorical variables. The significance level was set at p≤0.05., Results: The rate of cognitive decline was greater in +NTB (n = 74; 3.30 points/year) than -NTB (n = 330; 2.45 points/year) (p = 0.016), even if there was no difference in cognitive status at onset. This difference was restricted to APOE ɛ4 carriers (p = 0.049) and positive CAA participants (p = 0.020). Significance was not reached in non-carriers (p = 0.186) and negative CAA (p = 0.364). APOE and CAA were not differentially distributed between the NTB groups., Conclusion: NPI-Q assessed nighttime behaviors, a surrogate for sleep disturbances, are associated with more rapidly deteriorating cognition in patients with AD neuropathology who are also carriers of APOE ɛ4 or show CAA.
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- 2022
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46. Sex differences in acute and long-term brain recovery after concussion.
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Churchill NW, Hutchison MG, Graham SJ, and Schweizer TA
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- Adolescent, Adult, Athletic Injuries pathology, Athletic Injuries physiopathology, Brain Concussion pathology, Brain Concussion physiopathology, Diffusion Tensor Imaging, Female, Humans, Longitudinal Studies, Male, Recovery of Function physiology, White Matter pathology, Young Adult, Athletic Injuries diagnostic imaging, Brain Concussion diagnostic imaging, Cerebrovascular Circulation physiology, Magnetic Resonance Imaging, Sex Characteristics, White Matter diagnostic imaging
- Abstract
Concussion is associated with acute disturbances in brain function and behavior, with potential long-term effects on brain health. However, it is presently unclear whether there are sex differences in acute and long-term brain recovery. In this study, magnetic resonance imaging (MRI) was used to scan 61 participants with sport-related concussion (30 male, 31 female) longitudinally at acute injury, medical clearance to return to play (RTP), and 1-year post-RTP. A large cohort of 167 controls (80 male, 87 female) was also imaged. Each MRI session assessed cerebral blood flow (CBF), along with white matter fractional anisotropy (FA) and mean diffusivity (MD). For concussed athletes, the parameters were converted to difference scores relative to matched control subgroups, and partial least squares modeled the main and sex-specific effects of concussion. Although male and female athletes did not differ in acute symptoms or time to RTP , all MRI measures showed significant sex differences during recovery. Males had greater reductions in occipital-parietal CBF (mean difference and 95%CI: 9.97 ml/100 g/min, [4.84, 15.12] ml/100 g/min, z = 3.73) and increases in callosal MD (9.07 × 10
-5 , [-14.14, -3.60] × 10-5 , z = -3.46), with greatest effects at 1-year post-RTP. In contrast, females had greater reductions in FA of the corona radiata (16.50 × 10-3 , [-22.38, -11.08] × 10-3 , z = -5.60), with greatest effects at RTP. These findings provide new insights into how the brain recovers after a concussion, showing sex differences in both the acute and chronic phases of injury., (© 2021 The Authors. Human Brain Mapping published by Wiley Periodicals LLC.)- Published
- 2021
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47. Blunted sFasL signalling exacerbates TNF-driven neutrophil necroptosis in critically ill COVID-19 patients.
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Schweizer TA, Mairpady Shambat S, Vulin C, Hoeller S, Acevedo C, Huemer M, Gomez-Mejia A, Chang CC, Baum J, Hertegonne S, Hitz E, Scheier TC, Hofmaenner DA, Buehler PK, Moch H, Schuepbach RA, Brugger SD, and Zinkernagel AS
- Abstract
Objectives: Critically ill coronavirus disease 2019 (COVID-19) patients are characterised by a severely dysregulated cytokine profile and elevated neutrophil counts, impacting disease severity. However, it remains unclear how neutrophils contribute to pathophysiology during COVID-19. Here, we assessed the impact of the dysregulated cytokine profile on the regulated cell death (RCD) programme of neutrophils., Methods: Regulated cell death phenotype of neutrophils isolated from critically ill COVID-19 patients or healthy donors and stimulated with COVID-19 or healthy plasma ex vivo was assessed by flow cytometry, time-lapse microscopy and cytokine multiplex analysis. Immunohistochemistry of COVID-19 patients and control biopsies were performed to assess the in situ neutrophil RCD phenotype. Plasma cytokine levels of COVID-19 patients and healthy donors were measured by multiplex analysis. Clinical parameters were correlated to cytokine levels of COVID-19 patients., Results: COVID-19 plasma induced a necroptosis-sensitive neutrophil phenotype, characterised by cell lysis, elevated release of damage-associated molecular patterns (DAMPs), increased receptor-interacting serine/threonine-protein kinase (RIPK) 1 levels and mixed lineage kinase domain-like pseudokinase (MLKL) involvement. The occurrence of neutrophil necroptosis MLKL axis was further confirmed in COVID-19 thrombus and lung biopsies. Necroptosis was induced by the tumor necrosis factor receptor 1 (TNFRI)/TNF-α axis. Moreover, reduction of soluble Fas ligand (sFasL) levels in COVID-19 patients and hence decreased signalling to Fas directly increased RIPK1 levels, exacerbated TNF-driven necroptosis and correlated with disease severity, which was abolished in patients treated with glucocorticoids., Conclusion: Our results suggest a novel role for sFasL signalling in the TNF-α-induced RCD programme in neutrophils during COVID-19 and a potential therapeutic target to curb inflammation and thus influence disease severity and outcome., Competing Interests: The authors declare no conflict of interest., (© 2021 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.)
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- 2021
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48. Concussion Risk and Resilience: Relationships with Pre-Injury Salience Network Connectivity.
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Churchill NW, Hutchison MG, Graham SJ, and Schweizer TA
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- Adolescent, Anisotropy, Athletic Injuries diagnostic imaging, Brain Concussion diagnostic imaging, Brain Mapping, Case-Control Studies, Executive Function physiology, Female, Humans, Magnetic Resonance Imaging, Male, Prospective Studies, White Matter diagnostic imaging, Young Adult, Athletic Injuries etiology, Athletic Injuries physiopathology, Brain Concussion etiology, Brain Concussion physiopathology, Resilience, Psychological physiology
- Abstract
Concussion is a major health concern, making it critical to identify factors that influence risk and resilience. The salience network (SN) likely plays a key role in concussion risk, given its roles in orienting attention, functional adaptability, and interoceptive awareness. The SN's functions are thought to be mediated through causal control of other networks, including the default mode network (DMN) and executive control network (ECN). It was therefore hypothesized that the SN of at-risk individuals would have altered functional and structural connectivity with the DMN and ECN. For this prospective study, 167 university athletes had baseline clinical assessments and magnetic resonance imaging scans and were monitored for the rest of their varsity career, with any concussions recorded. Athletes concussed in the same season as imaging (CSS; n = 17) and those concussed in later seasons (CLS; n = 15) were matched to controls that were not concussed after imaging. Functional connectivity and white matter fractional anisotropy (FA) were compared between concussed and control groups. Prior to injury, CSS athletes had significantly elevated total symptom severity scores, elevated SN-DMN functional connectivity and reduced FA of connecting white matter tracts, whereas CLS athletes showed no significant clinical or imaging effects. These findings provide new insights into the neurobiology of concussion risk and resilience, as indices of SN-DMN network connectivity are associated with short-term but not long-term concussion risk.
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- 2021
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49. Cerebral blood flow is associated with matrix metalloproteinase levels during the early symptomatic phase of concussion.
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Churchill NW, Di Battista AP, Rhind SG, Richards D, Schweizer TA, and Hutchison MG
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- Adolescent, Brain diagnostic imaging, Brain Concussion blood, Brain Concussion diagnostic imaging, Female, Humans, Magnetic Resonance Imaging, Male, Spin Labels, Sports, Young Adult, Brain blood supply, Brain Concussion physiopathology, Cerebrovascular Circulation physiology, Matrix Metalloproteinases blood
- Abstract
Concussion is associated with disrupted cerebral blood flow (CBF), although there appears to be substantial inter-individual variability in CBF response. At present, the mechanisms of variable CBF response remain incompletely understood, but one potential contributor is matrix metalloproteinase (MMP) expression. In more severe forms of acquired brain injury, MMP up-regulation contributes to CBF impairments via increased blood-brain barrier permeability. A similar relationship is hypothesized for concussion, where recently concussed individuals with higher MMP levels have lower CBF. To test this hypothesis, 35 concussed athletes were assessed longitudinally at early symptomatic injury (median: 5 days post-injury) and at medical clearance (median: 24 days post-injury), along with 71 athletic controls. For all athletes, plasma MMPs were measured and arterial spin labelling was used to measure CBF. Consistent with our hypothesis, higher concentrations of MMP-2 and MMP-3 were correlated with lower global CBF. The correlations between MMPs and global CBF were also significantly diminished for concussed athletes at medical clearance and for athletic controls. These results indicate an inverse relationship between plasma MMP levels and CBF that is specific to the symptomatic phase of concussion. Analyses of regional CBF further showed that correlations with MMP levels exhibited some spatial specificity, with greatest effects in occipital, parietal and temporal lobes. These findings provide new insights into the mechanisms of post-concussion cerebrovascular dysfunction., Competing Interests: TAS and NWC received funding from Siemens Healthineers Canada to collect data included in this study. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
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- 2021
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50. Acute and Chronic Effects of Multiple Concussions on Midline Brain Structures.
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Churchill NW, Hutchison MG, Graham SJ, and Schweizer TA
- Abstract
Background and Objectives: To test the hypothesis that a history of concussion (HOC) causes greater disturbances in cerebral blood flow (CBF) and white matter microstructure of midline brain structures after subsequent concussions, during the acute and chronic phases of recovery., Methods: In this longitudinal MRI study, 61 athletes with uncomplicated concussion (36 with HOC) were imaged at the acute phase of injury (1-7 days after injury), the subacute phase (8-14 days), medical clearance to return to play (RTP), 1 month after RTP, and 1 year after RTP. A normative group of 167 controls (73 with HOC) were also imaged. Each session assessed CBF of the cingulate cortex, along with fractional anisotropy (FA) and mean diffusivity (MD) of the corpus callosum. Linear mixed models tested for interactions of HOC with time since injury. The Sport Concussion Assessment Tool (SCAT) was also used to evaluate effects of HOC on symptoms, cognition, and balance., Results: Athletes with HOC had significantly greater declines in midcingulate CBF subacutely ( z = -3.29, p = 0.002) and greater declines in posterior cingulate CBF at 1 year after RTP ( z = -2.42, p = 0.007). No significant effects of HOC were seen for FA, whereas athletes with HOC had higher MD of the splenium at RTP ( z = 2.54, p = 0.008). These effects were seen in the absence of significant differences in SCAT domains (| z | ≤ 1.14, p ≥ 0.256) or time to RTP ( z = 0.23, p = 0.818)., Discussion: Results indicate subacute and chronic effects of HOC on cingulate CBF and callosal microstructure in the absence of differences in clinical indices. These findings provide new insights into physiologic brain recovery after concussion, with cumulative effects of repeated injury detected among young, healthy athletes., (© 2021 American Academy of Neurology.)
- Published
- 2021
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