Anatomy and Neuroscience - Research Publications

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    Cognitive function with evolocumab in pediatric heterozygous familial hypercholesterolemia.
    Gaudet, D ; Ruzza, A ; Bridges, I ; Maruff, P ; Schembri, A ; Hamer, A ; Mach, F ; Bergeron, J ; Gaudet, I ; Pierre, JS ; Kastelein, JJP ; Hovingh, GK ; Wiegman, A ; Raal, FJ ; Santos, RD (Elsevier BV, 2022)
    BACKGROUND: Evolocumab is a fully human monoclonal antibody inhibitor of PCSK9 approved for lowering low-density lipoprotein cholesterol in adults and pediatric patients with familial hypercholesterolemia (FH). The cognitive safety of evolocumab has been established in adults but has not yet been described in pediatric patients. OBJECTIVE: To determine the effects of evolocumab on cognitive function in pediatric heterozygous FH. METHODS: Cognitive function was assessed during a 24-week, randomized, double-blind, placebo-controlled study (HAUSER-RCT) evaluating the efficacy, safety, and tolerability of 24 weeks of monthly subcutaneous injections of evolocumab in pediatric patients with FH. Cognitive safety endpoints included changes from baseline to week 24 in test scores in domains of psychomotor function, attention, visual learning, and executive function. Between-group differences in age-standardized mean test score changes were analyzed using analysis of covariance models and point estimates with 95% confidence interval (CI). Magnitudes of difference between treatment groups (Cohen's d) and reliable change indices were calculated for each cognitive function test. RESULTS: At week 24, changes from baseline in age-standardized cognitive test scores were similar between the treatment groups. Differences (95% CI) between the evolocumab and placebo groups in mean test score changes for the Groton Maze Learning, One-Card Learning, Identification, and Detection tests were 0.1 (-0.2, 0.4), -0.1 (-0.5, 0.4), 0.3 (0.0, 0.7), 0.3 (-0.1, 0.8), respectively. For all tests, abnormal and clinically important cognitive decline occurred with lesser frequency in the evolocumab group. CONCLUSION: In pediatric patients with FH, 24-week treatment with evolocumab did not negatively influence cognition. FUNDING: This study was funded and designed by Amgen.
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    Preclinical and randomized clinical evaluation of the p38α kinase inhibitor neflamapimod for basal forebrain cholinergic degeneration.
    Jiang, Y ; Alam, JJ ; Gomperts, SN ; Maruff, P ; Lemstra, AW ; Germann, UA ; Stavrides, PH ; Darji, S ; Malampati, S ; Peddy, J ; Bleiwas, C ; Pawlik, M ; Pensalfini, A ; Yang, D-S ; Subbanna, S ; Basavarajappa, BS ; Smiley, JF ; Gardner, A ; Blackburn, K ; Chu, H-M ; Prins, ND ; Teunissen, CE ; Harrison, JE ; Scheltens, P ; Nixon, RA (Springer Science and Business Media LLC, 2022-09-21)
    The endosome-associated GTPase Rab5 is a central player in the molecular mechanisms leading to degeneration of basal forebrain cholinergic neurons (BFCN), a long-standing target for drug development. As p38α is a Rab5 activator, we hypothesized that inhibition of this kinase holds potential as an approach to treat diseases associated with BFCN loss. Herein, we report that neflamapimod (oral small molecule p38α inhibitor) reduces Rab5 activity, reverses endosomal pathology, and restores the numbers and morphology of BFCNs in a mouse model that develops BFCN degeneration. We also report on the results of an exploratory (hypothesis-generating) phase 2a randomized double-blind 16-week placebo-controlled clinical trial (Clinical trial registration: NCT04001517/EudraCT #2019-001566-15) of neflamapimod in mild-to-moderate dementia with Lewy bodies (DLB), a disease in which BFCN degeneration is an important driver of disease expression. A total of 91 participants, all receiving background cholinesterase inhibitor therapy, were randomized 1:1 between neflamapimod 40 mg or matching placebo capsules (taken orally twice-daily if weight <80 kg or thrice-daily if weight >80 kg). Neflamapimod does not show an effect in the clinical study on the primary endpoint, a cognitive-test battery. On two secondary endpoints, a measure of functional mobility and a dementia rating-scale, improvements were seen that are consistent with an effect on BFCN function. Neflamapimod treatment is well-tolerated with no study drug associated treatment discontinuations. The combined preclinical and clinical observations inform on the validity of the Rab5-based pathogenic model of cholinergic degeneration and provide a foundation for confirmatory (hypothesis-testing) clinical evaluation of neflamapimod in DLB.
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    Plasma A beta 42/40 ratio, p-tau181, GFAP, and NfL across the Alzheimer's disease continuum: A cross-sectional and longitudinal study in the AIBL cohort
    Chatterjee, P ; Pedrini, S ; Doecke, JD ; Thota, R ; Villemagne, VL ; Dore, V ; Singh, AK ; Wang, P ; Rainey-Smith, S ; Fowler, C ; Taddei, K ; Sohrabi, HR ; Molloy, MP ; Ames, D ; Maruff, P ; Rowe, CC ; Masters, CL ; Martins, RN (WILEY, 2022-07-21)
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    Differential Role of mGluR5 in Cognitive Processes in Posttraumatic Stress Disorder and Major Depression.
    Esterlis, I ; DeBonee, S ; Cool, R ; Holmes, S ; Baldassari, SR ; Maruff, P ; Pietrzak, RH ; Davis, MT (SAGE Publications, 2022)
    BACKGROUND: A robust literature supports the role of the metabotropic glutamate receptor type 5 (mGluR5) in cognitive functioning. mGluR5 is also implicated in the pathophysiology of posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), which are characterized by cognitive alterations. However, the relationship between mGluR5 and cognition in MDD and PTSD has not yet been directly investigated. To address this gap, we examined the relationship between in vivo mGluR5 availability and cognition in PTSD, MDD, and matched healthy adults (HA). METHODS: Individuals with PTSD (N = 28) and MDD (N = 21), and HA (N = 28) were matched for age, gender, and smoking status. Participants completed 18F-FPEB positron emission tomography (PET) scan, psychiatric and cognitive assessments. RESULTS: Across models examining the relationship between mGluR5 availability and different domains of cognition across diagnostic groups, only the interaction of diagnosis*attention was significant (F 4,64 = 3.011, P = .024). Higher mGluR5 availability was associated with poorer attention in PTSD in 4 frontolimbic regions of interests (ROI's: OFC (r = -.441, P = .016), vmPFC (r = -.408, P = .028), dlPFC (r = -.421, P = .023), hippocampus (r = -.422, P = .025). By contrast, mGluR5 availability in the MDD group was positively related to Attention (ATTN) in the OFC (r = .590, P = .006), vmPFC (r = .653, P = .002), and dlPFC (r = .620, P = .004). Findings in the hippocampus for MDD followed the same pattern but did not survive correction for multiple comparisons (r = .480, P = .036). ATTN and mGluR5 availability were not significantly related in the HA group. Of note, in MANOVA analyses group*ATTN interaction results in the OFC did not survive multiple comparisons (P = .046). All other findings survived correction for multiple comparisons and remained significant when covarying for potential confounds (eg, depressed mood). CONCLUSIONS: We observed a significant relationship between frontolimbic mGluR5 availability and performance on tests of attention in individuals with MDD and PTSD. This finding aligns with animal work showing dysregulation in mGluR5 in cognitive functioning, and differed as a function of diagnosis. Results suggest interventions targeting mGluR5 may help bolster cognitive difficulties, highlighting the importance of employing different mGluR5 directed treatment strategies in MDD and PTSD.
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    Identification of Leukocyte Surface P2X7 as a Biomarker Associated with Alzheimer's Disease
    Li, Y ; Huang, X ; Fowler, C ; Lim, YY ; Laws, SM ; Faux, N ; Doecke, JD ; Trounson, B ; Pertile, K ; Rumble, R ; Dore, V ; Villemagne, VL ; Rowe, CC ; Wiley, JS ; Maruff, P ; Masters, CL ; Gu, BJ (MDPI, 2022-07-01)
    Alzheimer's disease (AD) has shown altered immune responses in the periphery. We studied P2X7 (a proinflammatory receptor and a scavenger receptor) and two integrins, CD11b and CD11c, on the surface of circulating leukocytes and analysed their associations with Aβ-PET, brain atrophy, neuropsychological assessments, and cerebrospinal fluid (CSF) biomarkers. Total 287 age-matched, sex-balanced participants were recruited in a discovery cohort and two validation cohorts through the AIBL study and studied using tri-colour flow cytometry. Our results demonstrated reduced expressions of P2X7, CD11b, and CD11c on leukocytes, particularly monocytes, in Aβ +ve cases compared with Aβ -ve controls. P2X7 and integrin downregulation was observed at pre-clinical stage of AD and stayed low throughout disease course. We further constructed a polygenic risk score (PRS) model based on 12 P2RX7 risk alleles to assess the genetic impact on P2X7 function in AIBL and ADNI cohorts. No significant association was identified between the P2RX7 gene and AD, indicating that P2X7 downregulation in AD is likely caused by environmental changes rather than genetic factors. In conclusion, the downregulation of P2X7 and integrins at pre-clinical stage of AD indicates altered pro-inflammatory responses, phagocytic functions, and migrating capabilities of circulating monocytes in early AD pathogenesis. Our study not only improves our understanding of peripheral immune involvement in early stage of AD but also provides more insights into novel biomarker development, diagnosis, and prognosis of AD.
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    Within subject rise in serum TNFα to IL-10 ratio is associated with poorer attention, decision-making and working memory in jockeys.
    Piantella, S ; O'Brien, WT ; Hale, MW ; Maruff, P ; McDonald, SJ ; Wright, BJ (Elsevier BV, 2022-05)
    Jockeys work in high-risk environments that rely heavily on attention- and decision-making to perform well and safely. Workplace stress literature has often overlooked the impact of stress on cognition, and designs that include physiological measures are rare. This study assessed the prospective concurrent relationships between workplace stress, depression symptoms and low-grade inflammation with cognitive performance among professional jockeys. Professional jockeys (N = 35, Mage = 32.29) provided information on workplace stress and depression symptoms, with serum levels of inflammatory cytokines (IL-6, IL-10, TNFα) and cytokine balance (IL-6: IL-10, TNFα: IL-10) quantified with SIMOA, and cognitive performance with CogSport computer-based testing battery. These measures were repeated after a twelve-month interval. Increased workplace stress between testing intervals was associated to an increased cytokine imbalance (β = 0.447, p = .015) after controlling for age and gender. Increases in cytokine imbalance occurred in unison with decreases in attention (β = 0.516, p = .002), decision-making (β = 0.452, p = .009) and working memory (β = 0.492, p = .004). These preliminary findings suggest the underlying mechanisms linking workplace stress and reduced cognitive performance may be influenced by measures of low-grade inflammation and specifically a cytokine imbalance. Our findings suggest a measure of cytokine balance may explain the heterogenous findings in previous studies that have focussed solely on the association of workplace stress with pro-inflammatory cytokines. Future work is needed however, to provide a broader evidence-base for our claims to better inform designs to intervene in the higher workplace stress-poorer cognition relationship.
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    Unsupervised Performance of the CogState Brief Battery in the Brain Health Registry: Implications for Detecting Cognitive Decline.
    Banh, T ; Jin, C ; Neuhaus, J ; Mackin, RS ; Maruff, P ; Stricker, N ; Weiner, MW ; Nosheny, RL (SERDI, 2022)
    INTRODUCTION: The feasibility and validity of unsupervised, longitudinal brief computerized cognitive batteries is unknown. METHODS: Participants aged 56-90 (N = 19476) from the Brain Health Registry (BHR) completed the CogState Brief Battery (CBB) at 6-month intervals over a period of 5 years. We used linear mixed-effects models to assess whether cross-sectional and longitudinal performance on CBB within BHR was associated with demographic and cognitive characteristics. We also defined a group of CBB decliners based on subject-specific slopes and estimated associations between decliner status and participant characteristics. RESULTS: We found weak associations between longitudinal change in CBB and participant characteristics. Cross-sectional CBB scores were significantly associated with participant characteristics such as age, gender, ethnicity, self-reported disease status, and memory concern. CBB decliners were more likely to self-report mild cognitive impairment (MCI) and memory concerns. DISCUSSION: Cross-sectional, remote CBB shows evidence of construct validity, but our results suggest that longitudinal assessment may not provide additional value for identifying those at risk for and with cognitive impairment.
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    No Influence of Age-Related Hearing Loss on Brain Amyloid-beta
    Sarant, JZ ; Harris, DC ; Busby, PA ; Fowler, C ; Fripp, J ; Masters, CL ; Maruff, P ; Bendlin, B (IOS PRESS, 2022-01-01)
    BACKGROUND: Hearing loss is independently associated with a faster rate of cognitive decline in older adults and has been identified as a modifiable risk factor for dementia. The mechanism for this association is unknown, and there has been limited exploration of potential casual pathology. OBJECTIVE: Our objective was to investigate whether there was an association between degree of audiometrically measured hearing loss (HL) and brain amyloid-β (Aβ) in a pre-clinical sample. METHODS: Participants of the Australian Imaging and Biomarker Longitudinal Study (AIBL; n = 143) underwent positron emission tomography (PET) imaging and objective measurement of hearing thresholds within 5 years of imaging, as well as cognitive assessment within 2 years of imaging in this observational cohort study. RESULTS: With one exception, study participants who had cognitive assessments within 2 years of their PET imaging (n = 113) were classified as having normal cognition. There was no association between cognitive scores and degree of hearing loss, or between cognitive scores and Aβ load. No association between HL and Aβ load was found once age was controlled for. As previously reported, positive Apolipoprotein E4 (APOE4) carrier status increased the risk of being Aβ positive (p = 0.002). CONCLUSION: Degree of HL was not associated with positive Aβ status.
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    Longitudinal Association of Intraindividual Variability With Cognitive Decline and Dementia: A Meta-Analysis
    Mumme, R ; Pushpanathan, M ; Donaldson, S ; Weinborn, M ; Rainey-Smith, SR ; Maruff, P ; Bucks, RS (AMER PSYCHOLOGICAL ASSOC, 2021-10-01)
    OBJECTIVE: Intraindividual variability (IIV)-variance in an individual's cognitive performance-may be associated with subsequent cognitive decline and/or conversion to dementia in older adults. This novel measure of cognition encompasses two main operationalizations: inconsistency (IIV-I) and dispersion (IIV-D), referring to variance within or across tasks, respectively. Each operationalization can also be measured with or without covariates. This meta-analytic study explores the association between IIV and subsequent cognitive outcomes regardless of operational definition and measurement approach. METHOD: Longitudinal studies (N = 13) that have examined IIV in association with later cognitive decline and/or conversation to MCI/dementia were analyzed. The effect of IIV operationalization was explored. Additional subgroup analysis of measurement approaches could not be examined due to the limited number of appropriate studies available for inclusion. RESULTS: Meta-analytic estimates suggest IIV is associated with subsequent cognitive decline and/or conversion to MCI/dementia (r = .20, 95% CI [.09, .31]) with no significant difference between the two operationalisations observed (Q = 3.41, p = .065). CONCLUSION: Cognitive IIV, including both IIV-I and IIV-D operationalizations, appears to be associated with subsequent cognitive decline and/or dementia and may offer a novel indicator of incipient dementia in both clinical and research settings. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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    Acute neuroimmune stimulation impairs verbal memory in adults: A PET brain imaging study
    Woodcock, EA ; Hillmer, AT ; Sandiego, CM ; Maruff, P ; Carson, RE ; Cosgrove, KP ; Pietrzak, RH (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2021-01-01)
    Psychiatric and neurologic disorders are often characterized by both neuroinflammation and cognitive dysfunction. To date, however, the relationship between neuroinflammation and cognitive dysfunction remains understudied in humans. Preclinical research indicates that experimental induction of neuroinflammation reliably impairs memory processes. In this paradigm development study, we translated those robust preclinical findings to humans using positron emission tomography (PET) imaging with [11C]PBR28, a marker of microglia, and lipopolysaccharide (LPS), a potent neuroimmune stimulus. In a sample of 18 healthy adults, we extended our previous findings that LPS administration increased whole-brain [11C]PBR28 availability by 31-50%, demonstrating a robust neuroimmune response (Cohen's ds > 1.6). We now show that LPS specifically impaired verbal learning and recall, hippocampal memory processes, by 11% and 22%, respectively (Cohen's ds > 0.9), but did not alter attention, motor, or executive processes. The LPS-induced increase in [11C]PBR28 binding was correlated with significantly greater decrements in verbal learning performance in the hippocampus (r = -0.52, p = .028), putamen (r = -0.50, p = .04), and thalamus (r = -0.55, p = .02). This experimental paradigm may be useful in investigating mechanistic relationships between neuroinflammatory signaling and cognitive dysfunction in psychiatric and neurologic disorders. It may also provide a direct approach to evaluate medications designed to rescue cognitive deficits associated with neuroinflammatory dysfunction.