Anatomy and Neuroscience - Research Publications

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    BDNF VAL66MET polymorphism and memory decline across the spectrum of Alzheimer's disease
    Lim, YY ; Laws, SM ; Perin, S ; Pietrzak, RH ; Fowler, C ; Masters, CL ; Maruff, P (WILEY, 2021-06)
    The brain-derived neurotrophic factor (BDNF) Val66Met (rs6265) polymorphism has been shown to moderate the extent to which memory decline manifests in preclinical Alzheimer's disease (AD). To date, no study has examined the relationship between BDNF and memory in individuals across biologically confirmed AD clinical stages (i.e., Aβ+). We aimed to understand the effect of BDNF on episodic memory decline and clinical disease progression over 126 months in individuals with preclinical, prodromal and clinical AD. Participants enrolled in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study who were Aβ + (according to positron emission tomography), and cognitively normal (CN; n = 238), classified as having mild cognitive impairment (MCI; n = 80), or AD (n = 66) were included in this study. Cognition was evaluated at 18 month intervals using an established episodic memory composite score over 126 months. We observed that in Aβ + CNs, Met66 was associated with greater memory decline with increasing age and were 1.5 times more likely to progress to MCI/AD over 126 months. In Aβ + MCIs, there was no effect of Met66 on memory decline or on disease progression to AD over 126 months. In Aβ + AD, Val66 homozygotes showed greater memory decline, while Met66 carriers performed at a constant and very impaired level. Our current results illustrate the importance of time and disease severity to clinicopathological models of the role of BDNF Val66Met in memory decline and AD clinical progression. Specifically, the effect of BDNF on memory decline is greatest in preclinical AD and reduces as AD clinical disease severity increases.
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    The Brain Chart of Aging: Machine-learning analytics reveals links between brain aging, white matter disease, amyloid burden, and cognition in the iSTAGING consortium of 10,216 harmonized MR scans
    Habes, M ; Pomponio, R ; Shou, H ; Doshi, J ; Mamourian, E ; Erus, G ; Nasrallah, I ; Launer, LJ ; Rashid, T ; Bilgel, M ; Fan, Y ; Toledo, JB ; Yaffe, K ; Sotiras, A ; Srinivasan, D ; Espeland, M ; Masters, C ; Maruff, P ; Fripp, J ; Volzk, H ; Johnson, SC ; Morris, JC ; Albert, MS ; Miller, M ; Bryan, RN ; Grabe, HJ ; Resnick, SM ; Wolk, DA ; Davatzikos, C (WILEY, 2021-01)
    INTRODUCTION: Relationships between brain atrophy patterns of typical aging and Alzheimer's disease (AD), white matter disease, cognition, and AD neuropathology were investigated via machine learning in a large harmonized magnetic resonance imaging database (11 studies; 10,216 subjects). METHODS: Three brain signatures were calculated: Brain-age, AD-like neurodegeneration, and white matter hyperintensities (WMHs). Brain Charts measured and displayed the relationships of these signatures to cognition and molecular biomarkers of AD. RESULTS: WMHs were associated with advanced brain aging, AD-like atrophy, poorer cognition, and AD neuropathology in mild cognitive impairment (MCI)/AD and cognitively normal (CN) subjects. High WMH volume was associated with brain aging and cognitive decline occurring in an ≈10-year period in CN subjects. WMHs were associated with doubling the likelihood of amyloid beta (Aβ) positivity after age 65. Brain aging, AD-like atrophy, and WMHs were better predictors of cognition than chronological age in MCI/AD. DISCUSSION: A Brain Chart quantifying brain-aging trajectories was established, enabling the systematic evaluation of individuals' brain-aging patterns relative to this large consortium.
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    Plasma p-tau181/Aβ1-42 ratio predicts Aβ-PET status and correlates with CSF-p-tau181/Aβ1-42 and future cognitive decline
    Fowler, CJ ; Stoops, E ; Rainey-Smith, SR ; Vanmechelen, E ; Vanbrabant, J ; Dewit, N ; Mauroo, K ; Maruff, P ; Rowe, CC ; Fripp, J ; Li, Q-X ; Bourgeat, P ; Collins, SJ ; Martins, RN ; Masters, CL ; Doecke, JD (WILEY, 2022)
    BACKGROUND: In Alzheimer's disease (AD), plasma amyloid beta (Aβ)1-42 and phosphorylated tau (p-tau) predict high amyloid status from Aβ positron emission tomography (PET); however, the extent to which combination of these plasma assays can predict remains unknown. METHODS: Prototype Simoa assays were used to measure plasma samples from participants who were either cognitively normal (CN) or had mild cognitive impairment (MCI)/AD in the Australian Imaging, Biomarkers and Lifestyle (AIBL) study. RESULTS: The p-tau181/Aβ1-42 ratio showed the best prediction of Aβ-PET across all participants (area under the curve [AUC] = 0.905, 95% confidence interval [CI]: 0.86-0.95) and in CN (AUC = 0.873; 0.80-0.94), and symptomatic (AUC = 0.908; 0.82-1.00) adults. Plasma p-tau181/Aβ1-42 ratio correlated with cerebrospinal fluid (CSF) p-tau181 (Elecsys, Spearman's ρ = 0.74, P < 0.0001) and predicted abnormal CSF Aβ (AUC = 0.816; 0.74-0.89). The p-tau181/Aβ1-42 ratio also predicted future rates of cognitive decline assessed by AIBL Preclinical Alzheimer Cognitive Composite or Clinical Dementia Rating Sum of Boxes (P < 0.0001). DISCUSSION: Plasma p-tau181/Aβ1-42 ratio predicted both Aβ-PET status and cognitive decline, demonstrating potential as both a diagnostic aid and as a screening and prognostic assay for preclinical AD trials.
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    Validation of a digit symbol substitution test for use in supervised and unsupervised assessment in mild Alzheimer's disease.
    Williamson, M ; Maruff, P ; Schembri, A ; Cummins, H ; Bird, L ; Rosenich, E ; Lim, YY (Informa UK Limited, 2022-12)
    INTRODUCTION: The Digit-Symbol-Substitution Test (DSST) is used widely in neuropsychological investigations of Alzheimer's Disease (AD). A computerized version of this paradigm, the DSST-Meds, utilizes medicine-date pairings and has been developed for administration in both supervised and unsupervised environments. This study determined the utility and validity of the DSST-Meds for measuring cognitive dysfunction in early AD. METHOD: Performance on the DSST-Meds was compared to performance on the WAIS Coding test, and a computerized digit symbol coding test (DSST-Symbols). The first study compared supervised performance on the three DSSTs versions in cognitively unimpaired (CU) adults (n = 104). The second compared supervised DSST performance between CU (n = 60) and mild-symptomatic AD (mild-AD, n = 79) groups. The third study compared performance on the DSST-Meds between unsupervised (n= 621) and supervised settings. RESULTS: In Study 1, DSST-Meds accuracy showed high correlations with the DSST-Symbols accuracy (r = 0.81) and WAIS-Coding accuracy (r = 0.68). In Study 2, when compared to CU adults, the mild-AD group showed lower accuracy on all three DSSTs (Cohen's d ranging between 1.39 and 2.56) and DSST-Meds accuracy was correlated moderately with Mini-Mental State Examination scores (r = 0.44, p < .001). Study 3 observed no difference in DSST-meds accuracy between supervised and unsupervised administrations. CONCLUSION: The DSST-Meds showed good construct and criterion validity when used in both supervised and unsupervised contexts and provided a strong foundation to investigate the utility of the DSST in groups with low familiarity to neuropsychological assessment.
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    Association of Elevated Amyloid and Tau Positron Emission Tomography Signal With Near-Term Development of Alzheimer Disease Symptoms in Older Adults Without Cognitive Impairment
    Strikwerda-Brown, C ; Hobbs, DA ; Gonneaud, J ; St-Onge, F ; Binette, AP ; Ozlen, H ; Provost, K ; Soucy, J-P ; Buckley, RF ; Benzinger, TLS ; Morris, JC ; Villemagne, VL ; Dore, V ; Sperling, RA ; Johnson, KA ; Rowe, CC ; Gordon, BA ; Poirier, J ; Breitner, JCS ; Villeneuve, S (AMER MEDICAL ASSOC, 2022-10)
    IMPORTANCE: National Institute on Aging-Alzheimer's Association (NIA-AA) workgroups have proposed biological research criteria intended to identify individuals with preclinical Alzheimer disease (AD). OBJECTIVE: To assess the clinical value of these biological criteria to identify older individuals without cognitive impairment who are at near-term risk of developing symptomatic AD. DESIGN, SETTING, AND PARTICIPANTS: This longitudinal cohort study used data from 4 independent population-based cohorts (PREVENT-AD, HABS, AIBL, and Knight ADRC) collected between 2003 and 2021. Participants were older adults without cognitive impairment with 1 year or more of clinical observation after amyloid β and tau positron emission tomography (PET). Median clinical follow-up after PET ranged from 1.94 to 3.66 years. EXPOSURES: Based on binary assessment of global amyloid burden (A) and a composite temporal region of tau PET uptake (T), participants were stratified into 4 groups (A+T+, A+T-, A-T+, A-T-). Presence (+) or absence (-) of neurodegeneration (N) was assessed using temporal cortical thickness. MAIN OUTCOMES AND MEASURES: Each cohort was analyzed separately. Primary outcome was clinical progression to mild cognitive impairment (MCI), identified by a Clinical Dementia Rating score of 0.5 or greater in Knight ADRC and by consensus committee review in the other cohorts. Clinical raters were blind to imaging, genetic, and fluid biomarker data. A secondary outcome was cognitive decline, based on a slope greater than 1.5 SD below the mean of an independent subsample of individuals without cognitive impairment. Outcomes were compared across the biomarker groups. RESULTS: Among 580 participants (PREVENT-AD, 128; HABS, 153; AIBL, 48; Knight ADRC, 251), mean (SD) age ranged from 67 (5) to 76 (6) years across cohorts, with between 55% (137/251) and 74% (95/128) female participants. Across cohorts, 33% to 83% of A+T+ participants progressed to MCI during follow-up (mean progression time, 2-2.72 years), compared with less than 20% of participants in other biomarker groups. Progression further increased to 43% to 100% when restricted to A+T+(N+) individuals. Cox proportional hazard ratios for progression to MCI in the A+T+ group vs other biomarker groups were all 5 or greater. Many A+T+ nonprogressors also showed longitudinal cognitive decline, while cognitive trajectories in other groups remained predominantly stable. CONCLUSIONS AND RELEVANCE: The clinical prognostic value of NIA-AA research criteria was confirmed in 4 independent cohorts, with most A+T+(N+) older individuals without cognitive impairment developing AD symptoms within 2 to 3 years.
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    Visually Identified Tau 18F-MK6240 PET Patterns in Symptomatic Alzheimer's Disease
    Krishnadas, N ; Huang, K ; Schultz, SA ; Dore, V ; Bourgeat, P ; Goh, AMY ; Lamb, F ; Bozinovski, S ; Burnham, SC ; Robertson, JS ; Laws, SM ; Maruff, P ; Masters, CL ; Villemagne, VL ; Rowe, CC ; Jacobs, H (IOS PRESS, 2022)
    BACKGROUND: In Alzheimer's disease, heterogeneity has been observed in the postmortem distribution of tau neurofibrillary tangles. Visualizing the topography of tau in vivo may facilitate clinical trials and clinical practice. OBJECTIVE: This study aimed to investigate whether tau distribution patterns that are limited to mesial temporal lobe (MTL)/limbic regions, and those that spare MTL regions, can be visually identified using 18F-MK6240, and whether these patterns are associated with different demographic and cognitive profiles. METHODS: Tau 18F-MK6240 PET images of 151 amyloid-β positive participants with mild cognitive impairment (MCI) and dementia were visually rated as: tau negative, limbic predominant (LP), MTL-sparing, and Typical by two readers. Groups were evaluated for differences in age, APOE ɛ4 carriage, hippocampal volumes, and cognition (MMSE, composite memory and non-memory scores). Voxel-wise contrasts were also performed. RESULTS: Visual rating resulted in 59.6% classified as Typical, 17.9% as MTL-sparing, 9.9% LP, and 12.6% as tau negative. Intra-rater and inter-rater reliability was strong (Cohen's kappa values of 0.89 and 0.86 respectively). Tracer retention in a "hook"-like distribution on sagittal sequences was observed in the LP and Typical groups. The visually classified MTL-sparing group had lower APOE ɛ4 carriage and relatively preserved hippocampal volumes. Higher MTL tau was associated with greater amnestic cognitive impairment. High cortical tau was associated with greater impairments on non-memory domains of cognition, and individuals with high cortical tau were more likely to have dementia than MCI. CONCLUSION: Tau distribution patterns can be visually identified using 18F-MK6240 PET and are associated with differences in APOE ɛ4 carriage, hippocampal volumes, and cognition.
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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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    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)
    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.