96 results on '"Rae CD"'
Search Results
2. Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies
- Author
-
von Jonquieres, G, Rae, CD, Housley, GD, von Jonquieres, G, Rae, CD, and Housley, GD
- Abstract
Central Nervous System (CNS) homeostasis and function rely on intercellular synchronization of metabolic pathways. Developmental and neurochemical imbalances arising from mutations are frequently associated with devastating and often intractable neurological dysfunction. In the absence of pharmacological treatment options, but with knowledge of the genetic cause underlying the pathophysiology, gene therapy holds promise for disease control. Consideration of leukodystrophies provide a case in point; we review cell type – specific expression pattern of the disease – causing genes and reflect on genetic and cellular treatment approaches including ex vivo hematopoietic stem cell gene therapies and in vivo approaches using adeno-associated virus (AAV) vectors. We link recent advances in vectorology to glial targeting directed towards gene therapies for specific leukodystrophies and related developmental or neurometabolic disorders affecting the CNS white matter and frame strategies for therapy development in future.
- Published
- 2021
3. Frequency drift in MR spectroscopy at 3T
- Author
-
Hui, SCN, Mikkelsen, M, Zollner, HJ, Ahluwalia, V, Alcauter, S, Baltusis, L, Barany, DA, Barlow, LR, Becker, R, Berman, J, Berrington, A, Bhattacharyya, PK, Blicher, JU, Bogner, W, Brown, MS, Calhoun, VD, Castillo, R, Cecil, KM, Choi, YB, Chu, WCW, Clarke, WT, Craven, AR, Cuypers, K, Dacko, M, de la Fuente-Sandoval, C, Desmond, P, Domagalik, A, Dumont, J, Duncan, NW, Dydak, U, Dyke, K, Edmondson, DA, Ende, G, Ersland, L, Evans, CJ, Fermin, ASR, Ferretti, A, Fillmer, A, Gong, T, Greenhouse, I, Grist, JT, Gu, M, Harris, AD, Hatz, K, Heba, S, Heckova, E, Hegarty, JP, Heise, K-F, Honda, S, Jacobson, A, Jansen, JFA, Jenkins, CW, Johnston, SJ, Juchem, C, Kangarlu, A, Kerr, AB, Landheer, K, Lange, T, Lee, P, Levendovszky, SR, Limperopoulos, C, Liu, F, Lloyd, W, Lythgoe, DJ, Machizawa, MG, MacMillan, EL, Maddock, RJ, Manzhurtsev, A, Martinez-Gudino, ML, Miller, JJ, Mirzakhanian, H, Moreno-Ortega, M, Mullins, PG, Nakajima, S, Near, J, Noeske, R, Nordhoy, W, Oeltzschner, G, Osorio-Duran, R, Otaduy, MCG, Pasaye, EH, Peeters, R, Peltier, SJ, Pilatus, U, Polomac, N, Porges, EC, Pradhan, S, Prisciandaro, JJ, Puts, NA, Rae, CD, Reyes-Madrigal, F, Roberts, TPL, Robertson, CE, Rosenberg, JT, Rotaru, D-G, Tuura, RLO, Saleh, MG, Sandberg, K, Sangill, R, Schembri, K, Schrantee, A, Semenova, NA, Singel, D, Sitnikov, R, Smith, J, Song, Y, Stark, C, Stoffers, D, Swinnen, SP, Tain, R, Tanase, C, Tapper, S, Tegenthoff, M, Thiel, T, Thioux, M, Truong, P, van Dijk, P, Vella, N, Vidyasagar, R, Vovk, A, Wang, G, Westlye, LT, Wilbur, TK, Willoughby, WR, Wilson, M, Wittsack, H-J, Woods, AJ, Wu, Y-C, Xu, J, Lopez, MY, Yeung, DKW, Zhao, Q, Zhou, X, Zupan, G, Edden, RAE, Hui, SCN, Mikkelsen, M, Zollner, HJ, Ahluwalia, V, Alcauter, S, Baltusis, L, Barany, DA, Barlow, LR, Becker, R, Berman, J, Berrington, A, Bhattacharyya, PK, Blicher, JU, Bogner, W, Brown, MS, Calhoun, VD, Castillo, R, Cecil, KM, Choi, YB, Chu, WCW, Clarke, WT, Craven, AR, Cuypers, K, Dacko, M, de la Fuente-Sandoval, C, Desmond, P, Domagalik, A, Dumont, J, Duncan, NW, Dydak, U, Dyke, K, Edmondson, DA, Ende, G, Ersland, L, Evans, CJ, Fermin, ASR, Ferretti, A, Fillmer, A, Gong, T, Greenhouse, I, Grist, JT, Gu, M, Harris, AD, Hatz, K, Heba, S, Heckova, E, Hegarty, JP, Heise, K-F, Honda, S, Jacobson, A, Jansen, JFA, Jenkins, CW, Johnston, SJ, Juchem, C, Kangarlu, A, Kerr, AB, Landheer, K, Lange, T, Lee, P, Levendovszky, SR, Limperopoulos, C, Liu, F, Lloyd, W, Lythgoe, DJ, Machizawa, MG, MacMillan, EL, Maddock, RJ, Manzhurtsev, A, Martinez-Gudino, ML, Miller, JJ, Mirzakhanian, H, Moreno-Ortega, M, Mullins, PG, Nakajima, S, Near, J, Noeske, R, Nordhoy, W, Oeltzschner, G, Osorio-Duran, R, Otaduy, MCG, Pasaye, EH, Peeters, R, Peltier, SJ, Pilatus, U, Polomac, N, Porges, EC, Pradhan, S, Prisciandaro, JJ, Puts, NA, Rae, CD, Reyes-Madrigal, F, Roberts, TPL, Robertson, CE, Rosenberg, JT, Rotaru, D-G, Tuura, RLO, Saleh, MG, Sandberg, K, Sangill, R, Schembri, K, Schrantee, A, Semenova, NA, Singel, D, Sitnikov, R, Smith, J, Song, Y, Stark, C, Stoffers, D, Swinnen, SP, Tain, R, Tanase, C, Tapper, S, Tegenthoff, M, Thiel, T, Thioux, M, Truong, P, van Dijk, P, Vella, N, Vidyasagar, R, Vovk, A, Wang, G, Westlye, LT, Wilbur, TK, Willoughby, WR, Wilson, M, Wittsack, H-J, Woods, AJ, Wu, Y-C, Xu, J, Lopez, MY, Yeung, DKW, Zhao, Q, Zhou, X, Zupan, G, and Edden, RAE
- Abstract
PURPOSE: Heating of gradient coils and passive shim components is a common cause of instability in the B0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites. METHOD: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC). RESULTS: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the f
- Published
- 2021
4. Brain amyloid in virally suppressed HIV-associated neurocognitive disorder
- Author
-
Howdle, GC, Quidé, Y, Kassem, MS, Johnson, K, Rae, CD, Brew, BJ, Cysique, LA, Howdle, GC, Quidé, Y, Kassem, MS, Johnson, K, Rae, CD, Brew, BJ, and Cysique, LA
- Abstract
OBJECTIVE: To determine whether virally suppressed HIV neuropathogenesis, a chronic neuroinflammatory state, promotes abnormal brain amyloid deposition. METHODS: A total of 10 men with virally suppressed HIV-associated neurocognitive disorder (HAND), aged 46-68 years, underwent 11C-labeled Pittsburgh compound B PET. Data from the Australian Imaging, Biomarkers and Lifestyle (AIBL), including 39 cognitively normal individuals (aged 60-74 years), 7 individuals with mild cognitive impairment (MCI) (aged 64-71 years), and 11 individuals with Alzheimer disease (AD) (aged 55-74 years), were used as reference. Apart from more women, the AIBL cohort was demographically comparable with the HIV sample. Also, the AIBL PET data did not differ by sex. Cerebellum standardized uptake value ratio amyloid values within 22 regions of interest were estimated. In the HIV sample, apolipoprotein E (APOE) was available in 80%, CSF biomarkers in 60%, and 8-10 years of long-term health outcomes in 100%. RESULTS: HAND and the AIBL group with no cognitive deficits had similar amyloid deposition, which was lower than that in both the MCI and AD groups. At the individual level, one HAND case showed high amyloid deposition consistent with AD. This case also had a CSF-AD-like profile and an E4/E4 for APOE. Clinically, this case declined over 18 years with mild HAND symptoms first, followed by progressive memory decline 8-9 years after the study PET, then progression to severe dementia within 2-3 years, and lived a further 6 years. Another HAND case showed increased amyloid deposition restricted to the hippocampi. Two other HAND cases showed abnormally decreased amyloid in subcortical areas. CONCLUSIONS: Relative to cognitively normal older controls, brain amyloid burden does not differ in virally suppressed HAND at the group level. However, individual analyses show that abnormally high and low amyloid burden occur.
- Published
- 2020
5. L-Aspartate, L-Ornithine and L-Ornithine-L-Aspartate (LOLA) and Their Impact on Brain Energy Metabolism
- Author
-
Das, A, Fröhlich, D, Achanta, LB, Rowlands, BD, Housley, GD, Klugmann, M, Rae, CD, Das, A, Fröhlich, D, Achanta, LB, Rowlands, BD, Housley, GD, Klugmann, M, and Rae, CD
- Abstract
L-Ornithine-L-aspartate (LOLA), a crystalline salt, is used primarily in the management of hepatic encephalopathy. The degree to which it might penetrate the brain, and the effects it might have on metabolism in brain are poorly understood. Here, to investigate the effects of LOLA on brain energy metabolism we incubated brain cortical tissue slices from guinea pig (Cavea porcellus) with the constituent amino acids of LOLA, L-ornithine or L-aspartate, as well as LOLA, in the presence of [1-13C]D-glucose and [1,2-13C]acetate; these labelled substrates are useful indicators of brain metabolic activity. L-Ornithine produced significant “sedative” effects on brain slice metabolism, most likely via conversion of ornithine to GABA via the ornithine aminotransferase pathway, while L-aspartate showed concentration-dependent excitatory effects. The metabolic effects of LOLA reflected a mix of these two different processes and were concentration-dependent. We also investigated the effect of an intraperitoneal bolus injection of L-ornithine, L-aspartate or LOLA on levels of metabolites in kidney, liver and brain cortex and brain stem in mice (C57Bl6J) 1 h later. No significant changes in metabolite levels were seen following the bolus injection of L-aspartate, most likely due to rapid metabolism of aspartate before reaching the target tissue. Brain cortex glutamate was decreased by L-ornithine but no other brain effects were observed with any other compound. Kidney levels of aspartate were increased after injection of L-ornithine and LOLA which may be due to interference by ornithine with the kidney urea cycle. It is likely that without optimising chronic intravenous infusion, LOLA has minimal impact on healthy brain energy metabolism due to systemic clearance and the blood - brain barrier.
- Published
- 2020
6. CRPS is not associated with altered sensorimotor cortex GABA or glutamate
- Author
-
Lee, B, Henderson, LA, Rae, CD, Di Pietro, F, Lee, B, Henderson, LA, Rae, CD, and Di Pietro, F
- Abstract
Complex regional pain syndrome (CRPS) is a debilitating chronic pain disorder typically in the upper or lower limbs. While CRPS usually develops from a peripheral event, it is likely maintained by CNS changes. Indeed, CRPS is reported to be associated with sensorimotor cortex changes, or functional “reorganization,” as well as deficits such as poor tactile acuity. While the mechanisms underpinning cortical reorganization in CRPS are unknown, some have hypothesized that it involves disinhibition (i.e., a reduction in GABA activity). In this study, we addressed this hypothesis by using edited magnetic resonance spectroscopy to determine sensorimotor GABA and glutamate concentrations in 16 humans with CRPS and 30 matched control subjects and the relationship of these concentrations with tactile acuity. We found that individuals with upper limb CRPS displayed reduced tactile acuity in the painful hand, compared with the nonpainful hand and pain-free control subjects. Despite this acuity deficit, CRPS was not associated with altered GABA or glutamate concentrations within the sensorimotor cortex on either the side that represents the affected or unaffected hand. Furthermore, there was no significant relationship between sensorimotor GABA or glutamate concentrations and tactile acuity in CRPS subjects or control subjects. Although our sample was small, these data suggest that CRPS is not associated with altered total sensorimotor GABA or glutamate concentrations. While these results are at odds with the sensorimotor cortex disinhibition hypothesis, it is possible that GABAergic mechanisms other than total GABA concentration may contribute to such disinhibition.
- Published
- 2020
7. Fine-Grained mapping of cortical somatotopies in chronic complex regional pain syndrome
- Author
-
Mancini, F, Wang, AP, Schira, MM, Isherwood, ZJ, McAuley, JH, Iannetti, GD, Sereno, MI, Moseley, GL, Rae, CD, Mancini, F, Wang, AP, Schira, MM, Isherwood, ZJ, McAuley, JH, Iannetti, GD, Sereno, MI, Moseley, GL, and Rae, CD
- Abstract
It has long been thought that severe chronic pain conditions, such as complex regional pain syndrome (CRPS), are not only associated with, but even maintained by a reorganization of the somatotopic representation of the affected limb in primary somatosensory cortex (S1). This notion has driven treatments that aim to restore S1 representations in CRPS patients, such as sensory discrimination training and mirror therapy. However, this notion is based on both indirect and incomplete evidence obtained with imaging methods with low spatial resolution. Here, we used fMRI to characterize the S1 representation of the affected and unaffected hand in humans (of either sex) with unilateral CRPS. The cortical area, location, and geometry of the S1 representation of the CRPS hand were largely comparable with those of both the unaffected hand and healthy controls. We found no differential relation between affected versus unaffected hand map measures and clinical measures (pain severity, upper limb disability, disease duration). Thus, if any map reorganization occurs, it does not appear to be directly related to pain and disease severity. These findings compel us to reconsider the cortical mechanisms underlying CRPS and the rationale for interventions that aim to "restore" somatotopic representations to treat pain.
- Published
- 2019
8. Understanding autism spectrum disorder and social functioning in children with neurofibromatosis type 1: Protocol for a cross-sectional multimodal study
- Author
-
Haebich, KM, Pride, NA, Walsh, KS, Chisholm, A, Rouel, M, Maier, A, Anderson, V, Barton, B, Silk, T, Korgaonkar, M, Seal, M, Lami, F, Lorenzo, J, Williams, K, Dabscheck, G, Rae, CD, Kean, M, North, KN, Payne, JM, Haebich, KM, Pride, NA, Walsh, KS, Chisholm, A, Rouel, M, Maier, A, Anderson, V, Barton, B, Silk, T, Korgaonkar, M, Seal, M, Lami, F, Lorenzo, J, Williams, K, Dabscheck, G, Rae, CD, Kean, M, North, KN, and Payne, JM
- Abstract
Introduction Children with the single-gene disorder neurofibromatosis type 1 (NF1) appear to be at an increased risk for autism spectrum disorder (ASD) and exhibit a unique social-cognitive phenotype compared with children with idiopathic ASD. A complete framework is required to better understand autism in NF1, from neurobiological levels through to behavioural and functional outcomes. The primary aims of this study are to establish the frequency of ASD in children with NF1, examine the social cognitive phenotype, investigate the neuropsychological processes contributing to ASD symptoms and poor social functioning in children with NF1, and to investigate novel structural and functional neurobiological markers of ASD and social dysfunction in NF1. The secondary aim of this study is to compare the neuropsychological and neurobiological features of ASD in children with NF1 to a matched group of patients with idiopathic ASD. Methods and analysis This is an international, multisite, prospective, cross-sectional cohort study of children with NF1, idiopathic ASD and typically developing (TD) controls. Participants will be 200 children with NF1 (3-15 years of age), 70 TD participants (3-15 years) and 35 children with idiopathic ASD (7-15 years). Idiopathic ASD and NF1 cases will be matched on age, sex and intelligence. All participants will complete cognitive testing and parents will rate their child's behaviour on standardised questionnaires. Neuroimaging will be completed by a subset of participants aged 7 years and older. Children with NF1 that screen at risk for ASD on the parent-rated Social Responsiveness Scale 2nd Edition will be invited back to complete the Autism Diagnostic Observation Scale 2nd Edition and Autism Diagnostic Interview-Revised to determine whether they fulfil ASD diagnostic criteria. Ethics and dissemination This study has hospital ethics approval and the results will be disseminated through peer-reviewed publications and international conferences.
- Published
- 2019
9. Reduced Glutamate in the Medial Prefrontal Cortex Is Associated With Emotional and Cognitive Dysregulation in People With Chronic Pain
- Author
-
Naylor, B, Hesam-Shariati, N, McAuley, JH, Boag, S, Newton-John, T, Rae, CD, Gustin, SM, Naylor, B, Hesam-Shariati, N, McAuley, JH, Boag, S, Newton-John, T, Rae, CD, and Gustin, SM
- Abstract
© Copyright © 2019 Naylor, Hesam-Shariati, McAuley, Boag, Newton-John, Rae and Gustin. A decrease in glutamate in the medial prefrontal cortex (mPFC) has been extensively found in animal models of chronic pain. Given that the mPFC is implicated in emotional appraisal, cognition and extinction of fear, could a potential decrease in glutamate be associated with increased pessimistic thinking, fear and worry symptoms commonly found in people with chronic pain? To clarify this question, 19 chronic pain subjects and 19 age- and gender-matched control subjects without pain underwent magnetic resonance spectroscopy. Both groups also completed the Temperament and Character, the Beck Depression and the State Anxiety Inventories to measure levels of harm avoidance, depression, and anxiety, respectively. People with chronic pain had significantly higher scores in harm avoidance, depression and anxiety compared to control subjects without pain. High levels of harm avoidance are characterized by excessive worry, pessimism, fear, doubt and fatigue. Individuals with chronic pain showed a significant decrease in mPFC glutamate levels compared to control subjects without pain. In people with chronic pain mPFC glutamate levels were significantly negatively correlated with harm avoidance scores. This means that the lower the concentration of glutamate in the mPFC, the greater the total scores of harm avoidance. High scores are associated with fearfulness, pessimism, and fatigue-proneness. We suggest that chronic pain, particularly the stress-induced release of glucocorticoids, induces changes in glutamate transmission in the mPFC, thereby influencing cognitive, and emotional processing. Thus, in people with chronic pain, regulation of fear, worry, negative thinking and fatigue is impaired.
- Published
- 2019
10. Brain bioenergetics during resting wakefulness are related to neurobehavioral deficits in severe obstructive sleep apnea: A 31 P magnetic resonance spectroscopy study
- Author
-
D'Rozario, AL, Bartlett, DJ, Wong, KKH, Sach, T, Yang, Q, Grunstein, RR, Rae, CD, D'Rozario, AL, Bartlett, DJ, Wong, KKH, Sach, T, Yang, Q, Grunstein, RR, and Rae, CD
- Abstract
Study Objectives: Obstructive sleep apnea (OSA) is a well-established cause of impaired daytime functioning. However, there is a complex interindividual variability in neurobehavioral performance in OSA patients. We previously reported compromised brain bioenergetics during apneic sleep in severe OSA. In this study, we investigate whether brain bioenergetics during resting wakefulness are related to neurobehavioral performance. Methods: Patients attended the sleep laboratory in the evening and were kept awake over-night. Repeated testing on the 10-minute psychomotor vigilance task (PVT, at 9 pm, 11 pm, 1 am, 3 am, 5 am) and 30-minute AusEd driving simulator task (9 pm and 5 am) was performed. Brain bioenergetics (inorganic phosphate/adenosine triphosphate ratio, Pi/ATP) were measured in the temporal lobe during resting wakefulness at 7 am in a 1.5T MRI scanner using phosphorus magnetic resonance spectroscopy (31P MRS). Results: Fifteen males with severe OSA (age 47.7 ± 10.4 years, body mass index [BMI] 34 ± 6.6 kg/m2, apnea hypopnea index [AHI] 79.7 ± 21.8/ hour) were investigated. A higher Pi/ATP ratio in the brain (lower phosphorylation potential) was correlated with worse PVT and driving simulator performance across the testing period (PVT lapses: r = 0.632, r2 = 0.399, p = 0.012; and AusEd braking reaction time: r = 0.609, p = 0.016). In contrast, the conventional AHI measure of disease severity was not significantly correlated with performance (PVT lapses: r = -0.084, p = 0.8; and AusEd braking reaction time: r = -0.326, p = 0.2). Conclusions: Lower phosphorylation potential was associated with worse performance. Compromised brain bioenergetics may in part underlie the neurobehavioral deficits in untreated OSA. We speculate that better brain bioenergetics may explain why some OSA patients are relatively asymptomatic compared with others.
- Published
- 2018
11. The relationship between thalamic GABA content and resting cortical rhythm in neuropathic pain
- Author
-
Di Pietro, F, Macey, PM, Rae, CD, Alshelh, Z, Macefield, VG, Vickers, ER, Henderson, LA, Di Pietro, F, Macey, PM, Rae, CD, Alshelh, Z, Macefield, VG, Vickers, ER, and Henderson, LA
- Abstract
Recurrent thalamocortical connections are integral to the generation of brain rhythms and it is thought that the inhibitory action of the thalamic reticular nucleus is critical in setting these rhythms. Our work and others' has suggested that chronic pain that develops following nerve injury, that is, neuropathic pain, results from altered thalamocortical rhythm, although whether this dysrhythmia is associated with thalamic inhibitory function remains unknown. In this investigation, we used electroencephalography and magnetic resonance spectroscopy to investigate cortical power and thalamic GABAergic concentration in 20 patients with neuropathic pain and 20 pain-free controls. First, we found thalamocortical dysrhythmia in chronic orofacial neuropathic pain; patients displayed greater power than controls over the 4–25 Hz frequency range, most marked in the theta and low alpha bands. Furthermore, sensorimotor cortex displayed a strong positive correlation between cortical power and pain intensity. Interestingly, we found no difference in thalamic GABA concentration between pain subjects and control subjects. However, we demonstrated significant linear relationships between thalamic GABA concentration and enhanced cortical power in pain subjects but not controls. Whilst the difference in relationship between thalamic GABA concentration and resting brain rhythm between chronic pain and control subjects does not prove a cause and effect link, it is consistent with a role for thalamic inhibitory neurotransmitter release, possibly from the thalamic reticular nucleus, in altered brain rhythms in individuals with chronic neuropathic pain.
- Published
- 2018
12. Uncoupling N-acetylaspartate from brain pathology: implications for Canavan disease gene therapy
- Author
-
von Jonquieres, G, Spencer, ZHT, Rowlands, BD, Klugmann, CB, Bongers, A, Harasta, AE, Parley, KE, Cederholm, J, Teahan, O, Pickford, R, Delerue, F, Ittner, LM, Fröhlich, D, McLean, CA, Don, AS, Schneider, M, Housley, GD, Rae, CD, Klugmann, M, von Jonquieres, G, Spencer, ZHT, Rowlands, BD, Klugmann, CB, Bongers, A, Harasta, AE, Parley, KE, Cederholm, J, Teahan, O, Pickford, R, Delerue, F, Ittner, LM, Fröhlich, D, McLean, CA, Don, AS, Schneider, M, Housley, GD, Rae, CD, and Klugmann, M
- Abstract
N-Acetylaspartate (NAA) is the second most abundant organic metabolite in the brain, but its physiological significance remains enigmatic. Toxic NAA accumulation appears to be the key factor for neurological decline in Canavan disease—a fatal neurometabolic disorder caused by deficiency in the NAA-degrading enzyme aspartoacylase. To date clinical outcome of gene replacement therapy for this spongiform leukodystrophy has not met expectations. To identify the target tissue and cells for maximum anticipated treatment benefit, we employed comprehensive phenotyping of novel mouse models to assess cell type-specific consequences of NAA depletion or elevation. We show that NAA-deficiency causes neurological deficits affecting unconscious defensive reactions aimed at protecting the body from external threat. This finding suggests, while NAA reduction is pivotal to treat Canavan disease, abrogating NAA synthesis should be avoided. At the other end of the spectrum, while predicting pathological severity in Canavan disease mice, increased brain NAA levels are not neurotoxic per se. In fact, in transgenic mice overexpressing the NAA synthesising enzyme Nat8l in neurons, supra-physiological NAA levels were uncoupled from neurological deficits. In contrast, elimination of aspartoacylase expression exclusively in oligodendrocytes elicited Canavan disease like pathology. Although conditional aspartoacylase deletion in oligodendrocytes abolished expression in the entire CNS, the remaining aspartoacylase in peripheral organs was sufficient to lower NAA levels, delay disease onset and ameliorate histopathology. However, comparable endpoints of the conditional and complete aspartoacylase knockout indicate that optimal Canavan disease gene replacement therapies should restore aspartoacylase expression in oligodendrocytes. On the basis of these findings we executed an ASPA gene replacement therapy targeting oligodendrocytes in Canavan disease mice resulting in reversal of pre-existing CN
- Published
- 2018
13. An objective short sleep insomnia disorder subtype is associated with reduced brain metabolite concentrations in vivo: A preliminary magnetic resonance spectroscopy assessment
- Author
-
Miller, CB, Rae, CD, Green, MA, Yee, BJ, Gordon, CJ, D'Rozario, AL, Kyle, SD, Espie, CA, Grunstein, RR, Bartlett, DJ, Miller, CB, Rae, CD, Green, MA, Yee, BJ, Gordon, CJ, D'Rozario, AL, Kyle, SD, Espie, CA, Grunstein, RR, and Bartlett, DJ
- Abstract
Objectives: To evaluate brain metabolites in objective insomnia subtypes defined from polysomnography (PSG): Insomnia with short sleep duration (I-SSD) and insomnia with normal sleep duration (I-NSD), relative to good sleeping controls (GSCs). Methods: PSG empirically grouped insomnia patients into I-SSD (n = 12: Mean [SD] total sleep time [TST] = 294.7 minutes [30.5]) or I-NSD (n = 19: TST = 394.4 minutes [34.9]). 1H magnetic resonance spectroscopy (MRS) acquired in the left occipital cortex (LOCC), left prefrontal cortex, and anterior cingulate cortex was used to determine levels of creatine, aspartate, glutamate, and glutamine (referenced to water). Glutathione, glycerophosphocholine, lactate, myoinositol, and N-acetylaspartate measurements were also obtained. Sixteen GSCs were included for comparison. Multivariate analysis of variance was used to evaluate differences in creatine, aspartate, glutamate, and glutamine. Results: Aspartate and glutamine concentrations were reduced in the LOCC in I-SSD compared with I-NSD (both p < .05, d = .80-.99). Creatine displayed a nonsignificant mean reduction in I-SSD compared with I-NSD (p = .05, d = .58). Glutamine was reduced in I-SSD compared with controls (p < .05, d = .93). There were no differences in metabolites between all (I-SSD and I-NSD) insomnia patients and controls. In patients with insomnia, LOCC glutamine concentrations were found to be positively correlated with TST (r = .43, p < .05) and negatively correlated with wake-time after sleep onset (r = -.40, p < .05). Conclusions: Results indicate that I-SSD is associated with reduced brain metabolites in the LOCC compared with I-NSD and control concentrations of aspartate, glutamine, and creatine.
- Published
- 2017
14. Glutathione in the human brain: Review of its roles and measurement by magnetic resonance spectroscopy
- Author
-
Rae, CD, Williams, SR, Rae, CD, and Williams, SR
- Abstract
We review the transport, synthesis and catabolism of glutathione in the brain as well as its compartmentation and biochemistry in different brain cells. The major reactions involving glutathione are reviewed and the factors limiting its availability in brain cells are discussed. We also describe and critique current methods for measuring glutathione in the human brain using magnetic resonance spectroscopy, and review the literature on glutathione measurements in healthy brains and in neurological, psychiatric, neurodegenerative and neurodevelopmental conditions In summary: Healthy human brain glutathione concentration is ∼1–2 mM, but it varies by brain region, with evidence of gender differences and age effects; in neurological disease glutathione appears reduced in multiple sclerosis, motor neurone disease and epilepsy, while being increased in meningiomas; in psychiatric disease the picture is complex and confounded by methodological differences, regional effects, length of disease and drug-treatment. Both increases and decreases in glutathione have been reported in depression and schizophrenia. In Alzheimer's disease and mild cognitive impairment there is evidence for a decrease in glutathione compared to age-matched healthy controls. Improved methods to measure glutathione in vivo will provide better precision in glutathione determination and help resolve the complex biochemistry of this molecule in health and disease.
- Published
- 2017
15. Toluene inhalation in adolescent rats reduces flexible behaviour in adulthood and alters glutamatergic and GABAergic signalling
- Author
-
Furlong, TM, Duncan, JR, Corbit, LH, Rae, CD, Rowlands, BD, Maher, AD, Nasrallah, FA, Milligan, CJ, Petrou, S, Lawrence, AJ, Balleine, BW, Furlong, TM, Duncan, JR, Corbit, LH, Rae, CD, Rowlands, BD, Maher, AD, Nasrallah, FA, Milligan, CJ, Petrou, S, Lawrence, AJ, and Balleine, BW
- Abstract
Toluene is a commonly abused inhalant that is easily accessible to adolescents. Despite the increasing incidence of use, our understanding of its long-term impact remains limited. Here, we used a range of techniques to examine the acute and chronic effects of toluene exposure on glutameteric and GABAergic function, and on indices of psychological function in adult rats after adolescent exposure. Metabolomics conducted on cortical tissue established that acute exposure to toluene produces alterations in cellular metabolism indicative of a glutamatergic and GABAergic profile. Similarly, in vitro electrophysiology in Xenopus oocytes found that acute toluene exposure reduced NMDA receptor signalling. Finally, in an adolescent rodent model of chronic intermittent exposure to toluene (10 000 ppm), we found that, while toluene exposure did not affect initial learning, it induced a deficit in updating that learning when response-outcome relationships were reversed or degraded in an instrumental conditioning paradigm. There were also group differences when more effort was required to obtain the reward; toluene-exposed animals were less sensitive to progressive ratio schedules and to delayed discounting. These behavioural deficits were accompanied by changes in subunit expression of both NMDA and GABA receptors in adulthood, up to 10 weeks after the final exposure to toluene in the hippocampus, prefrontal cortex and ventromedial striatum; regions with recognized roles in behavioural flexibility and decision-making. Collectively, our data suggest that exposure to toluene is sufficient to induce adaptive changes in glutamatergic and GABAergic systems and in adaptive behaviour that may underlie the deficits observed following adolescent inhalant abuse, including susceptibility to further drug-use.
- Published
- 2016
16. Alterations of GABA and glutamate-glutamine levels in premenstrual dysphoric disorder: A 3T proton magnetic resonance spectroscopy study
- Author
-
Liu, B, Wang, G, Gao, D, Gao, F, Zhao, B, Qiao, M, Yang, H, Yu, Y, Ren, F, Yang, P, Chen, W, Rae, CD, Liu, B, Wang, G, Gao, D, Gao, F, Zhao, B, Qiao, M, Yang, H, Yu, Y, Ren, F, Yang, P, Chen, W, and Rae, CD
- Abstract
Increasing evidence has suggested that the GABAergic neurotransmitter system is involved in the pathogenesis of premenstrual dysphoric disorder (PMDD). We used proton magnetic resonance spectroscopy (1H MRS) to investigate whether PMDD is associated with alterations in brain GABA levels. Levels of glutamate-glutamine (Glx) were also explored. Participants comprised 22 women with PMDD and 22 age-matched healthy controls who underwent 3T 1H MRS during the late luteal phase of the menstrual cycle. GABA+ and Glx levels were quantified in the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and the left basal ganglia (ltBG). Water-scaled GABA+ concentrations and GABA+/tCr ratios were significantly lower in both the ACC/mPFC and ltBG regions of PMDD women than in healthy controls. Glx/tCr ratios were significantly higher in the ACC/mPFC region of PMDD women than healthy controls. Our preliminary findings provide the first report of abnormal levels of GABA+ and Glx in mood-related brain regions of women with PMDD, indicating that dysregulation of the amino acid neurotransmitter system may be an important neurobiological mechanism in the pathogenesis of PMDD.
- Published
- 2015
17. Ethanol, not detectably metabolized in brain, significantly reduces brain metabolism, probably via action at specific GABA(A) receptors and has measureable metabolic effects at very low concentrations
- Author
-
Rae, CD, Davidson, JE, Maher, AD, Rowlands, BD, Kashem, MA, Nasrallah, FA, Rallapalli, SK, Cook, JM, Balcar, VJ, Rae, CD, Davidson, JE, Maher, AD, Rowlands, BD, Kashem, MA, Nasrallah, FA, Rallapalli, SK, Cook, JM, and Balcar, VJ
- Abstract
Ethanol is a known neuromodulatory agent with reported actions at a range of neurotransmitter receptors. Here, we measured the effect of alcohol on metabolism of [3-13C]pyruvate in the adult Guinea pig brain cortical tissue slice and compared the outcomes to those from a library of ligands active in the GABAergic system as well as studying the metabolic fate of [1,2- 13C]ethanol. Analyses of metabolic profile clusters suggest that the significant reductions in metabolism induced by ethanol (10, 30 and 60 mM) are via action at neurotransmitter receptors, particularly α4β3δ receptors, whereas very low concentrations of ethanol may produce metabolic responses owing to release of GABA via GABA transporter 1 (GAT1) and the subsequent interaction of this GABA with local α5- or α1-containing GABA(A)R. There was no measureable metabolism of [1,2-13C]ethanol with no significant incorporation of 13C from [1,2- 13C]ethanol into any measured metabolite above natural abundance, although there were measurable effects on total metabolite sizes similar to those seen with unlabelled ethanol. © 2013 International Society for Neurochemistry.
- Published
- 2014
18. A guide to the metabolic pathways and function of metabolites observed in human brain 1H magnetic resonance spectra
- Author
-
Rae, CD and Rae, CD
- Abstract
The current knowledge of the normal biochemistry of compounds that give rise to resonances in human brain proton magnetic resonance spectra measureable at readily available field strengths (i.e. ≤3 T) is reviewed. Molecules covered include myo- and scyllo-inositol, glycerophospho- and phospho-choline and choline, creatine and phosphocreatine, N-acetylaspartate, N-acetylaspartylglutamate, glutamate, glutamine, γ-aminobutyrate, glucose, glutathione and lactate. The factors which influence changes in the levels of these compounds are discussed. As most proton resonances in the brain at low field are derived from a combination of moieties whose biochemistry is complex and interrelated, an understanding of the mechanisms underlying why these species change is crucial to meaningful interpretation of human brain spectra. © 2013 Springer Science+Business Media New York.
- Published
- 2014
19. Alterations of GABA and glutamate-glutamine levels in premenstrual dysphoric disorder: A 3T proton magnetic resonance spectroscopy study
- Author
-
Liu, B, Wang, G, Gao, D, Gao, F, Zhao, B, Qiao, M, Yang, H, Yu, Y, Ren, F, Yang, P, Chen, W, Rae, CD, Liu, B, Wang, G, Gao, D, Gao, F, Zhao, B, Qiao, M, Yang, H, Yu, Y, Ren, F, Yang, P, Chen, W, and Rae, CD
- Abstract
Increasing evidence has suggested that the GABAergic neurotransmitter system is involved in the pathogenesis of premenstrual dysphoric disorder (PMDD). We used proton magnetic resonance spectroscopy (1H MRS) to investigate whether PMDD is associated with alterations in brain GABA levels. Levels of glutamate-glutamine (Glx) were also explored. Participants comprised 22 women with PMDD and 22 age-matched healthy controls who underwent 3T 1H MRS during the late luteal phase of the menstrual cycle. GABA+ and Glx levels were quantified in the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and the left basal ganglia (ltBG). Water-scaled GABA+ concentrations and GABA+/tCr ratios were significantly lower in both the ACC/mPFC and ltBG regions of PMDD women than in healthy controls. Glx/tCr ratios were significantly higher in the ACC/mPFC region of PMDD women than healthy controls. Our preliminary findings provide the first report of abnormal levels of GABA+ and Glx in mood-related brain regions of women with PMDD, indicating that dysregulation of the amino acid neurotransmitter system may be an important neurobiological mechanism in the pathogenesis of PMDD.
- Published
- 2014
20. Thalamic activity and biochemical changes in individuals with neuropathic pain following spinal cord injury
- Author
-
Wrigley, PJ, Gusin, SM, Youssef, AM, McIndoe, L, Wilcox, SL, Rae, CD, Edden, R, Siddal, PJ, Henderson, LA, Wrigley, PJ, Gusin, SM, Youssef, AM, McIndoe, L, Wilcox, SL, Rae, CD, Edden, R, Siddal, PJ, and Henderson, LA
- Abstract
There is increasing evidence relating thalamic changes to the generation and/or maintenance of neuropathic pain. We have recently reported that neuropathic orofacial pain is associated with altered thalamic anatomy, biochemistry, and activity, which may result in disturbed thalamocortical oscillatory circuits. Despite this evidence, it is possible that these thalamic changes are not responsible for the presence of pain per se, but result as a consequence of the injury. To clarify this subject, we compared brain activity and biochemistry in 12 people with below-level neuropathic pain after complete thoracic spinal cord injury with 11 people with similar injuries and no neuropathic pain and 21 age- and gender-matched healthy control subjects. Quantitative arterial spinal labelling was used to measure thalamic activity, and magnetic resonance spectroscopy was used to determine changes in neuronal variability quantifying N-acetylaspartate and alterations in inhibitory function quantifying gamma amino butyric acid. This study revealed that the presence of neuropathic pain is associated with significant changes in thalamic biochemistry and neuronal activity. More specifically, the presence of neuropathic pain after spinal cord injury is associated with significant reductions in thalamic N-acetylaspartate, gamma amino butyric acid content, and blood flow in the region of the thalamic reticular nucleus. Spinal cord injury on its own did not account for these changes. These findings support the hypothesis that neuropathic pain is associated with altered thalamic structure and function, which may disturb central processing and play a key role in the experience of neuropathic pain.
- Published
- 2014
21. HIV, Vascular and Aging Injuries in the Brain of Clinically Stable HIV-Infected Adults: A 1H MRS Study
- Author
-
Cysique, LA, Moffat, K, Moore, DM, Lane, TA, Davies, NWS, Carr, AD, Brew, BJ, Rae, CD, Cysique, LA, Moffat, K, Moore, DM, Lane, TA, Davies, NWS, Carr, AD, Brew, BJ, and Rae, CD
- Abstract
BACKGROUND:Cardiovascular disease (CVD) and premature aging have been hypothesized as new risk factors for HIV associated neurocognitive disorders (HAND) in adults with virally-suppressed HIV infection. Moreover, their significance and relation to more classical HAND biomarkers remain unclear.METHODS:92 HIV- infected (HIV+) adults stable on combined antiretroviral therapy (cART) and 30 age-comparable HIV-negative (HIV-) subjects underwent (1)H Magnetic Resonance Spectroscopy (MRS) of the frontal white matter (targeting HIV, normal aging or CVD-related neurochemical injury), caudate nucleus (targeting HIV neurochemical injury), and posterior cingulate cortex (targeting normal/pathological aging, CVD-related neurochemical changes). All also underwent standard neuropsychological (NP) testing. CVD risk scores were calculated. HIV disease biomarkers were collected and cerebrospinal fluid (CSF) neuroinflammation biomarkers were obtained in 38 HIV+ individuals.RESULTS:Relative to HIV- individuals, HIV+ individuals presented mild MRS alterations: in the frontal white matter: lower N-Acetyl-Aspartate (NAA) (p
- Published
- 2013
22. Combining MR elastography and diffusion tensor imaging for the assessment of anisotropic mechanical properties: A phantom study
- Author
-
Qin, E, Sinkus, R, Geng, G, Cheng, SK, Green, M, Rae, CD, Bilston, LE, Qin, E, Sinkus, R, Geng, G, Cheng, SK, Green, M, Rae, CD, and Bilston, LE
- Published
- 2013
23. Statistical integration of 1H NMR and MRS data from difefrent biofluids and tissues enhances recovery of biological information from individuals with HIV-1 infection
- Author
-
Maher, A, Cysique, LA, Brew, BJ, Rae, CD, Maher, A, Cysique, LA, Brew, BJ, and Rae, CD
- Abstract
Nuclear magnetic resonance (NMR) spectroscopy is widely used in metabonomics studies, but optimal recovery of latent biological information requires increasingly sophisticated statistical methods to identify quantitative relationships within these often highly complex data sets. Statistical heterospectroscopy (SHY) extracts latent relationships between NMR and mass spectrometry (MS) data from the same samples. Here we extend this concept to identify novel metabolic correlations between different biofluids and tissues from the same individuals. We acquired NMR data from blood plasma and cerebrospinal fluid (CSF) (N = 19) from HIV-1-infected individuals, who are known to be susceptible to neuropsychological dysfunction. We compared two computational approaches to SHY, namely the Pearson’s product moment correlation and the Spearman’s rank correlation. High correlations were observed for glutamine, valine, and polyethylene glycol, a drug delivery vehicle. Orthogonal projections to latent structures (OPLS) identified metabolites in blood plasma spectra that predicted the amounts of key CSF metabolites such as lactate, glutamine, and myo-inositol. Finally, brain metabolic data from magnetic resonance spectroscopy (MRS) measurements in vivo were integrated with CSF data to identify an association between 3-hydroxyvalerate and frontal white matter N-acetyl aspartate levels. The results underscore the utility of tools such as SHY and OPLS for coanalysis of high dimensional data sets to recover biological information unobtainable when such data are analyzed in isolation.
- Published
- 2011
24. Functional conductivity imaging: quantitative mapping of brain activity.
- Author
-
Cao J, Ball IK, Cassidy B, and Rae CD
- Abstract
Theory and modelling suggest that detection of neuronal activity may be feasible using phase sensitive MRI methods. Successful detection of neuronal activity both in vitro and in vivo has been described while others have reported negative results. Magnetic resonance electrical properties tomography may be a route by which signal changes can be identified. Here, we report successful and repeatable detection at 3 Tesla of human brain activation in response to visual and somatosensory stimuli using a functional version of tissue conductivity imaging (funCI). This detects activation in both white and grey matter with apparent tissue conductivity changes of 0.1 S/m (17-20%, depending on the tissue baseline conductivity measure) allowing visualization of complete system circuitry. The degree of activation scales with the degree of the stimulus (duration or contrast). The conductivity response functions show a distinct timecourse from that of traditional fMRI haemodynamic (BOLD or Blood Oxygenation Level Dependent) response functions, peaking within milliseconds of stimulus cessation and returning to baseline within 3-4 s. We demonstrate the utility of the funCI approach by showing robust activation of the lateral somatosensory circuitry on stimulation of an index finger, on stimulation of a big toe or of noxious (heat) stimulation of the face as well as activation of visual circuitry on visual stimulation in up to five different individuals. The sensitivity and repeatability of this approach provides further evidence that magnetic resonance imaging approaches can detect brain activation beyond changes in blood supply., (© 2024. The Author(s).)
- Published
- 2024
- Full Text
- View/download PDF
25. Brain energy metabolism: A roadmap for future research.
- Author
-
Rae CD, Baur JA, Borges K, Dienel G, Díaz-García CM, Douglass SR, Drew K, Duarte JMN, Duran J, Kann O, Kristian T, Lee-Liu D, Lindquist BE, McNay EC, Robinson MB, Rothman DL, Rowlands BD, Ryan TA, Scafidi J, Scafidi S, Shuttleworth CW, Swanson RA, Uruk G, Vardjan N, Zorec R, and McKenna MC
- Subjects
- Animals, Humans, Brain metabolism, Energy Metabolism
- Abstract
Although we have learned much about how the brain fuels its functions over the last decades, there remains much still to discover in an organ that is so complex. This article lays out major gaps in our knowledge of interrelationships between brain metabolism and brain function, including biochemical, cellular, and subcellular aspects of functional metabolism and its imaging in adult brain, as well as during development, aging, and disease. The focus is on unknowns in metabolism of major brain substrates and associated transporters, the roles of insulin and of lipid droplets, the emerging role of metabolism in microglia, mysteries about the major brain cofactor and signaling molecule NAD
+ , as well as unsolved problems underlying brain metabolism in pathologies such as traumatic brain injury, epilepsy, and metabolic downregulation during hibernation. It describes our current level of understanding of these facets of brain energy metabolism as well as a roadmap for future research., (© 2024 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)- Published
- 2024
- Full Text
- View/download PDF
26. AMP-activated protein kinase activators have compound and concentration-specific effects on brain metabolism.
- Author
-
Achanta LB, Thomas DS, Housley GD, and Rae CD
- Subjects
- Animals, Guinea Pigs, Male, Aminoimidazole Carboxamide analogs & derivatives, Aminoimidazole Carboxamide pharmacology, Ribonucleotides pharmacology, Glucose metabolism, Biphenyl Compounds, Dose-Response Relationship, Drug, Thiophenes pharmacology, Pyrones pharmacology, Enzyme Activators pharmacology, AMP-Activated Protein Kinases metabolism, Metformin pharmacology, Brain metabolism, Brain drug effects
- Abstract
AMP-activated protein kinase (AMPK) is a key sensor of energy balance playing important roles in the balancing of anabolic and catabolic activities. The high energy demands of the brain and its limited capacity to store energy indicate that AMPK may play a significant role in brain metabolism. Here, we activated AMPK in guinea pig cortical tissue slices, both directly with A769662 and PF 06409577 and indirectly with AICAR and metformin. We studied the resultant metabolism of [1-
13 C]glucose and [1,2-13 C]acetate using NMR spectroscopy. We found distinct activator concentration-dependent effects on metabolism, which ranged from decreased metabolic pool sizes at EC50 activator concentrations with no expected stimulation in glycolytic flux to increased aerobic glycolysis and decreased pyruvate metabolism with certain activators. Further, activation with direct versus indirect activators produced distinct metabolic outcomes at both low (EC50 ) and higher (EC50 × 10) concentrations. Specific direct activation of β1-containing AMPK isoforms with PF 06409577 resulted in increased Krebs cycle activity, restoring pyruvate metabolism while A769662 increased lactate and alanine production, as well as labelling of citrate and glutamine. These results reveal a complex metabolic response to AMPK activators in brain beyond increased aerobic glycolysis and indicate that further research is warranted into their concentration- and mechanism-dependent impact., (© 2023 The Authors. Journal of Neurochemistry published by John Wiley & Sons Ltd on behalf of International Society for Neurochemistry.)- Published
- 2024
- Full Text
- View/download PDF
27. Details matter in quality science. Adopting a checklist for magnetic resonance spectroscopy can help you get them right.
- Author
-
Rae CD and Williams SR
- Subjects
- Reproducibility of Results, Reference Standards, Magnetic Resonance Spectroscopy, Checklist
- Abstract
The ISMRM study group on magnetic resonance spectroscopy has produced recommendations for reporting methods. The Journal of Neurochemistry has decided to encourage the use of the checklist for these standards by authors and reviewers in order to improve reproducibility and reliability of the science, make it easier for reviewers and to help educate the scientific community. Here, we explain why getting the details right is important., (© 2022 International Society for Neurochemistry.)
- Published
- 2023
- Full Text
- View/download PDF
28. Motor cortical excitability and pre-supplementary motor area neurochemistry in healthy adults with substantia nigra hyperechogenicity.
- Author
-
Todd G, Rae CD, Taylor JL, Rogasch NC, Butler JE, Hayes M, Wilcox RA, Gandevia SC, Aoun K, Esterman A, Lewis SJG, Hall JM, Matar E, Godau J, Berg D, Plewnia C, von Thaler AK, Chiang C, and Double KL
- Subjects
- Humans, Aged, Motor Cortex diagnostic imaging, Parkinson Disease diagnostic imaging, Cortical Excitability
- Abstract
Substantia nigra (SN) hyperechogenicity, viewed with transcranial ultrasound, is a risk marker for Parkinson's disease. We hypothesized that SN hyperechogenicity in healthy adults aged 50-70 years is associated with reduced short-interval intracortical inhibition in primary motor cortex, and that the reduced intracortical inhibition is associated with neurochemical markers of activity in the pre-supplementary motor area (pre-SMA). Short-interval intracortical inhibition and intracortical facilitation in primary motor cortex was assessed with paired-pulse transcranial magnetic stimulation in 23 healthy adults with normal (n = 14; 61 ± 7 yrs) or abnormally enlarged (hyperechogenic; n = 9; 60 ± 6 yrs) area of SN echogenicity. Thirteen of these participants (7 SN- and 6 SN+) also underwent brain magnetic resonance spectroscopy to investigate pre-SMA neurochemistry. There was no relationship between area of SN echogenicity and short-interval intracortical inhibition in the ipsilateral primary motor cortex. There was a significant positive relationship, however, between area of echogenicity in the right SN and the magnitude of intracortical facilitation in the right (ipsilateral) primary motor cortex (p = .005; multivariate regression), evidenced by the amplitude of the conditioned motor evoked potential (MEP) at the 10-12 ms interstimulus interval. This relationship was not present on the left side. Pre-SMA glutamate did not predict primary motor cortex inhibition or facilitation. The results suggest that SN hyperechogenicity in healthy older adults may be associated with changes in excitability of motor cortical circuitry. The results advance understanding of brain changes in healthy older adults at risk of Parkinson's disease., (© 2022 The Authors. Journal of Neuroscience Research published by Wiley Periodicals LLC.)
- Published
- 2023
- Full Text
- View/download PDF
29. Elevation of cell-associated HIV-1 transcripts in CSF CD4+ T cells, despite effective antiretroviral therapy, is linked to brain injury.
- Author
-
Suzuki K, Zaunders J, Gates TM, Levert A, Butterly S, Liu Z, Ishida T, Palmer S, Rae CD, Jugé L, Cysique LA, and Brew BJ
- Subjects
- Humans, CD4-Positive T-Lymphocytes, Leukocytes, Mononuclear, HIV-1 genetics, HIV Seropositivity, HIV Infections drug therapy, Brain Injuries
- Abstract
Antiretroviral therapy (ART) can attain prolonged undetectable HIV-1 in plasma and cerebrospinal fluid (CSF), but brain injury remains prevalent in people living with HIV-1 infection (PLHIV). We investigated cell-associated (CA)-HIV-1 RNA transcripts in cells in CSF and blood, using the highly sensitive Double-R assay, together with proton Magnetic Resonance Spectroscopy (
1 H MRS) of major brain metabolites, in sixteen PLHIV. 14/16 CSF cell samples had quantifiable CA-HIV-1 RNA, at levels significantly higher than in their PBMCs (median 9,266 vs 185 copies /106 CD4+ T-cells; p<0.0001). In individual PLHIV, higher levels of HIV-1 transcripts in CSF cells were associated with greater brain injury in the frontal white matter (Std β=-0.73; p=0.007) and posterior cingulate (Std β=-0.61; p=0.03). 18-colour flow cytometry revealed that the CSF cells were 91% memory T-cells, equally CD4+ and CD8+ T-cells, but fewer B cells (0.4 %), and monocytes (3.1%). CXCR3+ CD49d+ integrin β7-, CCR5+ CD4+ T-cells were highly enriched in CSF, compared with PBMC (p <0.001). However, CA-HIV-1 RNA could not be detected in 10/16 preparations of highly purified monocytes from PBMC, and was extremely low in the other six. Our data show that elevated HIV-1 transcripts in CSF cells were associated with brain injury, despite suppressive ART. The cellular source is most likely memory CD4+ T cells from blood, rather than trafficking monocytes. Future research should focus on inhibitors of this transcription to reduce local production of potentially neurotoxic and inflammatory viral products.- Published
- 2022
- Full Text
- View/download PDF
30. Impact of Inhibition of Glutamine and Alanine Transport on Cerebellar Glial and Neuronal Metabolism.
- Author
-
Das A, Gauthier-Coles G, Bröer S, and Rae CD
- Subjects
- Acetates metabolism, Alanine metabolism, Alanine pharmacology, Animals, Carbon metabolism, Cerebellum metabolism, Glucose metabolism, Glutamates metabolism, Glutamic Acid metabolism, Guinea Pigs, Histidine metabolism, Ammonia metabolism, Glutamine metabolism
- Abstract
The cerebellum, or "little brain", is often overlooked in studies of brain metabolism in favour of the cortex. Despite this, anomalies in cerebellar amino acid homeostasis in a range of disorders have been reported. Amino acid homeostasis is central to metabolism, providing recycling of carbon backbones and ammonia between cell types. Here, we examined the role of cerebellar amino acid transporters in the cycling of glutamine and alanine in guinea pig cerebellar slices by inhibiting amino acid transporters and examining the resultant metabolism of [1-
13 C]d-glucose and [1,2-13 C]acetate by NMR spectroscopy and LCMS. While the lack of specific inhibitors of each transporter makes interpretation difficult, by viewing results from experiments with multiple inhibitors we can draw inferences about the major cell types and transporters involved. In cerebellum, glutamine and alanine transfer is dominated by system A, blockade of which has maximum effect on metabolism, with contributions from System N. Inhibition of neural system A isoform SNAT1 by MeAIB resulted in greatly decreased metabolite pools and reduced net fluxes but showed little effect on fluxes from [1,2-13 C]acetate unlike inhibition of SNAT3 and other glutamine transporters by histidine where net fluxes from [1,2-13 C]acetate are reduced by ~50%. We interpret the data as further evidence of not one but several glutamate/glutamine exchange pools. The impact of amino acid transport inhibition demonstrates that the cerebellum has tightly coupled cells and that glutamate/glutamine, as well as alanine cycling, play a major role in that part of the brain., Competing Interests: The authors declare no conflict of interest.- Published
- 2022
- Full Text
- View/download PDF
31. Brain aging and cardiovascular factors in HIV: a longitudinal volume and shape MRI study.
- Author
-
Jakabek D, Rae CD, Brew BJ, and Cysique LA
- Subjects
- Aging, Atrophy pathology, Brain diagnostic imaging, Brain pathology, Humans, Magnetic Resonance Imaging, HIV Infections complications, HIV Infections pathology
- Abstract
Objective: We aimed to examine the relative contributions of HIV infection, age, and cardiovascular risk factors to subcortical brain atrophy in people with HIV (PWH)., Design: Longitudinal observational study., Methods: Virally suppressed PWH with low neuropsychological confounds (n = 75) and demographically matched HIV-negative controls (n = 31) completed baseline and 18-month follow-up MRI scans, neuropsychological evaluation, cardiovascular assessments, and HIV laboratory tests. PWH were evaluated for HIV-associated neurocognitive disorder (HAND). Subcortical volumes were extracted with Freesurfer after removal of white matter hyperintensities. Volumetric and shape analyses were conducted using linear mixed-effect models incorporating interactions between age, time, and each of HIV status, HAND status, HIV disease factors, and cardiovascular markers., Results: Across baseline and follow-up PWH had smaller volumes of most subcortical structures compared with HIV-negative participants. In addition, over time older PWH had a more rapid decline in caudate volumes (P = 0.041), predominantly in the more severe HAND subgroups (P = 0.042). Higher CD4+ cell counts had a protective effect over time on subcortical structures for older participants with HIV. Increased cardiovascular risk factors were associated with smaller volumes across baseline and follow-up for most structures, although a more rapid decline over time was observed for striatal volumes. There were no significant shape analyses findings., Conclusion: The study demonstrates a three-hit model of general (as opposed to localized) subcortical injury in PWH: HIV infection associated with smaller volumes of most subcortical structures, HIV infection and aging synergy in the striatum, and cardiovascular-related injury linked to early and more rapid striatal atrophy., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2022
- Full Text
- View/download PDF
32. Brain mitochondrial dysfunction and driving simulator performance in untreated obstructive sleep apnea.
- Author
-
Vakulin A, Green MA, D'Rozario AL, Stevens D, Openshaw H, Bartlett D, Wong K, McEvoy RD, Grunstein RR, and Rae CD
- Subjects
- Brain diagnostic imaging, Creatine, Glutamates, Humans, Mitochondria, Automobile Driving, Sleep Apnea, Obstructive
- Abstract
It is challenging to determine which patients with obstructive sleep apnea (OSA) have impaired driving ability. Vulnerability to this neurobehavioral impairment may be explained by lower brain metabolites levels involved in mitochondrial metabolism. This study compared markers of brain energy metabolism in OSA patients identified as vulnerable vs resistant to driving impairment following extended wakefulness. 44 patients with moderate-severe OSA underwent 28hr extended wakefulness with three 90min driving simulation assessments. Using a two-step cluster analysis, objective driving data (steering deviation and crashes) from the 2nd driving assessment (22.5 h awake) was used to categorise patients into vulnerable (poor driving, n = 21) or resistant groups (good driving, n = 23).
1 H magnetic resonance spectra were acquired at baseline using two scan sequences (short echo PRESS and longer echo-time asymmetric PRESS), focusing on key metabolites, creatine, glutamate, N-acetylaspartate (NAA) in the hippocampus, anterior cingulate cortex and left orbito-frontal cortex. Based on cluster analysis, the vulnerable group had impaired driving performance compared with the resistant group and had lower levels of creatine (PRESS p = ns, APRESS p = 0.039), glutamate, (PRESS p < 0.01, APRESS p < 0.01), NAA (PRESS p = 0.038, APRESS p = 0.035) exclusively in the left orbito-frontal cortex. Adjusted analysis, higher glutamate was associated with a 21% (PRESS) and 36% (APRESS) reduced risk of vulnerable classification. Brain mitochondrial bioenergetics in the frontal brain regions are impaired in OSA patients who are vulnerable to driving impairment following sleep loss. These findings provide a potential way to identify at risk OSA phenotype when assessing fitness to drive, but this requires confirmation in larger future studies., (© 2021 European Sleep Research Society.)- Published
- 2022
- Full Text
- View/download PDF
33. Corrigendum: Reduced Glutamate in the Medial Prefrontal Cortex Is Associated With Emotional and Cognitive Dysregulation in People With Chronic Pain.
- Author
-
Naylor B, Hesam-Shariati N, McAuley JH, Boag S, Newton-John T, Rae CD, and Gustin SM
- Abstract
[This corrects the article DOI: 10.3389/fneur.2019.01110.]., (Copyright © 2022 Naylor, Hesam-Shariati, McAuley, Boag, Newton-John, Rae and Gustin.)
- Published
- 2022
- Full Text
- View/download PDF
34. Clinical predictors of working memory performance in obstructive sleep apnea patients before and during extended wakefulness.
- Author
-
Stevens D, D'Rozario A, Openshaw H, Bartlett D, Rae CD, Catcheside P, Wong K, Doug McEvoy R, Grunstein RR, and Vakulin A
- Subjects
- Adult, Humans, Memory, Short-Term, Middle Aged, Polysomnography, Sleep, Sleep Apnea, Obstructive complications, Wakefulness
- Abstract
Study Objectives: Extended wakefulness (EW) and obstructive sleep apnea (OSA) impair working memory (WM), but their combined effects are unclear. This study examined the impact of EW on WM function in OSA patients and identified clinical predictors of WM impairment., Methods: Following polysomnography (PSG), 56 OSA patients (mean ± SD, age 49.5 ± 8.9, apnea hypopnea index 38.1 ± 25.0) completed WM 2-back performance tasks 10 times over 24 h of wakefulness to assess average accuracy and completion times measured after 6-12 h awake (baseline) compared to 18-24 h awake (EW). Hierarchical cluster analysis classified participants with poorer versus better WM performance at baseline and during EW. Clinical predictors of performance were examined via regression and receiver operator characteristic (ROC) analyses., Results: WM performance decreased following EW and showed consistent correlations with age, Epworth Sleepiness Score (ESS), total sleep time, and hypoxemia (O2 nadir and mean O2 desaturation) at baseline and with EW (all p < .01). O2 nadir and age were significant independent predictors of performance at baseline (adjusted R2 = 0.30, p < .01), while O2 nadir and ESS were predictors of WM following EW (adjusted R2 = 0.38, p < .001). ROC analysis demonstrated high sensitivity and specificity of models to predict poorer versus better performing participants at baseline (83% and 69%) and during EW (84% and 74%)., Conclusions: O2 nadir, age, and sleepiness show prognostic value for predicting WM impairment in both rested and sleep-deprived OSA patients and may guide clinicians in identifying patients most at risk of impaired WM under both rested and heightened sleep pressure conditions.Clinical Trial Registration: This manuscript presents data collected as part of a larger trial-ANZCTR: Novel brain biomarkers of performance impairment in sleep apnea-https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363830, No. ACTRN12613001171707., (© Sleep Research Society 2021. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2022
- Full Text
- View/download PDF
35. Diffusion Tensor Imaging in Sport-Related Concussion: A Systematic Review Using an a priori Quality Rating System.
- Author
-
Lees B, Earls NE, Meares S, Batchelor J, Oxenham V, Rae CD, Jugé L, and Cysique LA
- Subjects
- Humans, Athletic Injuries diagnostic imaging, Brain Concussion diagnostic imaging, Diffusion Tensor Imaging, White Matter diagnostic imaging
- Abstract
Diffusion tensor imaging (DTI) of brain white matter (WM) may be useful for characterizing the nature and degree of brain injury after sport-related concussion (SRC) and assist in establishing objective diagnostic and prognostic biomarkers. This study aimed to conduct a systematic review using an a priori quality rating strategy to determine the most consistent DTI-WM changes post-SRC. Articles published in English (until June 2020) were retrieved by standard research engine and gray literature searches ( N = 4932), using PRISMA guidelines. Eligible studies were non-interventional naturalistic original studies that conducted DTI within 6 months of SRC in current athletes from all levels of play, types of sports, and sex. A total of 29 articles were included in the review, and after quality appraisal by two raters, data from 10 studies were extracted after being identified as high quality. High-quality studies showed widespread moderate-to-large WM differences when SRC samples were compared to controls during the acute to early chronic stage (days to weeks) post-SRC, including both increased and decreased fractional anisotropy and axial diffusivity and decreased mean diffusivity and radial diffusivity. WM differences remained stable in the chronic stage (2-6 months post-SRC). DTI metrics were commonly associated with SRC symptom severity, although standardized SRC diagnostics would improve future research. This indicates that microstructural recovery is often incomplete at return to play and may lag behind clinically assessed recovery measures. Future work should explore interindividual trajectories to improve understanding of the heterogeneous and dynamic WM patterns post-SRC.
- Published
- 2021
- Full Text
- View/download PDF
36. Disruption to normal excitatory and inhibitory function within the medial prefrontal cortex in people with chronic pain.
- Author
-
Kang D, Hesam-Shariati N, McAuley JH, Alam M, Trost Z, Rae CD, and Gustin SM
- Subjects
- Glutamic Acid, Humans, Prefrontal Cortex, gamma-Aminobutyric Acid, Chronic Pain
- Abstract
Background: Growing evidence indicates a link between changes in the medial prefrontal cortex and the pathophysiology of chronic pain. In particular, chronic pain is associated with altered medial prefrontal anatomy and biochemistry. Due to the comorbid affective disorders seen across all pain conditions, the medial prefrontal cortex is a region of significance as it is involved in emotional processing. We have recently reported that a decrease in medial prefrontal N-acetylaspartate and glutamate is associated with increased emotional dysregulation, indicating there are neurotransmitter imbalances in chronic pain. Therefore, we compared medial prefrontal neurochemistry in 24 people with chronic pain conditions to 24 age and sex-matched healthy controls with no history of chronic pain., Method: GABA-edited MEGA-PRESS was used to measure GABA
+ levels, and short TE PRESS was used to measure glutamate levels in the medial prefrontal cortex. Psychometric measures regarding pain intensity a week before scanning, during the scan and the total duration of chronic pain, were also recorded and compared to measured GABA+ and glutamate levels., Results: This study reveals that the presence of chronic pain is associated with significant decreases in medial prefrontal GABA+ and glutamate. These findings support the hypothesis that chronic pain is associated with altered medial prefrontal biochemistry., Conclusion: The dysregulation of glutamatergic and GABAergic neurotransmitter systems supports a model of disinhibition of chronic pain, which may play a key role in both the experience of persistent pain and its associated affective disturbances., Significance: This study reveals a significant reduction in γ-aminobutyric acid (GABA+ ) and glutamate within the medial prefrontal cortex in chronic pain sufferers. While the current findings should be considered with reference to a small sample size, the disruption to normal excitatory and inhibitory medial prefrontal cortex function may be key in the development and maintenance of chronic pain and comorbid mental health disorders., (© 2021 European Pain Federation - EFIC®.)- Published
- 2021
- Full Text
- View/download PDF
37. Frequency drift in MR spectroscopy at 3T.
- Author
-
Hui SCN, Mikkelsen M, Zöllner HJ, Ahluwalia V, Alcauter S, Baltusis L, Barany DA, Barlow LR, Becker R, Berman JI, Berrington A, Bhattacharyya PK, Blicher JU, Bogner W, Brown MS, Calhoun VD, Castillo R, Cecil KM, Choi YB, Chu WCW, Clarke WT, Craven AR, Cuypers K, Dacko M, de la Fuente-Sandoval C, Desmond P, Domagalik A, Dumont J, Duncan NW, Dydak U, Dyke K, Edmondson DA, Ende G, Ersland L, Evans CJ, Fermin ASR, Ferretti A, Fillmer A, Gong T, Greenhouse I, Grist JT, Gu M, Harris AD, Hat K, Heba S, Heckova E, Hegarty JP 2nd, Heise KF, Honda S, Jacobson A, Jansen JFA, Jenkins CW, Johnston SJ, Juchem C, Kangarlu A, Kerr AB, Landheer K, Lange T, Lee P, Levendovszky SR, Limperopoulos C, Liu F, Lloyd W, Lythgoe DJ, Machizawa MG, MacMillan EL, Maddock RJ, Manzhurtsev AV, Martinez-Gudino ML, Miller JJ, Mirzakhanian H, Moreno-Ortega M, Mullins PG, Nakajima S, Near J, Noeske R, Nordhøy W, Oeltzschner G, Osorio-Duran R, Otaduy MCG, Pasaye EH, Peeters R, Peltier SJ, Pilatus U, Polomac N, Porges EC, Pradhan S, Prisciandaro JJ, Puts NA, Rae CD, Reyes-Madrigal F, Roberts TPL, Robertson CE, Rosenberg JT, Rotaru DG, O'Gorman Tuura RL, Saleh MG, Sandberg K, Sangill R, Schembri K, Schrantee A, Semenova NA, Singel D, Sitnikov R, Smith J, Song Y, Stark C, Stoffers D, Swinnen SP, Tain R, Tanase C, Tapper S, Tegenthoff M, Thiel T, Thioux M, Truong P, van Dijk P, Vella N, Vidyasagar R, Vovk A, Wang G, Westlye LT, Wilbur TK, Willoughby WR, Wilson M, Wittsack HJ, Woods AJ, Wu YC, Xu J, Lopez MY, Yeung DKW, Zhao Q, Zhou X, Zupan G, and Edden RAE
- Subjects
- Humans, Magnetic Resonance Imaging methods, Magnetic Resonance Spectroscopy methods, Brain diagnostic imaging, Brain metabolism, Data Analysis, Databases, Factual standards, Magnetic Resonance Imaging standards, Magnetic Resonance Spectroscopy standards
- Abstract
Purpose: Heating of gradient coils and passive shim components is a common cause of instability in the B
0 field, especially when gradient intensive sequences are used. The aim of the study was to set a benchmark for typical drift encountered during MR spectroscopy (MRS) to assess the need for real-time field-frequency locking on MRI scanners by comparing field drift data from a large number of sites., Method: A standardized protocol was developed for 80 participating sites using 99 3T MR scanners from 3 major vendors. Phantom water signals were acquired before and after an EPI sequence. The protocol consisted of: minimal preparatory imaging; a short pre-fMRI PRESS; a ten-minute fMRI acquisition; and a long post-fMRI PRESS acquisition. Both pre- and post-fMRI PRESS were non-water suppressed. Real-time frequency stabilization/adjustment was switched off when appropriate. Sixty scanners repeated the protocol for a second dataset. In addition, a three-hour post-fMRI MRS acquisition was performed at one site to observe change of gradient temperature and drift rate. Spectral analysis was performed using MATLAB. Frequency drift in pre-fMRI PRESS data were compared with the first 5:20 minutes and the full 30:00 minutes of data after fMRI. Median (interquartile range) drifts were measured and showed in violin plot. Paired t-tests were performed to compare frequency drift pre- and post-fMRI. A simulated in vivo spectrum was generated using FID-A to visualize the effect of the observed frequency drifts. The simulated spectrum was convolved with the frequency trace for the most extreme cases. Impacts of frequency drifts on NAA and GABA were also simulated as a function of linear drift. Data from the repeated protocol were compared with the corresponding first dataset using Pearson's and intraclass correlation coefficients (ICC)., Results: Of the data collected from 99 scanners, 4 were excluded due to various reasons. Thus, data from 95 scanners were ultimately analyzed. For the first 5:20 min (64 transients), median (interquartile range) drift was 0.44 (1.29) Hz before fMRI and 0.83 (1.29) Hz after. This increased to 3.15 (4.02) Hz for the full 30 min (360 transients) run. Average drift rates were 0.29 Hz/min before fMRI and 0.43 Hz/min after. Paired t-tests indicated that drift increased after fMRI, as expected (p < 0.05). Simulated spectra convolved with the frequency drift showed that the intensity of the NAA singlet was reduced by up to 26%, 44 % and 18% for GE, Philips and Siemens scanners after fMRI, respectively. ICCs indicated good agreement between datasets acquired on separate days. The single site long acquisition showed drift rate was reduced to 0.03 Hz/min approximately three hours after fMRI., Discussion: This study analyzed frequency drift data from 95 3T MRI scanners. Median levels of drift were relatively low (5-min average under 1 Hz), but the most extreme cases suffered from higher levels of drift. The extent of drift varied across scanners which both linear and nonlinear drifts were observed., Competing Interests: Declaration of Competing Interest Jack J. Miller would like to acknowledge the support of a Novo Nordisk Research Fellowship run in conjunction with the University of Oxford. Francisco Reyes-Madrigal has served as a speaker for Janssen (Johnson & Johnson) and AstraZeneca. Marc Thioux and Pim van Dijk were supported by The Netherlands Organization for Health Research and Development (ZonMW) and the Dorhout Mees Foundation. All other authors have no conflict of interest to declare., (Copyright © 2021. Published by Elsevier Inc.)- Published
- 2021
- Full Text
- View/download PDF
38. Sleep spindle activity correlates with implicit statistical learning consolidation in untreated obstructive sleep apnea patients.
- Author
-
Stevens D, Leong CWY, Cheung H, Arciuli J, Vakulin A, Kim JW, Openshaw HD, Rae CD, Wong KKH, Dijk DJ, Siong Leow JW, Saini B, Grunstein RR, and D'Rozario AL
- Subjects
- Electroencephalography, Humans, Learning, Polysomnography, Sleep, Sleep Apnea, Obstructive
- Abstract
Objective/background: The aim of this study was to examine the relationship between overnight consolidation of implicit statistical learning with spindle frequency EEG activity and slow frequency delta power during non-rapid eye movement (NREM) sleep in obstructive sleep apnea (OSA)., Patients/methods: Forty-seven OSA participants completed the experiment. Prior to sleep, participants performed a reaction time cover task containing hidden patterns of pictures, about which participants were not informed. After the familiarisation phase, participants underwent overnight polysomnography. 24 h after the familiarisation phase, participants performed a test phase to assess their learning of the hidden patterns, expressed as a percentage of the number of correctly identified patterns. Spindle frequency activity (SFA) and delta power (0.5-4.5 Hz), were quantified from NREM electroencephalography. Associations between statistical learning and sleep EEG, and OSA severity measures were examined., Results: SFA in NREM sleep in frontal and central brain regions was positively correlated with statistical learning scores (r = 0.41 to 0.31, p = 0.006 to 0.044). In multiple regression, greater SFA and longer sleep onset latency were significant predictors of better statistical learning performance. Delta power and OSA severity were not significantly correlated with statistical learning., Conclusions: These findings suggest spindle activity may serve as a marker of statistical learning capability in OSA. This work provides novel insight into how altered sleep physiology relates to consolidation of implicitly learnt information in patients with moderate to severe OSA., (Copyright © 2021 Elsevier B.V. All rights reserved.)
- Published
- 2021
- Full Text
- View/download PDF
39. Emerging Concepts in Vector Development for Glial Gene Therapy: Implications for Leukodystrophies.
- Author
-
von Jonquieres G, Rae CD, and Housley GD
- Abstract
Central Nervous System (CNS) homeostasis and function rely on intercellular synchronization of metabolic pathways. Developmental and neurochemical imbalances arising from mutations are frequently associated with devastating and often intractable neurological dysfunction. In the absence of pharmacological treatment options, but with knowledge of the genetic cause underlying the pathophysiology, gene therapy holds promise for disease control. Consideration of leukodystrophies provide a case in point; we review cell type - specific expression pattern of the disease - causing genes and reflect on genetic and cellular treatment approaches including ex vivo hematopoietic stem cell gene therapies and in vivo approaches using adeno-associated virus (AAV) vectors. We link recent advances in vectorology to glial targeting directed towards gene therapies for specific leukodystrophies and related developmental or neurometabolic disorders affecting the CNS white matter and frame strategies for therapy development in future., 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 © 2021 von Jonquieres, Rae and Housley.)
- Published
- 2021
- Full Text
- View/download PDF
40. Long reach of the NAAG family tree: An Editorial for "Evidence of NAAG-family tripeptide NAAG2 in the Drosophila nervous system" on page 38.
- Author
-
Williams S and Rae CD
- Subjects
- Animals, Dipeptides, Drosophila melanogaster, Nervous System, Pedigree, Aspartic Acid, Drosophila
- Abstract
The last common ancestor of humans and fruit flies lived about 800 million years ago, yet both of us have nervous systems that share a number of common important features, for example the use of glutamate as a neurotransmitter. We can now possibly add another common feature to the neural tissue of humans and fruit flies which is that of N-acetylaspartylglutamate (NAAG) peptides. This Editorial highlights an article by Kozik and coworkers in the current issue of the Journal of Neurochemistry, in which the authors report the discovery, in Drosophila melanogaster nervous system, of NAA-glutamylglutamate (NAAG2)., (© 2020 International Society for Neurochemistry.)
- Published
- 2021
- Full Text
- View/download PDF
41. Actions of Alcohol in Brain: Genetics, Metabolomics, GABA Receptors, Proteomics and Glutamate Transporter GLAST/EAAT1.
- Author
-
Kashem MA, Šerý O, Pow DV, Rowlands BD, Rae CD, and Balcar VJ
- Subjects
- Acetylation, Amino Acid Transport System X-AG metabolism, Animals, Brain, Epigenesis, Genetic, Glutamate Plasma Membrane Transport Proteins metabolism, Histones metabolism, Humans, Metabolomics, Proteomics, Receptors, GABA metabolism, Signal Transduction, Alcoholism genetics, Alcoholism metabolism, Ethanol metabolism
- Abstract
We present an overview of genetic, metabolomic, proteomic and neurochemical studies done mainly in our laboratories that could improve prediction, mechanistic understanding and possibly extend to diagnostics and treatment of alcoholism and alcohol addiction. Specific polymorphisms in genes encoding for interleukins 2 and 6, catechol-O-methyl transferase (COMT), monaminooxidase B (MAO B) and several other enzymes were identified as associated with altered risks of alcoholism in humans. A polymorphism in the gene for BDNF has been linked to the risk of developing deficiences in colour vision sometimes observed in alcoholics. Metabolomic studies of acute ethanol effects on guinea pig brain cortex in vitro, lead to the identification of specific subtypes of GABA(A) receptors involved in the actions of alcohol at various doses. Acute alcohol affected energy metabolism, oxidation and the production of actaldehyde and acetate; this could have specific consequences not only for the brain energy production/utilization but could influence the cytotoxicity of alcohol and impact the epigenetics (histone acetylation). It is unlikely that brain metabolism of ethanol occurs to any significant degree; the reduction in glucose metabolism following alcohol consumption is due to ethanol effects on receptors, such as α4β3δ GABA(A) receptors. Metabolomics using post-mortem human brain indicated that the catecholaminergic signalling may be preferentially affected by chronic excessive drinking. Changes in the levels of glutathione were consistent with the presence of severe oxidative stress. Proteomics of the post-mortem alcoholic brains identified a large number of proteins, the expression of which was altered by chronic alcohol, with those associated with brain energy metabolism among the most numerous. Neurochemical studies found the increased expression of glutamate transporter GLAST/EAAT1 in brain as one of the largest changes caused by alcoholism. Given that GLAST/EAAT1 is one of the most abundant proteins in the nervous tissue and is intimately associated with the function of the excitatory (glutamatergic) synapses, this may be among the most important effects of chronic alcohol on brain function. It has so far been observed mainly in the prefrontal cortex. We show several experiments suggesting that acute alcohol can translocate GLAST/EAAT1 in astrocytes towards the plasma membrane (and this effect is inhibited by the GABA(B) agonist baclofen) but neither the mechanism nor the specificity (to alcohol) of this phenomenon have been established. Furthermore, as GLAST/EAAT1 is also expressed in testes and sperm (and could also be affected there by chronic alcohol), the levels of GLAST/EAAT1 in sperm could be used as a diagnostic tool in testing the severity of alcoholism in human males. We conclude that the reviewed studies present a unique set of data which could help to predict the risk of developing alcohol dependence (genetics), to improve the understanding of the intoxicating actions of alcohol (metabolomics), to aid in assessing the extent of damage to brain cells caused by chronic excessive drinking (metabolomics and proteomics) and to point to molecular targets that could be used in the treatment and diagnosis of alcoholism and alcohol addiction., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)
- Published
- 2021
- Full Text
- View/download PDF
42. Correction to: L-Aspartate, L-Ornithine and L-Ornithine-L-Aspartate (LOLA) and Their Impact on Brain Energy Metabolism.
- Author
-
Das A, Fröhlich D, Achanta LB, Rowlands BD, Housley GD, Klugmann M, and Rae CD
- Abstract
The original version of this published article, the bottom right hand panels of Figs. 3-6 were labelled as "Isotopomers formed from [1-
13 C]D-glucose". This is incorrect and should read "Isotopomers formed from [1,2-13 C]acetate". This has been corrected by publishing this correction article.- Published
- 2020
- Full Text
- View/download PDF
43. Additive and Synergistic Cardiovascular Disease Risk Factors and HIV Disease Markers' Effects on White Matter Microstructure in Virally Suppressed HIV.
- Author
-
Calon M, Menon K, Carr A, Henry RG, Rae CD, Brew BJ, and Cysique LA
- Subjects
- Aged, Biomarkers, Female, HIV Infections complications, HIV Infections pathology, Humans, Male, Middle Aged, Risk Factors, Anti-HIV Agents therapeutic use, Cardiovascular Diseases complications, HIV Infections drug therapy, HIV-1, White Matter pathology
- Abstract
Background: It is unclear whether intermediate to high cardiovascular disease (CVD) risk and HIV disease status may have additive (ie, independent statistical effects concomitantly tested) or synergistic effects on white matter microstructure and cognition in virally suppressed HIV-infected (HIV+) men relative to sex and age-matched controls., Setting: Tertiary health care observational cohort., Methods: Eighty-two HIV+ men (mean age 55 ± 6 years, 10%-30% on various CVD drugs; 20% with previous CVD) and 40 HIV-uninfected (HIV-) men (none with previous CVD; 10%-20% on various CVD drugs) underwent diffusion tensor imaging and neuropsychological testing. A standard classification of intermediate to high CVD risk (CVD+ group) was based on the Framingham score ≥15% cutoff and/or a history of CVD. Fractional anisotropy (FA) and mean diffusivity (MD) were quantified in 11 white matter tracts., Results: Within the HIV- group, the CVD+ group had lower FA (P = 0.03) and higher MD (P = 0.003) in the corona radiata and higher MD in the corpus callosum (P = 0.02) and superior fasciculi (P = 0.03) than the CVD- group. Within the HIV+ group, the CVD+ group had lower FA in the superior fasciculi (P = 0.04) and higher MD in the uncinate fasciculus (P = 0.04), and lower FA (P = 0.01) and higher MD (P = 0.03) in the fornix than the CVD- group. The fornix alterations were also abnormal compared with the HIV- groups. The HIV+ CVD+ was more likely to have HIV-associated dementia. Older age, antihypertensive use, longer HIV duration, and higher C-reactive protein associated with lower FA and higher MD. Higher blood CD4 lymphocyte count and CD4/CD8 ratio associated with higher FA and lower MD., Conclusions: In virally suppressed HIV, CVD risk factors have a mostly additive contribution to white matter microstructural alterations, leading to a different distribution of injury in HIV- and HIV+ persons with CVD. There was also evidence of a synergistic effect of CVD and HIV factors on the fornix white matter injury.
- Published
- 2020
- Full Text
- View/download PDF
44. L-Aspartate, L-Ornithine and L-Ornithine-L-Aspartate (LOLA) and Their Impact on Brain Energy Metabolism.
- Author
-
Das A, Fröhlich D, Achanta LB, Rowlands BD, Housley GD, Klugmann M, and Rae CD
- Subjects
- Animals, Aspartic Acid pharmacology, Brain drug effects, Dipeptides pharmacology, Dose-Response Relationship, Drug, Energy Metabolism drug effects, Female, Guinea Pigs, Male, Mice, Mice, Inbred C57BL, Ornithine pharmacology, Aspartic Acid metabolism, Brain metabolism, Dipeptides metabolism, Energy Metabolism physiology, Ornithine metabolism
- Abstract
L-Ornithine-L-aspartate (LOLA), a crystalline salt, is used primarily in the management of hepatic encephalopathy. The degree to which it might penetrate the brain, and the effects it might have on metabolism in brain are poorly understood. Here, to investigate the effects of LOLA on brain energy metabolism we incubated brain cortical tissue slices from guinea pig (Cavea porcellus) with the constituent amino acids of LOLA, L-ornithine or L-aspartate, as well as LOLA, in the presence of [1-
13 C]D-glucose and [1,2-13 C]acetate; these labelled substrates are useful indicators of brain metabolic activity. L-Ornithine produced significant "sedative" effects on brain slice metabolism, most likely via conversion of ornithine to GABA via the ornithine aminotransferase pathway, while L-aspartate showed concentration-dependent excitatory effects. The metabolic effects of LOLA reflected a mix of these two different processes and were concentration-dependent. We also investigated the effect of an intraperitoneal bolus injection of L-ornithine, L-aspartate or LOLA on levels of metabolites in kidney, liver and brain cortex and brain stem in mice (C57Bl6J) 1 h later. No significant changes in metabolite levels were seen following the bolus injection of L-aspartate, most likely due to rapid metabolism of aspartate before reaching the target tissue. Brain cortex glutamate was decreased by L-ornithine but no other brain effects were observed with any other compound. Kidney levels of aspartate were increased after injection of L-ornithine and LOLA which may be due to interference by ornithine with the kidney urea cycle. It is likely that without optimising chronic intravenous infusion, LOLA has minimal impact on healthy brain energy metabolism due to systemic clearance and the blood - brain barrier.- Published
- 2020
- Full Text
- View/download PDF
45. Brain amyloid in virally suppressed HIV-associated neurocognitive disorder.
- Author
-
Howdle GC, Quidé Y, Kassem MS, Johnson K, Rae CD, Brew BJ, and Cysique LA
- Subjects
- AIDS Dementia Complex diagnostic imaging, Aged, Alzheimer Disease diagnostic imaging, Aniline Compounds, Cognitive Dysfunction diagnostic imaging, Cohort Studies, Female, Humans, Male, Middle Aged, Positron-Emission Tomography, Thiazoles, AIDS Dementia Complex metabolism, Alzheimer Disease metabolism, Amyloid metabolism, Cognitive Dysfunction metabolism
- Abstract
Objective: To determine whether virally suppressed HIV neuropathogenesis, a chronic neuroinflammatory state, promotes abnormal brain amyloid deposition., Methods: A total of 10 men with virally suppressed HIV-associated neurocognitive disorder (HAND), aged 46-68 years, underwent
11 C-labeled Pittsburgh compound B PET. Data from the Australian Imaging, Biomarkers and Lifestyle (AIBL), including 39 cognitively normal individuals (aged 60-74 years), 7 individuals with mild cognitive impairment (MCI) (aged 64-71 years), and 11 individuals with Alzheimer disease (AD) (aged 55-74 years), were used as reference. Apart from more women, the AIBL cohort was demographically comparable with the HIV sample. Also, the AIBL PET data did not differ by sex. Cerebellum standardized uptake value ratio amyloid values within 22 regions of interest were estimated. In the HIV sample, apolipoprotein E (APOE) was available in 80%, CSF biomarkers in 60%, and 8-10 years of long-term health outcomes in 100%., Results: HAND and the AIBL group with no cognitive deficits had similar amyloid deposition, which was lower than that in both the MCI and AD groups. At the individual level, one HAND case showed high amyloid deposition consistent with AD. This case also had a CSF-AD-like profile and an E4/E4 for APOE. Clinically, this case declined over 18 years with mild HAND symptoms first, followed by progressive memory decline 8-9 years after the study PET, then progression to severe dementia within 2-3 years, and lived a further 6 years. Another HAND case showed increased amyloid deposition restricted to the hippocampi. Two other HAND cases showed abnormally decreased amyloid in subcortical areas., Conclusions: Relative to cognitively normal older controls, brain amyloid burden does not differ in virally suppressed HAND at the group level. However, individual analyses show that abnormally high and low amyloid burden occur., (Copyright © 2020 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)- Published
- 2020
- Full Text
- View/download PDF
46. CRPS Is Not Associated with Altered Sensorimotor Cortex GABA or Glutamate.
- Author
-
Lee B, Henderson LA, Rae CD, and Di Pietro F
- Subjects
- Glutamic Acid, Humans, Pain Measurement, gamma-Aminobutyric Acid, Complex Regional Pain Syndromes, Sensorimotor Cortex
- Abstract
Complex regional pain syndrome (CRPS) is a debilitating chronic pain disorder typically in the upper or lower limbs. While CRPS usually develops from a peripheral event, it is likely maintained by CNS changes. Indeed, CRPS is reported to be associated with sensorimotor cortex changes, or functional "reorganization," as well as deficits such as poor tactile acuity. While the mechanisms underpinning cortical reorganization in CRPS are unknown, some have hypothesized that it involves disinhibition (i.e., a reduction in GABA activity). In this study, we addressed this hypothesis by using edited magnetic resonance spectroscopy to determine sensorimotor GABA and glutamate concentrations in 16 humans with CRPS and 30 matched control subjects and the relationship of these concentrations with tactile acuity. We found that individuals with upper limb CRPS displayed reduced tactile acuity in the painful hand, compared with the nonpainful hand and pain-free control subjects. Despite this acuity deficit, CRPS was not associated with altered GABA or glutamate concentrations within the sensorimotor cortex on either the side that represents the affected or unaffected hand. Furthermore, there was no significant relationship between sensorimotor GABA or glutamate concentrations and tactile acuity in CRPS subjects or control subjects. Although our sample was small, these data suggest that CRPS is not associated with altered total sensorimotor GABA or glutamate concentrations. While these results are at odds with the sensorimotor cortex disinhibition hypothesis, it is possible that GABAergic mechanisms other than total GABA concentration may contribute to such disinhibition., (Copyright © 2020 Lee et al.)
- Published
- 2020
- Full Text
- View/download PDF
47. Reduced Glutamate in the Medial Prefrontal Cortex Is Associated With Emotional and Cognitive Dysregulation in People With Chronic Pain.
- Author
-
Naylor B, Hesam-Shariati N, McAuley JH, Boag S, Newton-John T, Rae CD, and Gustin SM
- Abstract
A decrease in glutamate in the medial prefrontal cortex (mPFC) has been extensively found in animal models of chronic pain. Given that the mPFC is implicated in emotional appraisal, cognition and extinction of fear, could a potential decrease in glutamate be associated with increased pessimistic thinking, fear and worry symptoms commonly found in people with chronic pain? To clarify this question, 19 chronic pain subjects and 19 age- and gender-matched control subjects without pain underwent magnetic resonance spectroscopy. Both groups also completed the Temperament and Character, the Beck Depression and the State Anxiety Inventories to measure levels of harm avoidance, depression, and anxiety, respectively. People with chronic pain had significantly higher scores in harm avoidance, depression and anxiety compared to control subjects without pain. High levels of harm avoidance are characterized by excessive worry, pessimism, fear, doubt and fatigue. Individuals with chronic pain showed a significant decrease in mPFC glutamate levels compared to control subjects without pain. In people with chronic pain mPFC glutamate levels were significantly negatively correlated with harm avoidance scores. This means that the lower the concentration of glutamate in the mPFC, the greater the total scores of harm avoidance. High scores are associated with fearfulness, pessimism, and fatigue-proneness. We suggest that chronic pain, particularly the stress-induced release of glucocorticoids, induces changes in glutamate transmission in the mPFC, thereby influencing cognitive, and emotional processing. Thus, in people with chronic pain, regulation of fear, worry, negative thinking and fatigue is impaired., (Copyright © 2019 Naylor, Hesam-Shariati, McAuley, Boag, Newton-John, Rae and Gustin.)
- Published
- 2019
- Full Text
- View/download PDF
48. Fine-Grained Mapping of Cortical Somatotopies in Chronic Complex Regional Pain Syndrome.
- Author
-
Mancini F, Wang AP, Schira MM, Isherwood ZJ, McAuley JH, Iannetti GD, Sereno MI, Moseley GL, and Rae CD
- Subjects
- Adult, Aged, Brain Mapping, Complex Regional Pain Syndromes diagnostic imaging, Female, Hand physiopathology, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Physical Stimulation, Somatosensory Cortex diagnostic imaging, Young Adult, Complex Regional Pain Syndromes physiopathology, Neuronal Plasticity, Somatosensory Cortex physiopathology
- Abstract
It has long been thought that severe chronic pain conditions, such as complex regional pain syndrome (CRPS), are not only associated with, but even maintained by a reorganization of the somatotopic representation of the affected limb in primary somatosensory cortex (S1). This notion has driven treatments that aim to restore S1 representations in CRPS patients, such as sensory discrimination training and mirror therapy. However, this notion is based on both indirect and incomplete evidence obtained with imaging methods with low spatial resolution. Here, we used fMRI to characterize the S1 representation of the affected and unaffected hand in humans (of either sex) with unilateral CRPS. The cortical area, location, and geometry of the S1 representation of the CRPS hand were largely comparable with those of both the unaffected hand and healthy controls. We found no differential relation between affected versus unaffected hand map measures and clinical measures (pain severity, upper limb disability, disease duration). Thus, if any map reorganization occurs, it does not appear to be directly related to pain and disease severity. These findings compel us to reconsider the cortical mechanisms underlying CRPS and the rationale for interventions that aim to "restore" somatotopic representations to treat pain. SIGNIFICANCE STATEMENT This study shows that the spatial map of the fingers in somatosensory cortex is largely preserved in chronic complex regional pain syndrome (CRPS). These findings challenge the treatment rationale for restoring somatotopic representations in complex regional pain syndrome patients., (Copyright © 2019 Mancini, Wang et al.)
- Published
- 2019
- Full Text
- View/download PDF
49. Imaging correlates of the blood-brain barrier disruption in HIV-associated neurocognitive disorder and therapeutic implications.
- Author
-
Chaganti J, Marripudi K, Staub LP, Rae CD, Gates TM, Moffat KJ, and Brew BJ
- Subjects
- AIDS Dementia Complex pathology, Anti-HIV Agents therapeutic use, Blood-Brain Barrier pathology, Cross-Sectional Studies, HIV Infections drug therapy, Humans, Male, Middle Aged, Neurocognitive Disorders pathology, Sustained Virologic Response, AIDS Dementia Complex diagnostic imaging, Blood-Brain Barrier diagnostic imaging, HIV Infections complications, Magnetic Resonance Imaging methods, Neurocognitive Disorders diagnostic imaging
- Abstract
Objective: HIV-associated neurocognitive disorders (HANDs) in the context of suppressive combination antiretroviral therapy (cART) still occur. We explored the role of blood-brain barrier (BBB) disruption in the pathogenesis of HAND in the context of fully suppressive cART using dynamic contrast enhanced perfusion (DCE-P) MRI. DCE-P is a new MRI technique that measures capillary permeability as an indicator for BBB integrity. We hypothesized that virally suppressed incident HAND would be associated with an impaired BBB as determined by DCE-P., Design: A cross sectional study., Methods: K-trans, a metric derivative of DCE-P, was obtained from different regions of the brain in a cohort of 20 patients with HAND who were virally suppressed in both cerebrospinal fluid (CSF) and blood compared with CSF and blood markers of neuroinflammation as well as with neurometabolites derived from magnetic resonance (MR) spectroscopy., Results: The K-trans data showed significantly impaired BBB in HAND patients when compared with the controls in the regions of the basal ganglia and anterior frontal white matter (both P < 0.0001). CSF neopterin and CSF/serum albumin ratio correlated positively with K-trans but not with blood levels., Conclusion: This study indicates that HAND in the context of viral suppression is associated with BBB disruption and the DCE MR derived K-trans metric is a very sensitive parameter to identify the BBB disruption. The finding of region-specific BBB disruption rather than globally and the lack of correlation with blood markers of neuroinflammation suggest that HIV and not systemic inflammation is driving the BBB disturbance and that the BBB disruption is a consequence of HIV already in the brain as opposed to HIV first causing BBB disruption then brain disease.
- Published
- 2019
- Full Text
- View/download PDF
50. Understanding autism spectrum disorder and social functioning in children with neurofibromatosis type 1: protocol for a cross-sectional multimodal study.
- Author
-
Haebich KM, Pride NA, Walsh KS, Chisholm A, Rouel M, Maier A, Anderson V, Barton B, Silk T, Korgaonkar M, Seal M, Lami F, Lorenzo J, Williams K, Dabscheck G, Rae CD, Kean M, North KN, and Payne JM
- Subjects
- Adolescent, Autism Spectrum Disorder genetics, Autism Spectrum Disorder physiopathology, Autism Spectrum Disorder psychology, Autistic Disorder psychology, Child, Child Development, Child, Preschool, Cross-Sectional Studies, Female, Humans, Male, Nervous System physiopathology, Neurofibromatosis 1 physiopathology, Neurofibromatosis 1 psychology, Prospective Studies, Research Design, Autism Spectrum Disorder etiology, Child Behavior, Cognition, Neurofibromatosis 1 complications, Phenotype, Social Behavior
- Abstract
Introduction: Children with the single-gene disorder neurofibromatosis type 1 (NF1) appear to be at an increased risk for autism spectrum disorder (ASD) and exhibit a unique social-cognitive phenotype compared with children with idiopathic ASD. A complete framework is required to better understand autism in NF1, from neurobiological levels through to behavioural and functional outcomes. The primary aims of this study are to establish the frequency of ASD in children with NF1, examine the social cognitive phenotype, investigate the neuropsychological processes contributing to ASD symptoms and poor social functioning in children with NF1, and to investigate novel structural and functional neurobiological markers of ASD and social dysfunction in NF1. The secondary aim of this study is to compare the neuropsychological and neurobiological features of ASD in children with NF1 to a matched group of patients with idiopathic ASD., Methods and Analysis: This is an international, multisite, prospective, cross-sectional cohort study of children with NF1, idiopathic ASD and typically developing (TD) controls. Participants will be 200 children with NF1 (3-15 years of age), 70 TD participants (3-15 years) and 35 children with idiopathic ASD (7-15 years). Idiopathic ASD and NF1 cases will be matched on age, sex and intelligence. All participants will complete cognitive testing and parents will rate their child's behaviour on standardised questionnaires. Neuroimaging will be completed by a subset of participants aged 7 years and older. Children with NF1 that screen at risk for ASD on the parent-rated Social Responsiveness Scale 2nd Edition will be invited back to complete the Autism Diagnostic Observation Scale 2nd Edition and Autism Diagnostic Interview-Revised to determine whether they fulfil ASD diagnostic criteria., Ethics and Dissemination: This study has hospital ethics approval and the results will be disseminated through peer-reviewed publications and international conferences., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2019
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.