Florey Department of Neuroscience and Mental Health - Research Publications

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    Cortical thinning 3 years after ischaemic stroke is associated with cognitive impairment and APOE ε4.
    Salah Khlif, M ; Egorova-Brumley, N ; Bird, LJ ; Werden, E ; Brodtmann, A (Elsevier BV, 2022)
    Cortical thinning has been described in many neurodegenerative diseases and used for both diagnosis and disease monitoring. The imaging signatures of post-stroke vascular cognitive impairment have not been well described. We investigated the trajectory of cortical thickness over 3 years following ischaemic stroke compared to healthy stroke-free age- and sex-matched controls. We also compared cortical thickness between cognitively normal and impaired stroke survivors, and between APOE ɛ4 carriers and non-carriers. T1-weighted MRI and cognitive data for 90 stroke survivors and 36 controls from the Cognition And Neocortical Volume After Stroke (CANVAS) study were used. Cortical thickness was estimated using FreeSurfer volumetric reconstruction according to the Desikan-Killiany parcellation atlas. Segmentation inaccuracies were manually corrected and infarcted ipsilesional vertices in cortical thickness maps were identified and excluded using stroke lesion masks traced a-priori. Mixed-effects regression was used to compare cortical thickness cross-sectionally between groups and longitudinally between timepoints. Healthy control and stroke groups did not differ on demographics and most clinical characteristics, though controls were less likely to have atrial fibrillation. Age was negatively associated with global mean cortical thickness independent of sex or group, with women in both groups having significantly thicker cortex. Three months post-stroke, cortical thinning was limited and focal. From 3 months to 3 years, the rate of cortical thinning in stroke was faster compared to that in healthy controls. However, this difference in cortical thinning rate could not survive family-wise correction for multiple comparisons. Yet, cortical thinning at 3 years was found more spread especially in ipsilesional hemispheres in regions implicated in motor, sensory, and memory processing and recovery. The cognitively impaired stroke survivors showed greater cortical thinning, compared to controls, than those who were cognitively normal at 3 years. Also, carriers of the APOE ɛ4 allele in stroke exhibited greater cortical thinning independent of cognitive status. The temporal changes of cortical thickness in both healthy and stroke cohorts followed previously reported patterns of cortical thickness asymmetry loss across the human adult life. However, this loss of thickness asymmetry was amplified in stroke. The post-stroke trajectories of cortical thickness reported in this study may contribute to our understanding of imaging signatures of vascular cognitive impairment.
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    Implementing education: Personal communication with a healthcare professional is a critical step to address vaccine hesitancy for people with multiple sclerosis
    Panisset, MG ; Kilpatrick, T ; Lizama, LEC ; Galea, MP (ELSEVIER SCI LTD, 2022-07-01)
    BACKGROUND: People with Multiple Sclerosis (PwMS) were first able to access COVID-19 vaccines in Australia from March 2021, when vaccine hesitancy in the general population was high (14-43%). High uptake of vaccination is important globally and critical to protect this vulnerable population. We conducted an on-line survey to examine factors influencing COVID-19 vaccination willingness among PwMS in Australia. METHODS: 149 PwMS living in Australia completed the on-line survey (April-September 2021) examining demographic, environmental and clinical factors with respect to vaccine willingness, including attitudes towards COVID-19 illness and vaccines. Additional items explored the influence of different information sources on vaccination decisions. Continuous and ordinal data were compared using the Mann-Whitney U test. All tests were two-tailed, with alpha set at 0.5. RESULTS: A majority of the respondents were female (87.2%) with relapsing-remitting MS (77.5%) treated by a neurologist (94.0%). A majority were on high efficacy disease-modifying therapies (DMTs) (64.9%), while 19.9% were on no DMTs. About one third of respondents (32.9%) had had two doses, 20.8% had received their first dose, and 22.1% were unvaccinated, while 24.2% of responses were missing. When asked about vaccine intentions, 60.6% of the unvaccinated indicated they were likely to extremely likely to get vaccinated, while 15.2% were very unlikely or extremely unlikely to do so and 24.2% were undecided. Unvaccinated people were significantly more concerned about vaccine side effects (mean 5.3 versus 3.1/10; p < .001). Only 53.3% of people on DMTs were vaccinated, compared to 75% of those who were not. People on ocrelizumab therapy (n = 35) had a lower vaccination rate (39%) than those on other medications (n = 86, 59%). Vaccine willingness in the unvaccinated was most highly correlated with knowledge regarding the vaccine (rs2=.709), agreement with the statement that COVID-19 vaccination is "too new for me to be confident about getting vaccinated" (rs2= -.709), anticipation of regret due to side effects of vaccination (rs2= -.642), and lack of knowledge regarding interactions between COVID-19 vaccines and DMTs (rs2= -.570). Almost two thirds had read MS-specific information about COVID-19 vaccinations and found it easy to understand (67.6%) and applicable to their situation (53.6%). However, less than half (47.8%) reported the information helped them make a personal vaccination decision. Over two-thirds (64.9%) had discussed vaccinations with their healthcare professional and 31.1% had not. Those who had not, were significantly more uninformed about the interactions of the vaccine with MS medications (mean 3.9 versus 2.9/10; p = .044) and significantly lower intention of vaccine uptake than those who had (mean 5.8 versus 7.9/10; p = .009). CONCLUSION: Our study highlights that vaccination efforts should be delivered by healthcare professionals, focus on educating those who are managed with DMTs, and include individual recommendations related to specific DMTs, how the vaccines work, expectations regarding potential side-effects, potential exacerbation of MS symptoms, likelihood of recovery from any exacerbation, and the relative risks of side effects versus COVID-19 infection. Specific recommendations are provided.
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    Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies
    Krueger, J ; Schubert, J ; Kegele, J ; Labalme, A ; Mao, M ; Heighway, J ; Seebohm, G ; Yan, P ; Koko, M ; Aslan-Kara, K ; Caglayan, H ; Steinhoff, BJ ; Weber, YG ; Keo-Kosal, P ; Berkovic, SF ; Hildebrand, MS ; Petrou, S ; Krause, R ; May, P ; Lesca, G ; Maljevic, S ; Lerche, H (ELSEVIER, 2022-09-09)
    BACKGROUND: De novo missense variants in KCNQ5, encoding the voltage-gated K+ channel KV7.5, have been described to cause developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease-related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms. METHODS: 1292 families with GGE were studied by next-generation sequencing. Whole-cell patch-clamp recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with homology modelling. FINDINGS: We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures; two variants were also associated with mild to moderate ID. All missense variants displayed a strongly decreased current density indicating a loss-of-function (LOF). When mutant channels were co-expressed with wild-type (WT) KV7.5 or KV7.5 and KV7.3 channels, three variants also revealed a significant dominant-negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The R359C variant altered PI(4,5)P2-interaction. INTERPRETATION: Our study identified deleterious KCNQ5 variants in GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant-negative effects through functional deficits. LOF of KV7.5 channels will reduce the M-current, likely resulting in increased excitability of KV7.5-expressing neurons. Further studies on network level are necessary to understand which circuits are affected and how this induces generalized seizures. FUNDING: DFG/FNR Research Unit FOR-2715 (Germany/Luxemburg), BMBF rare disease network Treat-ION (Germany), foundation 'no epilep' (Germany).
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    Clinician guidelines for the treatment of psychiatric disorders with nutraceuticals and phytoceuticals: The World Federation of Societies of Biological Psychiatry (WFSBP) and Canadian Network for Mood and Anxiety Treatments (CANMAT) Taskforce
    Sarris, J ; Ravindran, A ; Yatham, LN ; Marx, W ; Rucklidge, JJ ; McIntyre, RS ; Akhondzadeh, S ; Benedetti, F ; Caneo, C ; Cramer, H ; Cribb, L ; de Manincor, M ; Dean, O ; Deslandes, AC ; Freeman, MP ; Gangadhar, B ; Harvey, BH ; Kasper, S ; Lake, J ; Lopresti, A ; Lu, L ; Metri, N-J ; Mischoulon, D ; Ng, CH ; Nishi, D ; Rahimi, R ; Seedat, S ; Sinclair, J ; Su, K-P ; Zhang, Z-J ; Berk, M (TAYLOR & FRANCIS LTD, 2022-03-16)
    OBJECTIVES: The therapeutic use of nutrient-based 'nutraceuticals' and plant-based 'phytoceuticals' for the treatment of mental disorders is common; however, despite recent research progress, there have not been any updated global clinical guidelines since 2015. To address this, the World Federation of Societies of Biological Psychiatry (WFSBP) and the Canadian Network for Mood and Anxiety Disorders (CANMAT) convened an international taskforce involving 31 leading academics and clinicians from 15 countries, between 2019 and 2021. These guidelines are aimed at providing a definitive evidence-informed approach to assist clinicians in making decisions around the use of such agents for major psychiatric disorders. We also provide detail on safety and tolerability, and clinical advice regarding prescription (e.g. indications, dosage), in addition to consideration for use in specialised populations. METHODS: The methodology was based on the WFSBP guidelines development process. Evidence was assessed based on the WFSBP grading of evidence (and was modified to focus on Grade A level evidence - meta-analysis or two or more RCTs - due to the breadth of data available across all nutraceuticals and phytoceuticals across major psychiatric disorders). The taskforce assessed both the 'level of evidence' (LoE) (i.e. meta-analyses or RCTs) and the assessment of the direction of the evidence, to determine whether the intervention was 'Recommended' (+++), 'Provisionally Recommended' (++), 'Weakly Recommended' (+), 'Not Currently Recommended' (+/-), or 'Not Recommended' (-) for a particular condition. Due to the number of clinical trials now available in the field, we firstly examined the data from our two meta-reviews of meta-analyses (nutraceuticals conducted in 2019, and phytoceuticals in 2020). We then performed a search of additional relevant RCTs and reported on both these data as the primary drivers supporting our clinical recommendations. Lower levels of evidence, including isolated RCTs, open label studies, case studies, preclinical research, and interventions with only traditional or anecdotal use, were not assessed. RESULTS: Amongst nutraceuticals with Grade A evidence, positive directionality and varying levels of support (recommended, provisionally recommended, or weakly recommended) was found for adjunctive omega-3 fatty acids (+++), vitamin D (+), adjunctive probiotics (++), adjunctive zinc (++), methylfolate (+), and adjunctive s-adenosyl methionine (SAMe) (+) in the treatment of unipolar depression. Monotherapy omega-3 (+/-), folic acid (-), vitamin C (-), tryptophan (+/-), creatine (+/-), inositol (-), magnesium (-), and n-acetyl cysteine (NAC) (+/-) and SAMe (+/-) were not supported for this use. In bipolar disorder, omega-3 had weak support for bipolar depression (+), while NAC was not currently recommended (+/-). NAC was weakly recommended (+) in the treatment of OCD-related disorders; however, no other nutraceutical had sufficient evidence in any anxiety-related disorder. Vitamin D (+), NAC (++), methylfolate (++) were recommended to varying degrees in the treatment of the negative symptoms in schizophrenia, while omega-3 fatty acids were not, although evidence suggests a role for prevention of transition to psychosis in high-risk youth, with potential pre-existing fatty acid deficiency. Micronutrients (+) and vitamin D (+) were weakly supported in the treatment of ADHD, while omega-3 (+/-) and omega-9 fatty acids (-), acetyl L carnitine (-), and zinc (+/-) were not supported. Phytoceuticals with supporting Grade A evidence and positive directionality included St John's wort (+++), saffron (++), curcumin (++), and lavender (+) in the treatment of unipolar depression, while rhodiola use was not supported for use in mood disorders. Ashwagandha (++), galphimia (+), and lavender (++) were modestly supported in the treatment of anxiety disorders, while kava (-) and chamomile (+/-) were not recommended for generalised anxiety disorder. Ginkgo was weakly supported in the adjunctive treatment of negative symptoms of schizophrenia (+), but not supported in the treatment of ADHD (+/-). With respect to safety and tolerability, all interventions were deemed to have varying acceptable levels of safety and tolerability for low-risk over-the-counter use in most circumstances. Quality and standardisation of phytoceuticals was also raised by the taskforce as a key limiting issue for firmer confidence in these agents. Finally, the taskforce noted that such use of nutraceuticals or phytoceuticals be primarily recommended (where supportive evidence exists) adjunctively within a standard medical/health professional care model, especially in cases of more severe mental illness. Some meta-analyses reviewed contained data from heterogenous studies involving poor methodology. Isolated RCTs and other data such as open label or case series were not included, and it is recognised that an absence of data does not imply lack of efficacy. CONCLUSIONS: Based on the current data and clinician input, a range of nutraceuticals and phytoceuticals were given either a supportive recommendation or a provisional recommendation across a range of various psychiatric disorders. However several had only a weak endorsement for potential use; for a few it was not possible to reach a clear recommendation direction, largely due to mixed study findings; while some other agents showed no obvious therapeutic benefit and were clearly not recommended for use. It is the intention of these guidelines to inform psychiatric/medical, and health professional practice globally.
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    Head-to-Head Comparison of Different Blood Collecting Tubes for Quantification of Alzheimer's Disease Biomarkers in Plasma
    Jiang, L ; Ding, X ; Wang, W ; Yang, X ; Li, T ; Lei, P (MDPI, 2022-09-01)
    To examine whether the type of blood collection tubes affects the quantification of plasma biomarkers for Alzheimer's disease analyzed with a single-molecule array (Simoa), we recruited a healthy cohort (n = 34, 11 males, mean age = 28.7 ± 7.55) and collected plasma in the following tubes: dipotassium ethylenediaminetetraacetic acid (K2-EDTA), heparin lithium (Li-Hep), and heparin sodium (Na-Hep). Plasma tau, phosphorylated tau 181 (p-tau181), amyloid β (1-40) (Aβ40), and amyloid β (1-42) (Aβ42) were quantified using Simoa. We compared the value of plasma analytes, as well as the effects of sex on the measurements. We found that plasma collected in Li-Hep and Na-Hep tubes yielded significantly higher tau and p-tau181 levels compared to plasma collected in K2-EDTA tubes from the same person, but there was no difference in the measured values of the Aβ40, Aβ42, and Aβ42/40 ratio. Therefore, the type of blood collecting tubes should be considered when planning studies that measure plasma tau.
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    Novel Anti-Neuroinflammatory Properties of a Thiosemicarbazone-Pyridylhydrazone Copper(II) Complex
    Choo, XY ; McInnes, LE ; Grubman, A ; Wasielewska, JM ; Belaya, I ; Burrows, E ; Quek, H ; Martin, JC ; Loppi, S ; Sorvari, A ; Rait, D ; Powell, A ; Duncan, C ; Liddell, JR ; Tanila, H ; Polo, JM ; Malm, T ; Kanninen, KM ; Donnelly, PS ; White, AR (MDPI, 2022-09-01)
    Neuroinflammation has a major role in several brain disorders including Alzheimer's disease (AD), yet at present there are no effective anti-neuroinflammatory therapeutics available. Copper(II) complexes of bis(thiosemicarbazones) (CuII(gtsm) and CuII(atsm)) have broad therapeutic actions in preclinical models of neurodegeneration, with CuII(atsm) demonstrating beneficial outcomes on neuroinflammatory markers in vitro and in vivo. These findings suggest that copper(II) complexes could be harnessed as a new approach to modulate immune function in neurodegenerative diseases. In this study, we examined the anti-neuroinflammatory action of several low-molecular-weight, charge-neutral and lipophilic copper(II) complexes. Our analysis revealed that one compound, a thiosemicarbazone-pyridylhydrazone copper(II) complex (CuL5), delivered copper into cells in vitro and increased the concentration of copper in the brain in vivo. In a primary murine microglia culture, CuL5 was shown to decrease secretion of pro-inflammatory cytokine macrophage chemoattractant protein 1 (MCP-1) and expression of tumor necrosis factor alpha (Tnf), increase expression of metallothionein (Mt1), and modulate expression of Alzheimer's disease-associated risk genes, Trem2 and Cd33. CuL5 also improved the phagocytic function of microglia in vitro. In 5xFAD model AD mice, treatment with CuL5 led to an improved performance in a spatial working memory test, while, interestingly, increased accumulation of amyloid plaques in treated mice. These findings demonstrate that CuL5 can induce anti-neuroinflammatory effects in vitro and provide selective benefit in vivo. The outcomes provide further support for the development of copper-based compounds to modulate neuroinflammation in brain diseases.
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    Topographical Distribution and Phenotype of Resident Meibomian Gland Orifice Immune Cells (MOICs) in Mice and the Effects of Topical Benzalkonium Chloride (BAK)
    Wu, CY ; Wu, M ; Huang, X ; Gu, BJ ; Maldonado-Codina, C ; Morgan, PB ; Downie, LE ; Chinnery, HR (MDPI, 2022-09-01)
    Meibomian gland orifices (MGOs) are located along the eyelid margin and secrete meibum into the tear film. The profile of resident innate immune cells (ICs) at this site is not well understood. The distribution and phenotype of resident ICs around MGOs in mice was investigated and herein defined as MGO-associated immune cells (MOICs). The effect of topical 0.1% benzalkonium chloride (BAK) on MOICs was also assessed. Eyelids from healthy CD11ceYFP and Cx3cr1gfp/gfp mice aged three or seven months were compared. ICs were identified as CD11c+, Cx3cr1+, and MHC-II+ using four-colour immunostaining and confocal microscopy. MOIC density was variable but clustered around MGOs. There were more CD11c+ MOICs in three-month-old compared with seven-month-old mice (three-month-old: 893&nbsp;±&nbsp;449 cells/mm2 vs. seven-month-old: 593&nbsp;±&nbsp;493 cells/mm2, p = 0.004). Along the eyelid margin, there was a decreasing gradient of CD11c+ MOIC density in three-month-old mice (nasal: 1003&nbsp;±&nbsp;369 cells/mm2, vs. central: 946&nbsp;±&nbsp;574 cells/mm2, vs. temporal: 731&nbsp;±&nbsp;353 cells/mm2, p = 0.044). Cx3cr1-deficient mice had two-fold fewer MHC-II+ MOICs, suggesting a role for Cx3cr1 receptor signaling in meibomian gland surveillance. CD11c+ MOIC density was lower in BAK-exposed eyes compared to saline-treated controls, suggesting a change in homeostasis. This study provides novel insight into resident ICs located at MGOs, and their contribution to MG homeostasis.
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    Dioscorea nipponica Makino Rhizome Extract and Its Active Compound Dioscin Protect against Neuroinflammation and Scopolamine-Induced Memory Deficits
    Azam, S ; Kim, Y-S ; Jakaria, M ; Yu, Y-J ; Ahn, J-Y ; Kim, I-S ; Choi, D-K (MDPI, 2022-09-01)
    Activation of microglial cells by intrinsic or extrinsic insult causes neuroinflammation, a common phenomenon in neurodegenerative diseases. Prevention of neuroinflammation may ameliorate many neurodegenerative disease progressions. Dioscorea nipponica Makino (DN) extract can alleviate muscular atrophy and inflammatory diseases; however, the efficacy and mechanism of action in microglial cells remain unknown. The current study investigates the possible anti-inflammatory effects and mechanisms of Dioscorea nipponica Makino ethanol extract and its steroidal saponin dioscin. Our in vitro study shows that Dioscorea nipponica rhizome ethanol extract (DNRE) and dioscin protect against lipopolysaccharide (LPS)-activated inflammatory responses in BV-2 microglial cells by inhibiting phosphorylation and the nuclear translocation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), resulting in the downregulation of pro-inflammatory cytokines and enzymes. Consistent with our previous report of dioscin-mediated enhancement of neurotrophic factors in dopaminergic cells, here we found that dioscin upregulates brain-derived neurotrophic factor (BDNF) and cAMP-response element binding protein (CREB) phosphorylation (pCREB) in the cerebral cortex and hippocampus regions of the mouse brain. Scopolamine treatment increased pro-inflammatory enzyme levels and reduced the expression of BDNF and pCREB in the hippocampus and cortex regions, which led to impaired learning and referencing memory in mice. Pre-treatment of dioscin for 7 days substantially enhanced mice performances in maze studies, indicating amelioration in cognitive deficits. In conclusion, DNRE and its active compound dioscin protect against neurotoxicity most likely by suppressing NF-κB phosphorylation and upregulating neurotrophic factor BDNF.
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    Synthetic short-chain peptide analogues of H1 relaxin lack affinity for the RXFP1 receptor and relaxin-like bioactivity. Clues to a better understanding of relaxin agonist design.
    D'Ercole, A ; Nistri, S ; Pacini, L ; Carotenuto, A ; Santoro, F ; Papini, AM ; Bathgate, RAD ; Bani, D ; Rovero, P (Frontiers Media SA, 2022)
    The peptide hormone relaxin (RLX), also available as clinical-grade recombinant protein (serelaxin), holds great promise as a cardiovascular and anti-fibrotic agent but is limited by the pharmacokinetic issues common to all peptide drugs. In this study, by a computational modelling chemistry approach, we have synthesized and tested a set of low molecular weight peptides based on the putative receptor-binding domain of the B chain of human H1 RLX isoform, with the objective to obtain RLX analogues with improved pharmacokinetic features. Some of them were stabilized to induce the appropriate 3-D conformation by intra-chain tri-azolic staples, which should theoretically enhance their resistance to digestive enzymes making them suited for oral administration. Despite these favourable premises, none of these H1 peptides, either linear or stapled, revealed a sufficient affinity to the specific RLX receptor RXFP1. Moreover, none of them was endowed with any RLX-like biological effects in RXFP1-expressing THP-1 human monocytic cells and mouse NIH-3T3-derived myofibroblasts in in vitro culture, in terms of significantly relevant cAMP elevation and ERK1/2 phosphorylation, which represent two major signal transduction events downstream RXFP1 activation. This was at variance with authentic serelaxin, which induced a clear-cut, significant activation of both these classical RLX signaling pathways. Albeit negative, the results of this study offer additional information about the structural requirements that new peptide therapeutics shall possess to effectively behave as RXFP1 agonists and RLX analogues.