bruce brew | The University of New South Wales (original) (raw)

Papers by bruce brew

BMC Neurology, Apr 1, 2015

Background: Cerebrospinal fluid (CSF) biomarkers Aβ1-42, t-tau and p-tau have a characteristic pa... more Background: Cerebrospinal fluid (CSF) biomarkers Aβ1-42, t-tau and p-tau have a characteristic pattern in Alzheimer's Disease (AD). Their roles in HIV-associated neurocognitive disorder (HAND) remains unclear. Methods: Adults with chronic treated HIV disease were recruited (n = 43, aged 56.7 ± 7.9; 32% aged 60+; median HIV duration 20 years, >95% plasma and CSF HIV RNA <50 cp/mL, on cART for a median 24 months). All underwent standard neuropsychological testing (61% had HAND), APOE genotyping (30.9% carried APOE ε4 and 7.1% were ε4 homozygotes) and a lumbar puncture. Concentrations of Aβ1-42, t-tau and p-tau were assessed in the CSF using commercial ELISAs. Current neurocognitive status was defined using the continuous Global Deficit Score, which grades impairment in clinically relevant categories. History of HAND was recorded. Univariate correlations informed multivariate models, which were corrected for nadir CD4-T cell counts and HIV duration. Results: Carriage of APOE ε4 predicted markedly lower levels of CSF Aβ1-42 in univariate (r = -.50; p = .001) and multivariate analyses (R 2 = .25; p < .0003). Greater levels of neurocognitive impairment were associated with higher CSF levels of p-tau in univariate analyses (r = .32; p = .03) and multivariate analyses (R 2 = .10; p = .03). AD risk prediction cut-offs incorporating all three CSF biomarkers suggested that 12.5% of participants had a high risk for AD. Having a CSF-AD like profile was more frequent in those with current (p = .05) and past HIV-associated dementia (p = .03). Conclusions: Similarly to larger studies, APOE ε4 genotype was not directly associated with HAND, but moderated CSF levels of Aβ1-42 in a minority of participants. In the majority of participants, increased CSF p-tau levels were associated with current neurocognitive impairment. Combined CSF biomarker risk for AD in the current HIV+ sample is more than 10 times greater than in the Australian population of the same age. Larger prospective studies are warranted.

Journal of Neurology, Neurosurgery, and Psychiatry, Oct 1, 1997

Aids Research and Therapy, 2013

Background: HIV-associated distal sensory polyneuropathy (HIV-DSP) is the most frequently reporte... more Background: HIV-associated distal sensory polyneuropathy (HIV-DSP) is the most frequently reported neurologic complication associated with HIV infection. NGX-4010 is a capsaicin 8% dermal patch with demonstrated efficacy in the treatment of HIV-DSP. Data from two phase III, double-blind studies were integrated to further analyze the efficacy and safety of NGX-4010 and explore the effect of demographic and baseline factors on NGX-4010 treatment in HIV-DSP. Methods: Data from two similarly designed studies in which patients with HIV-DSP received NGX-4010 or a low-concentration control patch (capsaicin 0.04% w/w) for 30 or 60 minutes were integrated. Efficacy assessments included the mean percent change from baseline in Numeric Pain Rating Scale (NPRS) scores to Weeks 2-12. Safety and tolerability assessments included adverse events (AEs) and pain during and after treatment. Results: Patients (n = 239) treated with NGX-4010 for 30 minutes demonstrated significantly (p = 0.0026) greater pain relief compared with controls (n = 100); the mean percent change in NPRS scores from baseline to Weeks 2-12 was -27.0% versus -15.7%, respectively. Patients who received a 60-minute application of NGX-4010 (n = 243) showed comparable pain reductions (-27.5%) to patients treated for 30 minutes, but this was not statistically superior to controls (n = 115). NGX-4010 was effective regardless of gender, baseline pain score, duration of HIV-DSP, or use of concomitant neuropathic pain medication, although NGX-4010 efficacy was greater in patients not receiving concomitant neuropathic pain medications. NGX-4010 was well tolerated; the most common AEs were application-site pain and erythema, and most AEs were mild to moderate. The transient increase in pain associated with NGX-4010 treatment decreased the day after treatment and returned to baseline by Day 2. Conclusions: A single 30-minute application of NGX-4010 provides significant pain relief for at least 12 weeks in patients with HIV-DSP and is well tolerated.

American Journal of Neuroradiology, Jun 8, 2017

BACKGROUND AND PURPOSE: HIV-associated neurocognitive disorder still occurs despite virally suppr... more BACKGROUND AND PURPOSE: HIV-associated neurocognitive disorder still occurs despite virally suppressive combination antiretroviral therapy. In the pre-combination antiretroviral era and in patients without HIV suppression, HIV-associated neurocognitive disorder was caused by synaptodendritic injury resulting in impairment of neural networks, characterized by decreased attention, psychomotor slowing, and working memory deficits. Whether similar pathogenesis is true for HIV-associated neurocognitive disorder in the context of viral suppression is not clear. Resting-state fMRI has been shown to be efficient in detecting impaired neural networks in various neurologic illnesses. This pilot study aimed to assess resting-state functional connectivity of the brain in patients with active HIV-associated neurocognitive disorder in the context of HIV viral suppression in both blood and CSF. Eighteen patients with active HIV-associated neurocognitive disorder (recent diagnosis with progressing symptoms) on combination antiretroviral therapy with viral suppression in both blood and CSF and 9 demographically matched control subjects underwent resting-state functional MR imaging. The connectivity in the 6 known neural networks was assessed. To localize significant ROIs within the HIV and control group, we performed a seed-based correlation for each known resting-state network. RESULTS: There were significant group differences between the control and HIV-associated neurocognitive disorder groups in the salience (0.26 versus 0.14, t ϭ 2.6978, df ϭ 25, P ϭ .0123) and executive networks (0.52 versus 0.32, t ϭ 2.2372, df ϭ 25, P ϭ .034). The covariate analysis with neuropsychological scores yielded statistically significant correlations in all 6 studied functional networks, with the most conspicuous correlation in salience networks. Active HIV-associated neurocognitive disorder in virally suppressed patients is associated with significantly decreased connectivity in the salience and executive networks, thereby making it potentially useful as a biomarker.

Current Hiv/aids Reports, Jan 21, 2017

Purpose of review: To evaluate current barriers to HIV cure strategies and interventions for neur... more Purpose of review: To evaluate current barriers to HIV cure strategies and interventions for neurocognitive dysfunction with a particular focus on recent advancements over the last three years. Recent findings: Optimal anti-retroviral therapy (ART) poses challenges to minimise neurotoxicity, whilst ensuring blood brain barrier penetration and minimising the risk of cerebrovascular disease. CSF biomarkers, BCL11B and neurofilament light chain may be implicated with a neuroinflammatory cascade leading to cognitive impairment. Diagnostic imaging with diffusion tensor imaging as well as resting-state fMRI show promise in future diagnosis and monitoring of HAND. Summary: The introduction of ART has resulted in a dramatic decline in HIV-associated dementia. Despite this reduction, milder forms of HIV-associated neurocognitive disorder (HAND) are still prevalent and are clinically significant. The central nervous system (CNS) has been recognised as a probable reservoir and sanctuary for HIV, representing a significant barrier to management interventions.

BMC Neurology, Dec 1, 2006

Background: Valproic acid (VPA) is often used to control pain in HIV-related neuropathy. However,... more Background: Valproic acid (VPA) is often used to control pain in HIV-related neuropathy. However, the effect of VPA on cognitive functions in advanced HIV-infected individuals is largely unknown. A recent study would suggest that it may have a neuroprotective effect, the doses used were low and the observation period short. We used a well studied HIV-infected cohort assessed for a median of 15 (range 6-27 months) to determine whether individuals who were receiving VPA showed any cognitive benefits. Multiple regression procedures allowed us to control for the effects of HAART and HIV disease status as well as numbers of visits and variation in VPA intake over-time. We found a negative effect of VPA (mean dose of 850 mg/d for 18 months on average; range 6-27 months) on cognitive performance in eight advanced HIV-infected individuals compared to 32 advanced HIV-infected individuals on no VPA who had comparable neuropsychological performance at baseline. Control for plasma HIV viral load provided similar results. Our results suggest that further studies of VPA in advanced HIV-infection should cautiously include high doses over prolonged periods of at least 18 months in order to more accurately determine whether the posited neuroprotective benefit of VPA still occurs or whether it is replaced by toxicity.

Journal of Virology, Sep 15, 2004

AIDS dementia complex (ADC) in human immunodeficiency virus (HIV)-infected patients continues to ... more AIDS dementia complex (ADC) in human immunodeficiency virus (HIV)-infected patients continues to be a problem in the era of highly active antiretroviral therapy (HAART). A better understanding of the drug resistance mutation patterns that emerge in the central nervous system (CNS) during HAART is of paramount importance as these differences in drug resistance mutations may explain underlying reasons for poor penetration of antiretroviral drugs into the CNS and suboptimal concentrations of the drugs that may reside in the brains of HIV-infected individuals during therapy. Thus, we provide a detailed analysis of HIV type 1 (HIV-1) protease and reverse transcriptase (RT) genes derived from different regions of the brains of 20 HIV-1-infected patients (5 without ADC, 2 with probable ADC, and 13 with various stages of ADC) on antiretroviral therapy. We show the compartmentalization and independent evolution of both primary and secondary drug resistance mutations to both RT and protease inhibitors in diverse regions of the CNS of HIV-infected patients, with and without dementia, on antiretroviral therapy. Our results suggest that the independent evolution of drug resistance mutations in diverse areas of the CNS may emerge as a consequence of incomplete suppression of HIV, probably related to suboptimal drug levels in the CNS and drug selection pressure. The emergence of resistant virus in the CNS may have considerable influence on the outcome of neurologic disease and also the reseeding of HIV in the systemic circulation upon failure of therapy.

Pathology, Apr 1, 2018

Autoantibodies have been described in samples from HIV + patients, but the effects of antiretrovi... more Autoantibodies have been described in samples from HIV + patients, but the effects of antiretroviral therapy (ART) remain unclear. In a retrospective longitudinal study, we applied clinical assays for autoantibodies to sera collected from 13 HIV + patients as they began ART with <210 CD4 T-cells/µl and over 2 years on treatment. All 13 patients had at least one autoantibody. The incidence peaked before ART (21 from 156 assays) and declined to 8/143 positive reactions after 2 years. As anti-smooth muscle (ASM) antibodies remained common, these assays were applied to HIV patients (n=67) who had <50 copies HIV RNA/mL plasma after 13(2-17) years on ART, and healthy controls (n=55). The incidence of ASM was high in these patients and correlated with levels of total IgG. Hence the high incidence of autoantibodies before ART declined, but did not disappear, with successful therapy. Autoantibody levels may reflect B-cell hyperactivity in patients stable on ART.

Neuroimmunology and Neuroinflammation, 2018

To assess whether HIV-related brain injury is progressive in persons with suppressed HIV infectio... more To assess whether HIV-related brain injury is progressive in persons with suppressed HIV infection. Seventy-three HIV+ virally suppressed men and 35 HIV-men, screened for psychiatric and alcohol/drug use disorders, underwent neuropsychological evaluation and proton magnetic resonance spectroscopy ( 1 H-MRS) at baseline and after and 23 ± 5 months. 1 H-MRS included brain regions known to be vulnerable to HIV and aging: frontal white matter (FWM), posterior cingulate cortex (PCC), and caudate area (CA). Major brain metabolites such as creatine (Cr: marker of cellular energy), N-acetyl aspartate (NAA: marker of neuronal integrity), choline (marker of cellular membrane turnover), glutamate/glutamine (excitatory/inhibitory neurotransmitter), and myo-Inositol (mI: marker of neuroinflammation) were calculated with reference to water signal. Neurocognitive decline was corrected for practice effect and baseline HIV-associated neurocognitive disorder (HAND) status. Across the study period, 44% had intact cognition, 42% stable HAND (including the single case that improved), 10% progressing HAND, and 4% incident HAND. When analyzing the neurochemical data per neurocognitive trajectories, we found decreasing PCC Cr in all subgroups compared with controls (p < 0.002). In addition, relative to the HIV-group, stable HAND showed decreasing FWM Cr, incident HAND showed steep FWM Cr reduction, whereas progressing HAND had a sharply decreasing PCC NAA and reduced but stable CA NAA. When analyzing the neurochemical data at the group level (HIV+ vs HIV-groups), we found stable abnormal metabolite concentrations over the study period: decreased FWM and PCC Cr (both p < 0.001), decreased PCC NAA and CA NAA (both p < 0.05) and PCC mI increase (p < 0.05). HIV duration and historical HAND had modest effects on metabolite changes. Our study reveals covertly active or progressing HIV-related brain injury in the majority of this virally suppressed cohort, reflecting ongoing neuropathogenic processes that are only partially worsened by historical HAND and HIV duration. Longer-term studies will be important for determining the prognosis of these slowly evolving neurochemical abnormalities.

Neuroimmunology and Neuroinflammation, May 11, 2020

To determine whether virally suppressed HIV neuropathogenesis, a chronic neuroinflammatory state,... more To determine whether virally suppressed HIV neuropathogenesis, a chronic neuroinflammatory state, promotes abnormal brain amyloid deposition. 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%. 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. 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.

PLOS ONE, Mar 6, 2017

The longitudinal rate and profile of cognitive decline in persons with stable, treated, and viral... more The longitudinal rate and profile of cognitive decline in persons with stable, treated, and virally suppressed HIV infection is not established. To address this question, the current study quantifies the rate of cognitive decline in a cohort of virally suppressed HIV+ persons using clinically relevant definitions of decline, and determine cognitive trajectories taking into account historical and baseline HAND status. Ninety-six HIV+ (clinically stable and virally undetectable) and 44 demographically comparable HIV-participants underwent standard neuropsychological testing at baseline and 18months follow-up. We described clinically relevant cognitive trajectories based on standard definitions of historical and baseline HAND status and cognitive decline. Historical, moderate to severe HAND was formally diagnosed at the start of the cART era in 15/96 participants based on clinical neurological and neuropsychological assessment. The same standard of care has been applied to all participants at St. Vincent's Hospital Infectious Disease Department for the duration of their HIV infection (median of 20 years). Relative to HIV-controls (4.5%), 14% of HIV+ participants declined (p = .11), they also scored significantly lower on the global change score (p = .03), processing speed (p = .02), and mental flexibility/inhibition (p = .02) domains. Having HAND at baseline significantly predicted cognitive decline at follow up (p = .005). We determined seven clinically relevant cognitive trajectories taking into account whether participant has a history of HAND prior to study entry (yes/no); their results on the baseline assessment (baseline impairment: yes/no) and their results on the 18-month follow up (decline or stable) which in order of prevalence were: 1) No HAND history, no baseline impairment, 18-month follow-up stable (39%), 2

Conclusion Acute causes of bilateral ophthalmoplegia include Wernicke's encephalopathy, Miller-Fi... more Conclusion Acute causes of bilateral ophthalmoplegia include Wernicke's encephalopathy, Miller-Fisher Syndrome (MFS) variant of Guillain Barre Syndrome, brainstem stroke, myasthenia gravis and botulism. Of these, only MFS and botulism will cause both internal and external ophthalmoplegia.

BMC Infectious Diseases, Aug 28, 2013

Background: Posterior reversible encephalopathy syndrome (PRES) is an uncommon pathology characte... more Background: Posterior reversible encephalopathy syndrome (PRES) is an uncommon pathology characterized by the acute onset of headache, vomiting, altered consciousness, seizures and focal neurological deficits. It was initially described in the setting of hypertension, uremia and immunosuppression. In the last decade there have been emerging reports of PRES in patients with advanced human immunodeficiency virus (HIV)-infection in the presence of hypertension, dialysis, hypercalcaemia and two opportunistic infections: blastomycosis and tuberculosis (TB). Case presentation: Here we present the case of a 54 year old male being treated for disseminated varicella zoster virus (VZV) and vasculopathy in the setting of HIV infection who acutely deteriorated to the point of requiring intubation. His clinicoradiological diagnosis was of PRES and he subsequently improved within 72 h with supportive management. Serial neuroimaging correlated with the clinical findings. The pathogenesis of PRES is poorly understood but is thought to stem from vasogenic oedema either as a result of loss of endothelial integrity and transudate of fluid across the blood-brain barrier, or secondary to vasospasm resulting in tissue oedema in the absence of infarction. How HIV infection impacts on this model is unclear. It is possible the HIV infection causes endothelial dysfunction and disruption of the blood-brain barrier that may be further exacerbated by infections in the central nervous system. The phenomenon of PRES in advanced HIV is an important clinical entity for both physicians and critical care doctors to recognize firstly given its potential mortality but also because of its favourable prognosis and reversibility with supportive care and treatment of underlying causes.

Journal of NeuroVirology, Mar 21, 2017

The objective of the current study was to quantify the degree of white matter (WM) abnormalities ... more The objective of the current study was to quantify the degree of white matter (WM) abnormalities in chronic and virally suppressed HIV-infected (HIV+) persons while carefully taking into account demographic and disease factors. Diffusion tensor imaging (DTI) was conducted in 40 HIV-and 82 HIV+ men with comparable demographics and life style factors. The HIV+ sample was clinically stable with successful viral control. Diffusion was measured across 32 non-colinear directions with a b-value of 1000 s/mm 2 ; fractional anisotropy (FA) and mean diffusivity (MD) maps were quantified with Itrack IDL. Using the ENIGMA DTI protocol, FA and MD values were extracted for each participant and in 11 skeleton regions of interest (SROI) from standard labels in the JHU ICBM-81 atlas covering major striato-frontal and parietal tracks. We found no major differences in FA and MD values across the 11 SROI between study groups. Within the HIV+ sample, we found that a higher CNS penetrating antiretroviral treatment, higher current CD4+ T cell count, and immune recovery from the nadir CD4+ T cell count were associated with increased FA and decreased MD (p < 0.05-0.006), while HIV duration, symptomatic, and asymptomatic cognitive impairment were associated with decreased FA and increased MD (p < 0.01-0.004). Stability of HIV treatment and antiretroviral CNS penetration efficiency in addition to current and historical immune recovery were related to higher FA and lower MD (p = 0.04-p < 0.01). In conclusion, WM DTI measures are near normal except for patients with neurocognitive impairment and longer HIV disease duration.

Journal of NeuroVirology, Jun 4, 2013

y findings. Decrease in CSF JCV DNA load from baseline to week 4 was associated with a better cli... more y findings. Decrease in CSF JCV DNA load from baseline to week 4 was associated with a better clinical outcome at 16 weeks, as measured by Karnofsky scores. This study found no evidence of anti-JCV activity by mefloquine. An early decrease of CSF JCV DNA load appears to be associated with a better clinical outcome.

Retrovirology, May 1, 2010

BMC Neurology, Nov 22, 2011

Background: There is conflicting information as to whether antiretroviral drugs with better centr... more Background: There is conflicting information as to whether antiretroviral drugs with better central nervous system (CNS) penetration (neuroHAART) assist in improving neurocognitive function and suppressing cerebrospinal fluid (CSF) HIV RNA. The current review aims to better synthesise existing literature by using an innovative two-phase review approach (qualitative and quantitative) to overcome methodological differences between studies. Methods: Sixteen studies, all observational, were identified using a standard citation search. They fulfilled the following inclusion criteria: conducted in the HAART era; sample size > 10; treatment effect involved more than one antiretroviral and none had a retrospective design. The qualitative phase of review of these studies consisted of (i) a blind assessment rating studies on features such as sample size, statistical methods and definitions of neuroHAART, and (ii) a non-blind assessment of the sensitivity of the neuropsychological methods to HIVassociated neurocognitive disorder (HAND). During quantitative evaluation we assessed the statistical power of studies, which achieved a high rating in the qualitative analysis. The objective of the power analysis was to determine the studies ability to assess their proposed research aims. Results: After studies with at least three limitations were excluded in the qualitative phase, six studies remained. All six found a positive effect of neuroHAART on neurocognitive function or CSF HIV suppression. Of these six studies, only two had statistical power of at least 80%. Conclusions: Studies assessed as using more rigorous methods found that neuroHAART was effective in improving neurocognitive function and decreasing CSF viral load, but only two of those studies were adequately statistically powered. Because all of these studies were observational, they represent a less compelling evidence base than randomised control trials for assessing treatment effect. Therefore, large randomised trials are needed to determine the robustness of any neuroHAART effect. However, such trials must be longitudinal, include the full spectrum of HAND, ideally carefully control for co-morbidities, and be based on optimal neuropsychology methods.

The Journal of Infectious Diseases, Aug 1, 1996

Journal of Neurology, Neurosurgery, and Psychiatry, Jul 1, 2019

estimate the cost and morbidity associated with the diagnostic investigation of patients with tum... more estimate the cost and morbidity associated with the diagnostic investigation of patients with tumefactive demyelination (TD) compared to patients with conventional relapsing-remitting MS. Methods Retrospective review of patients seen between 2013-2018 in clinics at the Brain and Mind Centre, Sydney; a centre with tertiary referral expertise in MS. Records were searched for the terms 'tumefactive' and 'pseudotumour'. All patients diagnosed with TD were included and paired with a patient of similar age diagnosed in the same year with MS according to 2010 McDonald criteria. Results There were 31 patients with TD and 31 patients with conventional relapsing remitting MS. The estimated cost of investigating TD was more than 7.5 times higher per patient than in MS ($18,300 AUD vs $2,418 AUD, p<0.001). Brain biopsy was performed in 6/31 TD patients and 0/31 MS patients and was the cause of more adverse outcomes in the TD versus MS group. More patients in the TD group were admitted to hospital (22/31 vs 10/31) and ICU admissions only occurred in the TD group (10/22 vs 0/10). Conclusion The cost and adverse outcomes associated with investigating TD are higher than in conventional MS. Improvements in the diagnosis of TD have the potential to improve health and economic outcomes.