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    Nitrous oxide-induced neurological disorders: an increasing public health concern.
    Redmond, J ; Cruse, B ; Kiers, L (Wiley, 2022-05)
    BACKGROUND: Neurological presentations resulting from nitrous oxide (N2 O) abuse are increasing in Australia and worldwide. Despite known neuropsychiatric sequelae, N2 O canisters remain readily available and its use unregulated. AIMS: To examine the demographics, clinical and electrophysiological findings of patients presenting with neurological complications of N2 O abuse, and thus inform clinicians and public health decision-makers of the significant public health concerns of this increasing practice. METHODS: Consecutive patients presenting to a tertiary referral metropolitan hospital were included in this series. Patients were identified by a search of discharge summaries of patients admitted with acute or subacute neuropathy or myelopathy and a history of N2 O abuse, and from the electrophysiology database. RESULTS: Thirteen patients were identified, most presenting with subacute paraesthesia, sensory ataxia and lower limb weakness. Eleven had low serum vitamin B12 . Spinal magnetic resonance imaging was consistent with subacute combined degeneration in eight. Nerve conduction studies revealed a motor or sensorimotor axonal neuropathy (three with motor predominance). There was a bimodal demographic distribution consisting of socially isolated, international university students and local residents with a history of mental illness and polydrug abuse. CONCLUSIONS: Recreational N2 O use is an emerging health problem in Australia. International university students and patients with pre-existing mental illness or polydrug use appear to be at increased risk. A severe motor neuropathy may emerge following vitamin B12 replacement. Public health measures are required to limit the availability of N2 O and to educate adolescents and young adults about the potential for significant harm.
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    Examining the structural correlates of amyloid‐beta in people with DLB
    Gajamange, S ; Yassi, N ; Chin, KS ; Desmond, PM ; Villemagne, VL ; Rowe, CC ; Watson, R (Wiley, 2021-12)
    Background Dementia with Lewy bodies (DLB) is a neurodegenerative disorder characterized pathologically by the deposition of alpha synuclein. Many patients with DLB also have brain compatible with Alzheimer’s disease (namely Amyloid‐β and tau), which can lead to challenges with clinical diagnosis and management. In this study we aim to understand the influence of Aβ on brain atrophy in DLB patients. Method 19 participants with probable DLB underwent 3T MRI T1‐weighted (voxel size=0.8x0.8x0.8mm3, TR=2400ms, TE=2.31ms) and β‐amyloid (Aβ) PET (radiotracer 18F‐NAV4694) imaging. Participants were grouped into Aβ negative (n=10; age=71.6±5.8 years) and Aβ positive (n=9; age=75.1±4.3 years) with a threshold of 50 centiloid units to identify neuropathological change (Amadoru et al. 2020). Brain volume measures (regional subcortical grey matter and global white and grey matter) were segmented from T1‐weighted images with FreeSurfer (Fischl et al. 2002, Fischl 2012). Given previous literature suggesting prominence of thalamic structural changes in DLB, we also specifically analysed changes in the thalamus by segmenting the thalamus into 25 nuclei, which were then grouped into six regions (anterior, lateral, ventral, intralaminar, medial and posterior) (Watson et al. 2017, Iglesias et al. 2018). All brain volumes were expressed as fractions of intracranial volume to account for differences in head size. Group comparison analyses were not controlled for age and sex as both these covariates did not statistically differ between groups. Result Brain volume differed significantly between Aβ‐ and Aβ+ DLB patients in the left thalamus (Aβ‐:4.39±0.37x103, Aβ+:4.07±0.19x103, p=0.03) and right thalamus (Aβ‐:4.17±0.34x103, Aβ+:3.84±0.22 x103, p=0.03). Specifically, the ventral (LEFT; Aβ‐:1.78±0.15, Aβ+:1.63±0.14, p=0.03. RIGHT; Aβ‐:1.83±0.15, Aβ+:1.65±0.12, p=0.01) and posterior (LEFT; Aβ‐:1.30±0.12, Aβ+:1.17±0.10, p=0.04. RIGHT; Aβ‐:1.42±0.14, Aβ+:1.21±0.12, p=0.003) regions were significantly reduced in Aβ+ compared to Aβ‐ DLB patients. Conclusion We demonstrated significant thalamic atrophy in Aβ+ patients compared to Aβ‐ DLB patients. We did not observe significant differences in grey matter and hippocampal volume between patient groups. This study showed that AD‐related processes in DLB patients are associated with thalamic atrophy, specifically in the ventral and posterior regions. Future studies would benefit a larger DLB cohort to further understand the association between AD‐related pathology and the regional thalamic correlates of clinical function.
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    Differential associations of modifiable and non‐modifiable dementia risk factors with memory decline and hippocampal volume loss in Aβ‐ and Aβ+ cognitively normal older adults
    Rosenich, E ; Pase, MP ; Yassi, N ; Fripp, J ; Laws, SM ; Fowler, CJ ; Rowe, CC ; Masters, CL ; Maruff, PT ; Lim, YY ; Group, AIBLR (Wiley, 2021-12)
    Abstract Background The extent to which modifiable and non‐modifiable risk factors contribute to cognitive decline in older people remains unclear. We sought to determine the association of modifiable and non‐modifiable components included in the Cardiovascular Risk Factors, Aging, and Incidence of Dementia (CAIDE) score with memory decline and brain volume loss in cognitively normal (CN) older adults, taking Aβ status into account. Method AIBL study participants (age range: 60‐90) who completed ≥2 neuropsychological assessments and an Aβ PET scan (N=626) were included in this study. We computed the standard CAIDE (age, sex, APOE ε4 status, education, hypertension, body mass index, hypercholesterinemia, physical inactivity), and a modifiable CAIDE (modCAIDE; education, modifiable vascular risk factors) for each participant. Aβ+ was classified using a Centiloid ≥25. Linear mixed models assessed interactions between each CAIDE score on episodic memory (EM) and hippocampal volume (HV) over time in Aβ‐ and Aβ+ CNs. Non‐modifiable variables from the standard CAIDE (age, sex, ε4) were included as separate predictors in all modCAIDE models to assess differential associations. Result We observed a significant standard CAIDE x time interaction on EM decline in Aβ+ (β=‐0.08(0.04); p=0.02) and Aβ‐ participants (β=‐4.07(1.13); p<0.001), and a significant standard CAIDE x time interaction on HV loss in Aβ+ participants only (β=‐0.06(0.02); p=0.003). When modifiable and non‐modifiable CAIDE components were considered separately, we observed a significant ε4 x time interaction only for EM decline (β=‐0.32(0.07); p<0.001) and HV loss (β=‐0.13(0.04); p<0.001) in Aβ+ participants, but no significant modCAIDE x time interaction (both p’s>0.29). In Aβ‐ participants, we observed a significant modCAIDE x time interaction on memory decline (β=‐0.04(0.02); p=0.02), but no significant ε4 x time interaction (β=‐0.07(0.04); p=0.11). No significant ε4 x time or modCAIDE x time interactions were observed for HV loss in Aβ‐ participants. Conclusion Our results are consistent with previous studies showing that ε4 is associated with an increased rate of EM decline and HV loss in Aβ+ CNs. In Aβ‐ CNs, lower prevalence of modifiable cardiovascular risk factors was associated with better EM performance over time, suggesting interventions to reduce modifiable risk factors could be beneficial in this group.
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    Association of neighborhood‐level socioeconomic advantage with cognition and dementia risk factors in an Australian cohort
    Cavuoto, MG ; Rowsthorn, E ; Lavale, A ; Yassi, N ; Maruff, PT ; Buckley, RF ; Lim, YY ; Pase, MP (Wiley, 2021-12)
    Abstract Background Residing in areas of low socioeconomic advantage is associated with increased risk of dementia1 and associated brain pathology2,3. Given the long and insidious course of dementia pathologies, it is critical to establish the effect of ‘exposomic’ risk factors in midlife and to understand which groups of people are particularly vulnerable. Therefore, the objective of this study was to examine whether cognitive performance or dementia risk factors differed according to neighborhood‐level socioeconomic advantage in cognitively normal middle‐aged people. Methods Our sample comprised 4798 participants from the Healthy Brain Project, an online cohort of community‐dwelling Australians aged 40‐70 years. Socioeconomic advantage was computed by matching participants’ residential address to the Australian Bureau of Statistics’ Index of Relative Socioeconomic Advantage and Disadvantage (IRSAD), assigning each participant a decile score (10 being the most advantaged). Scores were related to dementia risk estimated using the CAIDE dementia risk score and cognitive performance measured with the Cogstate Brief Battery (CBB) in linear regression models. Results Of the 4798 participants (mean age±SD 56±7 years, 26% male), 2762 (58%) were classified as living within an area of high neighbourhood socioeconomic advantage (IRSAD scores ≥ 8th decile), 1296 resided in rural or regional areas (27%), and 984 identified as “non‐European” (21%). Each decile unit increase in neighborhood socioeconomic advantage was associated with a lower CAIDE dementia risk score (β±SE= ‐0.088±0.024, p <0.001), following adjustments for race and rurality, and with better memory performance (β±SE= 0.084±0.024, p <0.001), following adjustments for age, sex, race, education, and rurality. An interaction was observed with differences in memory performance between levels of neighborhood advantage (comparing scores above and below the 8th decile) being larger at older ages and in people with higher dementia risk scores (Figure 1). There was no association between neighborhood‐level advantage and attention. Conclusions In a middle‐aged Australian cohort, higher neighborhood‐level socioeconomic advantage was associated with superior memory and lower dementia risk scores. Efforts to lower dementia risk factors, particularly in relation to reducing the negative impacts of disadvantage, are needed to curtail the growing burden of dementia.
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    The cumulative effect of cognitive engagement on cognitive function in middle‐aged adults
    Bransby, L ; Buckley, RF ; Yassi, N ; Pase, MP ; Lim, YY (Wiley, 2021-12)
    Abstract Background Engagement in cognitively stimulating work and activities is proposed to slow cognitive decline and delay dementia. Few studies have considered the cumulative effect of multiple cognitively engaging factors on cognitive function. In middle‐aged adults, this study aimed to determine the individual and combined associations of four cognitive engagement factors (i.e., educational attainment, occupational complexity, social engagement and cognitively stimulating leisure activities) with objectively measured cognitive performance and subjective ratings of cognitive function. Method A total of 1864 cognitively normal middle‐aged adults (aged 40‐70) enrolled in the Healthy Brain Project, a study with an online remote assessment platform seeking to understand midlife risk factors for dementia. Cognitive engagement factors were measured by online self‐report questionnaires. The Cogstate Brief Battery was used to measure cognitive domains of attention and memory. Subjective ratings of cognitive function were measured using the Cognitive Function Instrument. Result After controlling for age, sex, ethnicity and mood symptomatology, participants with high educational attainment or high occupational complexity performed significantly better on attention and memory tasks and reported less subjective ratings of cognitive concern. Higher participation in cognitively engaging leisure activities was significantly associated with better attention and memory performance, but not with subjective ratings of cognitive function. Social engagement was not associated with any outcome. The magnitude of these effects was small and trivial (Cohen’s d ranging from 0‐0.17). Participants were then classified into five groups based on whether they rated highly in 0‐4 cognitive engagement factors. Compared to participants with no factors, participants scoring highly in 2 or more factors performed significantly better on the memory tasks, with the magnitude of difference moderate (Cohen’s d ranging from 0.30‐0.49). Conclusion These results suggest a cumulative relationship between high cognitive engagement across several domains of life and better memory performance in cognitively normal middle‐aged adults.
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    Comparison of white matter hyperintensity abnormalities and cognitive performance in individuals with low and high cardiovascular risk: Data from the Diabetes and Dementia (D2) study
    Restrepo, C ; Patel, S ; Khlif, MS ; Bird, LJ ; Singleton, R ; Yiu, CHK ; Werden, E ; Ekinci, E ; MacIsaac, R ; Burrell, L ; Brodtmann, A (Wiley, 2021-12)
    Abstract Background Type 2 diabetes Mellitus (T2DM) is recognised as a major contributor to cognitive decline. People with T2DM demonstrate increased white matter hyperintensity (WMH) abnormalities on MRI compared to control individuals. We investigated associations between a validated vascular risk score: The Framingham Risk Score (FRS), WMH volumes and cognitive function in the Diabetes‐and‐Dementia (D2) study, a longitudinal cohort study of community dwelling people with T2DM. Method One hundred and twenty‐three non‐demented participants with T2DM (age 66.7±6.8 years, range 50‐80, 68M/55F) completed neuropsychological assessments, health questionnaires to allow FRS calculation, 24‐hour ambulatory blood pressure monitoring, and a 3T‐MRI scan. WMH were calculated using the functionality "run‐samseg" in FreeSurfer 7. Quality control on the traced lesions was performed using an in‐house semi‐automated MATLAB tool. Periventricular and deep WMH volumes were estimated based on the edited lesion traces. We divided participants into low (n=61) and high (n=62) FRS groups based on the median score (x=48.7). Differences in WMH volumes were compared between the FRS groups after correcting for sex and age. We compared cognitive performance between low/high FRS individuals across five composite cognitive domains: memory, language, visuospatial skills, executive function, and attention‐and‐processing‐speed. The composite score for each domain was the normalised z‐scores average for the respective tests. Result Participants with high FRS (implicating greater vascular risk) were significantly older (age F(1, 122)=14.97; p<0.001), were less likely to be female (sex χ2=16.73, p<0.001), and tend to have less than 12 years of education (χ2= 3.69, p = 0.041). Relative to individuals with low FRS, those with high FRS showed significantly higher WMH volumes (F(1, 121)=6.11; p=0.015). Significant differences were also identified for periventricular (F(1, 121)=6.16; p=0.014) and deep (F(1, 121)=4.25; p=0.042) WMH volumes. When the cognitive data were analysed, the low FRS group performed signifcantly better than the high FRS group only on the attention‐and‐processing‐speed factor (F(1,115)=5.17; p=0.025). Conclusion High cardiovascular risk, defined as a high FRS, in participants with T2DM was associated with greater WMH volume, a marker of white matter dysfunction, and with deficits in processing speed and attention. Subclinical cognitive deficits were common in our community dwelling cohort without known or preceding cognitive dysfunction.
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    Plasma neurofilament light chain and phosphorylated tau 181 in neurodegenerative and psychiatric disorders: moving closer towards a simple diagnostic test like a 'C‐reactive protein' for the brain?
    Eratne, D ; Santillo, A ; Li, Q ; Kang, M ; Keem, M ; Lewis, C ; Loi, SM ; Walterfang, M ; Hansson, O ; Janelidze, S ; Yassi, N ; Watson, R ; Berkovic, SF ; Masters, CL ; Collins, S ; Velakoulis, D (Wiley, 2021-12)
    Abstract Background Accurate, timely diagnosis of neurodegenerative disorders, in particular distinguishing primary psychiatric from neurological disorders and in younger people, can be challenging. There is a need for biomarkers to reduce the diagnostic odyssey and improve outcomes. Neurofilament light (NfL) has shown promise as a diagnostic biomarker in a wide range of disorders. Our Markers in Neuropsychiatric Disorders (MiND) Study builds on our pilot (Eratne et al, ANZJP, 2020), to explore the diagnostic and broader utility of plasma and cerebrospinal fluid (CSF) NfL and other novel markers such as phosphorylated tau 181 (p‐tau181), in a broad range of psychiatric and neurodegenerative/neurological disorders, with a view of translation into routine clinical practice. Methods We assessed plasma and/or CSF NfL and p‐tau181 concentrations in broad cohorts, including: patients assessed for neurocognitive/psychiatric symptoms at Neuropsychiatry and Melbourne Young‐Onset Dementia services and other services, in a wide range of disorders including Alzheimer disease, frontotemporal dementia, schizophrenia, bipolar disorder, depression, Niemann‐Pick Type C, epilepsy, functional neurological disorders. The most recent primary consensus diagnosis informed by established diagnostic criteria was categorised: primary psychiatric disorder (PPD), neurodegenerative/neurological disorder (ND), or healthy controls (HC). Results Findings from over 500 patients/participants will be presented, which indicate that CSF and plasma NfL levels are significantly elevated in a broad range of ND compared to a broad range of PPD, and HC, and bvFTD progressors from phenocopy syndromes, differentiating with areas under the curve of >0.90, sensitivity and specificity >90%. Plasma P‐tau181 levels distinguished Alzheimer disease (mainly younger sporadic), compared to other neurodegenerative disorders, with AUC 0.90, 90% sensitivity and specificity. As recruitment, sample analysis, data collection is ongoing, the most up to date results will be presented. Conclusions NfL shows great promise as a diagnostic test to assist with the common, challenging diagnostic dilemma of distinguishing neurodegenerative from non‐neurodegenerative and primary psychiatric disorders. Plasma p‐tau181 shows strong diagnostic utility in younger‐onset Alzheimer disease. A significantly elevated NfL in someone with a psychiatric diagnosis should prompt consideration of neurodegenerative differentials. Plasma NfL could dramatically alter clinical care of patients with neuropsychiatric and neurological symptoms, improving outcomes for patients, their families, the healthcare system, and clinical trials.
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    Could cerebrospinal fluid neurofilament light chain reduce misdiagnosis in neurodegenerative and neuropsychiatric disorders in a real‐world setting? A retrospective clinical and diagnostic utility study
    Kang, M ; Dobson, H ; Li, Q ; Keem, M ; Loi, SM ; Masters, CL ; Collins, S ; Velakoulis, D ; Eratne, D (Wiley, 2021-12)
    Abstract Background Patients presenting with neuropsychiatric symptoms often face significant diagnostic odyssey. Our recent research (Eratne et al, ANZJP, 2020) found neurofilament light (NfL) differentiated between neurodegenerative and psychiatric disorders, with high accuracy. Yet the clinical utility of NfL, as to whether it can aid clinicians in avoiding misdiagnosis in a real‐world clinical setting, is unknown. Our primary aim was to measure the rates of diagnostic change in patients with neuropsychiatric symptoms assessed at a tertiary multidisciplinary service, and determine whether baseline cerebrospinal (CSF) NfL level could have prevented misdiagnoses, by predicting the final diagnosis after follow up. Methods We conducted a retrospective file review of patients assessed at an Australian neuropsychiatry and young‐onset dementia service between 2009‐2020. NfL levels were measured from CSF collected at their baseline assessment. Blinded investigators (MK, HD, DE) extracted clinical data including diagnoses from discharge summaries and outpatient letters from the initial assessment and re‐assessment. Baseline and final diagnoses were categorised as neurodegenerative disorder [ND], or, other non‐neurodegenerative conditions including primary psychiatric disorder [Other/PPD]. We also obtained follow‐up information on patients that were subsequently seen at external services where available. Results From a preliminary analysis of those with follow‐up information for at least a year (N=32), six patients’ diagnostic categories (19%) were revised (ND to Other/PPD=5; Other/PPD to ND=1). In all six cases (figure 2), baseline CSF NfL levels, using our previously established cut‐off, would have predicted the final revised diagnosis. As this study is underway, findings for over 200 patients will be presented for the Conference. Conclusions In a real‐world tertiary clinical setting, baseline CSF NfL would have accurately predicted diagnostic change, showing promise to aid clinicians assessing patients with neuropsychiatric symptoms, and reduce misdiagnosis. An elevated level could help exclude primary psychiatric provisional or differential diagnoses, and prompt assertive investigations for neurological and neurodegenerative causes. Conversely, a low NfL, could reassure against a neurodegenerative disorder, preventing unnecessary assessments. Timely and accurate diagnosis will reduce uncertainty, enable early care planning, reduce patient and carer burden, thus improving outcomes and the diagnostic odyssey faced by patients and families.
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    The diagnostic challenge among young onset dementia syndromes and primary psychiatric diseases: Results of a retrospective, 20‐year cross‐sectional study
    Tsoukra, P ; Velakoulis, D ; Wibawa, P ; Malpas, CB ; Walterfang, M ; Evans, AH ; Farrand, S ; Kelso, W ; Eratne, D ; Loi, SM (Wiley, 2021-12)
    Abstract Background Distinguishing a dementia syndrome from a primary psychiatric disease in younger patients can be challenging and may lead to diagnostic change over time. The aim of this study was to examine diagnostic stability in a cohort of patients with younger‐onset neurocognitive disorders. Method We retrospectively reviewed records of patients that were admitted to our unit between 2000 and 2019, were followed‐up for ≥12 months and received a diagnosis of young onset dementia at any time point. Initial diagnosis included Alzheimer disease (AD)‐type dementia (n= 30), frontotemporal dementia (FTD) syndromes (n=44), vascular dementia (VaD, n=7), mild cognitive impairment (MCI, n= 10), primary psychiatric diseases (n=6) and other conditions such as Lewy Body Dementia (n=30). Result In a total of n=127 patients, 49 (39%) changed their initial diagnoses during follow‐up. Behavioural variant FTD (bvFTD) was the least stable diagnosis, followed by dementia not otherwise specified and MCI. Compared to patients with a stable diagnosis, those who changed exhibited: a higher cognitive score at baseline, a longer follow‐up period, greater delay to final diagnosis, and no family history of dementia. Patients switching from a neurodegenerative to a psychiatric diagnosis more likely had a long psychiatric history, while those changing from a psychiatric to a neurodegenerative diagnosis had a recent manifestation of psychiatric symptoms. Conclusion Misdiagnosis in younger patients with neurocognitive disorders is not uncommon, especially in cases of behavioural variant FTD. Late‐onset psychiatric symptoms may be the harbinger to a neurodegenerative disease. Close follow‐up and monitoring of these patients are necessary.
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    Mortality in FTD: An Australian perspective.
    Loi, SM ; Chen, B ; Tsoukra, P ; Eratne, D ; Wibawa, P ; Farrand, S ; Kelso, W ; Evans, AH ; Walterfang, M ; Velakoulis, D (Wiley, 2021-12)
    THEME: Clinical manifestations TOPIC: Neuropsychiatry & beh neurology SUBTOPIC: Neuropsychiatry BACKGROUND: Survival duration in frontotemporal dementia (FTD) remains inconsistent, depending on the clinical phenotype with different risk factors identified. Risk factors to mortality include the FTD-MND presentation, a genetic predisposition (Agarwal S et al. 2019), deficits in neuropsychological tests, imaging changes (Agarwal et al. 2019; Hodges et al. 2003) and non-tau pathology (Roberson et al. 2005; Hodges et al. 2003). We aimed to identify survival duration and cause of death in this group. METHOD: All inpatients admitted to Neuropsychiatry, based at the Royal Melbourne Hospital, in metropolitan Australia from 1992 - 2014, who were diagnosed with probably FTD of any subtype were included. Linkage data was obtained by the Australian Institute of Health and Welfare (AIHW). We reviewed their clinical information including demographics, age of symptom onset, type of presenting symptom, neuroimaging and diagnosis. RESULT: Of the 528 individual inpatients identified with a dementia, there were n=100 who had a diagnosis of probable FTD. There were n=76 who had a behavioural-variant FTD (bv-FTD), n=14 who had a language-variant FTD (lang-FTD) and n=10 who had FTD-MND. 67% of the group had died. Overall median duration of survival was 10.5 years (95% CI 7.9, 12.2). There were no differences in age of death nor age onset between the three FTD-subtypes (p=0.479, p=0.289, respectively). As expected, there were significant differences in the median survival duration of the three FTD subtypes, with FTD-MND having the shortest duration (p=0.004). Causes of death based on ICD-10 were predominantly dementia-related (26.3% Other degenerative diseases of nervous system; 17.5% unspecified dementia) but also included acute myocardial infarction (7%) and alcohol-related (7%). Standardised mortality ratios (SMRs) revealed that compared to population norms, people with FTD had 8x mortality rate. CONCLUSION: Not unsurprisingly, FTD-MND had the shortest duration compared to the other subtypes of FTD. The duration of survival was comparable to other studies. Causes of death revealed that a dementia was identified in almost half of cases. High SMRs suggest that FTD is a particularly "fatal" type of dementia in younger people. Investigation into risk factors to death is required.