Medicine (RMH) - Research Publications
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ItemPlasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders(SAGE PUBLICATIONS LTD, 2024-01)OBJECTIVE: Blood biomarkers of neuronal injury such as neurofilament light (NfL) show promise to improve diagnosis of neurodegenerative disorders and distinguish neurodegenerative from primary psychiatric disorders (PPD). This study investigated the diagnostic utility of plasma NfL to differentiate behavioural variant frontotemporal dementia (bvFTD, a neurodegenerative disorder commonly misdiagnosed initially as PPD), from PPD, and performance of large normative/reference data sets and models. METHODS: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), bvFTD (n = 22), and compared to the reference cohort (Control Group 2, n = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, n = 96, using general linear models). RESULTS: Large differences were seen between bvFTD (mean NfL 34.9 pg/mL) and all PPDs and controls (all < 11 pg/mL). NfL distinguished bvFTD from PPD with high accuracy, sensitivity (86%), and specificity (88%). GAMLSS models using reference Control Group 2 facilitated precision interpretation of individual levels, while performing equally to or outperforming models using local controls. Slightly higher NfL levels were found in BPAD, compared to controls and TRS. CONCLUSIONS: This study adds further evidence on the diagnostic utility of NfL to distinguish bvFTD from PPD of high clinical relevance to a bvFTD differential diagnosis, and includes the largest cohort of BPAD to date. Using large reference cohorts, GAMLSS modelling and the interactive Internet-based application we developed, may have important implications for future research and clinical translation. Studies are underway investigating utility of plasma NfL in diverse neurodegenerative and primary psychiatric conditions in real-world clinical settings.
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ItemNo Preview AvailableAssociations between dual‐decline in cognition and gait speed with risk of dementia – results from the ASPREE trial cohort(Wiley, 2022-12)Background Dual decline in gait speed and cognition is associated with an increased risk of dementia. However, it is unclear if risks are conferred by decline in domain‐specific cognition and gait. We aimed to examine associations between dual decline in gait speed and cognition (global cognition, memory, processing speed and verbal fluency) with risk of dementia. Methods Prospective cohort study. Participants were from the ASPREE (ASPirin in Reducing Events in the Elderly) study, a double‐blind, randomized, placebo‐controlled trial of low dose aspirin in older adults (≥70 years; ≥65 if US minority). Of 19,114 randomized participants, 16,855 (88%) had longitudinal gait and cognitive data. Gait speed was measured at 0, 2, 4, 6 years and close‐out. Cognitive measures included Modified Mini‐Mental State examination (3MS, global cognition), Hopkins Verbal Learning Test‐Revised (HVLT‐R, memory), Symbol Digit Modalities (SDMT, processing speed) and Controlled Oral Word Association Test (COWAT‐F, verbal fluency), assessed at years 0, 1, 3, 5, and close‐out. Participants were classified into four groups: 1) dual decline in gait and cognition; 2) gait decline only; 3) cognitive decline only and 4) non‐decliners. Cognitive decline was defined as membership of the lowest tertile of annual change. Gait decline was defined as decline in gait speed ≥0.05 m/s per year across the study. Dementia (DSM‐IV criteria) was adjudicated by an expert panel using cognitive tests, functional status and clinical records. Cox proportional hazard models were used to estimate risk of dementia adjusting for covariates with death as competing risk. Results The mean age of participants was 75.0 (SD4.4) years. Compared with non‐decliners, risk of dementia was highest in the gait+HVLT‐R decliners (HR 24.7; 95% CI 16.3‐37.3), followed by the gait+3MS (HR 22.2; 95% CI 15.0‐32.9), gait+COWAT‐F (HR 4.66 95%; CI 3.5‐6.3) and gait+SDMT (HR 4.3 95% CI 3.2‐5.8) groups. Dual decliners also had higher risk of dementia than those with either gait or cognitive decline alone for 3MS and HVLT‐R. Conclusion The combination of decline in gait speed and memory may be the best suited to predict future dementia risk.
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ItemNo Preview AvailableINCREASED PLASMA NEUROFILAMENT LIGHT AND CEREBRAL ATROPHY IN PATIENTS WITH TYPE 2 DIABETES AND LEFT VENTRICULAR HYPERTROPHY(LIPPINCOTT WILLIAMS & WILKINS, 2023-01)
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ItemNo Preview AvailableChampioning Better Care for Young People with Stroke: Australia's New Young Stroke Service(Sage, 2023-08)Background: The Australian Stroke Clinical Registry collects information on national acute stroke care standards. Variation in care between hospitals impacts patient outcomes. Aims: To illustrate hospital performance in four priority areas of acute stroke care (stroke unit treatment, time to neuroimaging, thrombolysis door-to-needle time (DTNT), and swallowing assessments). Methods: Across 7 states/territories, 60 adult public hospitals provided 2021 data. Adherence was determined as the percentage of eligible patients treated. Funnel plots were used identify exceptional (>3 standard deviations above national average) and poor (>3 standard deviations below national average) performance. For continuous outcomes (neuroimaging timing or DTNT), we described hospitals with performance outside of the national interquartile range. Results: Overall, 16,458 episodes of stroke were analysed (median age 75 years, 43% female, 81% ischaemic). There were 27 hospitals with exceptional adherence to stroke unit care, 13 with poor adherence and 3 with no episodes treated in a stroke unit. Stroke unit treatment was less common in regional hospitals (68% vs metropolitan 80%, p<0.001). Median time from arrival to neuroimaging was 41 minutes, 2 hospitals were above the 75th percentile (>87 minutes) and 5 hospitals were below the 25th percentile (<20 minutes). Among 1320 patients with ischaemic stroke who received intravenous thrombolysis, the median DTNT was 77 minutes. Only 5 (8%) hospitals had a median DTNT ⩽60 minutes, 4 (7%) below the 25th percentile (56.5 minutes), while 18 (30%) had DTNT above the 75th percentile (107 minutes). Only 58% of all patients had their swallowing screened/assessed prior to oral intake; and 29% within 4 hours of arrival (9 hospitals with exceptional adherence; 12 with poor adherence). Conclusion: Despite strong evidence for recommended acute stroke care practices, there remains significant variation between Australian hospitals. The standardised registry data are essential to identifying areas for improvement against national benchmarks and to support stroke unit certification.
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ItemNo Preview AvailableContinued white matter fibre degeneration over 3 years after ischemic stroke(Wiley, 2021-12)Abstract Background We aimed to chart white matter integrity over 3 years after stroke, to examine if post‐stroke loss of white matter continues to be accelerated compared to control participants. Method We applied a longitudinal “fixel”‐based analysis, sensitive to fibre tract‐specific differences within a voxel, to assess axonal loss in stroke (N=71, 22 women) compared to control participants (N=36, 13 women) across the whole brain. We studied microstructural differences in fibre density and macrostructural (morphological) changes in fibre cross‐section. Result In stroke participants, we observed significantly lower fibre density and cross‐section from 3 months to 3 years. The changes were widespread and affected the corpus callosum, bilateral inferior fronto‐occipital fasciculus, right superior longitudinal fasciculus. Conclusion We conclude that ischemic stroke is associated with extensive and continued neurodegeneration that significantly affects white matter micro and macrostructure across the whole brain. These findings confirm that the deleterious effects of stroke on white matter continue several years following the event.
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ItemNo Preview AvailableThe effects of concurrent cognitive and meta-cognitive training on neuropsychiatric symptoms of people living with younger onset dementia: Protocol for a pilot trial(Wiley, 2021-12-01)BACKGROUND: Neuropsychiatric symptoms (NPS) are behavioural and psychological disturbances frequent in people with dementia that have been linked with lower quality of life, lower cognitive functioning and greater caregiver distress, especially for caregivers of people with younger-onset dementia (YOD) (1). Several drug and non-drug treatments targeting NPS have been investigated in recent years. However, to the best of our knowledge, no treatment has been developed that concurrently targets and trains cognitive and meta-cognitive processes which are implicated in the expression of NPS. The aim of this pilot trial is to investigate the effects on NPS of a mobile application-based intervention simultaneously training both processes by incorporating elements of cognitive training and cognitive-behavioural therapy. METHOD: Twenty participants with YOD will be randomised to the training group or to a control group. Participants in the experimental condition will train at home three times a week for four weeks with remote therapist support. NPS, cognitive, psychological and caregiver outcomes will be assessed before and immediately after the intervention. RESULT: The mobile application is in the design stage and further studies are underway to incorporate the views of people with YOD and their care-partners, as well as clinicians, to the design. Recruitment of participants is expected in the second half of 2021. CONCLUSION: Findings from this trial will further our understanding of the utility of concurrently targeting cognitive and meta-cognitive processes in people with YOD when treating NPS and will inform a revision of the application. We believe that results from this study will have important implications for the management and treatment of NPS in the ever-growing field of interventions utilising technology. 1 Baillon, S., Gasper, A., Wilson-Morkeh, F., Pritchard, M., Jesu, A. and Velayudhan, L., 2019. Prevalence and Severity of Neuropsychiatric Symptoms in Early- Versus Late-Onset Alzheimer's Disease. American Journal of Alzheimer's Disease & Other Dementias®, 34(7-8), pp.433-438.
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ItemNo Preview AvailableComparison of white matter hyperintensity abnormalities and cognitive performance in individuals with low and high cardiovascular risk: Data from the Diabetes and Dementia (D2) study(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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ItemNo Preview AvailableThe relationship between long-term blood pressure variability and cortical thickness in older adults(ELSEVIER SCIENCE INC, 2023-09)High blood pressure variability (BPV) is a risk factor for cognitive decline and dementia, but its association with cortical thickness is not well understood. Here we use a topographical approach, to assess links between long-term BPV and cortical thickness in 478 (54% men at baseline) community dwelling older adults (70-88 years) from the ASPirin in Reducing Events in the Elderly NEURO sub-study. BPV was measured as average real variability, based on annual visits across three years. Higher diastolic BPV was significantly associated with reduced cortical thickness in multiple areas, including temporal (banks of the superior temporal sulcus), parietal (supramarginal gyrus, post-central gyrus), and posterior frontal areas (pre-central gyrus, caudal middle frontal gyrus), while controlling for mean BP. Higher diastolic BPV was associated with faster progression of cortical thinning across the three years. Diastolic BPV is an important predictor of cortical thickness, and trajectory of cortical thickness, independent of mean blood pressure. This finding suggests an important biological link in the relationship between BPV and cognitive decline in older age.
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ItemPsychometric deficits in autoimmune encephalitis: A retrospective study from the Australian Autoimmune Encephalitis Consortium(WILEY, 2022-08)BACKGROUND AND PURPOSE: Despite the rapid increase in research examining outcomes in autoimmune encephalitis (AE) patients, there are few cohort studies examining cognitive outcomes in this population. The current study aimed to characterise psychometric outcomes in this population, and explore variables that may predict psychometric outcomes. METHODS: This retrospective observational study collected psychometric data from 59 patients across six secondary and tertiary referral centres in metropolitan hospitals in Victoria, Australia between January 2008 and July 2019. Frequency and pattern analysis were employed to define and characterize psychometric outcomes. Univariable logistic regression was performed to examine predictors of intact and pathological psychometric outcomes. RESULTS: Deficits in psychometric markers of executive dysfunction were the most common finding in this cohort, followed by deficits on tasks sensitive to memory. A total of 54.2% of patients were classified as having psychometric impairments across at least two cognitive domains. Twenty-nine patterns were observed, suggesting outcomes in AE are complex. None of the demographic data, clinical features or auxiliary examination variables were predictors of psychometric outcome. CONCLUSIONS: Cognitive outcomes in AE are complex. Further detailed and standardized cognitive testing, in combination with magnetic resonance imaging volumetrics and serum/cerebrospinal fluid biomarkers, is required to provide rigorous assessments of disease outcomes.