Melbourne School of Psychological Sciences - 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 AvailableThe diagnostic challenge among young onset dementia syndromes and primary psychiatric diseases: Results of a retrospective, 20‐year cross‐sectional study(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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ItemNo Preview AvailableCerebrospinal fluid neurofilament light predicts longitudinal diagnostic change in patients with psychiatric and neurodegenerative disorders(CAMBRIDGE UNIV PRESS, 2024-02)OBJECTIVE: People with neuropsychiatric symptoms often experience delay in accurate diagnosis. Although cerebrospinal fluid neurofilament light (CSF NfL) shows promise in distinguishing neurodegenerative disorders (ND) from psychiatric disorders (PSY), its accuracy in a diagnostically challenging cohort longitudinally is unknown. METHODS: We collected longitudinal diagnostic information (mean = 36 months) from patients assessed at a neuropsychiatry service, categorising diagnoses as ND/mild cognitive impairment/other neurological disorders (ND/MCI/other) and PSY. We pre-specified NfL > 582 pg/mL as indicative of ND/MCI/other. RESULTS: Diagnostic category changed from initial to final diagnosis for 23% (49/212) of patients. NfL predicted the final diagnostic category for 92% (22/24) of these and predicted final diagnostic category overall (ND/MCI/other vs. PSY) in 88% (187/212), compared to 77% (163/212) with clinical assessment alone. CONCLUSIONS: CSF NfL improved diagnostic accuracy, with potential to have led to earlier, accurate diagnosis in a real-world setting using a pre-specified cut-off, adding weight to translation of NfL into clinical practice.
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ItemNo Preview AvailableSelective perforant-pathway atrophy in Huntington disease: MRI analysis of hippocampal subfields(WILEY, 2023-09)INTRODUCTION: While individuals with Huntington disease (HD) show memory impairment that indicates hippocampal dysfunction, the available literature does not consistently identify structural evidence for involvement of the whole hippocampus but rather suggests that hippocampal atrophy may be confined to certain hippocampal subregions. METHODS: We processed T1-weighted MRI from IMAGE-HD study using FreeSurfer 7.0 and compared the volumes of the hippocampal subfields among 36 early motor symptomatic (symp-HD), 40 pre-symptomatic (pre-HD), and 36 healthy control individuals across three timepoints over 36 months. RESULTS: Mixed-model analyses revealed significantly lower subfield volumes in symp-HD, compared with pre-HD and control groups, in the subicular regions of the perforant-pathway: presubiculum, subiculum, dentate gyrus, tail, and right molecular layer. These adjoining subfields aggregated into a single principal component, which demonstrated an accelerated rate of atrophy in the symp-HD. Volumes between pre-HD and controls did not show any significant difference. In the combined HD groups, CAG repeat length and disease burden score were associated with presubiculum, molecular layer, tail, and perforant-pathway subfield volumes. Hippocampal left tail and perforant-pathway subfields were associated with motor onset in the pre-HD group. CONCLUSIONS: Hippocampal subfields atrophy in early symptomatic HD affects key regions of the perforant-pathway, which may implicate the distinctive memory impairment at this stage of illness. Their volumetric associations with genetic and clinical markers suggest the selective susceptibility of these subfields to mutant Huntingtin and disease progression.
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ItemCerebrospinal fluid neurofilament light and cerebral atrophy in younger-onset dementia and primary psychiatric disorders(WILEY, 2023-09)BACKGROUND AND AIMS: Neurodegeneration underpins the pathological processes of younger-onset dementia (YOD) and has been implicated in primary psychiatric disorders (PSYs). Cerebrospinal fluid (CSF) neurofilament light (NfL) has been used to investigate neurodegeneration severity through correlation with structural brain changes in various conditions, but has seldom been evaluated in YOD and PSYs. METHODS: This retrospective study included patients with YOD or PSYs with magnetic resonance imaging (MRI) of the brain and CSF NfL analysis. Findings from brain MRI were analysed using automated volumetry (volBrain) to measure white matter (WM), grey matter (GM) and whole brain (WB) volumes expressed as percentages of total intracranial volume. Correlations between NfL and brain volume measurements were computed whilst adjusting for age. RESULTS: Seventy patients (47 with YOD and 23 with PSY) were identified. YOD types included Alzheimer disease and behavioural variant frontotemporal dementia. PSY included schizophrenia and major depressive disorder. MRI brain sequences were either fast spoiler gradient-echo (FSPGR) or magnetization-prepared rapid acquisition gradient-echo (MPRAGE). In the total cohort, higher NfL was associated with reduced WB in the FSPGR and MPRAGE sequences (r = -0.402 [95% confidence interval (CI), -0.593 to -0.147], P = 0.008 and r = -0.625 [95% CI, -0.828 to -0.395], P < 0.001, respectively). Higher NfL was related to reduced GM in FSPGR (r = 0.385 [95% CI, -0.649 to -0.014], P = 0.017) and reduced WM in MPRAGE (r = -0.650 [95% CI, -0.777 to -0.307], P < 0.001). Similar relationships were seen in YOD, but not in PSY. CONCLUSION: Higher CSF NfL is related to brain atrophy in YOD, further supporting its use as a nonspecific marker of neurodegeneration severity.
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ItemNo Preview AvailablePlasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree relatives(SAGE PUBLICATIONS LTD, 2022-10)OBJECTIVE: Schizophrenia, a complex psychiatric disorder, is often associated with cognitive, neurological and neuroimaging abnormalities. The processes underlying these abnormalities, and whether a subset of people with schizophrenia have a neuroprogressive or neurodegenerative component to schizophrenia, remain largely unknown. Examining fluid biomarkers of diverse types of neuronal damage could increase our understanding of these processes, as well as potentially provide clinically useful biomarkers, for example with assisting with differentiation from progressive neurodegenerative disorders such as Alzheimer and frontotemporal dementias. METHODS: This study measured plasma neurofilament light chain protein (NfL) using ultrasensitive Simoa technology, to investigate the degree of neuronal injury in a well-characterised cohort of people with treatment-resistant schizophrenia on clozapine (n = 82), compared to first-degree relatives (an at-risk group, n = 37), people with schizophrenia not treated with clozapine (n = 13), and age- and sex-matched controls (n = 59). RESULTS: We found no differences in NfL levels between treatment-resistant schizophrenia (mean NfL, M = 6.3 pg/mL, 95% confidence interval: [5.5, 7.2]), first-degree relatives (siblings, M = 6.7 pg/mL, 95% confidence interval: [5.2, 8.2]; parents, M after adjusting for age = 6.7 pg/mL, 95% confidence interval: [4.7, 8.8]), controls (M = 5.8 pg/mL, 95% confidence interval: [5.3, 6.3]) and not treated with clozapine (M = 4.9 pg/mL, 95% confidence interval: [4.0, 5.8]). Exploratory, hypothesis-generating analyses found weak correlations in treatment-resistant schizophrenia, between NfL and clozapine levels (Spearman's r = 0.258, 95% confidence interval: [0.034, 0.457]), dyslipidaemia (r = 0.280, 95% confidence interval: [0.064, 0.470]) and a negative correlation with weight (r = -0.305, 95% confidence interval: [-0.504, -0.076]). CONCLUSION: Treatment-resistant schizophrenia does not appear to be associated with neuronal, particularly axonal degeneration. Further studies are warranted to investigate the utility of NfL to differentiate treatment-resistant schizophrenia from neurodegenerative disorders such as behavioural variant frontotemporal dementia, and to explore NfL in other stages of schizophrenia such as the prodome and first episode.
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ItemCerebrospinal fluid neurofilament light chain differentiates primary psychiatric disorders from rapidly progressive, Alzheimer's disease and frontotemporal disorders in clinical settings(WILEY, 2022-11)INTRODUCTION: Many patients with cognitive and neuropsychiatric symptoms face diagnostic delay and misdiagnosis. We investigated whether cerebrospinal fluid (CSF) neurofilament light (NfL) and total-tau (t-tau) could assist in the clinical scenario of differentiating neurodegenerative (ND) from psychiatric disorders (PSY), and rapidly progressive disorders. METHODS: Biomarkers were examined in patients from specialist services (ND and PSY) and a national Creutzfeldt-Jakob registry (Creutzfeldt-Jakob disease [CJD] and rapidly progressive dementias/atypically rapid variants of common ND, RapidND). RESULTS: A total of 498 participants were included: 197 ND, 67 PSY, 161 CJD, 48 RapidND, and 20 controls. NfL was elevated in ND compared to PSY and controls, with highest levels in CJD and RapidND. NfL distinguished ND from PSY with 95%/78% positive/negative predictive value, 92%/87% sensitivity/specificity, 91% accuracy. NfL outperformed t-tau in most real-life clinical diagnostic dilemma scenarios, except distinguishing CJD from RapidND. DISCUSSION: We demonstrated strong generalizable evidence for the diagnostic utility of CSF NfL in differentiating ND from psychiatric disorders, with high accuracy.
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ItemSodium selenate as a therapeutic for tauopathies: A hypothesis paper(FRONTIERS MEDIA SA, 2022-08-05)In a large proportion of individuals with fronto-temporal lobar degeneration (FTLD), the underlying pathology is associated with the misfolding and aggregation of the microtubule associated protein tau (FTLD-tau). With disease progression, widespread protein accumulation throughout cortical and subcortical brain regions may be responsible for neurodegeneration. One of the syndromes of FTLD is the behavioral variant of frontotemporal dementia (bvFTD), in which the underlying pathology is heterogenous, with half of the cases being related to FTLD-tau. Currently, there are no approved disease-modifying treatments for FTLD-tau, therefore representing a major unmet therapeutic need. These descriptive, preliminary findings of the phase 1 open-label trial provide data to support the potential of sodium selenate to halt the cognitive and behavioral decline, as well as to reduce tau levels in a small group of participants with bvFTD (N = 11). All participants were treated with sodium selenate over a period of 52 weeks. Cognition was assessed with the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG, total scores), social cognition with the Revised Self-Monitoring Scale (RSMS, total scores), behavior with the Cambridge Behavioral Inventory (CBI), and carer burden with the Caregiver Buden Scale (CBS). Fluid biomarker measures include cerebrospinal fluid of total tau (t-tau), phosphorylated tau (p-tau181), NfL, p-tau181/t-tau, t-tau/Aβ1-42, and p-tau181/Aβ1-42 levels. After treatment at follow-up, cognition and behavior showed further negative change (based on a reliable change criterion cut-off of annual NUCOG decline) in the "progressors," but not in the "non-progressors." "Non-progressors" also showed elevated baseline CSF tau levels and no increase after treatment, indicating underlying tau pathology and a positive response to sodium selenate treatment. Significant changes in MRI were not observed. The findings provide useful information for future clinical trials to systematically assess the disease-modifying treatment effects of sodium selenate in randomized controlled designs for bvFTD and FTLD-tau pathologies.
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ItemA phase 1b open-label study of sodium selenate as a disease-modifying treatment for possible behavioral variant frontotemporal dementia(WILEY, 2022)INTRODUCTION: Sodium selenate increases tau dephosphorylation through protein phosphatase 2 activation. Here we report an open-label Phase 1b study of sodium selenate as a disease-modifying treatment for behavioral variant frontotemporal dementia (bvFTD). METHODS: Twelve participants with bvFTD received sodium selenate (15 mg, three times a day) for 52 weeks. Safety assessments were carried out throughout the trial. Primary outcomes were frequency of adverse events (AEs), serious adverse events (SAEs), and discontinuations. Secondary outcomes of potential efficacy included cognitive and behavioral assessments, magnetic resonance imaging (MRI) whole brain volume, and cerebrospinal fluid (CSF) and blood total tau (t-tau), phosphorylated tau (p-tau), and neurofilament light (NfL) levels, which were measured at baseline and at week 52. RESULTS: Sodium selenate was safe and well tolerated. All participants completed the study, and the majority (64.7%) of reported AEs were mild. One SAE occurred, which was not treatment related. Small declines in MRI and cognitive and behavioral measures were observed over the treatment period. There was no evidence for change in CSF protein levels (t-tau, p-tau, or NfL). Further analysis showed two distinct groups when measuring disease progression markers over the course of the study-one (n = 4) with substantial brain atrophy (2.5% to 6.5% reduction) and cognitive and behavioral decline over the 12-month treatment period, and the second group (n = 7) with no detectable change in cognitive and behavioral measures and less brain atrophy (0.3% to 1.7% reduction). CONCLUSION: Sodium selenate is safe and well tolerated in patients with bvFTD. Randomized-controlled trials are warranted to investigate potential efficacy.
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ItemNo Preview AvailableSchizophrenia-like psychosis and aceruloplasminemia.(Informa UK Limited, 2006-12)Schizophrenia-like illnesses occur in a variety of medical and neurological conditions but to date have not been described in association with aceruloplasminemia. Aceruloplasminemia is an autosomal recessive disorder of iron metabolism which leads to iron deposition in the basal ganglia, thalamus, cerebellum and hippocampus and which usually presents in middle age with extrapyramidal symptoms and dementia. We describe a 21-year-old woman on treatment for aceruloplasminemia who presented with schizophrenia-like psychosis and declining function in the absence of neurological signs. Neuropsychological testing showed significant dominant hemisphere deficits. Magnetic resonance imaging showed bilateral iron deposition in the cerebellar dentate nuclei and thalami, frontal atrophy, and periventricular white matter hyperintensities. Functional imaging suggested global hypoperfusion. The clinical, cognitive and imaging findings were not typical for either aceruloplasminemia or schizophrenia alone and the possible relationship between the two disorders is discussed with particular reference to implications for our understanding of schizophrenia.