Psychiatry - 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 AvailableCerebrospinal fluid neurofilament light chain differentiates behavioural variant frontotemporal dementia progressors from ‘phenocopy’ non‐progressors(Wiley, 2022-12)Background Distinguishing behavioural variant frontotemporal dementia (bvFTD) from non‐neurodegenerative ‘non‐progressor’, ‘phenocopy’ mimics of frontal lobe dysfunction, can be one of the most challenging clinical dilemmas. A biomarker of neuronal injury, neurofilament light chain (NfL), could reduce misdiagnosis and delay. Method Cerebrospinal fluid (CSF) NfL, amyloid beta 1‐42 (AB42), total and phosphorylated tau (T‐tau, P‐tau) levels were examined in patients with an initial diagnosis of bvFTD. Based on follow up information, patients were categorised as Progressors. Non‐Progressors were subtyped in to Phenocopy Non‐Progressors (non‐neurological/neurodegenerative final diagnosis), and Static Non‐Progressors (static deficits, not fully explained by non‐neurological/neurodegenerative causes). Result Forty‐three patients were included: 20 Progressors, 23 Non‐Progressors (15 Phenocopy, 8 Static), 20 controls. NfL concentrations were lower in Non‐Progressors (Non‐Progressors Mean, M=554pg/mL, 95%CI:[461, 675], Phenocopy Non‐Progressors M=459pg/mL, 95%CI:[385, 539], Static Non‐Progressors M=730pg/mL, 95%CI:[516, 940]), compared to bvFTD Progressors (M=2397pg/mL, 95%CI:[1607, 3332]). NfL distinguished Progressors from Non‐Progressors with the highest accuracy (area under the curve 0.92, 90%/87% sensitivity/specificity, 86%/91% positive/negative predictive value, 88% accuracy). Static Non‐Progressors tended to have higher T‐tau and P‐tau levels compared to Phenocopy Non‐Progressors. Conclusion This study demonstrated strong diagnostic utility of CSF NfL in distinguishing bvFTD from phenocopy non‐progressor variants, at baseline, with high accuracy, in a real‐world clinical setting. This has important clinical implications to improve outcomes for patients and clinicians facing this challenging clinical dilemma, as well as for healthcare services, and clinical trials. Further research is required to investigate heterogeneity within the non‐progressor group and potential diagnostic algorithms, and prospective studies are underway assessing plasma NfL.
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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 AvailableDynamics between Neuropsychiatric Symptoms and Biomarkers: A Pilot Study(Wiley, 2021-12)Background The aetiology of neuropsychiatric symptoms (NPS) in dementia remains unclear, and currently, it is challenging to distinguish neuropsychiatric manifestations related to younger‐onset neurodegenerative diseases from those of primary psychiatric disorders. Neurofilament light chain (NfL) is a promising biomarker for axonal injury and has been found to differentiate between neurodegenerative diseases and primary psychiatric disorders. The aim was to investigate cerebrospinal fluid (CSF) NfL and its relationship with NPS and compare it with traditional biomarkers, namely Aβ and tau. Methods Retrospective data for 54 patients with younger‐onset dementia was collated (mean age ± SD, 57.9 ± 7.1, females n = 15 [28%], co‐morbid psychiatric diagnoses n = 17 [31%]). Of these, 23 had Alzheimer’s disease (AD), 14 had frontotemporal dementia (FTD), 9 had mild cognitive impairment (MCI), and 8 were diagnosed with other types of dementia. Neuropsychiatric measures were extracted from the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), the Depression Anxiety and Stress Scale 21 (DASS‐21), and the revised Cambridge Behavioural Inventory (CBI‐R). CSF biomarkers included NfL, Ab‐42, p‐tau and t‐tau. Results No significant associations between NPS and NfL was seen in patients with AD, FTD, MCI or other diagnoses. In the combined cohort, a positive correlation was found between the overall cognitive functioning and Ab‐42 levels (r = 0.47, p = 0.01), and visuoconstruction, a specific domain of cognitive functioning, was found to be positively correlated with Ab‐42 levels (r = 0.44, p = 0.03) and negatively correlated with t‐tau levels (r = ‐0.43, p = 0.03). In FTD, a positive correlation was found between stress and p‐tau levels (n = 8, r = 0.89, p = 0.04), and this correlation was stronger in patients without co‐morbid psychiatric diagnoses (n = 7, r = 0.93, p = 0.03). Conclusion The results suggest that levels of CSF biomarkers, especially Ab‐42, are linked to deficits in cognitive functioning in patients with younger‐onset dementia, and levels of p‐tau are strongly related to stress particularly in the absence of co‐morbid psychiatric diagnoses. Therefore, these biomarkers may assist in the identification of patients who are at an increased risk of developing cognitive impairment and stress.
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ItemNo Preview AvailablePlasma 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?(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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ItemNo Preview AvailableCould cerebrospinal fluid neurofilament light chain reduce misdiagnosis in neurodegenerative and neuropsychiatric disorders in a real‐world setting? A retrospective clinical and diagnostic utility study(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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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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ItemCarer burden and behavioral disturbance is similar between younger-onset Alzheimer's disease and behavioral variant frontotemporal dementia(CAMBRIDGE UNIV PRESS, 2023-02-09)OBJECTIVES: Carer burden is common in younger-onset dementia (YOD), often due to the difficulty of navigating services often designed for older people with dementia. Compared to Alzheimer's disease (AD), the burden is reported to be higher in behavioral variant frontotemporal dementia (bvFTD). However, there is little literature comparing carer burden specifically in YOD. This study hypothesized that carer burden in bvFTD would be higher than in AD. DESIGN: Retrospective cross-sectional study. SETTING: Tertiary neuropsychiatry service in Victoria, Australia. PARTICIPANTS: Patient-carer dyads with YOD. MEASUREMENTS: We collected patient data, including behaviors using the Cambridge Behavioral Inventory-Revised (CBI-R). Carer burden was rated using the Zarit Burden Inventory-short version (ZBI-12). Descriptive statistics and Mann-Whitney U tests were used to analyze the data. RESULTS: Carers reported high burden (ZBI-12 mean score = 17.2, SD = 10.5), with no significant difference in burden between younger-onset AD and bvFTD. CBI-R stereotypic and motor behaviors, CBI-R everyday skills, and total NUCOG scores differed between the two groups. There was no significant difference in the rest of the CBI-R subcategories, including the behavior-related domains. CONCLUSION: Carers of YOD face high burden and are managing significant challenging behaviors. We found no difference in carer burden between younger-onset AD and bvFTD. This could be due to similarities in the two subtypes in terms of abnormal behavior, motivation, and self-care as measured on CBI-R, contrary to previous literature. Clinicians should screen for carer burden and associated factors including behavioral symptoms in YOD syndromes, as they may contribute to carer burden regardless of the type.
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ItemNo Preview AvailableMortality in FTD: An Australian perspective.(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.