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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.

Objectives: Vascular dementia (VD) is one of the more common types of dementia. Much is known about VD in older adults in terms of survival and associated risk factors, but comparatively less is known about VD in a younger population. This study aimed to investigate survival in people with young-onset VD (YO-VD) compared to those with late-onset VD (LO-VD) and to investigate predictors of mortality. Design: Retrospective file review from 1992 to 2014. Setting: The inpatient unit of a tertiary neuropsychiatry service in Victoria, Australia. Participants: Inpatients with a diagnosis of VD. Measurements and methods: Mortality information was obtained from the Australian Institute of Health and Welfare. Clinical variables included age of onset, sex, vascular risk factors, structural neuroimaging, and Hachinksi scores. Statistical analyses used were Kaplan–Meier curves for median survival and Cox regression for predictors of mortality. Results: Eighty-four participants were included with few clinical differences between the LO-VD and YO-VD groups. Sixty-eight (81%) had died. Median survival was 9.9 years (95% confidence interval 7.9, 11.7), with those with LO-VD having significantly shorter survival compared to those with YO-VD (6.1 years and 12.8 years, respectively) and proportionally more with LO-VD had died (94.6%) compared to those with YO-VD (67.5%), χ2(1) = 9.16, p = 0.002. The only significant predictor of mortality was increasing age (p = 0.001). Conclusion: While there were few clinical differences, and older age was the only factor associated with survival, further research into the effects of managing cardiovascular risk factors and their impact on survival are recommended.

Background: Insomnia is one of the most common sleep disorders yet its relationship to the biology of Alzheimer’s disease remains equivocal. Objective: We investigated the cross-sectional relationship between insomnia symptom severity and cerebrospinal fluid (CSF) concentrations of Alzheimer’s disease biomarkers in a cognitively unimpaired middle-aged community sample. Methods: A total of 63 participants from the Healthy Brain Project (age = 59±7 years; 67% women) completed a lumbar puncture and two weeks of actigraphy to measure two of insomnia’s core features: difficulty initiating sleep (prolonged sleep onset latency) and difficulty maintaining sleep (wake after sleep onset [WASO] and number of awakenings). Additionally, the Insomnia Severity Index (ISI) was completed by 58 participants. Linear and Tobit regression were used to estimate the associations between each insomnia variable and CSF Aβ42, phosphorylated tau 181 (p-tau181), total-tau, and neurofilament light chain protein (NfL), adjusting for age, sex, and APOE ɛ4 genotype. Results: Higher ISI score was associated with greater average levels of CSF Aβ42 (per point: 30.7 pg/mL, 95% CI: 4.17–57.3, p = 0.023), as was higher WASO (per 10 min: 136 pg/mL, 95% CI: 48–223, p = 0.002) and more awakenings (per 5:123 pg/mL, 95% CI = 55–192, p

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.

Background: Frontotemporal dementia (FTD) syndromes, mimics, phenocopy (phFTD), and slowly progressive behavioral variant FTD (bvFTD) can be difficult to distinguish clinically. Biomarkers such as neurofilament light chain (NfL) may be helpful. Objective: To study plasma NfL levels in people with FTD syndromes and determine if plasma NfL can distinguish between FTD syndromes and phFTD. Methods: Plasma NfL levels were estimated using both Simoa® Quanterix HD-X™ and SR-X™ machines grouped via final diagnosis after investigation and review. Results: Fifty participants were studied: bvFTD = 20, semantic variant FTD (svFTD) = 11, non-fluent variant FTD (nfvFTD) = 9, FTD with motor neuron disease (MND) = 4, phFTD = 2, slow progressors = 3, FTD mimic = 1, mean age 67.2 (SD 8.4) years. NfL levels were significantly higher in the FTD group compared to phenocopy group (p = 0.003). Median NfL (IQR) pg/mL was comparable in the FTD syndromes: bvFTD 41.10 (50.72), svFTD 44.38 (16.61), and nfvFTD 42.61 (22.93), highest in FTD with MND 79.67 (45.32) and lowest in both phFTD 13.99 (0.79) and slow progressors 17.97 (3.62). Conclusion: Plasma NfL appears to differentiate FTD syndromes and mimics. However, a lower NfL may predict a slower, but not necessarily absence of neurodegeneration, and therefore appears limited in distinguishing slow progressors from FTD phenocopies. Larger numbers of patients from all clinical groups are required to strengthen diagnostic utility.

Younger-onset dementia (YOD) refers to onset before 65 years of age and may be associated with a genetic cause. Family communication surrounding any genetic risk is complex, and this process may be further complicated in a YOD context due to its effects on cognition, behaviour, and associated psychosocial consequences. This study aimed to investigate how individuals experience family communication about potential genetic risk and testing for YOD. Thematic analysis was performed on verbatim transcripts of nine semi-structured interviews undertaken with family members who attended a neurogenetics clinic due to a relative diagnosed with YOD. The interviews explored the participants’ experiences of learning that YOD might be inherited and the ensuing family communication about genetic testing. Four key themes emerged: (1) a clinical diagnostic odyssey was common and could be a motivator for genomic testing, (2) pre-existing family tension and/or disconnection was a common barrier, (3) family members’ autonomy was considered, and (4) avoidant coping strategies influenced communication. Communication regarding potential YOD genetic risk is a complicated process and may be influenced by pre-existing family dynamics, individual coping mechanisms, and a desire to promote autonomy in relatives. To promote effective risk communication, genetic counsellors should pre-emptively address family tensions that may be exacerbated in the context of genetic testing for YOD, with awareness that family strain during a preceding period of diagnostic odyssey is common. Genetic counsellors can offer psychosocial support to facilitate coping with this tension in an adaptive way. The findings also indicated the importance of extending genetic counselling support to relatives.

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.

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.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.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.Higher CSF NfL is related to brain atrophy in YOD, further supporting its use as a nonspecific marker of neurodegeneration severity.

Objectives: Survival information in dementia is important for future planning and service provision. There have been limited Australian data investigating survival duration and risk factors associated with mortality in younger-onset dementia. Methods: This was a cross-sectional retrospective study investigating survival in inpatients with a diagnosis of dementia admitted to a tertiary neuropsychiatry service from 1991 to 2014. The Australian Institute of Health and Welfare National Death Index was used to obtain mortality information. Results: A total of 468 inpatients were identified, of which 75% had symptom onset at ⩽65 years of age (defined as younger-onset dementia). Dementia was categorised into four subtypes, Alzheimer’s dementia, frontotemporal dementia, vascular dementia and other dementias; 72% of the patients had died. Overall median survival duration was 10.6 years with no significant differences in duration within the dementia subtypes ( p = 0.174). Survival in older-onset dementia (symptom onset at >65 years of age) was about half of that in younger-onset dementia (median survival 6.3 years compared to 12.7 years, respectively). Independent predictors of mortality were having older-onset dementia (hazard ratio: 3.2) and having initial presenting symptoms being cognitive in nature (hazard ratio: 1.5). Females with an older-onset dementia had longer survival compared to males with an older-onset dementia, and this was reversed for younger-onset dementia. Older-onset dementia and younger-onset dementia conferred 3 and 6 times, respectively, increased risk of death compared to the general population. Conclusion: This is the largest Australian study to date investigating survival and risk factors to mortality in dementia. We report important clinical information to patients with dementia and their families about prognosis which will assist with future planning. Our findings suggest that for both older-onset dementia and younger-onset dementia, ‘new onset’ psychiatric symptoms precede the cognitive symptoms of a neurodegenerative process. This, and sex differences in survival depending on the age of onset of the dementia warrant further investigation.

Sporadic Creutzfeldt-Jakob disease (sCJD) is the most common form of CJD and is believed to be caused by the misfolding and aggregation of endogenous prion protein. Several classification systems have been developed to correlate the molecular characteristics of these misfolded prions (PrPSc) to the heterogeneous clinical presentations of sCJD. A central component of these systems is glycotyping, which involves the interpretation of the results of western immunoblotting of the protease-resistant fragment of the misfolded prion protein (PrPres). The two main classification systems differ in their recognition of a unique banding pattern on electrophoretic gels correlating to a putative clinical subtype. The perpetuation of both classification systems within scientific literature is, in part, due to a paucity of high-level evidence that conclusively addresses the merit of recognising each unique banding pattern. Here, 110 post-mortem confirmed cases of sCJD collected at the Australian Creutzfeldt-Jakob Disease Registry (ANCJDR) between 1993 and 2018 were analysed and classified as per the London classification system. The data presented here demonstrated that sCJD cases with 'type 1' and 'type 2' PrPSc as defined by the London classification system differ in their disease duration. No other differences in clinical phenotype or biological characteristics were found to be statistically significant. These findings highlight the importance of sample size and replicability in analyses of this rare disease process. Recognising these glycotypes as phenotypically distinct may represent 'best practice' in the collection and processing of sCJD samples within international registries for research purposes.

ObjectivePeople 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.MethodsWe 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>582pg/mL as indicative of ND/MCI/other.ResultsDiagnostic 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.ConclusionsCSF 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.

Objective: The volumes of various brain regions can be rapidly quantified using automated magnetic resonance imaging tools. While these appear to be useful at face value, their formal clinical utility is not yet understood, particularly for non-neuroradiologists and in patients presenting with suspected dementia. This study investigated the utility of an automated normative morphometry tool on determinations of brain atrophy by psychiatrists and radiologists in a tertiary hospital. Methods: Consecutive magnetic resonance scans ( n = 110) of patients referred with suspected neurodegenerative disorders were obtained retrospectively and rated by two neuroradiologists, two general radiologists and four psychiatrists over two sessions. First, conventional magnetic resonance sequences were shown. Then, morphometry colour-coded maps, which segmented T1-weighted magnetisation prepared rapid gradient echo images into brain regions and visualised these regions in colour according to their volumetric standard deviation from a normative population, were added to the second reading which occurred ⩾6 weeks later. Presence and laterality of atrophy in frontal, parietal and temporal lobes and hippocampal regions were measured using a digital checklist. The primary outcome of inter-rater agreement on atrophy was measured with Fleiss’ Kappa (κ). We also evaluated the accuracy of the atrophy ratings for differentiating post hoc diagnosis of subjective cognitive impairment, mild cognitive impairment and dementia. Results: Agreement among all raters was fair in frontal lobe and moderate in other regions with conventional method (κ = 0.362–0.555). With morphometry, higher agreement was seen in all regions (κ = 0.551–0.654), reaching significant improvement in the frontal and temporal lobes. No significant improvement was seen within the various disciplines, except in frontal lobes rated by psychiatrists. Accuracy of atrophy ratings on determining post hoc diagnosis was significantly improved for distinguishing subjective cognitive impairment versus dementia. Conclusion: In routine clinical assessment, automated normative morphometry complements the determination of regional atrophy and improves inter-rater agreement regardless of neuroradiology experience.

The behavioural variant of frontotemporal dementia (bvFTD) is a frequent cause of early-onset dementia. The diagnosis of bvFTD remains challenging because of the limited accuracy of neuroimaging in the early disease stages and the absence of molecular biomarkers, and therefore relies predominantly on clinical assessment. BvFTD shows significant symptomatic overlap with non-degenerative primary psychiatric disorders including major depressive disorder, bipolar disorder, schizophrenia, obsessive-compulsive disorder, autism spectrum disorders and even personality disorders. To date, ∼50% of patients with bvFTD receive a prior psychiatric diagnosis, and average diagnostic delay is up to 5–6 years from symptom onset. It is also not uncommon for patients with primary psychiatric disorders to be wrongly diagnosed with bvFTD. The Neuropsychiatric International Consortium for Frontotemporal Dementia was recently established to determine the current best clinical practice and set up an international collaboration to share a common dataset for future research. The goal of the present paper was to review the existing literature on the diagnosis of bvFTD and its differential diagnosis with primary psychiatric disorders to provide consensus recommendations on the clinical assessment. A systematic literature search with a narrative review was performed to determine all bvFTD-related diagnostic evidence for the following topics: bvFTD history taking, psychiatric assessment, clinical scales, physical and neurological examination, bedside cognitive tests, neuropsychological assessment, social cognition, structural neuroimaging, functional neuroimaging, CSF and genetic testing. For each topic, responsible team members proposed a set of minimal requirements, optimal clinical recommendations, and tools requiring further research or those that should be developed. Recommendations were listed if they reached a ≥ 85% expert consensus based on an online survey among all consortium participants. New recommendations include performing at least one formal social cognition test in the standard neuropsychological battery for bvFTD. We emphasize the importance of 3D-T1 brain MRI with a standardized review protocol including validated visual atrophy rating scales, and to consider volumetric analyses if available. We clarify the role of 18F-fluorodeoxyglucose PET for the exclusion of bvFTD when normal, whereas non-specific regional metabolism abnormalities should not be over-interpreted in the case of a psychiatric differential diagnosis. We highlight the potential role of serum or CSF neurofilament light chain to differentiate bvFTD from primary psychiatric disorders. Finally, based on the increasing literature and clinical experience, the consortium determined that screening for C9orf72 mutation should be performed in all possible/probable bvFTD cases or suspected cases with strong psychiatric features.

BackgroundDistinguishing 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.MethodsCerebrospinal 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).ResultsForty-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.ConclusionThis study demonstrated strong diagnostic utility of CSF NfL to distinguish 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

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.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).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.We demonstrated strong generalizable evidence for the diagnostic utility of CSF NfL in differentiating ND from psychiatric disorders, with high accuracy.

There has not been any examination of the risk factors associated with mortality in Huntington's Disease (HD) in an Australian cohort.This retrospective study included inpatients admitted to a specialist neuropsychiatry service in Melbourne, Australia. HD status was based on genetic testing. Risk factors included age of onset, CAG repeat length and neuroimaging. Mortality data was acquired through the Australian Institute of Health and Welfare National Death Index.The cohort included 83 participants, with 44 (53%) deceased. The median age of death was 59 years and median survival was 18.8 years from onset age (median 41.0 years). CAG repeat length (median 44.0, IQR 42.5, 47.0) was inversely correlated with age of onset (r = -0.73) and age at death (r = -0.80) but was not correlated with mortality status. There was no difference in functional and cognitive assessments, nor brain volumes, in the alive group compared to the deceased group. There were more people who were alive who had a positive family history of a psychiatric condition (p = 0.006) or dementia (p = 0.009). Standardised mortality ratios demonstrated a 5.9× increased risk of death for those with HD compared to the general population.This is the first study to examine risk factors of mortality in HD in an Australian cohort. Median survival in our cohort is consistent with previous studies in HD, and markedly reduced compared to the general Australian population. CAG repeat length was not associated with mortality suggesting that non-genetic factors contribute to mortality status and warrant further investigation.

Distinguishing behavioural variant frontotemporal dementia (bvFTD) from non-neurodegenerative 'non-progressor' 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.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 or Non-Progressors: further subtyped into Non-Progressor Revised (non-neurological/neurodegenerative final diagnosis), and Non-Progressor Static (static deficits, not fully explained by non-neurological/neurodegenerative causes).Forty-three patients were included: 20 Progressors, 23 Non-Progressors (15 Non-Progressor Revised, 8 Non-Progressor Static), and 20 controls. NfL concentrations were lower in Non-Progressors (Non-Progressors Mean, M = 554 pg/mL, 95%CI:[461, 675], Non-Progressor Revised M = 459 pg/mL, 95%CI:[385, 539], and Non-Progressor Static M = 730 pg/mL, 95%CI:[516, 940]), compared to Progressors (M = 2397 pg/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). Non-Progressor Static tended to have higher T-tau and P-tau levels compared to Non-Progressor Revised Diagnoses.This study demonstrated strong diagnostic utility of CSF NfL to distinguish bvFTD from 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, 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.

BackgroundIn the clinical setting, identification of the genetic cause in patients with early-onset dementia (EOD) is challenging due to multiple types of genetic tests required to arrive at a diagnosis. Whole-genome sequencing (WGS) has the potential to serve as a single diagnostic platform, due to its superior ability to detect common, rare and structural genetic variation.MethodsWGS analysis was performed in 50 patients with EOD. Point mutations, small insertions/deletions, as well as structural variants (SVs) and short tandem repeats (STRs), were analysed. An Alzheimer’s disease (AD)-related polygenic risk score (PRS) was calculated in patients with AD.ResultsClinical genetic diagnosis was achieved in 7 of 50 (14%) of the patients, with a further 8 patients (16%) found to have established risk factors which may have contributed to their EOD. Two pathogenic variants were identified through SV analysis. No expanded STRs were found in this study cohort, but a blinded analysis with a positive control identified aC9orf72expansion accurately. Approximately 37% (7 of 19) of patients with AD had a PRS equivalent to >90th percentile risk.DiscussionWGS acts as a single genetic test to identify different types of clinically relevant genetic variations in patients with EOD. WGS, if used as a first-line clinical diagnostic test, has the potential to increase the diagnostic yield and reduce time to diagnosis for EOD.

Frontotemporal dementia (FTD) is a common cause of dementia in younger people. There is less information known about risk factors to mortality such as the type of symptom onset and cause of death in this group.This was a retrospective file review of inpatients with FTD admitted to a tertiary neuropsychiatry unit located in Australia from 1992 to 2014. Mortality information including linkage of names and causes of death were obtained from the Australian Institute Health and Welfare National Death Index.One hundred inpatients were diagnosed with FTD, including behavioural-variant, language-variant FTDs and FTD-motor neuron disease (FTD-MND). Mean age was 52.8 years (SD = 10, range 31-76 years). Sixty-seven of them had died at linkage. Median survival of the sample was 10.5 years and FTD-MND had the shortest survival, 3.5 years. Increasing age of onset and FTD-MND were found to be significant predictors of association for mortality. Compared to the general population, having a FTD had an 8× increased risk of death. Females had double the standardised mortality ratio compared to males.This study provides important prognostic information for people diagnosed with FTD living in Australia. It highlights the importance of obtaining a definitive diagnosis as early as possible for future planning. More investigation into the relationship of symptom onset type and sex differences in FTD is required.

BackgroundYounger-onset dementia (YOD) can be challenging to diagnose due to its younger age of onset, heterogeneous aetiologies and broad range of presentations. Misdiagnosis is common with psychiatric conditions often diagnosed initially and diagnostic delay of five years is common. More information is needed to better understand and diagnose YOD, including the nature of symptom onset, progression of the disease, the relationship between cognition and functional outcomes for patients and carers, imaging changes and novel biomarkers. This paper reports on the background behind the “Investigating the clinical utility of biomarkers and other novel tests in younger-onset neurocognitive disorders”, the BeYOND study, and its methodology.MethodsBeYOND is a clinically-oriented “real-world” longitudinal study that follows younger people presenting with an onset of neuropsychiatric symptoms ≤ 65 years of age. We aim to collect information on participants’ cognition, neuroimaging, mental health, and blood and cerebrospinal fluid (CSF) biomarkers at 18-month time-points over 3 years. We also aim to collect information regarding the experience of carers and/or family of participants.ConclusionSerial assessment of symptomatology, cognition, imaging, and blood and CSF biomarkers will be correlated with eventual diagnosis to determine the usefulness of these measures in determining a confident diagnosis. In addition, repeat measurements of the mental health and well-being of the participant and that of their carers/family while they traverse their diagnostic journey will provide important information about service provision and how they can be better supported.

Currently there is no secured ongoing funding in Australia for next generation sequencing (NGS) such as exome sequencing (ES) for adult neurological disorders. Studies have focused on paediatric populations in research or highly specialised settings, utilised standard NGS pipelines focusing only on small insertions, deletions and single nucleotide variants, and not explored impacts on management in detail. This prospective multi-site study performed ES and an extended bioinformatics repeat expansion analysis pipeline, on patients with broad phenotypes (ataxia, dementia, dystonia, spastic paraparesis, motor neuron disease, Parkinson's disease and complex/not-otherwise-specified), with symptom onset between 2 and 60 years. Genomic data analysis was phenotype-driven, using virtual gene panels, reported according to American College of Medical Genetics and Genomics guidelines. One-hundred-and-sixty patients (51% female) were included, median age 52 years (range 14-79) and median 9 years of symptoms. 34/160 (21%) patients received a genetic diagnosis. Highest diagnostic rates were in spastic paraparesis (10/25, 40%), complex/not-otherwise-specified (10/38, 26%) and ataxia (7/28, 25%) groups. Findings were considered 'possible/uncertain' in 21/160 patients. Repeat expansion detection identified an unexpected diagnosis of Huntington disease in an ataxic patient with negative ES. Impacts on management, such as more precise and tailored care, were seen in most diagnosed patients (23/34, 68%). ES and a novel bioinformatics analysis pipepline had a substantial diagnostic yield (21%) and management impacts for most diagnosed patients, in heterogeneous, complex, mainly adult-onset neurological disorders in real-world settings in Australia, providing evidence for NGS and complementary multiple, new technologies as valuable diagnostic tools.

NCKAP1/NAP1 regulates neuronal cytoskeletal dynamics and is essential for neuronal differentiation in the developing brain. Deleterious variants in NCKAP1 have been identified in individuals with autism spectrum disorder (ASD) and intellectual disability; however, its clinical significance remains unclear. To determine its significance, we assemble genotype and phenotype data for 21 affected individuals from 20 unrelated families with predicted deleterious variants in NCKAP1. This includes 16 individuals with de novo (n = 8), transmitted (n = 6), or inheritance unknown (n = 2) truncating variants, two individuals with structural variants, and three with potentially disruptive de novo missense variants. We report a de novo and ultra-rare deleterious variant burden of NCKAP1 in individuals with neurodevelopmental disorders which needs further replication. ASD or autistic features, language and motor delay, and variable expression of intellectual or learning disability are common clinical features. Among inherited cases, there is evidence of deleterious variants segregating with neuropsychiatric disorders. Based on available human brain transcriptomic data, we show that NCKAP1 is broadly and highly expressed in both prenatal and postnatal periods and demostrate enriched expression in excitatory neurons and radial glias but depleted expression in inhibitory neurons. Mouse in utero electroporation experiments reveal that Nckap1 loss of function promotes neuronal migration during early cortical development. Combined, these data support a role for disruptive NCKAP1 variants in neurodevelopmental delay/autism, possibly by interfering with neuronal migration early in cortical development.

Objectives:While early diagnosis of younger-onset dementia (YOD) is crucial in terms of accessing appropriate services and future planning, diagnostic delays are common. This study aims to identify predictors of delay to diagnosis in a large sample of people with YOD and to investigate the impact of a specialist YOD service on this time to diagnosis.Design:A retrospective cross-sectional study.Setting:The inpatient unit of a tertiary neuropsychiatry service in metropolitan Victoria, Australia.Participants:People diagnosed with a YOD.Measurements and methods:We investigated the following predictors using general linear modeling: demographics including sex and location, age at onset, dementia type, cognition, psychiatric diagnosis, and number of services consulted with prior to diagnosis.Results:A total of 242 inpatients were included. The mean time to diagnosis was 3.4 years. Significant predictors of delay included younger age at onset, dementia type other than Alzheimer’s disease (AD) and behavioral-variant frontotemporal dementia (bvFTD), and increased number of services consulted. These predictors individually led to an increased diagnostic delay of approximately 19 days, 5 months, and 6 months, respectively. A specialized YOD service reduced time to diagnosis by 12 months.Conclusion:We found that younger age at onset, having a dementia which was not the most commonly occurring AD or bvFTD, and increasing number of services were significant predictors of diagnostic delay. A novel result was that a specialist YOD service may decrease diagnostic delay, highlighting the importance of such as service in reducing time to diagnosis as well as providing post-diagnostic support.

BACKGROUND/OBJECTIVES: The aim was to identify whether performance on olfactory identification can distinguish neurological/neurodegenerative disorders (NNDs) from primary psychiatric disorders (PPDs). METHODS: This is a cross-sectional retrospective study of inpatients assessed in Neuropsychiatry, Royal Melbourne Hospital. Data extracted from the admission records included: demographics, tobacco use, medical comorbidities, cognitive function using the Neuropsychiatry Unit Cognitive Assessment Tool (NUCOG), and odor identification using the Sniffin' Sticks Screening 12 test. The final diagnosis for patients was informed by established diagnostic criteria. RESULTS: A total 121 patients were included. Eighty-eight patients (73%) were diagnosed with neurological or neurodegenerative disease, including Alzheimers dementia, frontotemporal dementia, Lewy body parkinsonian-related dementias (Parkinson disease, multiple system atrophy, dementia with Lewy bodies) and other neurological causes of dementia; 33 patients (27%) were diagnosed with PPDs (including mood and psychotic disorders). Patients who scored ≤8 on the Sniffin' Sticks Screening 12 test were more likely to have NND than PPD, even after adjustment for age, sex and tobacco use (P=0.009, adjusted odds ratios=3.85, 95% confidence interval=1.40-10.62). Receiver operating characteristic curve analyses demonstrated that a score of ≤8 differentiated NND from PPD with sensitivity of 57% and specificity of 73% (receiver operating characteristic area under the curve of 0.67, P=0.004). CONCLUSIONS: Patients with neuropsychiatric difficulties who score 8 or less on Sniffin' Sticks are more likely to have a neurodegenerative illness. A cut-off score of 8 is potentially a "red flag" for clinicians faced with the diagnostic question of PPD versus NND.

Niemann-Pick disease type C (NPC) is a lysosomal storage disorder that presents with a spectrum of clinical manifestations from infancy and childhood or in early or mid-adulthood. Progressive neurological symptoms including ataxia, dystonia and vertical gaze palsy are a hallmark of the disease, and psychiatric symptoms such as psychosis and mood disorders are common. These latter symptoms often present early in the course of NPC and thus these patients are often diagnosed with a major psychotic or affective disorder before neurological and cognitive signs present and the diagnosis is revised. The commonalities and characteristics of psychotic symptoms in both NPC and schizophrenia may share neuronal pathways and mechanisms and provide potential targets for research in both disorders. The neurobiology of NPC and its relationship to the pattern of neuropsychiatric and cognitive symptoms is described in this review. A number of neurobiological models are proposed as mechanisms by which NPC causes psychiatric and cognitive symptoms, informed from models proposed in schizophrenia and other metabolic disorders. There are a number of symptomatic and illness-modifying treatments for NPC currently available. The current evidence is discussed; focussing on two medications which have shown promise, miglustat and hydroxypropyl-β-cyclodextrin.

Objectives: This clinical update review focuses on the management of cognition and the neuropsychiatric features of Alzheimer’s disease (AD) and highlights current issues regarding pharmacological and non-pharmacological treatment, putative therapeutics and recent relevant research findings in this area. Conclusions: AD is a neurodegenerative progressive condition characterised by cognitive impairment and functional decline. Most people with AD will demonstrate neuropsychiatric features, better known as behavioural and psychological symptoms of dementia (BPSD). Early recognition and treatment of BPSD are essential, as these cause considerable distress and carer burden. While there are many disease-modifying therapies for the cognitive symptoms still in the research stage, only symptomatic treatments are currently available for these and the BPSD.

Objectives: To provide a clinical update for general psychiatrists on the assessment and diagnosis of Alzheimer’s disease (AD), highlighting current issues regarding epidemiology, risk factors and pathophysiology from recent relevant research findings. Conclusions: Psychiatrists can apply their skills and training in the diagnosis of AD, which is based upon a comprehensive assessment comprising history, investigations, and cognitive and functional assessment, guided by accepted diagnostic criteria.

Background:Younger-onset dementia (YOD) is a dementia of which symptom onset occurs at 65 years or less. There are approximately 27000 people in Australia with a YOD and the causes can range from Alzheimer’s dementia (AD), frontotemporal dementia (FTD), metabolic and genetic disorders. It is crucial to obtain a definitive diagnosis as soon as possible in order for appropriate treatment to take place and future planning. Previous research has reported 4-5 years to get a diagnosis (Draper et al. 2016) and factors associated with delay include younger age (van Vliet et al. 2013) and psychiatric comorbidity (Draper et al. 2016). We report on our experience of diagnostic delay.Methods:This was a retrospective file review of 10 years of inpatients from Neuropsychiatry, Royal Melbourne Hospital, Australia. Neuropsychiatry is a tertiar service which provides assessment of people with cognitive, psychiatric, neurological and behavioural symptoms. Factors such as age of onset, number of services/specialists seen were extracted and analysed using multivariate regression.Results:Of the 306 individual patients who had a YOD, these were grouped into the major dementia groups (such as AD, FTD, Huntington’s disease, vascular dementia, alcohol-related dementia). The most commonly occurring dementia was AD (24.2%), followed by FTD (23%). There was an average of 3.7 years (SD=2.6), range 0.5-15 years, of delay to diagnosis. Cognitive impairment, as measured using the Neuropsychiatry Unit Cognitive Assessment (NUCOG) was moderate, with a mean score of 68.9 (SD=17.9). Within the groups of dementia, patients with Niemann-Pick type C (NPC) had the longest delay to diagnosis F(11,272)=3.677, p211.6.Discussion and conclusions:This was an eclectic group of people with YOD. The results of regression suggests that there are other factors which contribute to the delay, which are not just demographic related. Rarer disorders, such as NPC which present at an early age, and present with symptoms that are not cognitive in nature, can contribute to diagnostic delay.

Objectives Younger-onset dementia (YOD) refers to a dementia where symptom onset occurs when the patient is less than 65 years of age. YOD is far less common than late-onset dementia (occurring when patients are over 65 years old) and more challenging to diagnose due to its heterogeneous presentation. There have been relatively few studies describing demographic and diagnostic characteristics of patients with YOD in the community, particularly with follow-up information. Methods A retrospective cohort study was performed of inpatients admitted to a tertiary neuropsychiatry service, located in metropolitan Victoria, Australia, from 2009 to 2019. Inpatients with a YOD diagnosis were identified and data regarding diagnosis, demographics and investigations were obtained. Results There were 849 individual inpatients who were admitted to the service in the 10-year period and received comprehensive assessment. There were 306 individuals who received a YOD diagnosis, using contemporaneous diagnostic criteria (frequency 36%). The most common diagnoses were Alzheimer's disease (24.2%), frontotemporal dementia (23.1%), Huntington's disease (16.7%) and vascular dementia (7.8%). More than half of these inpatients were followed up and 6.5% had a diagnostic change when reviewed. Conclusions This study reports on the largest cohort of YOD to date, with diagnostic breakdown similar to previous retrospective file reviews. The neuropsychiatry service is funded to follow-up its patients, thus allowing re-assessment and continuity of care. While there are limitations in this study such as the lack of neuropathological outcomes, the findings emphasise the strengths of follow-up and appropriate service provision for these patients.

Introduction This study assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) in Alzheimer's disease (AD) diagnosis, its association with amyloid and tau pathology, as well as its potential to predict brain atrophy, cognition, and amyloid accumulation. Methods CSF NfL concentration was measured in 221 participants from the Australian Imaging, Biomarkers & Lifestyle Flagship Study of Ageing (AIBL). Results CSF NfL levels as well as NfL/amyloid β (Aβ42) were significantly elevated in AD compared to healthy controls (HC; P < .001), and in mild cognitive impairment (MCI) compared to HC (P = .008 NfL; P < .001 NfL/Aβ42). CSF NfL and NfL/Aβ42 differentiated AD from HC with an area under the receiver operating characteristic (ROC) curve (AUC) of 0.84 and 0.90, respectively. CSF NfL and NfL/Aβ42 predicted cortical amyloid load, brain atrophy, and cognition. Discussion CSF NfL is a biomarker of neurodegeneration, correlating with cognitive impairment and brain neuropathology.