Plasma neurofilament light in behavioural variant frontotemporal dementia compared to mood and psychotic disorders.

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.

Plasma neurofilament light chain is increased in Niemann-Pick Type C but glial fibrillary acidic protein remains normal.

OBJECTIVE: Niemann-Pick Type C (NPC) is a genetic neurodegenerative lysosomal storage disorder commonly associated with psychiatric symptoms and delays to accurate diagnosis and treatment. This study investigated biomarker levels and diagnostic utility of plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) in NPC compared to healthy controls. METHODS: Patients with NPC were recruited from a specialist assessment and management service. Data was available from an age and sex-matched healthy control group. NfL and GFAP were measured on Quanterix Simoa HD-X analysers and groups compared using generalised linear models. NfL levels were compared to, and percentiles derived from, recently developed NfL reference ranges. RESULTS: Plasma NfL was significantly elevated in 11 patients with NPC compared to 25 controls (mean 17.1 vs. 7.4 pg/ml, p < 0.001), and reference ranges (all >98th percentile). NfL distinguished NPC from controls with high accuracy. GFAP levels were not elevated in NPC (66.6 vs. 75.1 pg/ml). DISCUSSION: The study adds important evidence on the potential diagnostic utility of plasma NfL in NPC, extends the literature of NfL as a diagnostic tool to differentiate neurodegenerative from primary psychiatric disorders, and adds support to the pathology in NPC primarily involving neuronal, particularly axonal, degeneration.

Cerebrospinal fluid neurofilament light predicts longitudinal diagnostic change in patients with psychiatric and neurodegenerative disorders.

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.

NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism.

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.

Survival in Huntington's disease and other young-onset dementias.

OBJECTIVES: To compare survival and risk factors associated with mortality in common young-onset dementias (YOD) including Huntington's disease. METHODS: This retrospective cohort study included inpatients from an Australian specialist neuropsychiatry service, over 20 years. Dementia diagnoses were based on consensus criteria and Huntington's disease (HD) was confirmed genetically. Mortality and cause of death were determined using linkage to the Australian Institute of Health and Welfare National Death Index. RESULTS: There were 386 individuals with YOD included. The dementia types included frontotemporal dementia (FTD) (24.5%), HD (21.2%) and Alzheimer's disease (AD) (20.5%). 63% (n = 243) individuals had died. The longest median survival was for those who had HD, 18.8 years from symptom onset and with a reduced mortality risk compared to AD and FTD (hazard ratio 0.5). Overall, people with YOD had significantly increased mortality, of 5-8 times, compared to the general population. Females with a YOD had higher standardised mortality ratio compared to males (9.3 vs. 4.9) overall. The most frequent cause of death in those with HD was reported as HD, with other causes of death in the other YOD-subtypes related to dementia and mental/behavioural disorders. DISCUSSION: This is the first Australian study to investigate survival and risk factors of mortality in people with YOD. YOD has a significant risk of death compared to the general population. Our findings provide useful clinical information for people affected by YOD as well as future planning and service provision.

Carer burden and behavioral disturbance is similar between younger-onset Alzheimer's disease and behavioral variant frontotemporal dementia.

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.

Comparing survival and mortality in patients with late-onset and young-onset vascular dementia.

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.

Cerebrospinal fluid neurofilament light and cerebral atrophy in younger-onset dementia and primary psychiatric disorders.

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.

Clinical impact of whole-genome sequencing in patients with early-onset dementia.

BACKGROUND: In 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. METHODS: WGS 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. RESULTS: Clinical 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 a C9orf72 expansion accurately. Approximately 37% (7 of 19) of patients with AD had a PRS equivalent to >90th percentile risk. DISCUSSION: WGS 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.

The Diagnostic Challenge of Young-Onset Dementia Syndromes and Primary Psychiatric Diseases: Results From a Retrospective 20-Year Cross-Sectional Study.

OBJECTIVE: Distinguishing a dementia syndrome from a primary psychiatric disease in younger patients can be challenging and may lead to diagnostic change over time. The investigators aimed to examine diagnostic stability in a cohort of patients with younger-onset neurocognitive disorders. METHODS: A retrospective review of records was conducted for patients who were admitted to an inpatient neuropsychiatry service unit between 2000 and 2019, who were followed up for at least 12 months, and who received a diagnosis of young-onset dementia at any time point. Initial diagnosis included Alzheimer's disease-type dementia (N=30), frontotemporal dementia (FTD) syndromes (N=44), vascular dementia (N=7), mild cognitive impairment (N=10), primary psychiatric diseases (N=6), and other conditions, such as Lewy body dementia (N=30). RESULTS: Among 127 patients, 49 (39%) had a change in their initial diagnoses during the follow-up period. Behavioral variant FTD (bvFTD) was the least stable diagnosis, followed by dementia not otherwise specified and mild cognitive impairment. Compared with 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 whose diagnosis changed from a neurodegenerative to a psychiatric diagnosis were more likely to have a long psychiatric history, while those whose diagnosis changed from a psychiatric to a neurodegenerative one had a recent manifestation of psychiatric symptoms. CONCLUSIONS: Misdiagnosis of younger patients with neurocognitive disorders is not uncommon, especially in cases of bvFTD. Late-onset psychiatric symptoms may be the harbinger to a neurodegenerative disease. Close follow-up and monitoring of these patients are necessary.

Time to diagnosis in younger-onset dementia and the impact of a specialist diagnostic service.

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.

Mortality in dementia is predicted by older age of onset and cognitive presentation.

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.

Plasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree 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.

Cerebrospinal fluid neurofilament light chain differentiates primary psychiatric disorders from rapidly progressive, Alzheimer's disease and frontotemporal disorders in clinical settings.

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.

Odor Identification Testing Can Assist in the Clinical Distinction Between Psychiatric Disorders and Neurological/Neurodegenerative Disorders.

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.

Recommendations to distinguish behavioural variant frontotemporal dementia from psychiatric disorders.

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.

Risk factors to mortality and causes of death in frontotemporal dementia: An Australian perspective.

OBJECTIVES: 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. METHOD: 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. RESULTS: 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. DISCUSSION: 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.

A 10 year retrospective cohort study of inpatients with younger-onset dementia.

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.

Bringing psychiatrists into the picture: Automated measurement of regional MRI brain volume in patients with suspected dementia.

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.

A pilot study of the utility of cerebrospinal fluid neurofilament light chain in differentiating neurodegenerative from psychiatric disorders: A 'C-reactive protein' for psychiatrists and neurologists?

OBJECTIVE: Neurofilament light has shown promise as a biomarker for diagnosis, staging and prognosis in a wide range of neurological and neurodegenerative disorders. This study explored the utility of cerebrospinal fluid neurofilament light in distinguishing primary psychiatric disorders from neurodegenerative and neurological disorders, a common diagnostic dilemma for psychiatrists and neurologists. METHODS: This cross-sectional retrospective pilot study assessed cerebrospinal fluid neurofilament light on patients referred to a tertiary neuropsychiatry service from 2009 to 2017 for diagnostic assessment of neuropsychiatric and neurocognitive symptoms, where a neurodegenerative disorder was a differential diagnosis, who received lumbar punctures as part of a comprehensive workup. The most recent gold-standard clinical consensus diagnosis was categorised into psychiatric disorder or neurodegenerative or neurological disorder. Data from healthy controls were available for comparison. Data extraction and diagnostic categorisation was blinded to neurofilament light results. RESULTS: A total of 129 participants were included: 77 neurodegenerative or neurological disorder (mean age 57 years, including Alzheimer's dementia, frontotemporal dementia), 31 psychiatric disorder (mean age 51 years, including schizophrenia, major depressive disorder) and 21 healthy controls (mean age 66 years). Neurofilament light was significantly higher in neurodegenerative or neurological disorder (M = 3560 pg/mL, 95% confidence intervals = [2918, 4601]) compared to psychiatric disorder (M = 949 pg/mL, 95% confidence intervals = [830, 1108]) and controls (M = 1036 pg/mL, 95% confidence intervals = [908, 1165]). Neurofilament light distinguished neurodegenerative or neurological disorder from psychiatric disorder with an area under the curve of 0.94 (95% confidence intervals = [0.89, 0.98]); a cut-off of 1332 pg/mL was associated with 87% sensitivity and 90% specificity. CONCLUSION: Cerebrospinal fluid neurofilament light shows promise as a diagnostic test to assist with the often challenging diagnostic dilemma of distinguishing psychiatric disorders from neurodegenerative and neurological disorders. Further studies are warranted to replicate and expand on these findings, including on plasma neurofilament light.