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.

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.

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).

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.

There is an urgent need for clinical blood biomarkers which can rule in/out neurological disorders early in those with psychiatric symptoms, personality or behavioural changes and/or functional decline together with cognitive symptoms. The neuronal axonal protein neurofilament light (NfL) is released from damaged neuronal axons and can be measured in in blood and cerebrospinal fluid (CSF). We have undertaken a series of studies aimed at examining the clinical utility of blood and CSF NfL in assisting with the distinction between psychiatric and neurodegenerative / neurological disorders.

Since 2016 we have measured blood and CSF NfL levels across multiple psychiatric and neurological populations recruited through Neuropsychiatry, Royal Melbourne Hospital and our collaborators (national and international). We have described our findings in a series of published studies. Data from our ongoing work, in larger cohorts and diagnostic groups, will be presented. The diagnostic groups include people with psychiatric disorders (schizophrenia, bipolar disorder, depression, functional neurological disorders), neurodegenerative disorders (Alzheimer’s disease, frontotemporal dementia, Huntington’s disease, Niemann-Pick Type C) and neurological disorders (e.g., epilepsy).

Our initial pilot study (n=129) found that CSF NfL was a promising biomarker in differentiating psychiatric from neurological disorders. In our larger follow up larger study (n=498) which included more diagnostic groups CSF NfL levels exhibited high accuracy (91%), sensitivity (92%), and specificity (87%) in differentiating psychiatric from neurological disorders, and distinguished behavioural variant frontotemporal dementia from frontal lobe syndrome phenocopies/mimics, with high accuracy. We have found that NfL is not elevated in people with treatment resistant schizophrenia compared to controls and is elevated in people with Niemann-Pick Type C compared to people with psychiatric disorders and controls. Further (unpublished) data has shown that these findings are replicated with plasma NfL levels across 400 further psychiatric, neurological and control participants.

NfL is a highly promising biomarker which differentiates psychiatric from neurological disorders with high sensitivity and specificity. The translation of NfL levels into standard clinical practice could substantially improve the clinical diagnostic process in people with complex neuropsychiatric and cognitive disorders.

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.

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.

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.

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.

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.

Retrospective file review from 1992 to 2014.

The inpatient unit of a tertiary neuropsychiatry service in Victoria, Australia.

Inpatients with a diagnosis of VD.

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.

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).

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.

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.

Retrospective cross-sectional study.

Tertiary neuropsychiatry service in Victoria, Australia.

Patient-carer dyads with YOD.

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.

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.

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.

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.

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.

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, p<0.0001, with 6.3 years delay. Age of symptom onset and number of specialists/services seen were the significant predictors of delay to diagnosis F(7, 212)=3.975, p<0.001, R211.6.

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.

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.

A retrospective cross-sectional study.

The inpatient unit of a tertiary neuropsychiatry service in metropolitan Victoria, Australia.

People diagnosed with a YOD.

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.

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.

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.