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.

Visuospatial skills are frequently assessed with drawing tests. Research has suggested that the use of drawing tasks in low educated groups may lack the ability to discriminate healthy individuals from clinical populations. The aims of this study were to investigate the validity of visuoconstructional tests in a sample of older Greek Australian immigrants and compare their performances to a matched sample of patients with Alzheimer’s disease (AD).

We assessed visuoconstructional performances in a sample of 90 healthy older Greek Australians, with a primary school level of education, and compared performances to a demographically matched sample of 20 Greek Australians with a diagnosis of AD on four visuoconstructional drawing tests: Greek cross, four-pointed star, intersecting pentagons, and the Necker Cube.

While healthy participants tended to outperform the AD group on most copy tasks, high fail rates within the healthy sample were observed for the intersecting pentagons and Necker cube (78% and 73% fail rates respectively) when using established clinical cutoff scores. High rates of curved angle, omission, distorted relation between elements, spatial disorganization and three-dimensional design errors were found across the four-pointed star, intersecting pentagons, and the Necker cube in both healthy participants and those with AD. Exploratory receiver operating characteristic curve analysis revealed that, with perhaps the exception of the Greek cross, meaningful sensitivity and specificity could not be reached for the four-pointed star, intersecting pentagons, and Necker cube.

Cognitively healthy immigrants with low education appear to be at a disadvantage when completing visuoconstructional drawing tests, as their performance may be misinterpreted as indicating cognitive impairment. Future research is needed to identify alternative approaches to assess visuoconstructional ability in low education older cohorts.

This study aimed to compare Greek Australian and English language normative data with regard to impairment rates yielded within a healthy Greek Australian older adult sample. We also examined whether optimal cut scores could be identified and capable of sensitively and specifically distinguishing between healthy Greek Australians from those with a diagnosis of Alzheimer’s disease (AD).

Ninety healthy Greek Australian older adults and 20 demographically matched individuals with a diagnosis of AD completed a range of neuropsychological measures, including the Wechsler Adult Intelligence Scale-Fourth Edition, Greek Adaptation (WAIS-IV GR), verbal and visual memory, language and naming, and executive functions. Impairment rates derived from the use of either Greek Australian or English language normative data were calculated and compared, using a 1.5 standard deviation criterion to denote impairment. Receiver operating characteristics curve analysis was used to investigate the sensitivity and specificity of alternate cut scores.

Impairment rates derived from the Greek Australian normative data showed that rates of impairment generally fell within the expected 7% range. In contrast, impairment rates for all tests derived using English language normative data were significantly higher and ranged from 11%–66%. Comparisons between healthy and AD participants with moderate dementia showed significant differences across all measures. Area under the curve results ranged from .721 to .999 across all measures, with most tests displaying excellent sensitivity and specificity.

English language normative data were found to be inappropriate for use with Greek Australian elders, potentially leading to erroneous diagnostic outcomes. The use of minority group specific normative data and associated cut points appear to partially ameliorate this issue. Clinical implications are discussed alongside future research directions.

A range of neuropathological changes occur in the brains of individuals with adult Niemann-Pick type C disease (NPC), a recessive disorder of cholesterol trafficking that results in accumulation of cholesterol and gangliosides in lysosomes, particularly in neurons. One of the most significant regions of grey matter loss occurs in the thalami, which abut the midline. What is not known is whether these are neurodevelopmental in origin well prior to symptomatic onset. We aimed to examine other markers of midline developmental anomalies in adults with NPC.

We examined the size of adhesio interthalamica (AI) and cavum septum pellucidum (CSP) (if present) in nine individuals diagnosed with NPC and nine healthy comparison subjects, matched for age and gender, using a 3T magnetic resonance volumetric sequence and measured the length of the AI and CSP in mm.

We found that 5/9 NPC patients and 0/9 controls had a missing AI. AI length was significantly shorter in the patient group. No subject in other group had a large CSP, and CSP length did not differ. Duration of illness showed a trend to a negative correlation with AI length in patients.

Our findings suggest that adult NPC patients show some markers of early neurodevelopmental disturbance, matching findings seen in psychotic disorders. The differences in AI, but not CSP, suggest neurodevelopmental change may occur early in gestation rather than post-partum. The relationship with duration of illness suggests that there may be atrophy over time in these structures, consistent with prior analyses of grey matter regions in NPC.

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.

Exploration of the themes and content of psychotic symptoms in young-onset dementia (YOD) is limited to case analysis. The primary objective of this study was to determine the themes of psychotic symptoms in individuals diagnosed with YOD.

Comprehensive retrospective file review of discharge summaries.

Neuropsychiatry, a specialist mental health service located at the Royal Melbourne Hospital, Australia.

Inpatients at Neuropsychiatry admitted between 2018 and 2020 (inclusive).

Data extracted included descriptions and prevalence of psychotic symptoms as well as general demographic and clinical data. Data analysis was conducted using a thematic approach.

Twenty-three inpatients had a diagnosis of YOD with psychotic symptoms. Themes were identified in the domains of delusions (six themes), auditory hallucinations (five themes), and visual hallucinations (two themes). Strong recurring themes across the modalities of hallucinations and delusions were beliefs and experiences relating to paranoia, suspicion, harm, and abuse. Themes did not clearly intersect across the modalities of hallucinations and delusions. A degree of thematic heterogeneity existed within individuals, and individuals experienced delusions or hallucinations of multiple themes. The themes of the psychotic symptoms did not clearly relate to diagnostic category, nor to time from diagnosis.

This study is the first thematic analysis of psychotic symptoms in YOD and provides further understanding of patient phenomenology and experiences of psychosis in YOD.

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.

There is currently debate about when a clinician should consider neuroimaging for patients with a known psychiatric illness. We consider this topic and propose a set of ‘red flags’ to use to aid decision-making.

None.

In spite of the recognized physical and psychosocial effects of caring for patients with Parkinson's disease (PD), caregiver burden (CB) in this setting is poorly understood. The objective of this research was to identify factors that were associated with CB in an Australian population of PD caregivers using a novel instrument – the Parkinson's Disease Caregiver Burden (PDCB) questionnaire.

Fifty patient–caregiver couples were recruited from three movement disorders clinics in Melbourne, Australia. Burden on caregivers was rated using the PDCB questionnaire. Burden scores were correlated with patient factors, including motor symptom severity (Unified Parkinson's Disease Ratings Scale and Hoehn & Yahr (H&Y) scale), patient cognition (Neuropsychiatry Unit Cognitive Assessment Tool; NUCOG), presence of impulsive and compulsive behaviors (Questionnaire for Impulsive–Compulsive Disorders in Parkinson's disease), and patient olfaction. Caregiver and patient demographics, as well as results for depression and anxiety (Hospital Anxiety and Depression Scale; HADS), were also examined for their relationship with CB.

H&Y stage, depression or anxiety in either caregiver or patient, and decreased patient NUCOG score were significantly associated with higher PDCB score. Multiple linear regression analysis identified caregiver and patient depression score and patient score for the visuoconstructional subscale of NUCOG to predict burden score. In addition, disease duration, duration of caregiving, and increased hours per day spent in giving care were significantly associated with increased burden.

We found psychiatric and cognitive factors to be the most relevant factors in the perception of burden in PD caregivers. On top of this, we found deficits in the domain of visuoconstruction predicted burden – a relationship not yet described in literature. Targeting depression and anxiety in this setting as well as identifying caregivers at high risk of burden may give clinicians the chance to optimize care of patients with PD through the caregiver.

Previous studies on substance-dependent populations have shown that age of first use and duration of use are associated with alterations in regional brain volumes. However, it is not clear whether such alterations are factors that predispose young people to use, and so are also present in recreational users, or are a consequence of chronic exposure to substances and/or comorbid psychopathology.

To investigate relationships between key brain structures and parameters of alcohol and cannabis use, in otherwise healthy male recreational users.

High-resolution magnetic resonance imaging was used to measure hippocampal, amygdala, whole-brain and intracranial cavity (ICC) volumes in 22 young men with a history of both alcohol and cannabis use.

Linear regression analyses with hippocampal, amygdala and whole-brain volumes as the dependent variables and age and ICC as covariates were performed. Findings showed that use of cannabis and alcohol at an earlier age were independently predictive of larger amygdala volumes, whereas longer duration of cannabis use was predictive of smaller hippocampal volumes.

Our findings offer preliminary support for a relationship between patterns of substance use and regional brain volumes in recreational users. It is speculative, but possible that this relationship is an evidence of a neurobiological vulnerability to drug-taking behaviour.

The perception of music without a stimulus, or musical hallucination, is reported in both organic and psychiatric disorders. It is most frequently described in the elderly with associated hearing loss and accompanied by some degree of insight. In this setting it is often referred to as ‘musical hallucinosis’. The aim of the authors was to present examples of this syndrome and review the current understanding of its neurobiological basis.

We describe three cases of persons experiencing musical hallucinosis in the context of hearing deficits with varying degrees of associated central nervous system abnormalities.

Putative neurobiological mechanisms, in particular those involving de-afferentation of a complex auditory recognition system by complete or partial deafness, are discussed in the light of current information from the literature.

Musical hallucinosis can be experienced in those patients with hearing impairment and is phenomenologically distinct for hallucinations described in psychiatric disorders.

In consultation-liaison settings, neuropsychiatrists are commonly asked to assess patients with hallucinatory syndromes and to differentiate ‘functional’ from ‘organic’ psychotic presentations.

The occurrence and management of visual hallucinations (VH) in healthy individuals, lesion states, neurodegenerative disorders, intoxication/withdrawal states and delirium are reviewed.

The presence of VH has been shown to predict a secondary rather than primary psychotic illness and an understanding of the neurobiology of the visual system – including how and where underlying neurotransmitter systems interact in visual processing and how perturbations can result in VH – allows for appropriate clinical assessment and management.

We describe the presentation of a young woman with long-standing complex partial seizures with occasional secondary generalization, who presented with complex visual hallucinations (CVHs) and delusions.

Routine biological workup including magnetic resonance imaging revealed an area of significant left-sided occipital gliosis. Video telemetry monitoring revealed a left occipital focus for the origin of the electrographic seizure discharge.

CVHs occur in a range of organic states, including epilepsy, and can be understood in terms of the underpinning neuroanatomy and neurotransmitter systems of the visual system.