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.

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.

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.

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.

Morphological abnormalities of the superior temporal gyrus have been consistently reported in schizophrenia, but the timing of their occurrence remains unclear.

To determine whether individuals exhibit superior temporal gyral changes before the onset of psychosis.

We used magnetic resonance imaging to examine grey matter volumes of the superior temporal gyrus and its subregions (planum polare, Heschl's gyrus, planum temporale, and rostral and caudal regions) in 97 antipsychotic-naive individuals at ultra-high risk of psychosis, of whom 31 subsequently developed psychosis and 66 did not, and 42 controls.

Those at risk of psychosis had significantly smaller superior temporal gyri at baseline compared with controls bilaterally, without any prominent subregional effect; however, there was no difference between those who did and did not subsequently develop psychosis.

Our findings indicate that grey matter reductions of the superior temporal gyrus are present before psychosis onset, and are not due to medication, but these baseline changes are not predictive of transition to psychosis.

Grey matter changes have been described in individuals who are pre- and peri-psychotic, but it is unclear if these changes are accompanied by changes in white matter structures.

To determine whether changes in white matter occur prior to and with the transition to psychosis in individuals who are pre-psychotic who had previously demonstrated grey matter reductions in frontotemporal regions.

We used magnetic resonance imaging (MRI) to examine regional white matter volume in 75 people with prodromal symptoms. A subset of the original group (n=21) were rescanned at 12–18 months to determine white matter volume changes. Participants were retrospectively categorised according to whether they had or had not developed psychosis at follow-up.

Comparison of the baseline MRI data from these two subgroups revealed that individuals who later developed psychosis had larger volumes of white matter in the frontal lobe, particularly in the left hemisphere. Longitudinal comparison of data in individuals who developed psychosis revealed a reduction in white matter volume in the region of the left fronto-occipital fasciculus. Participants who had not developed psychosis showed no reductions in white matter volume but increases in a region subjacent to the right inferior parietal lobule.

The reduction in volume of white matter near the left fronto-occipital fasciculus may reflect a change in this tract in association with the onset of frank psychosis.

The shape of the corpus callosum may differ in schizophrenia, although no study has compared first-episode with established illness.

To investigate the size and shape of the corpus callosum in a large sample of people with first-episode and established schizophrenia.

Callosal size and shape were determined using highresolution magnetic resonance imaging on 76 patients with first-episode schizophrenia-spectrum disorders, 86 patients with established schizophrenia and 55 healthy participants.

There were no significant differences in total area across groups. Reductions in callosal width were seen in the region of the anterior genu in first-episode disorder (P<0.005). Similar reductions were seen in the chronic schizophrenia group in the anterior genu, but also in the posterior genu and isthmus (P = 0.0005).

Reductions in anterior callosal regions connecting frontal cortex are present at the onset of schizophrenia, and in established illness are accompanied by changes in other regions of the callosum connecting cingulate, temporal and parietal cortices.