Biomarkers.

Background: The Markers in Neuropsychiatric Disorders Study (The MiND Study) is investigating the diagnostic and wider utility of blood based biomarkers such as neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and phosphorylated tau (p-tau), as well as other markers, to improve timely and accurate diagnosis of dementia and distinction from non-neurodegenerative and primary psychiatric disorder (PPD). This in-progress study has expanded significantly, becoming a robust platform for Australian and international collaborations.

Methods: Participants have been recruited and blood samples collected across Australia.

Associations between structural brain changes and blood neurofilament light chain protein in treatment-resistant schizophrenia.

Objective: Around 30% of people with schizophrenia are refractory to antipsychotic treatment (treatment-resistant schizophrenia). Abnormal structural neuroimaging findings, in particular volume and thickness reductions, are often described in schizophrenia. Novel biomarkers of active brain pathology such as neurofilament light chain protein are now expected to improve current understanding of psychiatric disorders, including schizophrenia.

Strong diagnostic performance of plasma ptau217 for CSF biomarker-defined young-onset Alzheimer disease in a diagnostically heterogeneous clinical cohort.

Objective: We investigated diagnostic utility of phosphorylated tau 217 and 181 (ptau217, ptau181), glial fibrillary acidic protein (GFAP), amyloid beta 42 and 40 (Aβ42, Aβ40), and neurofilament light (NfL) to distinguish biomarker-defined Alzheimer disease (AD) from non-AD conditions, in a heterogenous clinical cohort of younger people.

Methods: Plasma biomarkers were analysed using ultrasensitive technology, and compared in patients with CSF Alzheimer disease profiles (A+T+) to other CSF profiles (Other).

Results: Seventy-nine patients were included, median age 60.

Plasma neurofilament light outperforms glial fibrillary acidic protein in differentiating behavioural variant frontotemporal dementia from primary psychiatric disorders.

Objective: Timely, accurate distinction between behavioural variant frontotemporal dementia (bvFTD) and primary psychiatric disorders (PPD) is a clinical challenge. Blood biomarkers such as neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) have shown promise. Prior work has shown NfL helps distinguish FTD from PPD.

Neurofilament light and glial fibrillary acidic protein in mood and anxiety disorders: A systematic review and meta-analysis.

Neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are biomarkers of neuronal injury measurable in cerebrospinal fluid (CSF) and blood. Despite their potential as diagnostic tests for neurodegenerative disorders, it is unclear how they behave in mood and anxiety disorders. We conducted a systematic review and meta-analysis to investigate whether NfL and GFAP concentrations were altered in adults with mood and anxiety disorders compared to healthy controls.

Plasma neurofilament light protein is differentially associated with age in individuals with treatment-resistant schizophrenia and bipolar affective disorder compared to controls.

Accelerated brain ageing has been observed in multiple psychiatric disorders. This study examined whether relationships between age and plasma neurofilament light (NfL) protein differed in individuals with psychiatric disorders (major depressive disorder (n = 42), bipolar affective disorder (n = 121), treatment-resistant schizophrenia (TRS, n = 82)) compared to two healthy control (HC) groups (n = 1,926 and n = 59). Compared to two independent HC samples, individuals with TRS demonstrated a stronger positive relationship between age and NfL levels.

Structural and functional connectivity associations with anterior cingulate sulcal variability.

Sulcation of the anterior cingulate may be defined by presence of a paracingulate sulcus, a tertiary sulcus developing during the third gestational trimester with implications on cognitive function and disease. In this cross-sectional study we examine task-free resting state functional connectivity and diffusion-weighted tract segmentation data from a cohort of healthy adults (< 60-year-old, n = 129), exploring the impact of ipsilateral paracingulate sulcal presence on structural and functional connectivity. Presence of a left paracingulate sulcus was associated with reduced fractional anisotropy in the left cingulum bundle and the left peri-genual and dorsal bundle segments, suggesting reduced structural organisational coherence in these tracts.

Divergent functional connectivity changes associated with white matter hyperintensities.

Age-related white matter hyperintensities are a common feature and are known to be negatively associated with structural integrity, functional connectivity, and cognitive performance. However, this has yet to be fully understood mechanistically. We analyzed multiple MRI modalities acquired in 465 non-demented individuals from the Swedish BioFINDER study including 334 cognitively normal and 131 participants with mild cognitive impairment.

Associations between structural brain changes and blood neurofilament light chain protein in treatment-resistant schizophrenia.

Background And Hypothesis: Around 30% of people with schizophrenia are refractory to antipsychotic treatment (treatment-resistant schizophrenia; TRS). While abnormal structural neuroimaging findings, in particular volume and thickness reductions, are often observed in schizophrenia, it is anticipated that biomarkers of neuronal injury like neurofilament light chain protein (NfL) can improve our understanding of the pathological basis underlying schizophrenia. The current study aimed to determine whether people with TRS demonstrate different associations between plasma NfL levels and regional cortical thickness reductions compared with controls.

Large-scale network analysis of the cerebrospinal fluid proteome identifies molecular signatures of frontotemporal lobar degeneration.

The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. We leveraged aptamer-based proteomics (> 4,000 proteins) to identify dysregulated communities of co-expressed cerebrospinal fluid proteins in 116 adults carrying autosomal dominant FTLD mutations () compared to 39 noncarrier controls. Network analysis identified 31 protein co-expression modules.

Altered empathy processing in frontotemporal dementia A task-based fMRI study.

A lack of empathy, and particularly its affective components, is a core symptom of behavioural variant frontotemporal dementia (bvFTD). Visual exposure to images of a needle pricking a hand (pain condition) and Q-tips touching a hand (control condition) is an established functional magnetic resonance imaging (fMRI) paradigm used to investigate empathy for pain (EFP; pain condition minus control condition). EFP has been associated with increased blood oxygen level dependent (BOLD) signal in regions known to become atrophic in the early stages in bvFTD, including the anterior insula and the anterior cingulate.

Plasma neurofilament light chain is not elevated in people with first-episode psychosis or those at ultra-high risk for psychosis.

Introduction: Neurofilament light chain (NfL), a blood biomarker of neuronal injury, shows promise in distinguishing neurodegenerative disorders from psychiatric conditions. This is especially relevant in psychosis, given neurological conditions such as autoimmune encephalitis and Niemann Pick Type C disease (NPC) may initially present with psychotic symptoms. Whilst NfL levels have been studied in established schizophrenia cases, their levels in first-episode psychosis (FEP) and ultra-high risk (UHR) for psychosis individuals remain largely unexplored.

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.

Structural and functional connectivity associations with anterior cingulate sulcal variability.

Background: Sulcation of the anterior cingulate may be defined by presence of a paracingulate sulcus, a tertiary sulcus developing during the third gestational trimester with implications on cognitive function and disease.

Methods: In this retrospective analysis we examine task-free resting state functional connectivity and diffusion-weighted tract segmentation data from a cohort of healthy adults (< 60-year-old, n = 129), exploring the impact of ipsilateral paracingulate sulcal presence on structural and functional connectivity.

Results: Presence of a left paracingulate sulcus was associated with reduced fractional anisotropy in the left cingulum ( = 0.

Anterior cingulate sulcation is associated with onset and survival in frontotemporal dementia.

Frontotemporal dementia is the second most common form of early onset dementia (<65 years). Despite this, there are few known disease-modifying factors. The anterior cingulate is a focal point of pathology in behavioural variant frontotemporal dementia.

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, = 42), bipolar affective disorder (BPAD, = 121), treatment-resistant schizophrenia (TRS, = 82), bvFTD ( = 22), and compared to the reference cohort (Control Group 2, = 1926, using GAMLSS modelling), and age-matched controls (Control Group 1, = 96, using general linear models).

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.