Dennis Velakoulis

Background: Young-onset dementia is frequently misdiagnosed, particularly where neurodegenerative and primary psychiatric disorders (PPD) overlap. Plasma biomarkers measure current pathology, whereas polygenic risk scores (PRS) capture lifelong genetic risk. Whether PRS derived from late-onset and population samples transfer to young-onset presentations, and how they relate to plasma biomarkers, is unknown. Methods: We studied 687 participants of European ancestry from the Markers in Neuropsychiatric Disorders (MiND) Study, a prospective young-onset neuropsychiatry cohort: 195 healthy controls (HC), 283 PPD, 55 Alzheimer’s disease (AD) and 154 non-AD neurodegenerative disease (oNDG). PRS for AD, a cross-disorder psychiatric factor (PSY), frontotemporal dementia, Lewy body dementia and Parkinson’s disease were computed with PRS-CS, excluding the APOE locus. Plasma NfL, GFAP and p-tau217 were available for 332 participants. Models were adjusted for age, sex and APOE ε4 dose. Results: Relative to HC, the AD PRS was associated with AD (OR 1.69 per SD, 95% CI 1.17–2.45) but not PPD (0.95, 0.77–1.16). The PSY PRS showed the reciprocal pattern (PPD 1.29, 1.05–1.58; AD 1.00, 0.72–1.40). No PRS was associated with any plasma protein. In distinguishing PPD from oNDG, NfL was the strongest discriminator (OR 2.15, 1.62–2.83). The AD PRS was also associated with oNDG (1.38, 1.11–1.71), without improving discrimination (AUC 0.764 for NfL alone versus 0.773 combined). Conclusion: In young-onset presentations, AD and psychiatric polygenic risk are disease-specific and independent of plasma biomarkers of neurodegeneration. Their combined diagnostic value requires evaluation in larger, longitudinal pre-clinical cohorts.

Objective: To determine whether plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) are elevated in hospitalised patients with delirium relative to patients with dementia and primary psychiatric disorders (PPD). Methods and analysis: This was a cross-sectional observational study conducted at the Royal Melbourne Hospital, Melbourne, Australia, between April and October 2024, with comparator samples from a research biobank. In Phase 1 (Delirium Discovery Cohort), we measured plasma NfL and GFAP using the Single molecule array (Simoa) platform in hospitalised patients with delirium and compared them with dementia and PPD groups. Biomarker concentrations were the primary outcome and were compared using general linear models adjusted for age, sex, and estimated glomerular filtration rate, with bootstrapped confidence intervals. Discriminative performance was assessed as a secondary outcome using receiver operating characteristic (ROC) curve analysis,. In Phase 2, we applied this threshold to independent dementia and PPD groups. Results: In Phase 1 (n =176), inpatients with delirium showed higher concentrations of both NfL and GFAP than patients with dementia (β = 0.78; 95% CI [0.37, 1.20] and β = 0.39 [0.07, 0.73] respectively) or PPD groups (β = 1.17; [0.69, 1.66] and β = 0.83 [0.51, 1.24] respectively). ROC curve analysis for differentiating delirium from dementia and PPD groups yielded an optimal NfL threshold of 24.1 pg/mL (AUC = 0.89, 96% sensitivity, 70% specificity). In comparison, GFAP showed lower accuracy (AUC = 0.85), and combining NfL with GFAP (AUC = 0.90) did not significantly improve performance. In Phase 2 (n = 154), the NfL threshold of > 24 pg/ml maintained strong performance (AUC = 0.95, 96% sensitivity, and 77% specificity). Conclusions: Plasma NfL shows promise as a biomarker for delirium in hospitalised patients, distinguishing it with high sensitivity from patients with dementia and PPD. Larger multicentre studies are needed to refine cut-offs, evaluate temporal dynamics, and determine integration into acute hospital delirium pathways. What is already known on this topic: Delirium is highly prevalent in general hospitals but remains frequently underdiagnosed. Currently, no validated blood-based biomarker exists to reliably assist in clinical identification. What this study adds: Plasma neurofilament light chain (NfL) is substantially elevated in general hospital inpatients with delirium compared to those with dementia or primary psychiatric disorders. This includes patients with delirium superimposed on dementia, yielding a discriminative profile well-suited for ruling out the diagnosis. How this study might affect research, practice or policy: These findings support the prospective evaluation of plasma NfL as an objective adjunct to clinical bedside assessments. This biomarker could significantly aid in evaluating patients with acute confusion, particularly when hypoactive presentations make clinical diagnosis challenging.

Importance: Plasma phosphorylated tau 217 (p-tau217) is entering clinical use with fixed diagnostic threshold that do not account for kidney function. Chronic kidney disease (defined as estimated glomerular filtration rate (eGFR) below 60 mL/min/1.73 m ² ), raises plasma p-tau217 concentrations and can produce false positive results. It remains unclear whether milder reductions in kidney function, above the CKD threshold, have the same effect. Objective: To determine whether plasma p-tau217 is elevated with mildly reduced kidney function, above the chronic kidney disease threshold, in adults without neurological disease. Design: Cross-sectional analysis of a cohort enrolled between 2023 and 2025 and biomarker analysis blinded to clinical data. Setting: Two private psychiatric inpatient facilities in Australia. Participants: Adults admitted with psychiatric disorders and free of neurological disease. Exposures: eGFR calculated from serum creatinine using the CKD-EPI 2021 equation. Main Outcomes and Measures: Plasma p-tau217, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP), measured on the Simoa platform. Multivariable linear regression compared eGFR groups (< 60, 60 to 90, and ≥ 90 mL/min/1.73 m ² ), adjusted for age, BMI, and sex. Results: Among 180 participants (median age, 50.5 years [IQR, 38.0-61.5]; 94 [52%] female), eGFR was ≥ 90 mL/min/1.73 m ² in 106 (59%), 60 to 90 in 61 (34%), and < 60 in 13 (7.2%). Compared with an eGFR ≥ 90, plasma p-tau217 was 36% higher in both the 60 to < 90 group (β = 0.42 [95% CI: 0.11, 0.74]; P = .008) and 116% higher in the < 60 group (β = 1.05 [95% CI: 0.43, 1.72]; P = .002). Plasma NfL and GFAP were elevated in the < 60 group but differences in the 60 to < 90 group did not reach significance. Modelled continuously, plasma p-tau217 was 9.5% lower per 10 mL/min/1.73 m ² higher eGFR (95% CI: 3.3%, 15.4%). Conclusions and Relevance: Plasma p-tau217 was elevated in adults with mildly reduced kidney function, above the CKD threshold, in a cohort free of neurological disease. Kidney function across its full range should be incorporated into plasma p-tau217 reference ranges and clinical interpretation to reduce false positive and false negative results. KEY POINTS: Question: Is plasma p-tau217 elevated at mildly reduced kidney function, above the chronic kidney disease (CKD) threshold? Findings: In this cross-sectional study of 180 inpatients free of neurological disease, plasma p-tau217 was 36% higher in participants with an estimated glomerular filtration rate (eGFR) between 60 and 90 mL/min/1.73 m ² , and 116% higher in those below 60, compared with those at 90 or above. Meaning: Given that plasma p-tau217 varies with kidney function across its range, not only in CKD, eGFR should be incorporated into reference ranges and the interpretation of results to reduce false positive and false negative findings.

Herpes simplex virus encephalitis (HSVE) is a devastating neurological condition that frequently results in complex and persistent changes in language and cognition. This chapter explores the multifaceted impact of HSVE on cognitive-communication abilities, drawing on both research and clinical case studies to illustrate the diversity of clinical presentations. Common sequelae include impairments in expressive and receptive language, discourse cohesion, pragmatic communication, and executive functioning, related to temporal lobe damage. Cognitive deficits such as impaired attention, processing speed and memory further compound communication challenges, affecting daily functioning and social participation. This chapter outlines recommendations for comprehensive evaluation, including neuropsychological and speech-language pathology assessments in order to identify the individual pattern of deficits post-HSVE. In addition, approaches to rehabilitation are discussed with use of a clinical case study to highlight the individual nature of treatment in this area. Examples of rehabilitation techniques are discussed in order to provide clinicians with guidance on how to approach these complex and debilitating cognitive-communication deficits.

Objective: The Neuropsychiatry Unit Cognitive Assessment is a valid and reliable screening tool used in detecting cognitive deficits in a range of neurological and psychiatric conditions. We aimed to develop abbreviated versions of the Neuropsychiatry Unit Cognitive Assessment tool using retrospective data, and to assess their psychometric performance in distinguishing between healthy cognition and dementia. Methods: Healthy controls ( n = 132, 41%) and those with dementia ( n = 191, 59%) were randomised into a ‘training’ cohort ( n = 226, 70%) for the development and a ‘testing’ cohort ( n = 97, 30%) for validation of the short-form versions. Receiver-operating characteristic curves were first computed for each of the 24 original Neuropsychiatry Unit Cognitive Assessment items. Items were ranked according to area under the curve values to create five-, 10- and 15-item short-form versions, which were subsequently validated. Results: The psychometric properties of the Neuropsychiatry Unit Cognitive Assessment short-form versions were comparable with the original, with all maintaining high convergent validity and reliability. Of the three versions, the 10-item version strikes the ideal balance of breadth and brevity. With a cut-off score of 42/54, the 10-item version generated similar sensitivity, specificity and predictive values for dementia as the original Neuropsychiatry Unit Cognitive Assessment, with a sensitivity of 0.98, specificity of 0.95, and positive and negative predictive values of 0.97. Conclusions: The 10-item Neuropsychiatry Unit Cognitive Assessment has strengths in its shorter administration time, of approximately 10 minutes, high reliability and validity, and retention of items from each cognitive domain from the original Neuropsychiatry Unit Cognitive Assessment. Future research may involve testing these short forms in non-tertiary settings, across dementia subtypes and in non-dementia groups.

Brain network architecture is anticipated to influence future grey matter loss in individuals at Clinical High Risk (CHR) for psychosis. However, existing studies on grey matter structural network properties in CHR are scarce and constrained by small sample sizes. Here, we examined network topology differences comparing a) CHR versus healthy controls (HC); b) CHR who transitioned to psychosis (CHR-T) versus those who did not (CHR-NT); and c) different subsyndromes. We included structural scans from 1842 CHR individuals and 1417 HC individuals from 31 sites within the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) consortium. At the global level, CHR individuals exhibited lower structural covariance (q < 0.001; Cohen’s d = 0.164) and less optimal structural network configuration than HC (lower global efficiency and clustering coefficient, d = 0.100,0.087, qs <= 0.027). Though no global difference between CHR-T and CHR-NT, network distinctiveness of the frontal and temporal surface area networks was higher in CHR-T than CHR-NT (d = 0.223,0.237) and HC (d = 0.208,0.219) (qs < 0.001). Network distinctiveness of the frontal cortical thickness network was lower in CHR-T (d = 0.218, q < 0.001) than CHR-NT and HC (d = 0.165, q < 0.001). Importantly, higher network distinctiveness was associated with worse positive symptoms in CHR-NT (frontal surface area, q = 0.008, R² = 0.013) and at trend with worse negative symptoms in CHR-T (frontal thickness, q = 0.063, R² = 0.049). Further, the brief intermittent psychotic syndrome subgroup showed more severe network alterations. Together, brain structural networks inform symptoms and the risk of transition to psychosis in CHR individuals.

Objective: The Neuropsychiatry Unit Cognitive Assessment (NUCOG) is a valid and reliable screening tool used in detecting cognitive deficits in a range of neurological and psychiatric conditions. We aimed to develop abbreviated versions of the NUCOG tool using retrospective data, and to assess their psychometric performance in distinguishing between healthy cognition and dementia. Methods: Healthy controls ( n =132, 41%) and those with dementia ( n =191, 59%) were randomised into a ‘training’ cohort ( n =134, 70%) for the development and a ‘testing’ cohort ( n =57, 30%) for validation of the short-form versions. Receiver operating characteristic (ROC) curves were first computed for each of the 24 original NUCOG items. Items were ranked according to area under the curve (AUC) values to create 5-item, 10-item and 15-item short-form versions, which were subsequently validated. Results: The psychometric properties of the NUCOG short-form versions were comparable to the original, with all maintaining high convergent validity and reliability. Of the three versions, the 10-item version strikes the ideal balance of breadth and brevity. With a cut-off score of 42/54, the 10-item version generated similar sensitivity, specificity and predictive values for dementia as the original NUCOG, with a sensitivity of 0.98, specificity of 0.95, and positive and negative predictive values of 0.97. Conclusions: The 10-item NUCOG (“NUCOG10”) has strengths in its shorter administration time, of approximately 10 minutes, high reliability and validity, and retention of items from each cognitive domain from the original NUCOG. Future research may involve testing these short-forms in non-tertiary settings, across dementia subtypes and in non-dementia groups.

INTRODUCTION: Apathy and affective neuropsychiatric symptoms (NPS) are prevalent in Alzheimer's disease (AD), yet their neurobiological cause is still unclear. We examined associations between plasma neurofilament light chain (NfL) and tau pathology (p‐tau181) with apathy and affective symptoms in mild cognitive impairment (MCI) and AD dementia.METHODS: This longitudinal study analyzed data from 781 participants with MCI and AD dementia enrolled in ADNI, with annual blood samples collected over 4 years. NPS were assessed via the Neuropsychiatric Interview (NPI), and biomarker trajectories were analyzed using mixed‐effects models.RESULTS: Elevated plasma NfL levels were associated with apathy, anxiety and depression in MCI and AD dementia, with apathy linked to a significantly higher rate of NfL increase, indicating accelerated neurodegeneration.DISCUSSION: Apathy and affective symptoms may indicate greater neurodegenerative burden in AD independent of tau‐related pathology. Apathy was associated with a steeper rise in plasma NfL, suggesting a more aggressive disease progression.Highlights: Apathy and affective neuropsychiatric symptoms (NPS) are highly prevalent in clinical Alzheimer's disease (AD). The presence of apathy, depression or anxiety was associated with higher plasma levels of neurofilament light chain (NfL). Apathy was associated with an accelerated increase in plasma NfL levels over time. Apathy and affective NPS were not associated with p‐tau181 levels in plasma.

Background: Recent advances now allow detection of brain‐specific proteins in blood, including neurofilament light chain (NfL), a marker of axonal pathology, and glial fibrillary acidic protein (GFAP), indicative of astrocytic activation. Given the evidence of astroglial pathology and neuronal dysfunction in bipolar disorder, and ongoing debates on neuroprogression, we investigated plasma NfL and GFAP levels in affected individuals.Methods: This study analysed plasma NfL and GFAP measured in 216 individuals using Simoa. We used bootstrapped general linear models (GLM) to compare plasma NfL and GFAP levels between people with bipolar depression (n = 120) and healthy controls (n = 96), adjusting for age, sex, and weight. We examined associations between these biomarkers and clinical variables while adjusting for multiple comparisons. For sensitivity analyses, predictors were evaluated using Bayesian model averaging (BMA).Results: Plasma GFAP (β = 0.21 [0.07, 0.35], p = 0.006) and NfL (β = 0.06 [0.01, 0.10], p = 0.028) were elevated in people with bipolar depression. Illness duration was positively associated with NfL (r = 2.97, p = 0.002), and further supported by BMA analysis (posterior inclusion probability, PIP = 0.85). Age of onset was positively associated with GFAP (r = 0.246 p = 0.041), which was also supported by BMA analysis (PIP = 0.67).Conclusions: These findings indicate increased plasma NfL and GFAP levels in bipolar disorder. Our findings support the neuroprogression hypothesis, where prolonged illness duration contributes to neuroaxonal damage. Elevated GFAP in those with later onset suggests a role for neuroinflammation, potentially linked to increased cardiovascular and metabolic comorbidities.