Alexander Frizell Santillo

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.

Accurate diagnosis of frontotemporal dementia (FTD) with right anterior temporal lobe (RATL) predominance remains challenging due to lack of clinical characterization, and standardized terminology. The recent research of the International Working Group (IWG) identified common symptoms but also unveiled broad terminologies lacking precision and operationalization, with risk of misdiagnoses, inappropriate referrals and poor clinical management. Based on the published evidence (91267 articles screened) and expert opinion (105 FTD specialists across 52 centers) by using the nominal group technique, the IWG delineates three primary domains of impairment causing behavioral, memory and language problems: (i) multimodal knowledge of non-verbal information including people, living beings, landmarks, flavors/odors, sounds, bodily sensations, emotions and social cues; (ii) socioemotional behavior encompassing emotion expression, social response and motivation; and (iii) prioritization for focus on specific interests, hedonic valuation and personal preferences. This study establishes a consensus on clinical profile, phenotypic nomenclature, and future directions to enhance diagnostic precision and therapeutic interventions.

Objective: To investigate plasma neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) levels across a range of acute psychiatric disorder presentations, and to determine whether elevations are specific to certain diagnoses. Methods: We analysed biobanked lithium heparin plasma samples from 121 patients with acute psychiatric presentations (including mania, psychosis, alcohol use disorder, anorexia nervosa, depression, and adjustment disorder), and 59 healthy controls. NfL and GFAP were measured using Simoa assays. Group differences were compared via bootstrapped general linear models adjusted for age, sex, and weight. Results: NfL was significantly elevated in alcohol use disorder, anorexia nervosa, mania, and psychosis compared to controls, but not in depression or adjustment disorder. GFAP was elevated only in alcohol use disorder. Conclusions: Plasma NfL and GFAP are not uniformly elevated across psychiatric disorders. Elevations in specific acute disorders likely reflect underlying neuronal and astroglial injury. These results support nuanced, biologically grounded, diagnosis and stage-specific roles for these biomarkers in psychiatry. Statistical analysis conducted by: Dr Dhamidhu Eratne

Background: Reliable biomarkers for amyotrophic lateral sclerosis (ALS) are urgently needed due to diagnostic and prognostic challenges. This systematic review and meta‐analysis aimed to synthesize recent evidence on the utility of blood and cerebrospinal fluid (CSF) biomarkers for ALS. Methods: We systematically reviewed studies published from January 1, 2019 to March 25, 2025, that evaluated blood or CSF biomarkers for ALS. Eligible studies reported diagnostic performance, group‐level biomarker values, hazard ratios (HRs) for survival, or correlations with functional rating scales or disease progression rates. Study quality was assessed using the QUADAS‐2 and QUIPS frameworks. Random‐effects models were employed to pool summary receiver operating characteristic (SROC) curves, HRs, standardized mean differences, and correlation coefficients. Results: We included 47 studies in the SROC analysis and 27 in the HR analysis, covering 9078 participants (5556 ALS and 3522 controls). Neurofilament light chain (NfL) consistently demonstrated the highest diagnostic accuracy (sensitivity/specificity: 0.81–0.87 vs. ALS mimics) and high prognostic value (pooled HRs: 2.8–4.3) in both blood and CSF. CSF chitinases and the p‐tau/t‐tau ratio showed moderate utility. Other biomarkers, including interleukins, had limited clinical relevance. Most studies showed moderate to high risk of bias, with methodological heterogeneity and limited transparency. Conclusions: NfL is the most validated biomarker for ALS diagnosis and prognosis, in both blood and CSF. However, its limited accuracy when used alone carries a considerable risk of misclassification. Future studies should adopt prevalence‐specific strategies and integrate biomarkers within multimodal frameworks to enhance diagnostic and prognostic precision.

Importance Mechanisms behind the asymmetric left-hemispheric atrophy observed in primary progressive aphasia (PPA), a neurodegenerative disorder related to either frontotemporal lobar degeneration or Alzheimer’s disease, remains a mystery. There is an increased prevalence of dyslexia in PPA patients and their relatives, especially in the logopenic variant PPA (lvPPA). This co-occurrence questions whether genetic variants associated with dyslexia are linked to selective neurodegeneration in language-associated brain regions. Objective To understand if genetic risk for dyslexia contributes to selective vulnerability in PPA, we determined whether polygenic risk scores (PRS) for dyslexia are elevated in PPA in comparison to other dementias and healthy controls. Given previous literature, we hypothesized that PRS for dyslexia is highest in individuals with lvPPA. Participants Genotyped participants from Amsterdam Dementia Cohort (ADC) diagnosed with semantic variant PPA (svPPA), non-fluent variant PPA (nfvPPA), lvPPA, right-temporal variant FTD (rtvFTD), PPA not otherwise specified (PPA NOS), behavioral variant FTD (bvFTD), Alzheimer’s dementia (AD) and dementia with Lewy bodies (DLB), in addition to controls, were included. Sex, age at blood sampling and education was collected. For each participant, PRS for dyslexia were created using genome-wide association study summary statistics on dyslexia (n = 51,800 cases and 1,087,070 controls, a study from 23andMe, Research Institute.). PRS were computed with LDpred2 and standardized. Main outcome(s) and Measure(s) Differences in PRS across diagnostic groups were assessed using linear regression models, with age, sex, education, diagnosis, and the diagnosis × sex interaction term as predictors. Since interaction term diagnosis*sex was significant, analysis was stratified for sex. Results A total of 3,407 ADC participants were included, of which n=969 controls, n=66 svPPA, n=30 nfvPPA, n=38 lvPPA, n=51 rtvFTD, n=17 PPA NOS, n=230 bvFTD, n=1750 AD and n=256 DLB cases. Within males, PRS for dyslexia were significantly higher in svPPA compared to all other diagnoses and controls (all p-values Conclusion and Relevance Our findings reveal a shared genetic basis between neurodevelopmental dyslexia and svPPA, indicating a link between developmental and neurodegenerative language disorders.

INTRODUCTION: Plasma biomarkers offer promise for improving the diagnosis of Alzheimer's disease (AD) and differentiating AD and other neurodegenerative disorders (NDs) like frontotemporal dementia (FTD) from primary psychiatric disorders (PPDs), particularly in younger patients. METHODS: In this prospective study, we investigated plasma phosphorylated tau 217 (p‐tau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in 341 unselected participants from a neuropsychiatry memory clinic, including AD ( n = 40), behavioral variant FTD (bvFTD) ( n = 15), PPD ( n = 69), other NDs, and controls. RESULTS: Plasma p‐tau217 showed strong diagnostic performance for distinguishing AD from bvFTD (96% accuracy) and PPD (93% accuracy). NfL best distinguished all NDs from PPD, while GFAP did not bring additional value. Biomarker profiles using predefined cut‐offs and age‐adjusted z‐scores further clarified group differences. DISCUSSION: Plasma p‐tau217 and NfL have strong diagnostic utility in real‐world, diagnostically complex cohorts. These findings support implementation of scalable blood‐based biomarkers to improve early and accurate diagnosis in memory clinical settings. Highlights: Plasma p‐tau217 was significantly elevated in AD compared to other disorders. P‐tau217 distinguished AD from bvFTD with high accuracy. P‐tau217 distinguished AD from PPDs with high accuracy. NfL/p‐tau217 ratio and GFAP added limited diagnostic value compared to p‐tau217 and NfL. Findings support blood biomarkers in younger, real‐world clinical cohorts.

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.

INTRODUCTION: Plasma biomarkers offer promise for improving diagnosis of Alzheimer’s disease (AD) and differentiating AD and other neurodegenerative disorders (ND) like frontotemporal dementia (FTD) from primary psychiatric disorders (PPD), particularly in younger patients. METHODS: In this prospective study, we investigated plasma phosphorylated tau 217 (ptau217), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) in 341 unselected participants from a neuropsychiatry memory clinic, including AD (n=40), bvFTD (n=15), PPD (n=69), other ND, and controls. RESULTS: Plasma ptau217 showed strong diagnostic performance for distinguishing AD from bvFTD (96% accuracy) and PPD (93% accuracy). NfL best distinguished all ND from PPD, while GFAP showed limited diagnostic utility. Biomarker profiles using predefined cut-offs and age-adjusted z-scores further clarified group differences. DISCUSSION: Plasma ptau217 and NfL have strong diagnostic utility in real-world, diagnostically complex cohorts. These findings support implementation of scalable blood-based biomarkers to improve early and accurate diagnosis in memory clinic settings.

The pathophysiological mechanisms driving disease progression of frontotemporal lobar degeneration (FTLD) and corresponding biomarkers are not fully understood. Here 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 (C9orf72, GRN and MAPT) compared with 39 non-carrier controls. Network analysis identified 31 protein co-expression modules. Proteomic signatures of genetic FTLD clinical severity included increased abundance of RNA splicing (particularly in C9orf72 and GRN) and extracellular matrix (particularly in MAPT) modules, as well as decreased abundance of synaptic/neuronal and autophagy modules. The generalizability of genetic FTLD proteomic signatures was tested and confirmed in independent cohorts of (1) sporadic progressive supranuclear palsy-Richardson syndrome and (2) frontotemporal dementia spectrum clinical syndromes. Network-based proteomics hold promise for identifying replicable molecular pathways in adults living with FTLD. ‘Hub’ proteins driving co-expression of affected modules warrant further attention as candidate biomarkers and therapeutic targets.