Neurofilament Light Chain And Voice Acoustic Analyses In Dementia Diagnosis

Problem: There is no "gold-standard test" to detect all forms of dementia. People can present with subtle changes that are missed on standard cognitive screening tests, which are not designed for people whose first language is not English or from diverse cultural and educational backgrounds. State-of-the art brain imaging is only available to Australians living in large urban centres, further entrenching health care inequities. The lack of validated diagnostic tests and pathways causes diagnostic delays, increases patient and caregiver stress. Therapies are on the horizon for many forms of dementia - not only Alzheimer's disease - meaning that the lack of identification of simple dementia diagnostic biomarkers represents a critical knowledge gap.

Mission: New technologies now allow us to test abnormal brain protein levels in a routine peripheral blood test, record a voice sample to analyse its acoustics and reveal brain disease, and perform "mail-out" genetic tests using a simple saliva sample. The levels of a brain derived blood protein, neurofilament light chain (NfL), will be estimated and natural language processing and acoustic analysis will be measured in all patients presenting with cognitive complaints to a single healthcare network servicing 1 million ethnically and culturally diverse Australians. Researchers will investigate the utility of early genetic testing for those at high risk of a genetic cause for their disease. They will use these data to develop diagnostic pathways, leveraging existing collaborations to develop future screening programs. Early to mid-career researchers will be supported to translate new technologies into clinical practice in the shortest practicable time-frame.

Significance: Accessible and cost effective tests will inform new pathways to dementia diagnosis. This will transform the dementia landscape, shortening time to diagnosis, increasing diagnostic certainty, and allowing more Australians access to appropriate care, education, and future therapies.

• Venepuncture (Diagnostic test): A single blood draw at the time of presentation to clinic or whilst an inpatient.

Primary outcomes

• Baseline NfL level [Day 0]: Plasma Nfl (pg/ml), estimated using Quanterix SIMOA HD-X

Secondary outcomes

• Change in speech processing [Day 0 and 12-months]: Staff and/or self administered using Redenlab software and analysed by speech pathologist for acoustic measures of timing (e.g., pause length (seconds) in reading and monologue tasks), vocal control (e.g., fundamental frequency (hertz) and loudness variation (decibel) from vowel and monologue), and vocal quality (e.g., dysphonia measures derived from sustained vowel).
• Change in language processing [Day 0 and at 12-months]: Recorded by a member of the research team using Redenlab software and assessed by a speech therapist using Natural Language Processing techniques.
• Change in Direct Magnitude Estimation [Day 0 and at 12-months]: Perceptual rating of speech using Redenlab software; measuring intelligibility (i.e ability to be understood) and naturalness (deviation from healthy norm) of speech. Assessed by a speech therapist on a scale from 0 to 100; 0 indicates none of the speech is intelligible/natural, 100 indicates all the speech is intelligible/natural.

Other outcomes

• Modified Rankin Scale [Day 0 and at 12-months]: Functional screen; assessed by member of the research team based on clinical notes. Assessed as change from baseline. Scores ranging from 0-5, with higher scores indicating greater disability.
• Montreal Cognitive Assessment score [At 12-months]: Cognitive screen; staff administered via telephone. Scores include overall MoCA score (0-22) and Memory Index Score (0-15), greater scores indicate greater cognition.
• Hospital Anxiety and Depression Scale score [At 12-months]: Mood screen; staff administered via telephone. Scores include a total depression score (0-21) and total anxiety score (0-21); grouped according to normal (0-7), Borderline abnormal (8-10) and Abnormal (11-21).
• Clinical Global Impression score [At 12-months]: Global rating of improvement/change; staff administered via telephone. Scored on a 7 point scale, scores closer to 0 indicative of greater improvement and scores closer to 7 representing much worse).
• WHO Disability Assessment 12-item telephone interview score [At 12-months]: Functional screen, staff administered via telephone. Scored as an overall percentage (%) disability, higher scores indicating less function.
• WHO Disability Assessment 36-item self report score [At 12-months]: Functional screen, self administered. Scored as an overall percentage (%) disability, higher scores indicating less function.
• DNA sample for testing known pathogenic dementia mutations [Anytime over the study duration]: Self-administered saliva sample; Testing using Invitae Fronto-temporal dementia and AD panel: C9orf72, CHCHD10, CHMP2B, DCTN1, FUS, GRN, HNRNPA2B1, MAPT, SQSTM1, TARDBP, TBK1, TREM2, UBQLN2, VCP, APP, PSEN1 and PSEN2

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* All patients presenting to Eastern Health services with a cognitive complaint or potential neurodegenerative disorder

Exclusion Criteria:

* Prognosis <12 months
* No cognitive complaint
* Patients not involved within the single healthcare network

• Results publication: Ivanic S, Vogel AP, Chatterjee P, Baird J, Darby D, Werden E, Gao L, Darzins P, Patel SK, Burke I, Morris T, Churilov L, Bice J, Mielke MM, Brodtmann A. Neurofilament light chain and voice acoustics in dementia diagnosis (NAVAIDD): Protocol for a cohort study assessing the real-world diagnostic utility of blood and digital biomarkers in clinical settings. J Alzheimers Dis Rep. 2025 Dec 15;9:25424823251395325. doi: 10.1177/25424823251395325. eCollection 2025 Jan-Dec. PMID 41409494

• Informed Consent Form (PDF, 2025-03-11)

• Prof. Amy Brodtmann, MBBS, FRACP, PhD, FANZAN, Principal investigator, Monash University