where The MiND Study has come from, and where we’re headed

  • admin 

The background

We know that diagnosis, treatment, and care, for so many people with conditions like dementia, especially younger-onset dementia, is not straightforward.

A large part of this challenge is because symptoms, especially early in the illness, can overlap significantly with a range of other conditions. For example, stress, depression, anxiety, a range of medical conditions and medication side effects, can all be associated with changes in thinking and memory. Up to fifty percent of people eventually diagnosed with dementia, are initially diagnosed or misdiagnosed with a primary psychiatric illness. The average delay to an accurate diagnosis is approximately 3.5 years for people under 65, and 2-2.5 years for people over 65. Needless to say, this all has significant negative impacts for people, their families, as well as healthcare systems. 

This got us thinking a few years ago – could biomarkers or proteins that tell us about nerve cell injury and what’s going on at a protein level in the brain, help us with a common, challenging clinical scenario – distinguishing dementia from primary psychiatric illness. For example, distinguishing Alzheimer’s disease from depression (which can sometimes look like a dementia), or behavioural variant frontotemporal dementia (associated with changes in behaviour and personality) from bipolar disorder and schizophrenia (also associated with changes in behaviour and personality).

The pilot study

To test this hypothesis, we started by looking at cerebrospinal fluid (CSF) left over from clinical tests that were done for our patients at the Melbourne Younger Onset Dementia service, Neuropsychiatry, Royal Melbourne Hospital. We analysed CSF for a biomarker protein called neurofilament light (NfL), which has been shown to be elevated in spinal fluid when there is brain cell injury or loss (neurodegeneration). In this pilot study we found that NfL levels were significantly elevated in people who were eventually diagnosed with dementia, compared to people eventually diagnosed with primary psychiatric illnesses (remembering that they were all referred to our service for assessment, because of a suspicion of a possible dementia). This was published in the Australian and New Zealand Journal of Psychiatry (https://doi.org/10.1177/00048674211058684). This study and its promising findings, helped us get funding to significantly expand and explore whether NfL and other biomarkers could help in a broader range of neurological and psychiatric disorders, but especially to explore blood NfL. 

The large follow up study

We followed up on our pilot study by investigating spinal fluid in a much larger number of people with an even more diverse range of conditions, including rapidly progressive dementias like Creutztfeldt-Jakob disease. In 498 people, we found CSF NfL distinguished dementia from primary psychiatric conditions and health, with very high accuracy: 91%. This single test performed better than any other biomarker, and this was strong evidence that this single test could assist with the complexity and challenges faced by so many people, their families, and clinicians.

The pilot study and this study were the result of many years of hard work and large national and international collaborations, and the first of their kind to explore NfL in real-world clinical settings, in a diverse range of people and conditions, and with a focus on younger people. We were very proud to publish this important follow up study in the prestigious journal, Alzheimer’s & Dementia (https://doi.org/10.1002/alz.12549). In admission, Dr Eratne was awarded prizes for this work in recognition of the importance of this work, such as the best biomarker poster award at the Alzheimer’s Association International Conference in 2020, and the Early Career Psychiatrist Award from The Royal Australia and New Zealand College of Psychiatrists.

We also published an important study on blood NfL in treatment-resistant schizophrenia (https://doi.org/10.1177%2F00048674211058684). Contrary to what we thought we might find in a group of people with severe illness, often with cognitive and brain imaging changes, we found that blood NfL levels were not elevated. This filled an important gap in our understanding of NfL in a severe primary psychiatric disorder, and the possible underlying causes of the disorder. 

The future

The ultimate aim is to translate research findings to the real-world clinic – a simple blood test to diagnose (or rule out) dementia, reduce misdiagnosis, improve precision care and treatment, and potentially one day to help monitor risk before symptoms develop, and to even one day delay or prevent symptoms from developing. An additional aim of The MiND Study was to set up a platform for collaborations and support broad research exploring other biomarkers, imaging, clinical, cognitive, and wider psychosocial aspects. This has been working well – with numerous new collaborations and students and researchers joining us, while continuing to strengthen collaborations on our primary focus – blood NfL to potentially transform the care of all people with symptoms and illnesses of the mind and brain.

The first step was understanding how well NfL worked in CSF. We are currently working hard on the next steps – investigating NfL and other markers, in blood. We have analysed blood NfL and aim this year to publish a pilot study of blood NfL to improve accurate diagnosis of dementia (or rule it out), and another pilot study of phosphorylated tau in blood (showing promise as a ‘blood test for Alzheimer’s disease’). Both of these important studies are ahead of schedule. We have also investigated the utility of NfL to reduce misdiagnosis that is so common in clinical care, despite even all the best assessments currently available, and aim to publish this year as well. Finally, numerous studies are underway investigating blood NfL in conditions like epilepsy, functional neurological disorder, Creutzfeldt-Jakob disease, genetic dementias, Niemann-Pick Type C, and more!

We are excited about the future and tests that could significantly improve our clinical practice, and most importantly, improve the care of people all over Australia, with a widely available simple blood test that would reduce so many barriers still faced by so many people. Our early findings are promising, and we are quickly getting the number and diversity of participants (in terms of things like age, symptoms and no symptoms, backgrounds), to help us get critical information needed to get NfL available clinically. For example, the critical information we are rapidly gathering include: what are the ‘normal ranges’ in different ages and in different situations (e.g., in general practice, versus hospital/specialist settings), in what situations and for whom would NfL would be most helpful, and where would it be less helpful, what are the limitations and what other biomarkers or clinical variables would be needed in these situations, and so on.

We are grateful to all our wonderful collaborators, and for funding that supported this work: Trisno Family Research Grant in Old Age Psychiatry; NorthWestern Mental Health Research Seed Grants; and the CJDSGN Memorial Award in memory of Michael Luscombe, MACH MRFF, and NHMRC. 

We cannot do such research and get new tests available, without the help and generosity of all our participants, their families, clinicians, and our wonderful collaborators. We are so grateful, and thank you for joining and helping us on this journey.

Please don’t hesitate to get in touch with us if you have any questions or you’d like any more information. We’d love to hear from you!

Thank you,

Dr Dhamidhu Eratne, on behalf of The MiND Study Group

Here are details of the publications mentioned above, and a few others. We have also put copies of our research up on our website: https://themindstudy.org/our-research, snd please get in touch if you can’t access the full articles and we’d be happy to share them with you.

[1]

Eratne D, Loi SM, Li Q, Stehmann C, Malpas CB, Santillo A, et al. Cerebrospinal fluid neurofilament light chain differentiates primary psychiatric disorders from rapidly progressive, Alzheimer’s disease and frontotemporal disorders in clinical settings. Alzheimer’s & Dementia 2022:alz.12549. https://doi.org/10.1002/alz.12549.

[2]

Eratne D, Keem M, Lewis C, Kang M, Walterfang M, Loi S, et al. Cerebrospinal fluid neurofilament light chain differentiates behavioural variant frontotemporal dementia progressors from ‘phenocopy’ non-progressors. Neurology; 2022. https://doi.org/10.1101/2022.01.14.22269323.

[3]

Walia N, Eratne D, Loi SM, Li Q-X, Varghese S, Malpas CB, et al. Cerebrospinal fluid neurofilament light predicts the rate of executive function decline in younger-onset dementia. Journal of the Neurological Sciences 2022;432:120088. https://doi.org/10.1016/j.jns.2021.120088.

[4]

Ney B, Eratne D, Lewis V, Ney L, Li Q-X, Stehmann C, et al. The Three Glycotypes in the London Classification System of Sporadic Creutzfeldt-Jakob Disease Differ in Disease Duration. Mol Neurobiol 2021;58:3983–91. https://doi.org/10.1007/s12035-021-02396-9.

[5]

Eratne D, Loi SM, Li QX, Varghese S, McGlade A, Collins S, et al. Cerebrospinal fluid neurofilament light chain is elevated in Niemann–Pick type C compared to psychiatric disorders and healthy controls and may be a marker of treatment response. Australian and New Zealand Journal of Psychiatry 2020;54:648–9. https://doi.org/10.1177/0004867419893431.

[6]

Eratne D, Janelidze S, Malpas CB, Loi S, Walterfang M, Merritt A, et al. Plasma neurofilament light chain protein is not increased in treatment-resistant schizophrenia and first-degree relatives. Aust N Z J Psychiatry 2021:000486742110586. https://doi.org/10.1177/00048674211058684.

Leave a Reply

Your email address will not be published.