neurofilament light chain: a ‘c-reactive protein’ of the ... · 10y history of schizophrenia...

Neurofilament light chain: a ‘C-reactive protein’ of the brain for psychiatrists, neurologists, geriatricians(and general physicians, and emergency physicians, and GPs?)

Dr Dhamidhu EratneNeuropsychiatrist, Neuropsychiatry Unit, Royal Melbourne Hospital

Research Fellow / Flagship Clinician, Melbourne GenomicsHonorary Fellow, University of Melbourne and Florey Institute of Neuroscience and Mental Health

Thank you

Dr Dhamidhu EratneNeuropsychiatrist, Royal Melbourne Hospital

Research Fellow / Flagship Clinician, Melbourne GenomicsHonorary Fellow, University of Melbourne and Florey

Institute of Neuroscience and Mental Health

deratne@unimelb.edu.au

www.neuropsychiatry.org.au

Professor Dennis VelakoulisDr Samantha M Loi

Professor Mark WalterfangDr Sarah Farrand

Neuropsychiatry Unit, Royal Melbourne HospitalMelbourne Neuropsychiatry Centre, University of Melbourne

Dr Charles B MalpasThe University of Melbourne

A/Professor Veer GuptaDeakin University

Kunal DhimanEdith Cowan University, Melbourne

Dr Qiao-Xin LiShiji VargheseAmelia Glade

Professor Steven CollinsProfessor Colin L Masters

Florey Institute of Neuroscience and Mental Health, Melbourne

Patients and Families

A/Professor Rosie WatsonDr Nawaf Yassi

Professor Terence O’BrienDr Lucy Vivash

Professor Chris PantelisToni Merritt

Dr Vanessa Cropley

Dr Alexander SantilloDr Shorena Janelidze

Professor Oskar Hansson

Dr Christopher FowlerDr Christiane Stehmann

Matteo StenesiDr Vicki LewisTrisno Family Research Grant in Old Age

Psychiatry, three NorthWestern Mental Health Research Seed Grants, and the

CJDSGN Memorial Award in memory of Michael Luscombe

The problem

The neurofilament light

The studies

The future

The discussion

A C-Reactive Protein for Psychiatrists and Neurologists?(and geriatricians, general physicians, GPs)?

Neurofilament Light Chain in the Borderland of Early-Onset Neuropsychiatric

and Neurodegenerative Disorders

Dr Dhamidhu EratneNeuropsychiatrist, Neuropsychiatry Unit, Royal Melbourne Hospital

Research Fellow / Flagship Clinician, Melbourne Genomics

CSF

Neuropsychiatry

NeurologyNeuropsychology

Occupational Therapy

Social Work

Nursing

Bloods

MRI brain

SPECT/PET

Amyloid PETEEG

NCS/EMG

Metabolic

Genetics

MRI spine

Paediatrics Brain biopsy

Muscle biopsySkin biopsy

Psychiatry

Diagnostic uncertainty

Misdiagnosis

Diagnostic delay

Multiple opinions

Repeat investigations, costly, invasive

Imprecise or inaccurate counselling

Significant negative impacts

“Is this psychiatric illness, or neurodegenerative disease?”

“Is this psychiatric illness, or neurodegenerative disease?”

Well + Change + = bvFTD

“Is this psychiatric illness, or neurodegenerative disease?”

+

Schizophrenia/bipolar/depression from bvFTDDepressive pseudodementia from AD

Overlap of psychiatric, cognitive and neurological sx

Broader range of presentations in younger population

(Velakoulis et al., 2009; Woolley et al., 2011; Chan et al., 2014; Galimberti et al., 2015)

“Is this psychiatric illness, or neurodegenerative disease?”

Kate59F, diagnosis of EOAD, no family history

Overdose, significant depression and anxiety, cognitive impairment, early life traumaNon-specific neurological signs (leaning to left, occasional facial twitching)

Inconsistent performance on neuropsychologyBloods, SPECT, CSF including AD proteins normalMRI mild generalised atrophy, no specific pattern

“Is this psychiatric illness, or neurodegenerative disease?”

Major depressive disorder?Generalised anxiety?

Panic disorder with agoraphobia?Dependent personality traits?Cluster B personality traits?

MCI?Other neurodegenerative process?

Greg50M, history of anxiety, family history of anxiety and depressionCognitive impairment, stroke-like episodes, falls, tremor, anxiety

Multiple specialists over 2 yearsTIAs? Migraine? Essential tremor? Anxiety?

Conflicting opinions and uncertainty

Cognitive impairment, cerebellar signs and ataxia, myoclonus, anxietyElevated CSF protein, new FLAIR lesions on MRI

Extensive investigations including brain biopsy unrevealing

Neil Jane48M, R-handed, unemployed, 12y schooling, manual

jobs 56F, R-handed, unemployed, 9y schooling, manual jobs

10y history of schizophreniaChronic positive symptoms

1-2y progressive behavioural and personality changeDisinhibited, impulsive, stereotypys, executive

dysfunction

10y history of schizophreniaChronic positive symptoms

1-2y progressive behavioural and personality changeApathy, loss of empathy, stereotypys, executive

dysfunction

Fam Hx: mother dx AD in her 70s

Fam Hx: mother dx AD in her late 60s

Slightly increased upper limb tone Neurological exam NAD

MRI frontotemporal atrophySPECT frontotemporal hypoperfusion

MRI frontotemporal atrophySPECT frontotemporal hypoperfusion

bvFTD? Possible? Probable?Schizophrenia?

Other neurodegenerative?

bvFTD? Possible? Probable?Schizophrenia?

Other neurodegenerative?

CJDMND

FTDAD

PPAsMS

TBIPSP

HD

(Landqvist Waldö et al., 2013; Evered et al.,2018; Meeter et al., 2016; Meeter et al.,

2018; Scherling et al., 2014; Skillback et al., 2014; Zetterberg et al., 2015;

Zetterberg and Blennow, 2016; Rohrer et al., 2016; Byrne et al., 2017; Gaiani et al., 2017; Hansson et al., 2017; Mattsson

et al., 2017; Steinacker et al., 2017; Thompson et al., 2018; Zerr et al., 2018)

CJDMNDFTDADPPAsMSTBIPSPHD

Psychiatricdisorder vs CJDMNDFTDADPPAsMSTBIPSPHD

Psychiatricdisorder

Bipolar disorder (133 patients, mean age 35y) > controls(Jakobbson et al., 2014; Isgren et al., 2017)

bvFTD (22 patients, mean age 62.9) > psychiatric disorders (22, 60.6y)AUC 0.93

(Vijverberg et al., 2017)

Elderly women without dementia (mean age 73.9y)Major depressive disorder (MDD, 11 patients) > no MDD

(Gudmundsson et al., 2010)

The Study

The utility of CSF NfL in differentiating psychiatric disorders from neurodegenerative

and neurological disorders

03/2009 - 10/2017

Patients referred to neuropsychiatry unit

Comprehensive MDT assessment

CSF stored at NDDL

121 samples

108 samples (108 patients)

Insufficient sample (10)Collected in incorrect tube (1)

Duplicate sample (2)

Analysis for CSF NfLNF-Light ELISA (UmanDiagnostics)

Age, sex, medical and psychiatric comorbidities, investigation results, and bedside cognitive assessment

Primary consensus diagnosis

Most recent primary consensus diagnosis (where follow up was available)

Psychiatric DisorderPSY

Neurological or Neurodegenerative Disease

NND

Data extraction

Controls

AIBL

<70, “HC”AB PET, CSF -ve

2131 77

Psychiatric DisorderPSY

Neurological or Neurodegenerative Disease

NNDControls

General linear modelsCovariates: sex, age at CSF

Receiver operator curves, Youden’s method

Bias-corrected and accelerated confidence intervals via nonparametric bootstrapping

Mean [95% CIs]

Variable Total (n=108)

PSY (n=31) NND (n=77) Controls(n=21)

Difference*

Age at CSF 55 [53, 57]

51 [47, 55]

57 [55, 59]

66 [65, 67]

NND>PSY, C>NND, C>PSY

Female, n(%)

40 (37%)

12 (39%)

28 (36%)

16 (76%)

C>NND, C>PSY

NUCOG 70 [66, 74]

75 [67, 80]

68 [63, 72]

Mean MMSE > 28/30

So…

P<0.0001P<0.0001

Mean [95% CIs]

Variable Total (n=108)

PSY (n=31) NND (n=77) Controls(n=21)

Difference*

CSF NfL (pg/mL)

2810 [2338, 3648]

949 [830, 1108]

3560 [2918, 4601]

1036 [908, 1165]

NND>PSY, NND>C

CSF Aβ1-42 (pg/mL)

644 [602, 694]

704 [626, 820]

621 [570, 676]

844 [795, 889]

NND<C

CSF T-tau (pg/mL)

307 [268, 352]

162 [140, 193]

366 [316, 426]

178 [156, 206]

NND>PSY, NND>C

CSF P-tau (pg/mL)

54 [48, 61]

36 [32, 41]

61 [54, 69]

40 [36, 44]

NND>PSY, NND>C

1331.5pg/mL:

87% sensitivity

90% specificity

But wait, there’s more

(sorry)

AD vs PSY

AUC: 0.97

1339pg/mL:

94% sensitivity

90% specificity

AD vs Schizophrenia

AUC: 0.94

1836pg/mL:

81% sensitivity

89% specificity(1339pg/mL: 94%, 78%)

AD vs MDD

AUC: 0.98

1239pg/mL:

94% sensitivity

100% specificity

bvFTD vs PSY

AUC: 0.88

1239pg/mL:

81% sensitivity

84% specificity

bvFTD vs Schizophrenia

AUC: 0.83

1229pg/mL:

81% sensitivity

67% specificity

bvFTD vs MDD

AUC: 0.91

1239pg/mL:

81% sensitivity

100% specificity

Updates

(unpublished data)

So…

Neil Jane48M, R-handed, unemployed, 12y schooling, manual

jobs 56F, R-handed, unemployed, 9y schooling, manual jobs

10y history of schizophreniaChronic positive symptoms

1-2y progressive behavioural and personality changeDisinhibited, impulsive, stereotypys, executive

dysfunction

10y history of schizophreniaChronic positive symptoms

1-2y progressive behavioural and personality changeApathy, loss of empathy, stereotypys, executive

dysfunction

Fam Hx: mother dx AD in her 70s

Fam Hx: mother dx AD in her late 60s

Slightly increased upper limb tone Neurological exam NAD

MRI frontotemporal atrophySPECT frontotemporal hypoperfusion

MRI frontotemporal atrophySPECT frontotemporal hypoperfusion

bvFTD? Possible? Probable?Schizophrenia?

Other neurodegenerative?

bvFTD? Possible? Probable?Schizophrenia?

Other neurodegenerative?

Neil Jane48M, R-handed, unemployed, 12y schooling, manual

jobs 56F, R-handed, unemployed, 9y schooling, manual jobs

10y history of schizophreniaChronic positive symptoms

1-2y progressive behavioural and personality changeDisinhibited, impulsive, stereotypys, executive

dysfunction

10y history of schizophreniaChronic positive symptoms

1-2y progressive behavioural and personality changeApathy, loss of empathy, stereotypys, executive

dysfunction

Fam Hx: mother dx AD in her 70s

Fam Hx: mother dx AD in her late 60s

Slightly increased upper limb tone Neurological exam NAD

MRI frontotemporal atrophySPECT frontotemporal hypoperfusion

MRI frontotemporal atrophySPECT frontotemporal hypoperfusion

bvFTD? Possible? Probable?Schizophrenia?

Other neurodegenerative?

bvFTD? Possible? Probable?Schizophrenia?

Other neurodegenerative?

NfL: 740pg/mL NfL: 2552pg/mL

Neil Jane48M, R-handed, unemployed, 12y schooling, manual jobs 56F, R-handed, unemployed, 9y schooling, manual jobs

10y history of schizophreniaChronic positive symptoms

1-2y progressive behavioural and personality change

10y history of schizophreniaChronic positive symptoms

1-2y progressive behavioural and personality changeFam Hx:

mother dx AD in her 70sFam Hx:

mother dx AD in her late 60sSlightly increased upper limb tone Neurological exam NADMRI frontotemporal atrophy

SPECT frontotemporal hypoperfusionMRI frontotemporal atrophy

SPECT frontotemporal hypoperfusionbvFTD? Possible? Probable?

Schizophrenia?Other neurodegenerative?

bvFTD? Possible? Probable?Schizophrenia?

Other neurodegenerative?

NfL: 740pg/mL NfL: 2552pg/mL

Significant improvementsNil progressionSchizophrenia

Progressive declineNursing home care

bvFTD

Greg50M, history of anxiety, family history of anxiety and depressionCognitive impairment, stroke-like episodes, falls, tremor, anxiety

Multiple specialists over 2 yearsTIAs? Migraine? Essential tremor? Anxiety?

Conflicting opinions and uncertainty

Cognitive impairment, cerebellar signs and ataxia, myoclonus, anxietyElevated CSF protein, new FLAIR lesions on MRI

Extensive investigations including brain biopsy unrevealing

CJD?CNS vasculitis?

Paraneoplastic or autoimmune encephalitis?Atypical presentation of Alzheimer’s disease?

Mitochondrial disorder?Anxiety-related (or overlay of anxiety)?

NfL: 20658pg/mL

Suspected CNS vasculitisExcellent response to immunosuppression

CNS vasculitis

Kate59F, diagnosis of EOAD, no family history

Overdose, significant depression and anxiety, cognitive impairmentNon-specific neurological signs (leaning to left, occasional facial twitching)

Inconsistent performance on neuropsychologyBloods, SPECT, CSF including AD proteins normalMRI mild generalised atrophy, no specific pattern

Major depressive disorder?Generalised anxiety?

Panic disorder with agoraphobia?Dependent personality traits?Cluster B personality traits?

MCI?Other neurodegenerative process?

ConclusionsEvidence for NfL as a diagnostic test to distinguish PSY from NND

~90% sensitivity and specificity

Significantly elevated NfL should prompt review of psychiatric diagnosis

Potential marker of treatment response in Niemann-Pick Type C and AD

The FutureStudies underway:

BeYOND and Markers in Neuro/psychiatric Disorders (MiND) studies:plasma NfL, psychiatric disorders, treatment trials (NPC, FTD, AD),

memory clinics, general practice, CJD, epilepsy and beyond

“Just do a blood test”:Possibly a game-changer for clinical assessment, care and management,

and research

NfL assisted diagnosis?

?

Paradigm shift

? ?

CSF

Neuropsychiatry

NeurologyNeuropsychology

Occupational Therapy

Social Work

Nursing

Bloods

MRI brain

SPECT/PET

Amyloid PETEEG

NCS/EMG

Metabolic

Genetics

MRI spine

Paediatrics Brain biopsy

Muscle biopsySkin biopsy

Psychiatry

NfL

NNDPSY

AD bvFTD“Scz” “MDD”

NfL

TDP43 Tau

Thank you

NationalDementiaDiagnosticsLaboratoryAccreditedbyNATA/RCPA(accreditationnumber19256)

Director: Professor Steven Collins, Professor Colin Masters

Dr Qiao-Xin Li, Shiji Varghese (Alzheimer’s Disease)

Alison Boyd, Genevieve Klug, Shannon Sarros, Christiane Stehmann(Creutzfeldt-Jakob Disease)

Dr IanBirchall (Qualitymanager)

Thank you

Dr Dhamidhu EratneNeuropsychiatrist, Royal Melbourne Hospital

Research Fellow / Flagship Clinician, Melbourne GenomicsHonorary Fellow, University of Melbourne and Florey

Institute of Neuroscience and Mental Health

deratne@unimelb.edu.au

www.neuropsychiatry.org.au

Professor Dennis VelakoulisDr Samantha M Loi

Professor Mark WalterfangDr Sarah Farrand

Neuropsychiatry Unit, Royal Melbourne HospitalMelbourne Neuropsychiatry Centre, University of Melbourne

Dr Charles B MalpasThe University of Melbourne

A/Professor Veer GuptaDeakin University

Kunal DhimanEdith Cowan University, Melbourne

Dr Qiao-Xin LiShiji VargheseAmelia Glade

Professor Steven CollinsProfessor Colin L Masters

Florey Institute of Neuroscience and Mental Health, Melbourne

Patients and Families

A/Professor Rosie WatsonDr Nawaf Yassi

Professor Terence O’BrienDr Lucy Vivash

Professor Chris PantelisToni Merritt

Dr Vanessa Cropley

Dr Alexander SantilloDr Shorena Janelidze

Professor Oskar Hansson

Dr Christopher FowlerDr Christiane Stehmann

Matteo StenesiDr Vicki LewisTrisno Family Research Grant in Old Age

Psychiatry, three NorthWestern Mental Health Research Seed Grants, and the

CJDSGN Memorial Award in memory of Michael Luscombe

Thank you

Dr Dhamidhu EratneNeuropsychiatrist, Royal Melbourne Hospital

Research Fellow / Flagship Clinician, Melbourne GenomicsHonorary Fellow, University of Melbourne and Florey

Institute of Neuroscience and Mental Health

deratne@unimelb.edu.au

www.neuropsychiatry.org.au