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
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
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
www.neuropsychiatry.org.au