per borghammer - mondino.it
TRANSCRIPT
V
V
Per Borghammer
Brain-first vs. Body-first Parkinson’s disease
Per Borghammer
Dep. of Nuclear Medicine & PETAarhus University Hospital
- Bad news spreading through networks
Professor or Nuclear Medicine & Neuroscience
V
Per Borghammer
PARKINSON’S DISEASE
Motor symptoms• bradykinesia (slow)
• rigidity (stiff)
• tremor
Cause• Lewy pathology• Dopamine loss
Lewy body⍺-synuclein
PD
Normal
neuron loss
WORLDWIDE 6 mill. patients
Per Borghammer page 3
PARKINSON’S DISEASE
Motor symptoms
Pain
Sleep
Depression
Dementia
Anxiety
Hyposmia
Constipation
Bladder Sexual
Blood pressure
Autonomic damage
V
Per Borghammer
PROGRAM
HISTORY OF PD- neuropathology history- Braak’s contribution
DOES PD START IN THE GUT- evidence (epidemiology, histology, animals,
patient studies)
DOES PD START IN THE BRAIN- evidence (histology, patient studies)
IMPLICATIONS
INSTITUT FOR KLINISK MEDICIN
AARHUS UNIVERSITET AU
Friedrich Lewy(1885-1950)
1. Dorsal motor vagus2. Locus ceruleus3. Globus pallidus
Konstantin Trétiakoff(1892-1954)
Lewy bodiessubstantianigra
1912
1919
Per Borghammer
V
V
vagus
coeliacganglion
DMV
IML
ST
1912 20031928 1960 1988
Lewy Tretiakoff
1919
Wohlwill Den Hartog-Jager Wakabayashi Braak
1912DMV
L. coerule.
1919Nigra
1928Sympathetic
Nervous system
1960Gangl.
coeliacum
1988Myenteric
plexus
2003Braak
staging
Braak brought theperiphery back
INSTITUT FOR KLINISK MEDICIN
AARHUS UNIVERSITET AU
Aarhus University Hospital
BRAAK STAGES
stage I
stage I
stage II
stage III
Braak et al, Neurobiol aging 2003
Olfactory bulb
Heiko Braak
LewypathologyDorsal motor
nucleus of vagus
110 autopsies
Pattern of Lewy pathology in the brain
INSTITUT FOR KLINISK MEDICIN
AARHUS UNIVERSITET AU
Aarhus University Hospital
stage I
stage I
DUAL HITHYPOTHESIS
Braak et al, Neurobiol aging 2003Hawkes & Braak, 2007
heart
gut
parasympathetic
sympathetic
Braak suggests peripheral start
Lewypathology
NETWORK THEORY1. The pathology starts in one place2. Then spreads through networks
3. Late-stage it is everywhere
INSTITUT FOR KLINISK MEDICIN
AARHUS UNIVERSITET AU
Aarhus University Hospital
STAGE 1 - SYMPTOMS
stage I
Loss of olfaction yearsbefore diagnosis
stage I
Constipation yearsbefore diagnosis
Svensson et al, Mov Disord 2016Postuma et al., Mov Disord 2013 26(5)
-10-20 years
INSTITUT FOR KLINISK MEDICIN
AARHUS UNIVERSITET AU
Aarhus University Hospital
STAGE 2 - SYMPTOMS
stage I
stage I
stage II
DEPRESSION YEARSBEFORE DIAGNOSIS
SEROTONIN NUCLEI
-10 years
INSTITUT FOR KLINISK MEDICIN
AARHUS UNIVERSITET AU
Aarhus University Hospital
STAGE 2 – REM SLEEP
REM SLEEP BEHAVIOUR DISORDER
stage I
stage II
NORADRENALINNUCLEI
-10 år
DREAM ENACTMENT
0% Parkinson
80% Parkinson(after 10 y)
V
Per Borghammer
PROGRAM
HISTORY OF PD- neuropathology history- Braak’s contribution
DOES PD START IN THE GUT- evidence (epidemiology, histology, animals,
patient studies)
DOES PD START IN THE BRAIN- evidence (histology, patient studies)
IMPLICATIONS
INSTITUT FOR KLINISK MEDICIN
AARHUS UNIVERSITET AU
Aarhus University Hospital
Evidence for gut start Effect of vagotomy
Svensson et al., Ann Neurol 2015 Liu et al., Neurology 2017gut
VAGOTOMY
peptic ulcer
Controls (n=66.700)
vagotomy (n=5.300)
COMPLETE VAGOTOMY
VAGOTOMY ->47% DECREASED RISKFOR PARKINSON (20 years)
SWEDISH STUDY:40% REDUCED RISK (10 years)
INSTITUT FOR KLINISK MEDICIN
AARHUS UNIVERSITET AU
Aarhus University Hospital
Evidence for gut start
39 PD PATIENTS
archived GI tissueremoved 1-20 y before diagnosis
22/39 positive (phos-α-syn)up to 20 y before diagnosis
56% positive
12/62 controls also positive19% positive
Lewy pathology in gut20 years before diagnosis
Stokholm et al., Ann Neurol 2016
Ann Neurol 2016
Hilton et al., Acta Neuropathol 2014Shannon et al., Mov Disord 2012
An Offi cial Journal of the American Neurological Association and The Child Neurology Society
Volume 79, Issue 6 June 2016
ISSN 0364-5134
Esophagus – 7 y before diagnosis
INSTITUT FOR KLINISK MEDICIN
AARHUS UNIVERSITET AU
ANIMAL MODEL EVIDENCE
• Prion-like spreading• supports GUT-to-BRAIN spreading of a-syn
Other supportive studies:
Ulusoy et al., EMBO Mol 13Kim et al, Neuron 2019Anselmi et al., NPJ PD 2018Breid et al., J Virol 2016Ayers et al., J Virol 2017Holmqvist, Acta Neuropa 14Pan-Motojo PlosONE 2010
INSTITUT FOR KLINISK MEDICIN
AARHUS UNIVERSITET AU
Animal evidence
Van Den Berge et al., Acta Neuropathologica 2019Nathalie Van Den Bergepost.doc.
Other supportive studies:
Ulusoy et al., EMBO Mol 13Kim et al, Neuron 2019Anselmi et al., NPJ PD 2018Breid et al., J Virol 2016Ayers et al., J Virol 2017Holmqvist, Acta Neuropa 14Pan-Motojo PlosONE 2010
duodenum
PFF
PBS
coeliac gang.
PFF PBS
myocardiumPFF PBS
SNr
PFF PBS
DMVPFF PBS
LCPFF PBS
IML
2-4 monthslater
Van Den Berge et al., Acta Neuropathologica 2019
alpha-syn pathology• aggregated• proteinase K resistant• hyperphosphorylated
Transgenic RatBacterial artificial chromosome (BAC)expresses human WT alpha-syn
Nuber et al., Brain 2013
INSTITUT FOR KLINISK MEDICIN
AARHUS UNIVERSITET AU
HUMAN IMAGING STUDIESIs RBD a marker of gut-start?
stage II damagecauses RBD
heart
gut
damage
damage
lessdamage
damage
Lancet Neurol 2018
Knudsen et al., Lancet Neurol 2018
22 isolated RBD cases
compared to
PD patients
Healthy controls
INSTITUT FOR KLINISK MEDICIN
AARHUS UNIVERSITET AU
IMAGING THE BRAAK STAGES
lc
dmv
sn
11C-donepezil
11C-MeNER 18F-DOPA
123I-MIBG
NM MR
I
III II
I
II
Karoline Knudsen
Knudsen et al., Lancet Neurol 2018
TatyanaFedorova
AllanHansen11C-donepezil PET
Gjerløff et al, Brain 2015Fedorova et al, Neurology, 2017
11C-MeNER PETNahimi et al, J Nucl Med 2017Sommerauer et al, Brain, 2018
Neuromelanin MRISommerauer et al, Brain 2018Garcia-Lorenzo et al, Brain, 2013
parasympathetic
Braak stage IsympatheticBraak stage I
locus coeruleus
terminals
Braak stage II
locus coeruleuscell bodiesBraak stage II
dopamineterminalsBraak stage III
Per Borghammer
V
BODY-FIRST
PARKINSON
”NORMAL”
SEVEREDAMAGE
SEVEREDAMAGE
dopamine
parasympathetic
sympathetic
HC RBD PD0.7
1.1
1.5
1.9
2.3
2.7
SUV
Donepezil Colontotal
HC RBD PD4
6
8
10
12
14
SUV
Donepezil tyndtarm
HC RBD PD0.8
1.1
1.4
1.7
2.0
2.3
H/M
ratio
MIBG late image MIBG WR
HC RBD PD-0.3
-0.2
-0.1
0.0
0.1
0.2
was
hout
rate
A B C D DON small intest DON colon MIBG ratio MIBG washout
VOLUMECORRECTED
parasympathetic
HC RBD PD0.7
1.1
1.5
1.9
2.3
2.7
SUV
Donepezil Colontotal
HC RBD PD4
6
8
10
12
14
SUV
Donepezil tyndtarm
HC RBD PD0.8
1.1
1.4
1.7
2.0
2.3
H/M
ratio
MIBG late image MIBG WR
HC RBD PD-0.3
-0.2
-0.1
0.0
0.1
0.2
was
hout
rate
A B C D DON small intest DON colon MIBG ratio MIBG washout
VOLUMECORRECTED
sympathetic
HC RBD PD1.20
1.25
1.30
1.35
1.40
1.45
ratio
10PO-bilat PD combined
HC RBD PD0.1
0.2
0.3
0.4
0.5
0.6
BPn
d
BPnd_Thalamus_PD-combined
HC RBD PD0.000
0.004
0.008
0.012
0.016
0.020
Ki
HC RBD PD1.20
1.25
1.30
1.35
1.40
1.45
ratio
10PO-bilat PD combined
A
HC RBD PD0.1
0.2
0.3
0.4
0.5
0.6
BPn
d
BPnd_Thalamus_PD-combined
B
A B neuromelanin MeNER
C
C FDOPA
dopamine
Knudsen et al., Lancet Neurol 2018
Healthy RBD Parkinson
Per Borghammer
SO ALL IS GOOD
V
VAGUS
locus coeruleus
cortex
sub. nigra
dorsal motor
nucleus - vagus
gut
GUT-FIRST
PARKINSON
Braak et al., 2003
INCOMPLETEHYPOTHESIS
olf. bulb
BRAAKEPIDEMIOLOGYHISTOLOGYANIMAL STUDIESIMAGING STUDIES
V
Per Borghammer
PROGRAM
HISTORY OF PD- neuropathology history- Braak’s contribution
DOES PD START IN THE GUT- evidence (epidemiology, histology, animals,
patient studies)
DOES PD START IN THE BRAIN- evidence (histology, patient studies)
IMPLICATIONS
Per Borghammer
Braak et al., 2003
ALL CASES WERE SELECTED –PATHOLOGY IN DMV MANDATORY
Per Borghammer
NO PATHOLOGY INTHE DMV
V
No pathology
Per Borghammer
V
BRAIN-FIRST
PARKINSON
Borghammer & Van Den Berge, 2019
amygdala
nigra
LC
DMV
heart
gut
V
VAGUS
locus coeruleus
cortex
sub. nigra
dorsal motor
nucleus - vagus
olf. bulb
gut
BODY-FIRST
PARKINSON
Braak et al., 2003
BRAIN-FIRST vs BODY-FIRST PARKINSON
ob
V
LATE STAGE PDPathology everywhere
INSTITUT FOR KLINISK MEDICIN
AARHUS UNIVERSITET AU
Animal evidence
Ulusoy et al., Acta Neuropathologica 2017
Per Borghammer
V
Van Den Berge et al., Acta Neuropathol, 2019Holmqvist, Acta Nauropathol 2014Kim et al, Neuron 2019
V
VAGUS
GUT TO BRAIN
Ulusoy et al, Acta Neuropathol 2017
BIDIRECTIONAL SPREAD THROUGH VAGUSBRAIN TO GUT
VAGUS
Per Borghammer
VIMAGING – brain-first vs. body-first
V
GUT-FIRST
PARKINSONdopamine
parasympathetic
sympathetic
BRAIN-FIRST
PARKINSON
”NORMAL”
SEVEREDAMAGE
SEVEREDAMAGE
”NORMAL”
SEVEREDAMAGE
”NORMAL”
dopamine
parasympathetic
sympathetic
Per Borghammer
VTHE NEXT IMAGING STUDY
V
GUT-FIRST
PARKINSON
BRAIN-FIRST
PARKINSON
Isolated RBD patientsDenovo PD without RBD
Fdopa MIBG
Donepezil PET
Per Borghammer
VImaging body- vs. brain-first PD
V
submitted
La
te-s
tag
e P
D
LAG-TIME
iRBD
denovo PD + RBD
denovo PD no RBD
Brain-first
Bo
dy
-fir
st
healthy controls
MSA
0.5 1.0 1.5 2.0 2.5
1.0
1.5
2.0
FDOPA (min. put.)
MIB
G (H
/M la
te)
FDOPA vs MIBG
HC-MIBGHC-FDOPAiRBD outlierPAF
0.5 1.0 1.5 2.0 2.5
1.0
1.5
2.0
FDOPA (min. put.)
MIB
G (H
/M la
te)
FDOPA vs MIBG
iRBD
HC-MIBGHC-FDOPAiRBD outlierPAF
0.5 1.0 1.5 2.0 2.5
1.0
1.5
2.0
FDOPA (min. put.)
MIB
G (H
/M la
te)
FDOPA vs MIBG
iRBD
DN PD + RBD
HC-MIBGHC-FDOPAiRBD outlier
DN PD ?RBD
PAF
0.5 1.0 1.5 2.0 2.5
1.0
1.5
2.0
FDOPA (min. put.)
MIB
G (H
/M la
te)
FDOPA vs MIBG
iRBDDN PD - RBDDN PD + RBD
HC-MIBGHC-FDOPAiRBD outlier
DN PD ?RBD
PAFRBD top-down
VACUUM
FDOPA PETdopamine brain
MIB
G
sym
path
etic
hear
t
Per Borghammer
V
V
Brain-first
Bo
dy
-fir
st
healthy controls
0.5 1.0 1.5 2.0 2.5
1.0
1.5
2.0
FDOPA (min. put.)
MIB
G (H
/M la
te)
FDOPA vs MIBG
iRBDDN PD - RBDDN PD + RBD
HC-MIBGHC-FDOPAiRBD outlier
DN PD ?RBD
PAFRBD top-down
Top-down RBD vs bottom-up RBD
Top-down RBD
Bottom-up RBD
ALL THESE CASES HAD PRODROMAL RBD
FOR > 4-25 YEARS
RBD positive
SPECIAL CASES
RBD STARTED AFTERPARKINSONISM
submitted
Per Borghammer
VLongitudinal study
V
BRAIN-FIRST
PARKINSON
GUT-FIRST
PARKINSONControl data
Brain-first
Bo
dy
-fir
st
0.5 1.0 1.5 2.0 2.5
1.0
1.5
2.0
FDOPA (min. put.)
MIB
G (H
/M la
te)
FDOPA vs MIBG
iRBDDN PD - RBDDN PD + RBD
HC-MIBGHC-FDOPA
DN PD ?RBD
RBD follow-upRBD top-down
V
LATE STAGE PDPathology everywhere
submitted
Per Borghammer
VParasympathetic denervation
V
Brain-first
Bo
dy
-fir
st
Control data
HC RBD PD0.7
1.1
1.5
1.9
2.3
2.7
SUV
Donepezil Colontotal
HC RBD PD4
6
8
10
12
14
SUV
Donepezil tyndtarm
HC RBD PD0.8
1.1
1.4
1.7
2.0
2.3
H/M
ratio
MIBG late image MIBG WR
HC RBD PD-0.3
-0.2
-0.1
0.0
0.1
0.2
was
hout
rate
A B C D DON small intest DON colon MIBG ratio MIBG washout
VOLUMECORRECTED
DONEPEZIL PETCOLON
0.0 0.5 1.0 1.5 2.0 2.5
1.0
1.5
2.0
FDOPA (min. put.)
Col
on (S
UV)
FDOPA vs Donepezil (colon)
iRBDDN PD - RBDDN PD + RBD
submitted
Per Borghammer
124 Lewy-body positive…all 85+ living in Vantaain 1991 asked to participate
V300 autopsies of age 85+ peopleActa Neuropathol 2019
V
Per Borghammer
V300 autopsies of 85+ people
NONE
MILD
MODERATE
SEVERE
VERY SEVEREBRAAK STAGINGcluster
11 patients
BRAAK STAGE 1 1 2 3 4 4 5 5 5-6
V
Lewypathol
Per Borghammer
caudo-rostral gradient
3 medulla (DMV) - START
** * * *
time point 1 2 3 4 5
BRAAK STAGING
DMV
amygdala predominant
6 amygdala - START
*
* *
cluster not asigned
time point 1 2 3
*
* *amygdala
V mountainprofile
Vskiingslope
ARRANGING THE CLUSTERS BY TEMPORAL EVOLUTION
(hypothetical)
V
ARRANGING THE CLUSTERS BY TEMPORAL EVOLUTION (hypothetical)
Per Borghammer
caudo-rostral
gradient
amygdala
predominant
BODY-FIRST
BRAIN-FIRST
V
Per Borghammer
PROGRAM
HISTORY OF PD- neuropathology history- Braak’s contribution
DOES PD START IN THE GUT- evidence (epidemiology, histology, animals,
patient studies)
DOES PD START IN THE BRAIN- evidence (histology, patient studies)
IMPLICATIONS & NEW AVENUES
Per Borghammer
V– are there differences between the types ?
V
BRAIN-FIRST BODY-FIRST
a-syn strains
microbiome gut hyper-permeability
genetic factors
immunological
IMPLICATIONS
Per Borghammer
VSUMMARY
V
MULTI-MODALITY IMAGING
• BRAIN-FIRST PD
• BODY-FIRST PD
V
POST-MORTEM DATA
• CAUDO-ROSTRAL
• AMYGDALA BRAIN-FIRST BODY-FIRST
BRAIN-FIRST BODY-FIRST
V
QUESTIONS
What causes the different subtypes?
How do we diagnose them early?
Require personalized treatment ?
Propagation through networksis important
INSTITUT FOR KLINISK MEDICIN
AARHUS UNIVERSITET AU
SENDAI, JAPAN
Nobuyuki Okamura
THANK YOUStudy participants
INSTITUT FOR KLINISK MEDICIN
AARHUS UNIVERSITET AU
RADIOCHEMISTRY
Dirk Bender
Steen Jakobsen
Helene Audrain
Anna Schacht
Jan Jakobsen
NEUROLOGY
Erik H. Danielsen
Karen Østergaard
Mette Møller
Nicola Pavese
Astrid Terkelsen
Jacob Geday
Jonas Kraft
Einer Bech
Katrine Andersen, Jacob Horsager, Tanja Fedorova, Casper Skjærbæk, Karoline Knudsen, Nathalie van den Berge, Allan Hansen
KIEL, GERMANY
Daniela Berg
Eva Schäffer
Sarah Kim Bonkat
BONN, GERMANY
Erdem Tamguney
ANN ARBOR, USA
Nico Bohnen
YALE, USA
Rich Carson
STANFORD, USA
Kathleen Poston
HELSINKI, FINLAND
Filip Scheperjans
EPIDEMIOLOGY
Elisabeth Svensson
Henrik T. Sørensen
GRONINGEN, NETHERLANDS
Teus van Laar
AUTORADIOGRAPHY &
ANIMAL STUDIES
Aage K.O. Alstrup
Adjmal Nahimi
Morten Stokholm
Annie Landau
Thea Lillethorup
GASTROENTEROLOGY
Klaus Krogh
SLEEP CLINIC
Marit Otto
Kristina Svendsen
HISTOLOGY ETC.
Poul Henning Jensen
Steve Hamilton
Jens Nyengaard
NEUROPSYCHOLOGY
Malene Damholdt
NANTES, FRANCE
Pascal Derkinderen
VIENNA, AUSTRIA
Pai TsungPin