per borghammer - mondino.it

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