Examining Braak’s Hypothesis byImaging Parkinson’s Disease

David J. Brooks, MD, DSc, FRCP, FMed Sci*

MRC Clinical Sciences Centre and Division of Neuroscience and Mental Health, Faculty of Medicine,Imperial College, Hammersmith Hospital, London, United Kingdom

Abstract: In this review, in vivo patterns of structural,metabolic, and neurotransmitter binding changes revealed byimaging in both symptomatic Parkinson’s disease (PD) andat-risk subjects are compared with those predicted at differentBraak stages. It is concluded that the dysfunction revealed byimaging in PD is only partially in line with the sequentialascending topography of Lewy body pathology reported by

Braak, suggesting that neurons in different brain regions arelikely to be selectively vulnerable to the presence of intracel-lular synuclein aggregates. � 2010 Movement DisorderSocietyKey words: Parkinson’s disease; Braak staging; positron

emission tomography; SPECT; magnetic resonance imaging;transcranial sonography

Lewy bodies are abnormal intraneuronal proteina-

ceous inclusion bodies that are ubiquitin positive and

contain alpha synuclein and neurofilaments.1 In a series

of seminal articles, based on autopsy findings in brain-

banked healthy controls and Parkinson’s disease (PD)

patients, Braak et al. reported that the intracerebral

formation of intracellular Lewy inclusion bodies

and Lewy neurites has a topographically predictable

sequence.1 They suggested that during stages 1 and 2,

which could be presymptomatic, inclusion body pathol-

ogy is confined to the medulla and pontine tegmentum

and the olfactory bulbs. In stages 3 and 4, patients

develop the cardinal symptoms of PD as the substantia

nigra and other regions of the midbrain tegmentum and

the limbic system become involved. At the end stages

5 and 6 of the illness, Lewy body pathology is found

first in the association and then in the primary neocor-

tex, and the disease manifests itself as its full clinical

spectrum. This ascending sequence of Lewy body

pathology plus the early finding of synuclein positive

inclusions in the sympathetic ganglia has led to the

hypothesis that there could be a systemic etiology to

PD, which spreads to the brainstem and later to the

allocortex and the neocortex via a gut portal.

A criticism of Braak staging has been that, although

it reflects the topographical sequence of Lewy body

distribution, there has been no attempt to correlate

Lewy body and neurite density with loss of neurons

and synaptic connections. It seems unlikely that there

is a strict correlation as Braak staging would suggest

that PD patients should first experience dysautonomia

ahead of locomotor problems, which is rarely the case.

However, hyposmia2 and rapid eye movement (REM)

sleep behavior disorder3 (RBD) can be both early and

prodromal features of PD in line with the Braak’s

pathological observations. Although the substantia

nigra is only involved in Braak stage 3, the locus

ceruleus containing noradrenergic cell bodies is

targeted in stage 2, and the median raphe, containing

serotonergic cell bodies, is involved in both stages

2 and 3. Given this, Braak staging might predict

affective symptoms ahead of locomotor dysfunction,

Potential conflict of interest: None.

*Correspondence to: Dr. David J. Brooks, Hartnett Professor ofNeurology, Imperial College London, Cyclotron Building, Hammer-smith Hospital, Du Cane Road, London W12 0NN, United Kingdom.E-mail: david.brooks@csc.mrc.ac.uk

Received 6 November 2007; Revised 1 September 2008; Accepted6 July 2009

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/mds.22720

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Movement DisordersVol. 25, Suppl. 1, 2010, pp. S83–S88� 2010 Movement Disorder Society

and, indeed, depression and anxiety can be prodromal

symptoms of PD.4 The nucleus basalis, containing

cholinergic cells, is targeted in stages 3 and 4 along

with the dopaminergic system.

A major drawback of current in vivo imaging

approaches is their inability to directly image intracellu-

lar synuclein aggregates. Magnetic resonance imaging

(MRI) can reveal brain structural changes associated

with PD as regional reductions in volume, signal altera-

tions in water relaxation times or diffusion, and changes

in magnetization transfer coefficients. Transcranial so-

nography (TCS) can detect structural midbrain and basal

ganglia changes in parkinsonian disorders as hyperecho-

genicity. Positron emission tomography (PET) and sin-

gle-photon emission computed tomography (SPECT)

provide a means of detecting and characterizing the re-

gional changes in brain metabolism and receptor bind-

ing associated with PD and correlating these with motor

and nonmotor symptoms.

MICROGLIAL ACTIVATION IN PD

Although the Lewy body inclusions cannot be

directly imaged in vivo, the glial reaction to the

presence of pathology can be detected with PET and

provides a holistic picture of the extent of the problem

in PD. Microglia constitute 10 to 20% of white cells in

the brain and form its natural defense mechanism. They

are normally in a resting state, but any local

disturbance in milieu causes them to activate and swell,

expressing human leukocyte antigen (HLA) antigens on

the cell surface, and to release cytokines such as tumor

necrosis factor alpha (TNFa and interleukins. The mito-

chondria of activated but not resting microglia express

peripheral benzodiazepine (BDZ) sites that bind

PK11195, an isoquinoline, and so 11C-PK11195 PET

provides an in vivo marker of microglial activation.5

Loss of substantia nigra neurons in PD has been

shown to be associated with microglial activation,6 and

more recently, histochemical studies have shown that

activated microglia can also be seen in the basal

ganglia, cingulate, hippocampus, and cortical areas in

PD.7

11C-PK11195 PET has been used to study microglial

activation in PD, and increased midbrain signal in PD

was reported to correlate inversely with levels of

posterior putamen dopamine transporter (DAT) bind-

ing.8 Another series reported increased signal in the

substantia nigra, striatum, pallidum, and frontal cortex

(see Fig. 1), and this was present both in early and

later cases.9 Interestingly, these workers found little

change in the extent of microglial activation over a

2-year follow-up period, although the patients deterio-

rated clinically. More recently, we have detected a

similar level of cortical 11C-PK11195 uptake in both

nondemented PD patients and cases who have later

developed PD dementia (PDD) (I. Ahmed and D.J.

Brooks, unpublished observations). These findings sug-

gest that cortical disease activity is present even in

early PD cases and that they may already be Braak

stages 5 and 6. As postmortem studies have shown that

activated microglia present are still expressing mRNA

for cytokines such as TNFa in end-stage disease,7

it seems likely that they play a role in driving PD

progression.

RESTING REGIONAL CEREBRALMETABOLISM

Another approach to gaining a holistic view of the

dysfunction present in PD is to measure levels of

resting glucose metabolism in early and established

cases. 18FDG PET scans of frankly demented PD

patients show an Alzheimer pattern of impaired resting

brain glucose utilization, posterior parietal and tempo-

ral association, regional cerebral glucose metabolic rate

(rCMRGlc) being significantly reduced, frontal associa-

tion areas less affected, and primary cortical regions,

basal ganglia, and cerebellum being spared.10 Interest-

ingly, up to one-third of nondemented PD patients with

established disease also show significantly reduced

temporoparietal metabolism, though to a lesser

extent.11 This again suggests that they may already be

in Braak stages 5 and 6, even though no overt cogni-

tive dysfunction was evident.

FIG. 1. An 11C-PK11195 PET scan of a PD patient. Microglial acti-vation is evident in the brainstem, basal ganglia, and frontal cortex.Picture courtesy of Alex Gerhard. [Color figure can be viewed in theonline issue, which is available at www.interscience.wiley.com.]

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Movement Disorders, Vol. 25, Suppl. 1, 2010

As a caveat, it should be stated that it remains

unclear whether the pattern of resting glucose hypome-

tabolism in demented PD patients reflects cortical

Lewy body disease, coincidental Alzheimer’s disease,

or some other degenerative process. PET imaging

agents capable of assessing the beta-amyloid plaque

load in dementia patients are available now.12 Using11C-PIB PET, a thiofavin marker of amyloid deposi-

tion, Edison et al. have recently reported that only

20% of PDD cases have significantly raised cortical

amyloid loads, although temporoparietal glucose levels

are reduced.13 This finding suggests that Lewy

body rather than amyloid pathology is contributory to

late-onset dementia in a majority of PDD cases.

IMAGING THE SELECTIVITY OFPRESYNAPTIC DOPAMINERGIC

INVOLVEMENT

High-field MRI, utilizing special gray and white mat-

ter signal suppressing inversion recovery sequences, has

been reported to detect abnormal signal from the lateral

substantia nigra compacta in PD patients.14 This sug-

gests that cell body loss in the nigra is not uniform as

has been reported in postmortem studies.15 The function

of dopamine terminals in PD can be assessed in vivo via

measurements of dopa decarboxylase (DDC) activity

with 18F-dopa PET, DAT availability with tropane-

based PET and SPECT tracers, and vesicle monoamine

transporter (VMAT2) binding with 11C-dihydrotetrabe-

nazine (DHTBZ) PET.16 In early hemiparkinsonian

cases, all these radiotracer-based imaging approaches

show bilaterally reduced striatal dopaminergic function,

with the activity being most depressed in the posterior

putamen contralateral to the affected limbs that receive

projections from the lateral nigra.

Although nigrostriatal projections comprise the

densest dopamine pathway, there is a lesser medial

nigral-internal pallidal pathway. As 18F-dopa uptake in

the putamen falls by 30 to 50% at the onset of parkin-

sonian rigidity and bradykinesia, uptake of this tracer

into the internal global pallidus (GPi) increases possi-

bly as a compensatory action, but subsequently falls

below normal as the disease advances.17 Reduced pal-

lidal 18F-dopa storage coincides with the onset of

accelerated disability and treatment complications,

such as fluctuating responses to levodopa, suggesting

that both putamen and GPi require an intact dopamine

system to facilitate efficient fluent limb movements. In

Braak stage 3, the midbrain of PD patients becomes

involved with Lewy body pathology, but these findings

make the point that the involvement is highly selective.

While lateral nigral dopamine projections are targeted

and show reduced dopaminergic terminal function in

posterior putamen, the medial nigral projections to an-

terior putamen and internal pallidum show preserved

or upregulated dopaminergic function, which only fails

in end-stage disease.18F-dopa PET findings in PD patients with and

without dementia but matched for locomotor disability

have also been compared.18 The two PD cohorts

showed equivalent levels of putamen dopamine

storage capacity, but cingulate and mesial prefrontal18F-dopa uptake was reduced in the PD dementia

group. Frontal 18F-dopa uptake has previously been

shown to correlate with performance on executive

tasks by nondemented PD patients.19 These findings

suggest that involvement of midbrain tegmental-fron-

tal dopaminergic projections occurs late in PD,

despite technically being Braak stage 3, but when

present is associated with attentional difficulties and

frank dementia.

DETECTION OF SUBCLINICALDOPAMINERGIC FUNCTION IN SUBJECTS

AT-RISK FOR PD

According to Braak staging, elderly subjects with

idiopathic hyposmia could have stage 1 and patients

suffering from RBD stage 2 PD prior to onset of

locomotor difficulties. Subclinical midbrain hypere-

chogenicity, possibly reflecting increased nigral iron

deposition, has been reported with TCS in around

10% of elderly normals.20 PET and SPECT can detect

subclinical dopaminergic dysfunction evidenced as

involvement of the ‘‘asymptomatic’’ putamen contra-

lateral to clinically unaffected limbs. It has been esti-

mated that clinical Parkinsonism occurs when PD

patients have lost around 50% of their posterior

putamen dopamine terminal function, the most

targeted region.

Eleven of 30 cases of late-onset idiopathic olfactory

loss in one series showed midbrain hyperechogenicity,

and half of these had reduced striatal FP-CIT

binding.21 It has been reported that 4 of 40 (10%) of

elderly relatives of PD patients who had no overt

Parkinsonism but who manifested hyposmia on olfac-

tory screening converted to clinical PD over a 2-year

follow-up period.2 Seven of these 40 relatives showed

reduced 123I-beta-CIT uptake in one or more striatal

subregions, and it was the four with lowest DAT bind-

ing that subsequently converted to clinical PD. These

imaging findings are in line with Braak’s view that PD

can be preceded by hyposmia, subclinical nigral

S85EXAMINING BRAAK’S HYPOTHESIS

Movement Disorders, Vol. 25, Suppl. 1, 2010

structural changes, or dopaminergic dysfunction being

demonstrable in a significant minority of these subjects.

RBD is a clinical feature in around 15% of PD

cases,22 while, conversely, 38% of idiopathic RBD

cases have been reported to develop later Parkinson-

ism.23 In a seminal article, Eisensehr et al. measured

striatal DAT binding with IPT SPECT for five cases

of idiopathic RBD confirmed with polysomnography

(mean age, 69 years) who had no signs of Parkin-

sonism.24 The SPECT findings were compared with

those obtained for Hoehn and Yahr stage 1 PD

patients, where only one side was clinically affected,

and with healthy age-matched controls. All five RBD

cases showed significantly reduced striatal DAT bind-

ing to a level comparable with that seen in the PD

striata contralateral to the clinically unaffected limbs

but less than that in the symptomatic striata. These

workers concluded that idiopathic RBD is associated

with a striatal dopamine deficiency state. In a fol-

low-up study, these workers examined striatal DAT

binding for eight cases of subclinical RBD on poly-

somnography (REM sleep without atonia but no clin-

ical manifestations).25 Striatal IPT uptake was lower

in the subclinical RBD cases than in healthy controls

but not reduced to the same extent as clinical RBD

subjects. When controls and subclinical RBD cases

were combined as a single group, an inverse correla-

tion between striatal IPT uptake and duration of

REM sleep with muscle activity was noted. In a

separate study, striatal dopamine terminal function

was studied with a marker of VMAT2 11C-dihydrote-

trabenazine (DTBZ) PET in six cases of idiopathic

RBD.26 None of these subjects had overt Parkinson-

ism, but one was said to have soft neurological

signs. Four of the six RBD cases had low striatal

DTBZ uptake, reduced to a level between normal

and PD, and the pattern of loss showed a gradient

typical of that seen in PD, posterior putamen being

most affected. Again, these imaging findings support

Braak staging of PD, mild but significant dopaminer-

gic dysfunction being demonstrable in a majority of

subjects with chronic idiopathic RBD.

In a more recent series, 30 patients with RBD were

investigated for dopamine deficiency with FP-CIT

SPECT.3 These RBD cases were not strictly idiopathic

as signs of Parkinsonism were detectable in five

patients, while in another 19, the RBD was associated

with narcolepsy and in three more obstructive sleep

apnoea. Eleven of the 30 RBD patients agreed to have

SPECT and two of these showed reduced striatal DAT

binding—both of these two had clinical signs of Par-

kinsonism at the time of SPECT.

SEROTONERGIC, NORADRENERGIC, ANDCHOLINERGIC FUNCTIONS IN PD

Braak staging suggests that the serotonergic and nor-

adrenergic systems could become dysfunctional ahead

of the dopaminergic system in PD. 18F-dopa PET is a

marker of aromatic amino acid decarboxylase activity,

which is found in the terminals and dendrites of all

monoaminergic neurons. Studies of brainstem 18F-dopa

uptake in PD suggest that the median raphe signal is

raised in early disease only falling below normal in

end-stage patients (see Fig. 2).27 This would imply that

serotonergic cell function may actually increase rather

than fall in initial disease stages, possible helping to

promote dopamine turnover in nondopaminergic neu-

rons. A mean 25% loss of median raphe serotonin

HT1A binding in the midbrain, reflecting the functional

integrity of serotonergic cell bodies, has been reported

in established PD with 11C-WAY100635 PET com-

pared with the 50 to 60% loss of putamen 18F-dopa

uptake normally reported. Individual levels of raphe11C-WAY100635 binding correlated with severity of

rest tremor but not rigidity or bradykinesia.28 This sug-

gests that midbrain tegmentum pathology involving

serotonin projections is less severe than that involving

the nigrostriatal dopaminergic system, and that the for-

FIG. 2. PET images of 18F-dopa uptake in the median raphe andlocus ceruleus. These structures only show reduced uptake in end-stage PD. Pictures courtesy of James Rakshi and Alan Whone. [Colorfigure can be viewed in the online issue, which is available atwww.interscience.wiley.com.]

S86 D.J. BROOKS

Movement Disorders, Vol. 25, Suppl. 1, 2010

mer may be more relevant to the etiology of PD

tremor. No correlation between depressive symptoms

and either midbrain 11C-WAY100635 uptake or beta-

CIT uptake, a marker of serotonergic transporters, has

been found in PD arguing against a direct role of

serotonergic dysfunction.28,29

18F-dopa uptake has also been studied in the locus

ceruleus and appears to be preserved until late disease

(Fig. 2).27 This would argue that the loss of noradren-

ergic function is a late phenomenon in PD, despite the

presence of Lewy body pathology in Braak stage 2.11C-RTI 32 PET is a marker of both noradrenaline and

dopamine terminal transporter availability. Patients

with PD and depression compared with those equiva-

lently disabled but without depression have been

reported to show additional loss of thalamic, locus

ceruleus, and limbic 11C-RTI 32 uptake.30 These find-

ings imply that the presence of depression in PD is

influenced both by the integrity of noradrenergic and

limbic monoaminergic projections rather than by the

serotonergic system.

Cholinergic function can be assessed presynaptically

with 123I-benzovesamicol SPECT, while 11C-PMP PET

is a marker of acetylcholine esterase levels. In early

PD, there is a significant reduction of parietal and

occipital 123I-vesamicol and cortical 11C-PMP uptake

although this would represent stage 4 disease.31,32 PD

patients who develop dementia later (PDD) show

globally reduced 123I-vesamicol binding and further

reductions in cortical 11C-PMP binding.

CARDIAC SYMAPTHETIC INNERVATION123I-metaiodobenzylguanidine (MIBG) is a norepi-

nephrine analog that is taken up and stored in sympa-

thetic nerve endings. Imaging studies with [123I]MIBG

SPECT in PD patients have shown significantly

decreased cardiac uptake, indicating severe myocardial

postganglionic sympathetic dysfunction.33–36 Surpris-

ingly, in many of these cases cardiovascular reflexes

still remain intact. 18F-dopamine PET has been used to

examine the function of myocardial sympathetic inner-

vation in PD subjects with and without dysautono-

mia.37 These workers performed PET on 29 cases of

PD (nine with impaired cardiovascular reflexes) and

seven cases of pure autonomic failure.38 All nine PD

cases with orthostatic hypotension and another 11

without cardiac reflex problems showed reduced myo-

cardial 18F-dopamine uptake comparable with the low

levels seen in pure autonomic failure cases.

These MIBG and 18F-dopamine findings suggest

early involvement of the sympathetic ganglia in PD, in

line with Braak staging. Having said that, in Hoehn

and Yahr stage 1, PD 50% of cases still show normal

MIBG uptake39,40 and 9 of 20 (45%) of Goldstein’s

PD cases without dysautonomia had normal 18F-dopa-

mine uptake in their myocardium. This suggests that

Braak stage 3 disease is not necessarily associated

with cardiac sympathetic denervation and, when pres-

ent, such denervation does not necessarily manifest as

dysautonomia.

CONCLUSIONS

Measurements of microglial activation and regional

cerebral glucose metabolism suggest that cortical dys-

function can be present in early PD cases, implying

they are already Braak stages 5 and 6, despite their

intact cognition. In line with Braak’s predictions, sub-

clinical dopaminergic dysfunction is demonstrable in a

minority of patients with late-onset hyposmia and RBD

and the majority of PD cases show profound cardiac

sympathetic denervation. However, despite the pre-

dicted involvement of the pons in Braak stage 2, dys-

function of the noradrenergic and serotonergic systems

is a late feature of PD and, although the midbrain is

involved in stage 3, the topography of dopaminergic

dysfunction is highly selective. In summary, although

it is impossible to directly correlate the density of

Lewy body and neurite pathology with changes in

brain metabolism and neurotransmitter binding, in vivo

imaging findings suggest that brain regions are very

selective in their vulnerability to the presence of

intracellular synuclein aggregates, and that Braak stag-

ing is not helpful in predicting the patterns of regional

cerebral dysfunction.

Financial Disclosures: Nothing to disclose.

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