INTERNATIONAL SYMPOSIUM ON OLFACTION AND TASTE
The Dual Hit Theory Revisited
Christopher H. Hawkes,aKelly Del Tredici,band Heiko Braakb
aNeuroscience Centre, Institute of Cell and Molecular Science, Barts and The London
School of Medicine and Dentistry, London, United Kingdom
bInstitute for Clinical Neuroanatomy, Johann Wolfgang Goethe University,
Frankfurt am Main, Germany
Accumulating evidence suggests that sporadic Parkinson’s disease (sPD) has a long pro-
dromal period during which several nonmotor features develop; in particular, impair-
ment of olfaction, vagal dysfunction, and sleep disorder. Early sites of Lewy pathology
are the olfactory bulb and enteric plexuses of the foregut. We propose that a neurotropic
pathogen, probably viral, enters the brain via two routes: (a) nasal, with anterograde
progression into the temporal lobe; and (b) gastric, secondary to swallowing of nasal
secretions in saliva. These secretions might contain a neurotropic pathogen that, after
penetration of the epithelial lining, could enter axons of the Meissner’s plexus and via
transsynaptic transmission reach the preganglionic parasympathetic motor neurons of
the vagus nerve. This would allow retrograde transport into the medulla and from here
into the pons and midbrain until the substantia nigra is reached and typical aspects
of disease commence. Evidence for this theory from the perspective of olfactory and
autonomic dysfunction is reviewed and the possible routes of pathogenic invasion are
of sPD is pathogenic access to the brain through the foregut and nose—hence the term
Key words: Parkinson’s disease; etiology; autonomic regulation; olfaction; alpha-
The “Dual Hit” theory1proposes that an
unknown pathogen gains access to the brain
through two portals: the nose and gut. We sug-
gested that the initial process is nasal and that
the pathogen is swallowed in saliva and mucus,
and crosses the stomach wall to invade the dis-
motor vagus in retrograde fashion to damage
the vagal dorsal motor nucleus in the medulla.
Meanwhile, there is simultaneous anterograde
invasion of the brain from the nasal mucosa to
Address for correspondence: Professor Christopher H. Hawkes, Neu-
roscience Centre, Institute of Cell and Molecular Science, Barts and The
London School of Medicine and Dentistry, 4 Newark Street, London E1
the olfactory bulb and anterior olfactory nu-
cleus (AON) into the olfactory structures of the
The pathological process underlying spo-
radic Parkinson’s disease (sPD) is linked to
the development of α-synuclein-containing in-
clusion bodies in the form of Lewy bodies
(LBs) in perikarya and Lewy neurites (LNs)
in neuronal processes.2–4Vulnerable cells are
distributed throughout the peripheral, enteric,
and central portions of the nervous system
(PNS/ENS/CNS).5–8All susceptible cells are
projection neurons that generate a long and
thin axon, which is unmyelinated or poorly
myelinated.9It has been postulated that sPD
might be a primary disorder of olfaction, given
International Symposium on Olfaction and Taste: Ann. N.Y. Acad. Sci. 1170: 615–622 (2009).
c ?2009 New York Academy of Sciences.
Annals of the New York Academy of Sciences
that smell loss is an early event in the course
of this disorder.10Additional studies have cor-
roborated this and demonstrated early involve-
ment of the enteric nerve cell plexuses, vagal
dorsal motor nucleus, and the intermediate
reticular zone in the lower brainstem.11–15To
be plausible, any theory attempting to ex-
plain sPD must incorporate these extranigral
sites, which consistently become affected in the
course of the disorder.5Furthermore, any spec-
ulation regarding the cause and beginnings of
PD must take into account the involvement of
olfactory and autonomic systems that gener-
ally develop prior to the onset of the classical
We review evidence for early olfactory and
ENS damage and suggest a possible mecha-
nism to explain these distant and apparently
unconnected sites of damage.
Is Olfaction Involved in PD and, if
so, how Early on?
Evidence for this is reviewed from the
pathological, psychophysical, neurophysiolog-
ical, and clinical/epidemiological standpoint.
Pathological Changes in Olfactory
PD-associated α-synuclein-containing inclu-
sions as yet have not been found in the ol-
factory epithelium of autopsied PD patients.19
Nasal biopsy specimens from seven patients
with symptomatic PD20were compared to four
torymarker protein(OMP), neurotubulin, pro-
OMP. Irregular areas of olfactory epithelium
mostly negative for OMP, although mRNA for
OMP was found in the olfactory cleft and res-
piratory mucosa. In this small series there was
no clear difference between PD and anosmic
controls; however, sections were not examined
for the presence of LNs/LBs and it could be
argued that those with anosmia may have been
Hawkes21examined olfactory bulbs and tracts
in eight controls and eight patients with a clini-
the UK Parkinson’s Disease Brain Bank. All
PD cases contained LBs, which were most nu-
merous in AON but also were found in mitral
cells, the first projection neurons to receive in-
put from the bipolar neurons in the olfactory
of neurons in AON correlated with disease du-
ration.22One report23suggested that expres-
sion of tyrosine hydroxylase in the olfactory
bulb is increased 100-fold and that the con-
sequent excess of dopamine might explain the
hyposmia that develops in PD. Braak and col-
lesions in mitral cells, tufted neurons of the ol-
factory bulb and in projection neurons of the
AON, which is dispersed throughout the olfac-
tory tract. A tightly woven network of LNs was
observed to develop rapidly within the AON.
From there, the pathology spreads slowly into
more remote olfactory sites including the ol-
factory tubercle, piriform and periamygdalear
cortex, and entorhinal cortex of the ambient
gyrus24without advancing into nonolfactory
The first case–control study that demon-
by Ansari and Johnson25in 22 clinically diag-
nosed PD patients. A subsequent larger study
used detection threshold tests to amyl acetate
in 78 subjects and 40 controls.26Thresholds
were reduced but no correlation was found
with age, gender, or treatment with levodopa.
Unlike the first study, there was no association
with disease duration. The next sizable inves-
tigation using the University of Pennsylvania
Smell Identification Test (UPSIT) showed that
age-matched olfactory dysfunction did not re-
late to odor type, was independent of disease
duration, and did not correspond with motor
Hawkes et al.: Dual Hit Hypothesis
also demonstrated that the deficit was of the
same magnitude in both nostrils, and not influ-
enced by antiparkinsonian medication. A com-
tients and 156 age-matched controls.29UPSIT
scores for PD patients were dramatically lower
than those for controls but there was no cor-
relation between disease duration and UPSIT
score (r = 0.07). Although the psychophysical
factory involvement in PD, it does not com-
pletely eliminate the possibility of confounding
factors from cognitive dysfunction nor can it
be determined from this source of information
whether the smell defect is initially peripheral
A further measure of smell sense is the olfac-
tory event related potential (OERP) pioneered
by Kobal and Plattig,34which has the advan-
tage of minimizing the theoretical effect of cog-
patients with that of 47 controls of similar age
and gender.29In 36 patients (49%), responses
were either absent or unsatisfactory for techni-
cal reasons. Analysis of the 37 with a measur-
able trace showed that for hydrogen sulphide
(H2S) a highly significant latency difference ex-
isted between diagnostic groups. Similar re-
sults were obtained in 31 patients with clini-
cally labeled PD tested by OERP to vanillin
and H2S.35Prolonged latencies were seen in
these individuals whether they were taking an-
tiparkinson medication or not.
Clinical and Epidemiological Evidence
An important question is whether olfactory
features or commences synchronously? Apart
from suggestive neuropathological evidence of
priority,12four prospective studies address this.
first-degree relatives of nonfamilial PD patients
by olfactory tests and dopamine transporter
imaging (DATScan). Forty patients were se-
line DATScan. When reviewed 2 years later,
four had developed PD and all had abnor-
mal DATScans at the first assessment. Second,
Montgomery et al.37administered tests of mo-
tor function, olfaction (UPSIT), and mood in
first-degree relatives of PD patients. Using this
procedure, significant differences were found
in first-degree relatives (both sons and daugh-
ters) particularly where the affected parent was
the father. Third, Ross et al.38used the cross-
cultural Brief Smell Identification Test (BSIT)
in 2267 healthy Japanese-American men aged
71–95 years who participated in the Honolulu
Asia Aging Study. After 4 years follow-up, 19
developed PD, which gave relative odds for
PD in the lowest BSIT quartile of 5.2 (95%
CI 1.5, 25.6. P = 0.007) compared to those
in the highest two quartiles. In the same co-
hort 164 died without signs of PD or demen-
stains of midbrain and pons) revealed 17 with
incidental Lewy bodies (ILB), the postulated
pathological hallmark of the presymptomatic
phase.12,39,40Those who scored in the lowest
tertile of BSIT were significantly more likely to
have LB pathology. More detailed analysis of
colleagues42tested 30 people with idiopathic
anosmia but no motor deficit. All were tested
(UPDRS) and 26 had transcranial ultrasound
of the substantia nigra. Eleven displayed ab-
normal (increased) nigral echogenicity typical
of PD. Five of 10 subjects had a pathological
DATScan and an additional two were border-
line. At review 4 years later, two developed def-
inite PD and another two had abnormal UP-
DRS measurement.43The predictive value of
olfactory dysfunction was questioned by Mar-
ras et al.44who studied 62 male twin pairs
Annals of the New York Academy of Sciences
discordant for PD. At baseline the 40 odor
UPSIT scores were significantly abnormal in
affected twins, but not in their co-twins who
were rated normal on clinical examination. Af-
ter a mean of 7.3 years, 28 co-twins were still
aliveandofthese,19were retested using the12
odor, BSIT. Two of the 28 brothers had devel-
oped PD, neither of whom had impaired UP-
their olfactory identification score was greater
not developed the disease. Although it was sug-
gested that smell testing may not be a reliable
high and smell function was reassessed by dif-
procedure that would reduce sensitivity, given
the fewer test odors in BSIT (12 versus 40).
In summary, the above evidence shows be-
in PD is severely damaged and most likely at a
very early stage.
Is the ENS Involved in PD
and, if so, When?
Support for the involvement of ENS is avail-
able from pathological, clinical, and epidemio-
Pathological Changes in the Enteric
The gastrointestinal tract is supplied by two
major nerves: the vagus, which is for excita-
tory parasympathetic control, and the sym-
pathetic nerves, which are inhibitory. It is
known that ENS lesions occur in symptomatic
cases of PD45–49and there is abundant evi-
dence of abnormality in both systems. From
the clinical perspective, features of this pathol-
ogy become increasingly obvious with disease
advancement.50–53The inhibitory nitrergic va-
soactive intestinal polypeptide neurons have
been shown to develop LNs and LBs.48,49Ax-
ons containing α-synuclein from the submu-
cous plexus have been observed protruding
through the muscle layer of the mucosa, ex-
tending widely and ramifying within the mu-
cosal lamina propria.54,55Axons of affected
LNs of varying size. In the mucosal lamina
propria, the unmyelinated axons are only mi-
crometers away from the body’s innermost en-
vironment, their only protection being a single
layer of epithelial cells. Such involvement of
the ENS plexuses may represent a particularly
early event—if not the earliest vagal event—
because LNs were observed both in clinically
diagnosed cases and in nonsymptomatic indi-
viduals with PD-related brain lesions limited to
the lower brainstem54(Fig. 1). At present it is
not known whether ENS lesions develop in the
absence of lesions in the brain.
Clinical Evidence of Gastrointestinal
Dysphagia is a common feature and in one
survey of 17 autopsy confirmed cases of PD,
swallowing difficulties appeared after an av-
erage period of 10 years from onset of ini-
tial extrapyramidal symptoms.56Reduction of
appetite and weight loss is frequent, particu-
larly in more advanced cases—a feature that
may relate to impairment of smell and taste57
to poor diet, increased energy expenditure, or
depression.58Gastric dysfunction is a recog-
nized feature of established PD59–61with re-
ports of bloating or nausea, suggesting de-
layed gastric emptying and this phenomenon
has indeed been confirmed by measurement
of gastric emptying time.59Constipation is an
indirect measure of vagal function and retro-
spective studies suggest it may be an important
The only aspect of vagal function that has
been examined in a prospective epidemiolog-
ical study is constipation. Bowel habit was
Hawkes et al.: Dual Hit Hypothesis
Figure 1. Micrographs showing tangential sections (A: overview, B: detail) through the
Auerbach plexus of a nonsymptomatic individual (male, 65 years of age) with stage 3 brain
Lewy pathology. Syn-1 (BD Bioscience Laboratories, Mountain View, CA) immunoreactions
in 100 μm cryosections. (A) Here, axons containing immunoreactive Lewy neurites can be
followed for considerable distances in the tissue. In addition, three ganglia (right and middle,
one smaller one at lower left) display nerve cells that contain Lewy bodies. (B) Detail of the
middle ganglion. (In color in Annals online.)
analyzed in elderly patients who took part in
the Honolulu Heart Program.64Their cohort
comprised 6790 males without PD at enroll-
ment, who were subsequently monitored for
24 years. After a mean latent period of 10 years
(range 5 months−19 years) 96 developed PD.
The adjusted risk for PD in those with < 1
bowel movement per day compared to those
with one per day was 2.7 (95% CI: 1.3, 5.5;
P = 0.007) implying that constipation is a
harbinger of PD. In their subsequent and ex-
panded survey65(Honolulu Asia Aging Study),
Annals of the New York Academy of Sciences
bowel movement frequency was evaluated in
245 healthy males aged 71–93 years all of
whom had brain autopsy. None had evidence
of dementia or parkinsonism in life. Prelimi-
nary examination of the midbrain and pons
revealed 30 with ILB in the substantia nigra or
locus coeruleus and after age adjustment, a sig-
compared to those with > 1 bowel motion per
day. Thus, constipation predicts both clinically
defined PD and autopsy verified ILB.
We propose that an unknown neurotropic
pathogen adopts a two-pronged attack on the
nervous system: anterogradely, via olfactory
pathways, and retrogradely via the enteric
plexus and preganglionic vagal fibers. If the
pathogen is viral, then brain entry via the
nasal route or uptake through the gastrointesti-
nal tract has ample precedent.1,10A nasal in-
fection would have direct access to the olfac-
tory nerve, infected saliva or mucous could be
swallowed and reach the upper digestive tract
to infect axons of Meissner’s plexus and after
transneuronal passage ascend retrogradely in
preganglionic parasympathetic fibers of the va-
gus to the lower brainstem. Direct access to the
medulla via the viscerosensory fibers of the va-
gus in the pharynx or via the trigeminal nerve,
while anatomically appealing, is not compati-
ble with virtual sparing of the solitary tract and
trigeminal nuclei during the entire course of
the disorder. The olfactory and enteric means
of access are unique in that they are both in
close and constant contact with the potentially
hostile outer environment.
Recent evidence indicates that diseases of
intermediate type hypersensitivity (asthma, al-
lergic rhinitis, seasonal rhinitis) may be associ-
ated with PD.66The authors reviewed medi-
cal records in 196 cases of PD and 196 healthy
twofold, increase of prior intermediate type
sensitivity disorder in general, but particularly
for allergic rhinitis (OR 2.9. 95% CI: 1.3, 6.4.
P < 0.01). There was a trend toward protec-
tion against PD in those who had used anti-
inflammatory drugs. It is suggested that pa-
tients with PD might initiate an inflammatory
tral nervous system, but an obvious alternative
explanation is that chronic nasal disease ren-
ders the olfactory route an attractive option for
The work of Drs. Braak and Del Tredici
is supported by the German Research Coun-
cil (Deutsche Forschungsgemeinschaft, DFG).
The authors wish to thank Mr. Mohamed
Bouzrou for skillful technical assistance (im-
Conflicts of Interest
The authors declare no conflicts of interest.
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Smell andTaste Com-