Parkinsonism & Related Disorders
Volume 18, Issue 1 , Pages 1-9, January 2012

Asymmetry in parkinsonism, spreading pathogens and the nose

Department of Medicine, University of Manitoba, Deer Lodge Centre, 200 Woodlawn St., Winnipeg, MB R3J 2H7, Canada

Received 7 March 2011; received in revised form 17 June 2011; accepted 18 June 2011. published online 15 July 2011.

Article Outline

Abstract 

Parkinson’s disease, as well as many other parkinsonisms, including most toxic, neurodegenerative and familial types are typically asymmetric. No explanation for this phenomenon exists. A summary of the frequency of asymmetry in a spectrum of parkinsonian disorders is provided. Evidence against asymmetry being the result of normal asymmetries of the substantia nigrais reviewed. Asymmetry either results from a greater susceptibility on one side or a spreading pathology entering or starting on one side of the CNS. With the increasing evidence for spreading pathologies (toxins, viruses, α-synuclein), knowledge of neuroanatomical connections, and literature implicating spreading pathogens from the enteric and olfactory nerves, potential explanations can be theorized and explored, including the possibility of a pathogen preferentially entering or originating in the olfactory bulb on one side, with subsequent involvement of the other side.

Keywords: Asymmetry, Parkinson’s disease, Parkinsonism, Olfaction, Anatomy, Pathogenesis, Familial, Toxic, Nasal cavities

 

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1. Introduction 

The cause of Parkinson’s disease (PD), although typically described as unknown, is generally thought to be heterogeneous and relate to the effect of environmental pathogens in those of varying genetic susceptibility superimposed on the neuronal loss known to occur with aging [1], [2](a), [2](b). The following is a review of the “unresolved” [3] “mystery” [4] of asymmetry in PD and parkinsonisms, with the aim of exploring this feature as a clue to PD aetiology. Included is a discussion of spreading pathologies within known neuroanatomical connections and the multiple other mechanisms that might contribute to this common, clinical characteristic of asymmetry.

1.1. Asymmetry as a diagnostic criteria for Parkinson’s disease 

“ The first symptoms perceived are, a slight sense of weakness, with a proneness to trembling in some particular part; …. most commonly in one of the hands and arms… and at an uncertain period, but seldom in less than twelve months or more, the morbid influence is felt in some other part. Thus assuming one of the hands and arms to be first attacked, the other, at this period becomes similarly affected.”

The above account by James Parkinson arose from his observation of the unilateral onset of symptoms in 2 of 6 patients reported in 1817 [5]. Asymmetry in the others was not commented on. “Unilateral involvement only” defines Hoehn and Yahr’s Stage I [6] and “unilateral onset” and “persistent asymmetry” are supporting features for the diagnosis of PD (UK Brain Bank Criteria) [7]. Asymmetry was adopted as one of the 4 major criteria for diagnosis by the NINDS [8] while indicating it was neither sensitive or specific.

Keeping in mind, a universally accepted definition of asymmetry has not been established for PD [9]; at least 60% of cases, when first seen are asymmetric [3]. Clinical signs influenced by asymmetry include tremor, rigidity and bradykinesia. Asymmetry of these features is reported in up to 65% [10].

Asymmetry as an initial manifestation of the disease can be more common than tremor; present in 83% of 519 cases in one series with 74.1% having resting tremor [11]. The average time to progression to the contralateral side is 2.5 years [12].

1.2. The evolution of normal asymmetry 

Evidence of behavioral asymmetry and nervous system lateralization dates back to the beginning of the Palaeozoic [13]. With evolution, sensory structures (mouth, nose and eyes) migrated to the front of the organism, to encounter novel stimuli when moving through the environment. Most animal species deviate from true bilateral symmetry [14]. Humans, although generally bilaterally symmetric, have consistent asymmetries of the visceral organs and brain. In most people the left hemisphere plays the dominant role in motor function and language. This functional brain asymmetry may provide greater efficiency where specialization of one hemisphere allows the opposite “free to perform other tasks” [15].

During the gastrulation stage of embryogenesis with the formation of the primitive streak, bilateral symmetry begins. Left right cues can be affected by environment influences including electrical currents and magnetic fields. Light exposure to a developing chick embryo may influence aspects of asymmetry [17].

The initial step of left right differentiation is at a molecular intracellular cytoskeletal level. Next this single cell information is imposed on cell fields and leads to asymmetric gene expression. There are known genetically mediated cascades of induction and repression of cells developing lateral to the midline [16], which are responsible for programmed asymmetry. These asymmetric genetic cascades lead to asymmetric morphogenesis. Asymmetry of viscera begins at the blastomere stage. As cases of situs inversus do not affect normal right/left brain asymmetry, the mechanisms controlling brain asymmetry are thought to occur at an earlier initiated, separate pathway than body situs [17]. Neural progenitors are guided by intrinsic and extrinsic cues, guiding cell division, migration, and polarity. These mechanisms in part involve dynein, Pitx-2, fibroblastic growth factor 8, syndecans, adhesion junctions and gap junctions [17]. Core planar cell polarity proteins such as Vangl2 are also required for left right asymmetry [18] as are the ‘nodal’ family of proteins acting on the whole organism through a system of cell to cell networks via open gap junctions [15] designating the dorsal and ventral axis and the patterning of the nervous system [19]. Some proteins are only expressed on one side. Sonic Hedgehog homologue (SHH) gene, although initially expressed bilaterally, once activin begins to be expressed on the right, is repressed on the leaving only left sided expression. Nodal is also only expressed on the left of the embryonic midline [17].

Embryos exposed to toxins at an early stage can show side specific defects. For example, exposure to cadmium causes left sided limb deformities whereas acetazolamide causes right limb deformities in rats [20].

1.3. Normal substantia nigra symmetry 

Few human pathologic reports compare the number of neurons in a pair of SN nuclei in a single individual. This is the result of the typical approach of dividing the two halves of the brain, sending one for neurochemistry while performing pathologic analysis on the other. Monkey data show no baseline asymmetry in SN cell counts [21].

PET scan imaging of ‘normal’ human SN neuronal counts demonstrate relative symmetry [22] which is maintained with aging [23] and thus the asymmetric onset that typifies PD cannot be attributed to a normal, pre-morbid asymmetry of the dopaminergic system.

1.4. Substantia nigra asymmetry in Parkinson’s disease 

Depigmentation of the SN is more apparent contralateral to the involved side in PD [24]. The motor symptoms correlate with neuronal loss in the SN compacta [25], and develop when neuronal loss results in a dopamine production reduction of 70–80% [26]. This requires losses amounting to a minimal reduction of 45–60% of the cells in this region [27]. This loss is asymmetric both on pathology [24] and imaging studies including; [18F]dopa PET [28], transcranial sonography [29], VMAT2 PET imaging with dihydrotetrabenazine [30] and is in contrast with the confirmed symmetry in normal controls [28].

1.5. Clinical features of asymmetry 

When reported, in asymmetric onset cases, right hemibody onset is more common than left. In a study of 1277 individuals with PD [31], 46% of cases fit specific criteria (a modified UPDRS) for asymmetry at the time of exam. Unilateral onset occurred in 67% of the overall sample. Shorter duration of disease, younger age of onset and asymmetrical onset were predictors of later asymmetry. 41% started on the right hemibody, while 25% started on the left. The dominant side was the more likely to be affected (eg. right hand dominant cases tend to have more severe right hemibody signs). This was also demonstrated in a study of 1173 PD cases of whom 86.5% presented asymmetrically [32] and in other reports [33], [34] suggesting the side of onset can’t only be attributed to “pure chance” [4]. One reference does not support this conclusion [35].

1.6. Asymmetry of olfaction 

Hyposmia, first observed by Ansari in 1975 [36], is now recognized as one of the earliest clinical abnormalities in PD [37] and like asymmetry may be a more frequent sign than tremor [38]. In keeping with this, pathology within the olfactory anatomy is a common, early feature in PD [39]. Asymmetry in olfactory function has rarely been explored in PD. In 2004 a single case of right sided hemiparkinsonism and hemihyposmia was described. The smell deficit was on the left side, ipsilateral to the greater basal ganglia abnormality on 123I-FP-CIT SPECT [40]. Olfactory sensitivity in 6 early-stage parkinsons also demonstrated a more severe loss contralateral to the more affected hemibody [41]. No such correlation was identified in a study of 40 patients with longer duration PD [42].

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2. Asymmetry in familial PD 

Genetic mutations recognized to cause parkinsonisms resembling PD include; α-synuclein, Parkin, PINK1, DJ-1, LRRK2 and ATP13A2 [43]. A degree of asymmetry in familial cases is common and therefore generally not useful in differentiating between familial and sporadic PD [44]. Comparing phenotypes of 40 familial with 1277 sporadic PD cases, Baba et al. [9] found asymmetry in 95% of the familial and 87% of the sporadic cases. This could suggest that in some familial Parkinsonism, asymmetry may be contributed in part by gene defects subserving left/right differentiation.

The clinical phenotype of α-SNCA (Park1) consists of asymmetric rigidity, resting tremor, bradykinesia, and postural instability with response to levodopa [45]. In one series, 100% of patients reported with an SNCA (G209A) mutation had asymmetric onset [46]. 89% of 101 European Parkin (Park 2) cases were asymmetric when seen during the course of their disease [47] and 31 of 34 cases of PARK 2 in Hong Kong Chinese were asymmetric at onset [48]. PTEN-induced putative kinase (PINK1) or PARK 6 mutation pedigrees are of small size but asymmetry was noted in eight of thirteen cases of Asian origin [49] and eight of nine in another Italian series [50]. Pink1 is involved in mitochondrial function and may also have a role in embryogenesis [51]. One could postulate, with this role, if this gene was involved in left/right specialization, then mutations could preferentially cause the onset to start on the same side. Interestingly, in one review, all 10 affected members (symptomatic and asymptomatic) started on the right side of the body [52].

The typical LRRK2 phenotype is an asymmetrical parkinsonism with rest tremor [53]. 77% of 35 cases with a Gly2019Ser mutation had persistent asymmetry at a mean duration of 14 years. 9% had strictly unilateral symptoms after 3 years [54]. Asymmetric onset has been reported to range from 50% [55] to 100% [56], [57]. In a worldwide study of 356 cases [58] it took an average of 7.2 years for the cases to become bilateral after onset. DJ-1 (Park7) and ATP13A2 (Park9) case series are too small to draw any definite conclusion other than that they can present asymmetrically [59], [60], [61].

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3. Asymmetry in toxic parkinsonisms 

3.1. MPTP 

MPTP induces parkinsonism in humans [62] and is the most common toxin utilized to create animal models [63]. Repeated systemic administration over days to weeks produces a bilateral parkinsonism, whereas single dose, intra-carotid administration causes hemiparkinsonism. Intranasal MPTP application can produce parkinsonism [64]. The latter mouse model incorporated an alternating nostril application. Purely unilateral nasal exposure models have not been published to my knowledge. In humans, MPTP Parkinsonism is typically more symmetric than PD clinically and on imaging [65].

3.2. Parkinsonism–dementia complex of Guam 

The Parkinson dementia syndrome of the Guamanian Chamorros is postulated by some to be due to a neurotoxin, BMAA, within cycad plants, biomagnified in the food chain and unknowingly consumed by susceptible humans [66]. The atypical parkinsonism that results, is an early onset, symmetrical, akinetic–rigid parkinsonism [67].

3.3. Guadeloupian parkinsonism 

Another atypical Parkinson disorder that may be caused by environmental influences, identified on Guadeloupe, is a characteristically unclassifiable parkinsonism [68]; relatively symmetric with marked axial rigidity. The proposed toxin, the mitochondrial complex I inhibitor annonacin, enters humans through consumption of “soursop” fruit or a tea made from the leaves of the annonaceous plant [69].

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4. Asymmetry in other parkinsonisms 

Based on the emphasis on asymmetry as a diagnositic criteria for PD, one might conclude that lack of asymmetry would characterize atypical Parkinsonism. Although asymmetry is not as common among the atypical parkinsonism’s, it remains a frequent finding [70]. Thus it is not a particularly useful differentiating clinical clue.

The classification of progressive supranuclear palsy (PSP) now recognizes two subcategories. PSP-P represents up to 35% of cases and has an asymmetric onset in 45–47.1% [71]. Parkinsonism which was evident in 91% of 100 cases of MSA (“MSA-P”), in a review by Wenning et al. [72], was asymmetric in 74%when assessed during the course of the disease.

Hemiparkinsons–hemiatrophy, a syndrome of varied parthenogenesis, presents with atrophy on one side of the body associated with varying degrees of ipsilateral parkinsonism [73]. Half the cases have documented perinatal or childhood brain insults suggesting a heterogeneous syndrome representing the impact of varied types of injury to the brain very early in life [74].

In an early report of Parkinsonism resulting from encephalitis lethargica, tremor was reported to be unilateral or bilateral but “nearly always” asymmetric [75]. In another series of forty-nine cases an asymmetric pattern was “frequently” seen [76].

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5. Spreading pathogens causing spreading pathologies 

5.1. Toxins 

Intranasal application of MPTP creates an animal model of PD with SN pathology [65], [77]. Manganese (Mn), applied to the olfactory epithelium of a pike is taken up by the olfactory nerves and transported into the olfactory bulb ipsilaterally with some degree of cross over to the contralateral side at the level of the anterior commissure and then to the telencephalon, including the caudal palidum [78]. Autoradiography and gamma spectrometry show Mn, after a single intranasal application in rats, is taken up into the olfactory bulbs and then migrates via secondary and tertiary olfactory pathways into most parts of the brain and spinal cord [79].

In the latter two models, the transport is asymmetric early on, occurring at a faster rate and leading to a higher concentration ipsilateraly, later becoming more symmetric. Brainstem concentrations of Mn in animals exposed by intranasal application are four times greater in the midbrain than in the medulla at three weeks following exposure [80]. Intraperitoneal exposure leads to higher concentrations in the medulla than the midbrain. Inhaled Mn enters the brain through the olfactory route and not via the lung. Following inhaled exposure, Mn was observed in the olfactory bulb and tract and tubercle on the side with the open nostril within 1–2 days [80].

The latter models provide examples of unilateral toxic exposure through the nose creating an asymmetric toxic load to the brain and would be expected to lead to an asymmetric pathology.

5.2. Viruses 

Many viruses including influenza, coxsackie, herpes zoster, measles, Japanese encephalitis B, poliomyelitis, St. Louis, West Nile and HIV viruses can cause parkinsonism [81]. Their route of entry to the CNS is variable. Oral inoculation of mice with a strain of reovirus spreads through the enteric nerves to the DMNV independently of the blood stream [82]. Intranasal inoculation of H5N1 influenza virus into mice causes CNS invasion through the mesenteric and myenteric plexi, then to the dorsal root ganglia and rostrally into the vagal nuclei and then the SN. The virus was also detected in the olfactory bulb. This spread occurs via interneuronal transport [83].

5.3. Prions 

Prion disease pathophysiology includes spreading pathology [84]. While prion induced brain lesions are usually bilateral and symmetric they may be asymmetric or even unilateral [85].

There is increasing evidence that prion characteristics may underlie PD pathology [86] as well as other neurodegenerative diseases [87] and may explain spreading pathology subsequent to a variety of triggers. This possibility was raised early on by Braak [88].Evidence that α-synuclein behaves like a prion capable of cell to cell transfer, supports this notion [89] and is consistent with anatomical pathways of spread from the olfactory bulb [90].

Olfactory nerves are known to be affected in human prion disease. Nine of nine patients with sporadic Creutzfeldt–Jakob disease had prion protein deposition in the olfactory neuroepithelium as well as central olfactory pathways [91]. The route of neuroinvasion is dependent on the specific properties of the prion and the host. Prions can invade the brain from the nasal cavity of hampsters [92]. In sheep, deposition of natural scrapie onto nasal mucosa enters the brain via perineurium of the olfactory nerves, as well as subependymal, perivascular and submeningeal structures [93].

5.4. Alpha synuclein 

Braak’s staging system, based primarily on α-synuclein, [39] suggests onset of pathology in the DMNV and olfactory bulb with later caudal–rostral spread to the SN and eventually the cortex. Recent critical appraisals present frequent deviations from this migration of pathology [94], including cases with no pathology in the medulla at a stage when the cortex is involved [95]. Up to 8.3% of cases spare the medulla and up to 47% do not follow the expected rostral caudal progression [96], [97]. Alpha synuclein staining of over four hundred autopsied subjects (including PD, DLB incidental Lewy bodies and Alzeimer’s disease with Lewy bodies), indicated that one-third of cases had isolated olfactory bulb pathology and two-thirds had limbic system involvement without brainstem involvement [98].

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6. The olfactory bulb as a gateway to the brain 

Given the potential of targeting the CNS by taking advantage of direct nose to brain pathways, researchers have explored intranasal pharmaceuticals and the anatomical routes involved [99]. Absorption of substances from the nose into the CNS, can occur via olfactory nerves, trigeminal sensory nerves, local vasculature, extracellular fluid spaces, lymphatics or CSF pathways. Depending on the properties of the agent in question, any of these could predominate. All these pathways, by more directly entering the CNS, bypass sites of metabolism that would limit concentrations when given systemically or orally [100].

Intranasal interferon-β 1b is transported to the SN within 1 h of application in monkeys [101]. Stem cells delivered intranasally bypass the blood brain barrier and enter the brain [102]. Intranasally administered GDNF protects against 6-OHDA lesions in rats and can be traced following olfactory pathways being identified in the SN within 24 h [103].

The olfactory neural pathways involved are sequentially; the olfactory receptor neurons, the mitral cells of the olfactory bulb, the olfactory tract and then the anterior olfactory nuclei and olfactory tubercle [104]. Horseradish peroxidase injected into a hampster olfactory tubercle labels the substantia nigra [105]. Due to the speed of transfer of many therapeutics, extracellular movement may be more important than transneuronal transport [106]. The trigeminal nerve may provide the most direct neuroanatomical pathway from the nose to the caudal brainstem including the DMNV [101].

These access points are weak lines of defense against pathogens. The loss of the sense of smell in PD, makes the nose a plausible entry point. Potential pathogens confirmed to enter via this route include; viruses (eg influenza A), aerosolized metals (eg Manganese) and other toxins (eg. pesticides) [107].

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7. Possible explanations for asymmetries in PD 

Lewy body inclusions along with cell loss in other nuclei have been well documented for close to 100 years. Pathology in the DMNV was recognized first by Lewy in 1912 [108], confirmed by Foix and Nicolesco in 1925 [109], and brought forward, as one of the earliest areas of involvement by Braak et al. [39] subsequent to the identification and ability to stain tissue for Alpha synuclein.

None of the staging systems or critical appraisals of Braak’s hypothesis comment on, or explain asymmetry. Braak’s original hypothesis of spreading pathology did not address asymmetries (personal communication confirmed that only one side of the brains were studied).

The possible explanations for spreading pathology developing at varying rates in different regions of the CNS are two fold.

Firstly a generalized process may be occurring and those areas with greater susceptibility undergo pathologic changes earlier [110]. For asymmetry to be explained on this basis, one side would have to be rendered more susceptible early in development as otherwise regional susceptibilities would be expected to be similar from side to side.

Secondly, the asymmetric onset in idiopathic and familial PD, as well as other neurodegenerative parkinsonisms may be caused by a pathogenic process entering or beginning focally on one side. The CNS lesion would be asymmetric from the start and then follow an orderly progression through the anatomical connections with pathology progressively becoming bilateral, yet remaining asymmetric.

A discussion follows outlining the possible explanations for asymmetry in PD. Evidence providing support for and against these ideas is presented.

7.1. A symmetric pathology on a background of “normal” SN asymmetry 

One of the simplest explanations of asymmetry in PD is the idea that individuals are born with a lower number of SN neurons on one side and then suffer a symmetric process resulting in the side with less neurons reaching the threshold for clinical features first. If this were correct, there should be evidence in control cases of asymmetry on pathology or imaging. Yet normal humans have symmetric numbers of SN neurons, and the normal loss with aging is symmetric.

The evidence that PD starts more often on the dominant hemibody is a mystery within the puzzle of asymmetry and although this pattern does not occur in the vast majority of cases, it remains unexplained. It could suggest the dominant side is more prone to injury by whatever causes PD, or alternatively there is a higher rate of cell loss on the dominant side subsequent to injury, leading to clinical features earlier on that side. Given the dominant side is more active through life, this finding goes against the expected, based on evidence that exercise might delay neurodegeneration [111]. Alternatively, overuse of the dominant side might create a more susceptible side, or in a susceptible individual, contribute to abnormal physiology mirroring the dysfunction evident in the task specific dystonias, including writer’s cramp which has a documented association with PD [112], [113]. Additionally the increased activity present in the dominant motor circuitry could, by excitotoxic mechanisms, increase apoptosis [114].

7.2. An early developmental asymmetric injury followed by asymmetric process 

Current speculation suggests pathology in PD may begin up to 20 years before onset of the diagnostic motor symptoms [119]. If indeed the asymmetry evident in PD originates due to an injury during left – right differentiation, this suggests the initiating events might occur as early as an embryologic stage of development. Diverse causes of PD, including the familial forms, might act upon a host that was rendered asymmetrically susceptible by a very early life event that does not affect the normal population. With the plethora of molecular steps involved in normal left/right asymmetry, it would not be hard to imagine this as a possibility acting to either reduce the number of neurons on one side or leaving them more vulnerable [115]. Environmental perturbations during later development can also result in asymmetry [14]. This vulnerability could then become manifest with a subsequent insult or natural neuronal loss with aging [116].

One insult that could create focal injury and future asymmetry would be perinatal ischemia. Gardener et al. [117] explored this possibility in 659 cases of PD. They found no significant increase of PD despite obtaining a history of low birth weight, preterm birth or multiple births. This makes an early developmental perturbation as a potential explanation for later asymmetry less tenable. If early life pathology created an increased susceptibility on one side then the disease might be expected to get progressively more asymmetric with disease progression. This does not seem to be the case in PD.

With the possible exception of genetic forms, evidence supporting the onset of PD at an embryologic stage is lacking, although this remains a possibility.

7.3. Asymmetric influences of a genetic abnormality 

A variety of genes are responsible for the induction, specification and maintenance of substantia nigra dopaminergic neurons from the mesencephalic portion of the folding neural plate. Despite the numerous factors involved in the production of developmental asymmetry, to date there is no clear link between any of these factors and the etiology of PD, nor do the currently recognized familial forms of the disease have mutations known to have a role in these processes. With the increasingly recognized pleiotrophy of genes, there could well be a connection at some level. The pattern of left or right specialization is however consistent throughout all normal members of a species [118]. If PD asymmetry were created through a genetic error prior to, or at the stage of left/right differentiation, it might be expected to trigger PD more consistently on one characteristic side, be it left or right. This is generally not the case.

Although there has been an explosion of the knowledge of the genetics of PD, to date there has been no genetic form leading to a syndrome with a particular preference as to the affected side. The asymmetry reported in the familial cases may be caused by the same factors triggering asymmetry in non familial PD and may bear no relationship to genetic mutations or their direct consequences.

7.4. Asymmetric spread through the enteric nervous syndrome 

The early α-synuclein pathology in the DMNV has lead to the hypotheses that PD could be the result of a “dual hit” with a neurotropic pathogen entering through the olfactory bulb and the enteric nervous system [120]. Information suggesting the DMNV is not infrequently spared in PD may suggest the olfactory route may be a more important source of entry in some, if not the majority of cases.

As documented above, forms of human parkinsonism that occur from the ingestion of neurotoxins (Guadeloupian and Guamanian) are typically symmetric and the olfactory route of entry should be relatively unimportant. These examples allow exploration into the neuroanatomical connections expected with a pathogen entering only from the gut. The absorption could be into the splanchnic circulation thus entering the CNS diffusely (symmetrically), through the systemic vasculature or as in the case of some pathogens (viruses and peroxidase) indirectly from the vasculature to peripheral nerves and then to the brain [121]. Despite the possibility of the latter invasion routes, evidence suggests these neurotoxins enter the CNS via the enteric nervous system. Sympathetic spread to the CNS is reported to occur after the DMNV is involved [120]. At both a cord (sympathetics) and a brainstem (parasympathetics) level there are many sites of decussation across which a spreading pathogen could become bilateral after gut entry.

The innervation of the esophagus and stomach and the small and large intestine are subserved through plexi with bilateral innervation from the left and right vagal nerves. These anatomical features would be expected to cause a spreading pathogen to enter the CNS symmetrically, producing a symmetric clinical picture.

Despite reasons to expect symmetries, there are asymmetrical autonomic pathways to consider. The main vagal innervation of the intestines is by celiac branches, which are mainly derived from the right vagal nerve [122]. If the right vagal nerve was the primary route of ascent to the brainstem, this would impact the right DMNV earlier and more severely. As the ascending pathway targets (eg hypothalamus and olfactory tubercle) [123], [124], from brainstem autonomic nuclei are mainly ipsilateral via the dorsal longitudinal fasciculus [125], if any asymmetry were to result, the left hemibody would be more commonly affected. This however is not the case, suggesting spreading pathology from the enteric nervous system may not adequately explain asymmetry in PD.

7.5. Asymmetric spread through the olfactory route 

The pre motor hyposmia [36], [126] in PD cases, together with pathologic changes in the olfactory system [39] lend support for a neurotropic pathogen entering, at least in part, by a nasal route [120]. Diffusion weighted imaging reveals structural changes in the olfactory tracts early in PD [127]. Axons projecting from the olfactory epithelium lack a blood brain barrier. Thus a toxin or infective agent could access the CNS via this route. The hostile pathogen could follow an antegrade pathway to the medial amygdala, olfatory tubercle, piriform and periamygdalar cortex [128], [129]. Horseradish peroxidase techniques have demonstrated intranasal application in rats leads to transport as well to the raphe nucleus and locus coeruleus [130]. A direct connection between the olfactory tubercle and the SN has also been demonstrated [105]. Visceral afferent pathways connect the nucleus of the solitary tract with the olfactory tubercle allowing the proposed olfactory entry anatomy to connect with the other proposed CNS entry location; the DMNV [131].

To get to the olfactory area a pathogen must come through the nose. Only 10% of nasal airflow actually reaches the olfactory region [132]. Animal models of PD have been created using this entry point with direct intranasal application of toxins [77]. Air pollution has been demonstrated to lead to accumulation of α-synuclein in the olfactory bulbs of children living in Mexico City [133]. Once inside the CNS a spreading pathologic process could be triggered. Pathogen spread, in unilateral nasal models becomes bilateral, but spreads more quickly and to a greater degree unilaterally [134].

7.6. Implications of nasal asymmetry 

If PD is caused by an inhaled toxin or virus, into the nose and entering through olfactory neuroanatomy, then the side of the brain with greatest CNS pathology would be expected to suffer from a greater toxic load over the pre-morbid lifetime. The nose becomes an intake route of interest as there are two nostrils providing an opportunity for different levels of any inhaled pathogen to reach the two sides depending on asymmetric aerodynamics into olfactory regions. Although not previously suggested in the literature, asymmetric nasal passages could cause pathogens to preferentially enter the side with greater airflow, creating an asymmetric entry into the olfactory nervous system as well as the nasal trigeminal sensory nerves. Asymmetries of airflow have not been a common subject of study in the normal population. Global nasal airflow can be measured by a variety of techniques including by rhinomanometry and acoustic rhinometry [135]. The problem with these techniques is that they provide a poor estimate of the airflow reaching the olfactory area [132].

For this to be a tenable explanation for asymmetry in PD the frequency of asymmetric nasal passages would have to be as common as asymmetry in PD. A study of 2152 skulls noted bony septal deformities in 75% [136]. The incidence of septal deformity in 2380 infants and 2112 adult skulls was 58% and 79% respectively [137]. Maxillary molding by transmitted pressure during pregnancy or parturition is thought to be the main cause. 68% of sixty patients studied with nasal endoscopy had intranasal abnormalities resulting in one nostril being more patent than the other [138]. Even slight septal deviations can have major consequences on olfactory deposition [139].

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8. Conclusion 

An emerging theme linking diverse neurodegenerative diseases, consists of pathology developing as a result of increased production or impaired clearance of toxic oligomers, secondary in part to conformational changes, leading to the formation of aggregates and cell death [140]. In PD, α-synuclein sits at a central point, integrating a multitude of diverse genetic and environmental lesions [141]. Once native α-synuclein conformational changes are triggered, it may share the characteristics of prions, including a potential of cell to cell transmission, leading to spreading pathology. Entry of a pathogen through the enteric nervous system or systemic circulation should be delivered to the CNS symmetrically and result in symmetric clinical features. If, over a lifetime however, diverse environmental pathogens were to enter the nose and olfactory area bilaterally, but preferentially more on one side, this would be expected to lead to an asymmetric syndrome such as seen in PD. How this might occur remains to be determined but the common occurrence of asymmetric nostrils in humans may play a role.

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Conflict of interest 

The author has no conflict of interest or financial disclosures to report.

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Acknowledgment 

I would like to thank Shaun Hobson for her administrative support.

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PII: S1353-8020(11)00187-8

doi:10.1016/j.parkreldis.2011.06.011

Parkinsonism & Related Disorders
Volume 18, Issue 1 , Pages 1-9, January 2012

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