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Abstract

  1. Top of page
  2. Abstract
  3. Evidence That Xenobiotics Can Enter the Brain via the Olfactory Mucosa
  4. Early Olfactory Loss and Progression of Alzheimer's Disease– and Parkinson's Disease–Related Neuropathology
  5. Evidence against the Olfactory Vector Hypothesis
  6. Conclusion
  7. Disclosure
  8. Acknowledgements
  9. References

Environmental agents, including viruses, prions, and toxins, have been implicated in the cause of a number of neurodegenerative diseases, most notably Alzheimer's and Parkinson's diseases. The presence of smell loss and the pathological involvement of the olfactory pathways in the formative stages of Alzheimer's and Parkinson's diseases, together with evidence that xenobiotics, some epidemiologically linked to these diseases, can readily enter the brain via the olfactory mucosa, have led to the hypothesis that Alzheimer's and Parkinson's diseases may be caused or catalyzed by agents that enter the brain via this route. Evidence for and against this concept, the “olfactory vector hypothesis,” is addressed in this review. Ann Neurol 2008;63:7–15

The causes of Alzheimer's (AD) and Parkinson's diseases (PD), the two most common neurodegenerative disorders, are obscure. Familial concordance, genetic, and twin studies suggest that, although heritable factors play a role, environmental factors are prepotent.1 Thus, despite the fact that numerous genes have been identified for these two diseases, they usually relate to early-onset familial forms and account for less than 10% of all cases. Although largely distinct phenotypically and pathologically, AD and PD exhibit identical olfactory dysfunction early in their course,2 are often coexpressed,3 share a number of common risk factors (eg, age, head trauma, the apolipoprotein ε4 gene),1 and exhibit similar pathologies in brain regions such as the locus coeruleus.4

Among environmental risk factors reported for AD and PD are viruses, aerosolized metals, and toxins.1 Increased expression of β-amyloid (βA) and indicators of brain inflammation have been found in the olfactory bulbs and other olfactory-related brain regions of people and dogs exposed to extreme air pollution, likely reflecting exposures to airborne particulates and aerosolized metals.5 Previous occupational exposure to herbicides, as well as 20 or more years of occupational exposure to manganese (Mn), have been associated with 3- to 10-fold increased risks for development of PD.6, 7 Most cases of Mn-related parkinsonism, however, differ from classic PD on pathological and other grounds.8

The presence of smell loss and olfactory bulb pathology in the formative stages of AD and PD, together with evidence that airborne xenobiotics viewed as disease risk factors can enter the brain via the olfactory mucosa, has led to the hypothesis that these disorders may be caused or catalyzed by agents that enter the brain via the nose.9–12 This review assesses the viability of this “olfactory vector hypothesis” as a potential explanation for the induction of some cases of AD and PD.

Evidence That Xenobiotics Can Enter the Brain via the Olfactory Mucosa

  1. Top of page
  2. Abstract
  3. Evidence That Xenobiotics Can Enter the Brain via the Olfactory Mucosa
  4. Early Olfactory Loss and Progression of Alzheimer's Disease– and Parkinson's Disease–Related Neuropathology
  5. Evidence against the Olfactory Vector Hypothesis
  6. Conclusion
  7. Disclosure
  8. Acknowledgements
  9. References

The anatomy of the nose is well suited for the transfer of exogenous agents into the brain. Although some xenobiotics, notably viruses, can enter the brain via several cranial nerves, the olfactory nerve (cranial nerve I) is uniquely vulnerable to such penetration (Fig). Thus, the dendritic knobs and protruding cilia of the 6 to 10 million olfactory receptor cells that make up this nerve provide an exposed surface area conservatively estimated at 23 cm2.13 These cells are widely distributed throughout the rostral nasal cavity, embedded in a specialized neuroepithelium that lines the region of the cribriform plate, the dorsal septum, and sectors of the superior and middle turbinates. Unlike other receptor cells, these cells are also first-order neurons, projecting axons directly to the brain without an intervening synapse. Although they receive little benefit from the protection of the blood–brain barrier or the blood–nerve barrier, they are afforded some protection by secretions from Bowman's glands and by neighboring supporting cells, both of which express chemical metabolizing enzymes, including isozymes of cytochrome P450–dependent monooxygenases, aldehyde dehydrogenase, carboxyesterases, epoxide hydrolases, uridine diphosphate-glucuronyl transferase, glutathione S-transferase, and rhodanase.14 Some of these enzymes, for example, the P450 monooxygenases, are more active within the olfactory mucosa than within the liver, playing a key role in detoxifying xenobiotics within this vulnerable region. Other mechanisms that protect the olfactory mucosa from invasion or chemical damage include intracellular detoxification factors, ligand-specific binding proteins that remove agents from the mucosa, immune system cells, and the ability of the receptor cells to degenerate and then regenerate from stem cells within the basement membrane.15 Unfortunately, such protective mechanisms can be overwhelmed, resulting in enhanced levels of xenobiotics that, in some cases, enter the brain.

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Illustration 1. Fig. (A) Sagittal view of the rat brain showing olfactory neuroepithelium (OE) receptor cells and their axonal projections to the olfactory glomeruli (G). In the glomerulus, receptor cell axons contact the dendrites of periglomerular (PG) and mitral (M) cells. Mitral cells project to the piriform cortex (PC). Centrifugal afferent innervation comes from the horizontal limb of the diagonal band (HLDB), the substantia nigra (SN), the dorsal raphe (DR), and the locus ceruleus (LC). (B) The olfactory mucosa includes an epithelial cell layer (OE) and the lamina propria (LP) separated by the basal lamina (BL). The OE contains sustentacular (S), basal (B), and receptor (R) cells. Receptor cells have a dendritic knob (DN) from which cilia (C) project into the nasal cavity (NC). Unlike the cilia of the respiratory epithelium (C), these cilia do not beat in unison, but more or less waft in the mucus, lacking dynein (C) arms to induce motility. Receptor cell axons fasciculate to form the olfactory nerve (ON) that crosses the cribriform plate (CP) to enter the central nervous system. The axon and nerve are surrounded by a perineural sheath that forms the perineural space (PN). The lamina propria contains mucus secreting Bowman's glands (BG), axons of receptor cells, and numerous blood vessels (BV). Red and green dots depict possible entry pathways through neurons, glands, and blood vessels. (C) Respiratory neuroepithelium consists of columnar ciliated (C), goblet (G), and basal (B) cells, and is highly vascular (BV). (D) Hematoxylin-and-eosin (H&E)–stained section illustrating the layers of the OE and LP showing the numerous blood vessels in the lamina propria. Olfactory marker protein (OMP) immunostained section showing that only mature receptor neurons and their axons, not basal or sustentacular cells, contain OMP. (Reproduced from Baker and Genter,15 by permission.)

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The ability of foreign agents to move from the nasal cavity into the brain was noted as early as the second century.16 In the early twentieth century, olfactory receptor cells were identified as a major route of entry of poliomyelitis virus into the brain, affording an opportunity for direct neural infection without preliminary multiplication in nonneural tissue. By 1912, Flexner and others had shown that this virus could enter the monkey central nervous system via the olfactory nerve,17 and by the mid-1930s, it was apparent that such entry could be prevented by lesioning the olfactory neuroepithelium, bulbs, or tracts.18, 19 The presence of infected olfactory bulbs in children who had died of the disease implicated the olfactory system in viral transmission,20 because in monkeys only intranasal, not intracranial, subdural, or intrasciatic, viral inoculation induced such bulbar infection.21 The evidence for olfactory nerve transmission of the polio virus was so strong that, in the late 1930s, Canadian public health officials chemically cauterized the olfactory epithelia of large numbers of school children during polio epidemics in efforts to prevent the disease.22

Since these early studies, a range of viruses in addition to poliomyelitis virus have been shown capable of entering the brain via uptake into the olfactory receptor cells (Table 1). Entrance can also occur by penetration into associated lymphatic channels and into extraneural spaces within the nerve bundles that make up the cranial nerve I fila.23 In some cases, such as that of the arthropod-borne St. Louis encephalitis virus, brain entry via the olfactory path eventually occurs even when the virus is instilled intravenously, subdurally, or interperitonieally.24 In addition, lectins, dyes, solvents, metals, amino acids, nanoparticles, and numerous microbes have been shown capable of entering the brain via the olfactory mucosa (for review, see Baker and Genter15). Examples of metals capable of entering the olfactory receptor cells are listed in Table 2.

Table 1. Examples of Major Viruses Capable of Incorporation into Olfactory Receptor Cells from the Nasal Cavity and, in Some Cases, Transported Transneuronally to Other Brain Regions (Modified from Ref. 15)
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Table 2. Examples of Metals Shown to Be Capable of Incorporation into Olfactory Receptor Cells from the Nasal Cavity and, in Some Cases, Transported Transneuronally to Other Brain Regions (Modified from Ref. 15)
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Once internalized into the olfactory bulb, some xenobiotics penetrate into higher brain regions, often along neurotransmitter-specific lines. For example, herpes simplex virus type 1, placed intranasally in mice, is detected in the olfactory bulbs after several days. This virus subsequently infects cholinergic neurons in the horizontal limb of the diagonal band, serotonergic neurons in the dorsal and median raphe nuclei, and noradrenergic neurons in the locus coeruleus.25 Ionized metals (eg, aluminum, cadmium, gold, and Mn) can be transported to the brain via the olfactory receptor cell neurons at rates greater than 2mm/hr,26 with some, such as Mn, subsequently targeting astrocytes throughout the brain.27 Herbicides, such as the dioxins and chlorthiamid, are selectively taken up by the olfactory neuroepithelium even when administered systemically or to the surface of the cornea28, 29 and can damage the olfactory mucosa by causing necrosis of Bowman's glands.30 The pathological infectious prion protein PrPSc is consistently found in the olfactory cilia, receptor cells, bulbs, tracts, and primary olfactory cortices of patients with Creutzfeldt–Jakob disease, but not in the retina, optic nerves, or respiratory mucosa.31 A number of patients with this disease first present to the clinician with anosmia or complaints of taste and smell loss.31, 32

Although a wide range of xenobiotics can become incorporated into olfactory receptor cells, including dyes and amino acids, not all are transported across the synaptic membrane to neighboring cells. For many that cross the synapse, including a number of viruses, internalization into the cell initially occurs via receptor-mediated endocytosis. The xenobiotic is then transported within the cell via slow or rapid transport systems to the transmost saccule of the Golgi apparatus, where it is packaged into vesicles bound for axonal terminals.33 Usually there is minimal involvement of glial cells, implying limited release into the extracellular space.15 Agents that are not synaptically transported but yet enter the cell, such as leucine and horseradish peroxidase, are taken up by bulk endocytosis and processed into protein components of the cell, not the Golgi saccule.15

Early Olfactory Loss and Progression of Alzheimer's Disease– and Parkinson's Disease–Related Neuropathology

  1. Top of page
  2. Abstract
  3. Evidence That Xenobiotics Can Enter the Brain via the Olfactory Mucosa
  4. Early Olfactory Loss and Progression of Alzheimer's Disease– and Parkinson's Disease–Related Neuropathology
  5. Evidence against the Olfactory Vector Hypothesis
  6. Conclusion
  7. Disclosure
  8. Acknowledgements
  9. References

A key observation in potential accord with the olfactory vector hypothesis is that approximately 90% of patients with early-stage AD or PD exhibit olfactory dysfunction, as measured by psychophysical and electrophysiological tests.4 In well-documented PD, the dysfunction is unrelated to disease stage or the use of anti-PD medications (eg, L-dopa, dopamine agonists, anticholinergic compounds)34 and rivals or exceeds the prevalence rate of the defining motor signs of the disorder. Longitudinal studies suggest that, in both AD and PD, the olfactory deficit precedes the classic clinical signs by several years, serving as a “preclinical” marker.4 For example, in a study of 1,604 nondemented older adults, women with anosmia who possessed at least 1 apolipoprotein ε4 allele had an odds ratio of 9.71 for development of cognitive decline over the ensuing 2 years, compared with an odds ratio of 1.90 for women with no olfactory dysfunction and at least 1 such allele.35 In another study, 361 asymptomatic relatives of PD patients were administered olfactory tests. Those with olfactory test scores in the top and bottom 10% of the group underwent single-photon emission computed tomography (SPECT) with 2β-carboxymethoxy-3β (4-iodophenyl)tropane (β-CIT) labeled with iodine 123, a dopamine transporter measure of the health of this motor control brain region.36 At the 2-year follow-up, 4 of the 40 relatives with olfactory test scores in the bottom 10%, all of whom exhibited substantial reduction in transporter uptake at baseline, had experienced development of clinically defined PD, whereas none of the 38 relatives with test scores in the top 10% did. The remaining individuals in the bottom 10%, although not yet experiencing parkinsonian symptoms, exhibited significant declines in transporter uptake across the two tests, implying PD-related neuropathology was developing.

Congruent with the early olfactory loss of AD and PD is the early pathological involvement of the olfactory bulb and anterior olfactory nucleus, where marked cell loss and the presence of disease-related pathology (eg, neuritic plaques, neurofibrillary tangles, or Lewy bodies) are present.37, 38 In AD, tau-related pathology within these structures correlates with disease severity, cortical Lewy body counts, and apolipoprotein 4 carrier status.39, 40 Superoxide dismutases, enzymes that defend against reactive oxygen species, are abundant in the olfactory bulb, anterior olfactory nucleus, and neuroepithelium of patients with AD, where they are overexpressed relative to control subjects.41 Increases in other indices of oxidative damage within the olfactory neuroepithelium of patients with AD have also been reported, including heme oxygenase-1, a stress response protein.42

In PD, Braak and colleagues43 present evidence that the neuropathology, notably Lewy bodies and neurites, begins within the olfactory bulb, anterior olfactory nucleus, and dorsal motor nucleus of the vagus nerve (dmX) and then advances rostrally through susceptible regions of the medulla oblongata, pontine tegmentum, midbrain, and basal forebrain. In part because the anterior olfactory structures have fewer connections than the dmX with brain regions that subsequently exhibit the next proposed stage of pathology, these authors initially believed that the dmX is the most likely starting point. According to this concept, an unknown pathogen may enter the central nervous system from the stomach via the enteric nerves. However, the dmX involvement could be secondary to olfactory system involvement because connections exist between the olfactory bulb and this structure via several routes, for example, the amygdala and stria terminalis. Importantly, direct connections are present between central olfactory structures and the substantia nigra. Thus, horseradish peroxidase injected into the olfactory tubercle results in anterograde labeling of the substantia nigra, ipsilateral ventral tegmental area, pars reticulata, and ventral pallidum, as well as retrograde labeling of the ipsilateral olfactory bulb, anterior olfactory nucleus, and other olfactory areas.44 Recently, Hawkes,45 in collaboration with Braak and colleagues, has proposed a “dual hit” hypothesis in which both the olfactory and vagus nerves become involved simultaneously, perhaps from a pathogen that enters the nose and becomes swallowed with the nasal secretions, passing the stomach wall into Auerbach's and Meissner's plexuses.

If a pathogen related to PD enters the nose and induces smell loss, one might hypothesize that such a pathogen, injected into the bloodstream, would be less likely to damage the olfactory system. In support of this concept, the parkinsonism induced by the intravenous injection of a designer drug that inadvertently contained the proneurotoxin, 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP), is not associated with significant olfactory loss.46 The brains of three of these cases who have gone to autopsy lacked Lewy bodies, PD-related structures that are present within the olfactory bulb and anterior olfactory nucleus that are believed to be associated with olfactory dysfunction.47, 48 Interestingly, rats administered MPTP intranasally exhibit progressive impairments in olfactory, cognitive and motor function which appear to follow the sequence of neuropathological events proposed by Braak et al., although the olfactory deficit reverses itself over time.49 Rats are relatively insensitive to the effects of systemically introduced MPTP.50, 51

Evidence against the Olfactory Vector Hypothesis

  1. Top of page
  2. Abstract
  3. Evidence That Xenobiotics Can Enter the Brain via the Olfactory Mucosa
  4. Early Olfactory Loss and Progression of Alzheimer's Disease– and Parkinson's Disease–Related Neuropathology
  5. Evidence against the Olfactory Vector Hypothesis
  6. Conclusion
  7. Disclosure
  8. Acknowledgements
  9. References

Although xenobiotics can enter the brain via the olfactory nerve, evidence that they initiate or cause AD or PD is circumstantial. Potential opposition to the olfactory vector hypothesis comes from several sources, including: (1) the existence of genetic and familial forms of AD and PD52; (2) the lack of smell dysfunction in some AD and PD patients; and (3) a case report of a 65-year-old anosmic nondemented woman with AD-related neuropathology, an imperforate cribriform plate, rudimentary olfactory bulbs/tracts, and sulcal abnormalities of the orbitofrontal region.53 In addition, unlike PD, it is less clear whether the pathology of AD first appears within the peripheral olfactory system or in more central olfaction-related brain regions. According to Braak and colleagues,54 tau-related neurofibrillary tangles occur initially in the transentorhinal region between the hippocampus and the entorhinal cortex, not in the olfactory bulb or anterior olfactory nucleus. Others suggest the initial pathology may first appear in peripheral olfactory structures.40, 55 The lower density of plaques and tangles in the olfactory bulb and tract than in the amygdala and hippocampus has been interpreted as central to peripheral movement of pathology.56

For a number of reasons, such observations do not disprove the olfactory vector hypothesis. First, this hypothesis does not preclude other causes of AD and PD. Second, the mode of entry of pathogens into the brain need not be viewed as exclusive from genetic or other determinants of neurodegenerative disease. One would assume that most such putative agents would work in concert with genetic substrates. Third, the pattern of pathology may not show the direction of movement of a xenobiotic. Thus, some cell types may be more vulnerable to the pathogen than others, and not all pathological agents that enter the brain via the olfactory system need to induce olfactory system damage en passant.57 In some cases, a pathogen could reactivate latent viruses within central structures,58 potentially producing a central-to-peripheral propagation of damage. In other cases, the olfactory pathway could incur damage from the disease process initiated by the pathogen. Fourth, one cannot rule out, even in familial cases, a breakdown in protective processes within the olfactory mucosa at some point before phenotypic disease expression, opening the door to pathogen invasion. It is known, for example, that a mutation in the P450 cytochrome CYP2D6-debrisoquine hydroxylase gene increases the risk for development of PD.59 Fifth, not all familial cases of PD exhibit smell loss, including some with LRRK2-associated PD.60 Sixth, aside from interactions between environmental factors and genetic determinants, the heterogeneity of smell loss observed in AD and PD could reflect the following circumstances: (1) clinical misdiagnoses (more than 10% of AD and PD patients are misdiagnosed),61, 62 (2) individual differences in susceptibility of the olfactory pathways to damage from a pathogen or from subsequent disease induction, and (3) differences in the virulence of pathogens to induce damage to the olfactory system. Specificity of damage to central structures from viruses that enter the olfactory pathway is well documented. For example, when Barnett and colleagues63 tracked the spread of two viruses inoculated into the olfactory bulb, herpes simplex virus type 1 and mouse hepatitis virus strain JHM, only herpes simplex type 1 infected the noradrenergic neurons in the locus ceruleus; however, both infected dopaminergic neurons in the ventral tegmental area. Finally, aside from the possibility of multiple causes, the olfactory vector hypothesis is not disproved by a single case report of a woman with an imperforate cribriform plate who exhibited AD-related pathological lesions. Because the foramina of the cribriform plate close off from appositional bone growth in a significant number of people as they age,64 a pathogenic agent could have entered the brain via the olfactory fila before such occlusion.

An argument can be made that damage to the afferent olfactory pathways per se may predispose genetically or otherwise susceptible individuals to AD or PD, regardless of the cause of the olfactory damage. In other words, it is the damage to the olfactory system, rather than a xenobiotic agent that enters the brain, that initiates neurodegeneration in susceptible individuals. If this “olfactory damage” hypothesis is correct, then individuals with smell dysfunction due to any one or combination of a number of causes (exposure to toxic agents, head trauma, advanced age) would be more likely to acquire AD or PD than individuals without olfactory system compromise. It may be more than coincidental that major nongenetic risk factors for AD and PD, such as advanced age, head trauma, viruses, and exposure to heavy metals or extreme air pollution, are themselves directly related to olfactory system damage. The smell loss associated with the most salient of such risk factors, advanced age, is likely secondary to the aforementioned occlusion of the foramina of the cribriform plate by appositional bone growth and to cumulative damage to the olfactory neuroepithelium from bacteria, viruses, and other xenobiotic agents.65

In potential accord with the “olfactory damage” hypothesis for AD is the finding that removal of the olfactory bulbs of both rats and mice leads to decreased performance on cognitive tasks not dependent on olfaction,66 an effect attributed, in part, to degenerative disruption of interconnections with higher brain regions, such as those between the olfactory and septohippocampal systems.67 Although olfactory bulbectomy is a severe insult to a rodent, inducing a wide range of behavioral, hormonal, neurochemical, and anatomic changes including the rewiring of synaptic assemblies and rebalancing of neurochemical systems,68, 69 a number of these changes mimic key elements of AD-related neuropathology. Thus, bulbectomy results in degeneration within regions of the temporal cortex, hippocampus, and raphe nucleus; decreased density of cholinergic neurons within basal structures of the forebrain; and increased levels of βA within the hippocampus and other limbic structures.68–70 The increase in βA induced by bulbectomy in nontransgenic mice is comparable with the level of βA found in the early stage of plaque formation of transgenic mice expressing the mutated human βA precursor protein gene.71 Bulbectomy may, in fact, focus trauma-related injury into susceptible brain regions in a process analogous to that observed in diffuse brain injury, where long-term accumulation of βA and tau occurs within the damaged axons.72

It is unknown whether damage to the olfactory neuroepithelium per se can induce, in either humans or rodents, elements of the complex cascade of brain changes observed after bulbectomy. Axotomy or ZnSO4 irrigation of the olfactory neuroepithelium does lead to a 33 to 75% decrease of bulb weight in rats after a month,73–75 largely reflecting degenerative changes within the glomerular and external plexiform layers of the bulb. In humans, decreased olfactory bulb volumes determined using magnetic resonance imaging have been reported secondary to age,76 head trauma,77 upper respiratory infections that induce epithelial damage,78 and schizophrenia.79 Volume decrements of approximately 23% were reported for both older persons and those with schizophrenia.76, 79 In light of a finding of a −0.86 correlation between olfactory threshold sensitivity and magnetic resonance imaging–determined olfactory bulb volumes in 22 normal subjects,79 apparently olfactory bulb volume is a strong correlate of olfactory sensitivity. Research is sorely needed to determine whether the degeneration-produced decrements in olfactory bulb volume, particularly in individuals at risk for neurodegenerative disease such as the elderly, are associated with the induction of altered central neuropathology, transmitter function, and immunity.

Conclusion

  1. Top of page
  2. Abstract
  3. Evidence That Xenobiotics Can Enter the Brain via the Olfactory Mucosa
  4. Early Olfactory Loss and Progression of Alzheimer's Disease– and Parkinson's Disease–Related Neuropathology
  5. Evidence against the Olfactory Vector Hypothesis
  6. Conclusion
  7. Disclosure
  8. Acknowledgements
  9. References

Despite the intuitive appeal of the olfactory vector hypothesis, it remains to be determined whether it explains the cause of any case of AD or PD. To date, the evidence for this hypothesis, albeit compelling, is circumstantial. It is clear that viruses, bacteria, prions, and a range of airborne toxicants directly or indirectly implicated as risk factors for these diseases can enter the brain via the peripheral olfactory system and, in some instances, spread to brain regions classically associated with disease pathology. It is also clear that smell loss is among the first clinical signs of both AD and PD, occurring during their “preclinical phase” and disproportionately in persons at risk for the development of these disorders. However, what is unclear is whether the pathology of these diseases can be initiated by agents that specifically enter the brain via the olfactory pathways. Moreover, numerous basic questions remain unanswered. Is the olfactory dysfunction a product of the degenerative disease process or caused by agents that enter the brain via the olfactory fila? Does this differ from disease to disease? Can both occur? Are genetic and age-related substrates involved? Can damage to the olfactory system per se initiate disease pathology in genetically susceptible individuals, independent of the cause of such damage? Does damage to the olfactory system induce alterations in cytokines and other immune system mediators in susceptible persons that potentially regulate the induction of disease pathology? The answers to these and related questions will ultimately determine the viability of the olfactory vector hypothesis and whether novel prophylactic treatments involving the olfactory mucosa can be developed.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Evidence That Xenobiotics Can Enter the Brain via the Olfactory Mucosa
  4. Early Olfactory Loss and Progression of Alzheimer's Disease– and Parkinson's Disease–Related Neuropathology
  5. Evidence against the Olfactory Vector Hypothesis
  6. Conclusion
  7. Disclosure
  8. Acknowledgements
  9. References

This work was supported by the NIH (National Institute of Environmental Health Sciences, 1 P30 ES013508-02). I thank Leslie Cameron, John A. King, Bert Menco, Muhammad Shah, James B. Snow, Jr., Isabelle Tourbier, and Özüm Saygi for their constructive comments on an earlier version of the manuscript.

References

  1. Top of page
  2. Abstract
  3. Evidence That Xenobiotics Can Enter the Brain via the Olfactory Mucosa
  4. Early Olfactory Loss and Progression of Alzheimer's Disease– and Parkinson's Disease–Related Neuropathology
  5. Evidence against the Olfactory Vector Hypothesis
  6. Conclusion
  7. Disclosure
  8. Acknowledgements
  9. References