Handbook of Clinical Neurology, Vol. 164 (3rd series) Smell and Taste R.L. Doty, Editor https://doi.org/10.1016/B978-0-444-63855-7.00020-4 Copyright © 2019 Elsevier B.V. All rights reserved
Chemosensory dysfunction in neurodegenerative diseases RICHARD L. DOTY1* AND CHRISTOPHER H. HAWKES2 Smell and Taste Center and Department of Otorhinolaryngology: Head and Neck Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
Department of Neuroimmunology, Blizard Institute, London, United Kingdom
Abstract A number of neurodegenerative diseases are accompanied by disordered smell function. The degree of dysfunction can vary among different diseases, such that olfactory testing can aid in differentiating, for example, Alzheimer’s disease (AD) from major affective disorder and Parkinson’s disease (PD) from progressive supranuclear palsy. Unfortunately, altered smell function often goes unrecognized by patients and physicians alike until formal testing is undertaken. Such testing uniquely probes brain regions not commonly examined in physical examinations and can identify, in some cases, patients who are already in the “preclinical” stage of disease. Awareness of this fact is one reason why the Quality Standards Committee of the American Academy of Neurology has designated smell dysfunction as one of the key diagnostic criteria for PD. The same recommendation has been made by the Movement Disorder Society for both the diagnosis of PD and identification of prodromal PD. Similar suggestions are proposed to include olfactory dysfunction as an additional research criterion for the diagnosis of AD. Although taste impairment, i.e., altered sweet, sour, bitter, salty, and umami perception, has also been demonstrated in some disorders, taste has received much less scientific attention than smell. In this review, we assess what is known about the smell and taste disorders of a wide range of neurodegenerative diseases and describe studies seeking to understand their pathologic underpinnings.
INTRODUCTION Despite the fact that decreased chemosensory function is common in many neurologic disorders, in most cases, awareness of the disorder occurs only after formal testing (Doty et al., 1987; Nordin et al., 1995a; Fusetti et al., 2010). The majority of complaints of “taste” impairment actually reflect abnormal smell function. During deglutition, the olfactory receptors are stimulated from volatiles reaching them via the nasal pharynx, producing such “tastes” as strawberry, steak sauce, chicken, coffee, tea, chocolate, spaghetti sauce, and apple. Taste, as such, reflects only sensations derived from taste buds, i.e., sweet, sour, bitter, salty, savory (umami), and perhaps metallic or chalky. Surprisingly, few neurologists quantitatively assess either smell or taste function, even though olfactory
dysfunction, often subtle, has been designated by the Quality Standards Committee of the American Academy of Neurology as one of the diagnostic criteria for Parkinson’s disease (PD) (Suchowersky et al., 2006). The same recommendation has been made by the Movement Disorder Society for both the diagnosis of current and prodromal PD (Berg et al., 2015; Postuma et al., 2015). Similar proposals have been put forward for olfactory dysfunction as an additional research criterion in the diagnosis of Alzheimer’s disease (AD) (Foster et al., 2008). In addition to the diagnostic importance of such recommendations is the possibility that the olfactory system is a key element in the early pathogenesis of these conditions. This chapter reviews what is known about smell and taste function and their pathogenesis in a wide range of
*Correspondence to: Richard L. Doty, Ph.D., FAAN, Director, Smell & Taste Center, 5 Ravdin Building, Hospital of the University of Pennsylvania, Philadelphia, PA 19104, United States. Tel: +1-215-662-6580, Fax: +1-215-349-5266, E-mail: [email protected]
R.L. DOTY AND C.H. HAWKES
neurodegenerative diseases. Olfaction is described in the first section, followed by taste. Within each of these two sections, the diseases are divided into three broad categories: “Cognitive Disorders,” “Motor Disorders,” and “Other Disorders.” We include all conditions that have been assigned the term “neurodegeneration” for which there is a reasonable body of chemosensory data, as well as data from other ailments that are commonly misidentified as neurodegenerative diseases, such as severe depression.
widespread transneuronal propagation of PD-related pathology, i.e., a-synucleinopathy, occurs in mice whose OBs have been injected with fibrillary a-synuclein (Rey et al., 2016). Such observations are in accord with the concept that some neurodegenerative diseases may be initiated or catalyzed by viruses and other environmental agents that enter the brain via the olfactory receptor cells, possibly acting upon a genetically predisposed host (the olfactory vector hypothesis; (Doty, 2008)).
It is noteworthy that most neurodegenerative diseases in which olfactory dysfunction is evident are age-related. In some cases, it is unclear whether the deficit represents accelerated aging or a disease-specific pathologic process since over half the population between 65 and 80 years has some degree of demonstrable olfactory dysfunction; this figure rises to over three-quarters among those over the age of 80 years (Doty et al., 1984). According to one study of classical PD that used statistical modelling, the rate of olfactory decay with age exceeded that of simple ageing itself (Hawkes, 2008). The picture becomes particularly intriguing when environmental factors are considered since the olfactory epithelium is directly exposed to the outside environment and incurs cumulative damage throughout life from viral, bacterial, and xenobiotic insults. Viruses and other xenobiotics, including nanoparticles from polluted air, can enter the brain via the olfactory nerve filaments (Genter et al., 2018). In some cases, they can induce inflammatory and pathologic changes within the olfactory bulb (OB) similar to those observed in AD (Calderon-Garciduenas et al., 2018). It is noteworthy that
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Log concentration (± SEM)
UPSIT score (± SEM)
AD is the most prevalent neurodegenerative disease and is well known to be a prime example of a disorder in which olfactory dysfunction is a key component. Indeed, the number of olfactory studies of AD patients in the literature is only exceeded by those of PD (Doty et al., 2015). Such dysfunction is progressive and discernible in over 90% of patients by numerous types of olfactory tests (e.g., detection thresholds, odor identification tests) (Doty et al., 2015; Fig. 20.1). In one meta-analysis of 11 olfactory/AD studies, Cohen effect sizes relative to normal controls were enormous, being as large as 12 (Mesholam et al., 1998). The deficit is not confined to specific odors, although some odor/response subset combinations of the 40-item University of Pennsylvania Smell Identification Test (UPSIT) have been reported to improve discrimination between AD patients and nondemented controls (Tabert et al., 2005; Velayudhan et al., 2015; Gerkin et al., 2017). On the basis of smell dysfunction, AD can be differentiated from some commonly confused disorders such as major affective disorder or
Fig. 20.1. Mean (SEM) scores on the University of Pennsylvania Smell Identification Test (UPSIT) and a single ascending staircase detection threshold test using phenyl ethyl alcohol for patients with Alzheimer’s disease (AD) and age-, gender-, and race-matched controls. N ¼ 34 subjects in each group. Only AD subjects scoring 35 and higher on the Picture Identification Test (Vollmecke and Doty, 1985) were included in the analysis to ensure that subjects were not so demented as to lack understanding of the task. Data from Doty, R.L., Reyes, P.F., Gregor, T. 1987. Presence of both odor identification and detection deficits in Alzheimer’s disease. Brain Res Bull 18, 597–600. Copyright © 2013 Richard L. Doty.
CHEMOSENSORY DYSFUNCTION IN NEURODEGENERATIVE DISEASES depression. Using an 11-item odor identification test, Pentzek et al. (2007) differentiated between patients with AD and those with depression with a sensitivity of 100% and specificity of 95%. Even 3-odor identification tests made this differentiation, in one study with a sensitivity of 95% and specificity of 100% (McCaffrey et al., 2000) and another instance with a sensitivity of 80% and specificity of 100% (Solomon et al., 1998). It is important to note that the olfactory loss of AD occurs relatively early in the disease process, being present in many persons with mild cognitive impairment (MCI), a recognized precursor of AD. Indeed, in healthy older persons, smell loss is a better predictor of future cognitive decline than a global cognitive test, particularly for those carrying the ApoE E4 allele, a risk factor for AD (Graves et al., 1999). A higher conversion rate from mild cognitive decline to AD occurs in patients with olfactory dysfunction (Devanand et al., 2000, 2008).
OLFACTORY SYSTEM PATHOLOGY IN AD The physiologic basis for AD-related smell loss remains elusive. Genetics is clearly implicated in some cases since decreased smell function is found in: (a) some persons with the presenilin-1 mutation, a variant of AD (Nee and Lippa, 2001); (b) some close relatives of AD patients and individuals with a family history of dementia (Schiffman et al., 1990, 2002; Serby et al., 1996); and (c) a number of ApoE E4 allele carriers (Bacon et al., 1998; Wetter and Murphy, 2001; Wang et al., 2002; Hozumi et al., 2003; Gilbert and Murphy, 2004; Doty et al., 2011). A relationship has been shown between earlier age of AD onset and a high copy number of submicroscopic DNA segments in the olfactory receptor region of 14q11.2 (Shaw et al., 2011), an association independent of ApoE E4 allele status. Olfactory epithelium A focus on pathology within the olfactory neuroepithelium followed a report that AD could be diagnosed from postmortem samples of this epithelium, raising the possibility that in vivo biopsies might be possible in identifying early stages of the disease (Talamo et al., 1989). However, the control subjects were much younger than the AD patients and in vivo biopsies are not easy to obtain, reflecting, in part, the patchy nature of olfactory tissue within the epithelium secondary to progressive age-related metaplasia from xenobiotic damage. Subsequent studies have shown that analogous AD-related epithelial changes occur in the healthy elderly and in other neurodegenerative diseases, including those unaccompanied by significant olfactory dysfunction (Kishikawa et al., 1990). These observations assume that the apparent “healthy elderly” are not in the prodromal phase of AD.
Furthermore, increased amyloid b (Ab), a hallmark of AD, was reported by Kovacs et al. (2001) in the olfactory epithelial cells of 71% of neuropathologically confirmed AD cases compared to 22% of controls. Hyperphosphorylated tau (HPτ), primarily consisting of neuropil threads, was found in 55% of the cases and in 34% of controls, demonstrating low specificity. More recently, Moon et al. discovered that the olfactory mucosal microRNA-206 level within the olfactory epithelium was related to early AD, although olfactory testing was not performed (Moon et al., 2016). Olfactory bulbs Other research has focused on the OBs. Reduced OB volume has been noted on MRI images of AD patients (Thomann et al., 2009b). Pathologic studies find neurofibrillary tangles (NFTs) and amyloid plaques in all cell layers of the bulb, as well as the anterior olfactory nucleus (AON), a structure whose most peripheral segments are dispersed in patches within the main part of the bulb and its tract. HPτ pathology is even present in the OBs of early stage AD patients, unlike Ab plaques, which occur only in the later stages of the disease and typically in higher brain structures (Attems et al., 2014). In a study of 93 olfactory bulbs, Tsuboi et al. (2003) found tau pathology in all definite cases of AD. Central olfactory structures More central brain structures have also been implicated. According to Braak and associates (Braak and Del Tredici, 2011, 2016), the first pathologic changes of AD (intracellular HPτ deposits) occur within the locus coeruleus (pons), spread next to the transentorhinal cortex (posterior temporal zone), and then to the OBs, entorhinal zone, and hippocampus. In their study of 42 people, all below the age of 29 years (Braak and Del Tredici, 2011), tau pathology was found in the temporal lobes (transentorhinal region), as in classic disease, but the OBs were spared, suggesting that AD begins centrally and that OB involvement is a later feature. Conversely, Kovacs et al. (2001) found NFTs in the AON in some AD patients before their appearance in the entorhinal cortex. They also found that the medial orbitofrontal cortex (an olfactory association area) was more severely affected than the primary olfactory cortex and that the severity of pathology within the bulb correlated with that in some nonolfactory areas. Attems et al. (2005) also found evidence of tau changes within the OBs of 130 autopsy cases, but such pathology was most evident in later stages of the disease. Strong correlations were found between tau deposits in the olfactory and limbic systems as well as between such deposits and clinical dementia. A number of studies have sought to determine whether premortem olfactory test scores are correlated with postmortem pathologic markers of AD. In one study
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of 34 people with normal cognitive function who underwent autopsy, lower premortem scores on the 12-item Brief Smell Identification Test (B-SIT; a shorter version of the UPSIT) were associated with higher levels of AD pathology, principally NFTs in the entorhinal cortex and CA1/subiculum area (Wilson et al., 2007, 2009). These authors concluded that among older people without clinical manifestations of AD or MCI, olfactory dysfunction is related to the level of AD pathology in the brain and the risk of subsequent prodromal symptoms of the disease, an effect that is independent of APOEE4 status. Other studies have found correlations between premortem smell test scores and the presence of central Lewy bodies (e.g., dementia with Lewy bodies) but not with NFT or other AD-related pathology (McShane et al., 2001; Olichney et al., 2005). Despite the above studies the evidence overall for primacy of olfactory involvement is not as strong as that for PD, nor is it clear whether the olfactory deficit starts centrally or in the periphery. Imaging studies demonstrated that UPSIT scores were correlated with microstructural white matter changes and the volume of brain structures such as the hippocampus and amygdala (Devanand et al., 2010; Hagemeier et al., 2016; Woodward et al., 2017). While early positron emission tomography (PET) studies found lower UPSIT scores to be accompanied by decreased odor-related functional activation of both the piriform and the right anteroventral temporal lobe (Kareken et al., 2001), the nature or exact level of pathologic involvement could not be assessed. However, a recent PET study of persons with subjective cognitive decline or MCI found strong negative correlations between UPSIT scores and tau burden within the temporal and parietal lobes, as measured by tracers that target tau NFTs (Cecchini et al., 2016). Temporal lobe atrophy, but not amyloid burden (as measured by (18F)Florbetapir or (18F)Florbetaben), was also associated with lower UPSIT scores. There has has been considerable interest in the yet unproven concept that a prion-like agent progresses to higher brain structures from the OB (Braak and Del Tredici, 2016). This is of particular relevance in light of evidence that nanoparticles and other elements of air pollution have been associated with AD pathology within the bulbs of even young persons who have been chronically exposed to high levels of such pollution (Calderon-Garciduenas et al., 2018). As noted earlier, widespread transneuronal propagation of PD-related pathology does occur in mice whose OBs have been injected with fibrillary a-synuclein, adding credence to this possibility (Rey et al., 2016). If transneuronal propagation occurs, it could also reflect central to peripheral pathologic spread. Neurotransmitter/neuromodulator systems The involvement of central neurotransmitter systems has also been suggested as a potential cause of olfactory
dysfunction. Acetylcholine appears to be a prime candidate (Doty, 2017), in part because of its intimate association with cognitive dysfunction and evidence that olfactory loss is associated with lower scores on such neuropsychologic measures as immediate recall, delayed recall, category fluency, and naming ability. Importantly, OB and entorhinal cortex are rich in acetylcholine. One study found that changes in UPSIT scores were useful for assessing the effectiveness of acetylcholinesterase inhibitor donepezil on changes in cognition over time (Velayudhan and Lovestone, 2009). Another found that the degree to which intranasal administration of an atropine nasal spray (anticholinergic) decreases UPSIT scores at baseline. It is positively related to the subsequent efficacy of donepezil in improving cognition for patients with MCI (Devanand et al., 2017). Interestingly, older persons with olfactory loss tend to report more memory problems than older persons without such loss (Sohrabi et al., 2009).
Down syndrome Down syndrome (DS), a trisomy 21 disorder, is the most common form of intellectual impairment and accounts for 17% of those with such disability. It was noted as early as 1928 that DS was associated with difficulties in smelling odors (Brousseau and Brainerd, 1928). This has been confirmed by modern measures of odor identification, detection, memory, and odor-induced EEG responses (Hemdal et al., 1993; Murphy and Jinich, 1996; Warner et al., 1988;Wetter and Murphy, 1999; Zucco and Negrin, 1994; Cecchini et al., 2016). The average smell loss observed in DS is very close to the near complete anosmia observed in AD and PD (i.e., UPSIT scores 20; McKeown et al., 1996; Warner et al., 1988). Although DS clearly impacts olfaction, non-DS children with similar intellectual disabilities also exhibit the same degree of olfactory dysfunction. McKeown et al. (1996) administered the UPSIT and a 16-item odor discrimination test to 20 children with DS (mean age ¼ 13.89 years), 20 non-DS children with equivalent intellectual disability (mean age ¼ 13.77), and 20 normal children whose chronologic age matched the mental age scores of the other two groups (mean age¼ 5.98) on the Peabody Picture Vocabulary Test-Revised (PPVT-R) (Dunn, 1981). Although no meaningful differences in olfactory function were found among the three study groups, the test scores of both the DS and non-DS intellectually disabled subjects were markedly lower than nonretarded children matched on chronologic, rather than mental, age. Moreover, the UPSIT scores of these young people were similar in magnitude to those of adult DS subjects (20). It is tempting to assume that classic AD-related pathology might be the basis for the olfactory loss observed in DS, given that such pathology is well
CHEMOSENSORY DYSFUNCTION IN NEURODEGENERATIVE DISEASES documented in DS subjects in early adulthood (Oliver and Holland, 1986) and the deposition of amyloid in the form of senile plaques or diffuse amyloid deposits is evident in cortical brain regions associated with olfactory processing (e.g., entorhinal cortex) (Hof et al., 1995). However, the smell loss occurs in most DS children at an age before such pathology is established and, importantly, is equivalent to non-DS intellectually disabled children of the same mental age (McKeown et al., 1996). In keeping with AD and PD, it could reflect abnormal development of the cholinergic basal forebrain, which is known to be involved in both cognition and olfaction (BergerSweeney, 1998).
Fragile X syndrome Fragile X syndrome is the most common single gene cause of autism and a frequent cause of intellectual disability in males. This disorder is caused by a CGG trinucleotide repeat of the fragile X mental retardation gene (FMR1). In the early onset form of this disorder, a full mutation is expressed in children who display intellectual disability. Such children exhibit an elongated face, prominent ears, and large testes. The adult variation of this disorder, termed the Fragile X-tremor/ataxia syndrome (FXTAS), has fewer trinucleotide repeats (premutation). Ataxia and cerebellar tremor are common features, leading to confusion in some cases with PD and essential tremor. In a study of 41 FXTAS subjects, UPSIT scores were depressed and related to the degree of cognitive impairment (Juncos et al., 2012). However, like other trinucleotide repeat disorders (e.g., spinocerebelluar ataxias), the dysfunction is much less than that seen in AD, DS, or PD. The disparity from DS is interesting since the Fragile X mental retardation protein (FMRP) interacts with the DS critical gene region 1 (DSCR1) to regulate local protein synthesis and dendritic spine morphogenesis in numerous brain regions (Wang et al., 2012), An impairment in odor discrimination learning, but not in threshold sensitivity, was found in knock-out mice lacking the FMR1 gene (Larson et al., 2008), implying there may be a human correlate. In contrast, another group who used the same knock-out mouse model found a lowering of olfactory sensitivity but no change in their measures of odor habituation or discrimination (Schilit et al., 2015).
Frontotemporal dementia Frontotemporal dementia (FTD), also known Frontotemporal Lobar Degeneration, is characterized by striking personality changes and a breakdown in executive function and social conduct that reflects pathology within the frontal lobe and anterior temporal cortex. Some FTD patients exhibit symptoms of parkinsonism
or amyotrophic lateral sclerosis (ALS). All studies to date have shown that FTD patients exhibit considerable alteration in smell function. Thus, in one study of 11 FTD patients and 20 controls, patients performed significantly worse than the controls in odor discrimination, odor naming, and odor picture-matching in a manner similar to that seen for AD (Luzzi et al., 2007). Their performance did not differ from that of controls on nonodor tasks of picture naming and word picture-matching, indicating that the deficits were odor specific. Rami et al. (2007), in a case–control study of 3 FTD patients, reported a deficit in odor identification but not in odor discrimination, with the greatest deficits occurring for those with the most temporal lobe involvement, as determined from MRI (Bachmanov et al., 2001). McLaughlin and Westervelt (2008) found scores on the B-SIT of 14 FTD patients differed from those of 14 age- and education-matched normal controls (ps < 0.001), but did not differ from 14 AD patients (P ¼ 0.635). In a study of 22 patients with the frontal variant of FTD and 25 patients with corticobasal syndrome, Pardini et al. (2009) noted major UPSIT score reductions in FTD with only 1 person with normal values. Magerova et al. (2014) found lower performance on an 18-odor identification test in 22 FTD patients than in 15 controls, with all subgroups (behavioral variant, primary nonfluent dysphasia, semantic dementia) exhibiting the deficit. Omar et al. (2013) assessed odor and flavor identification prospectively in 25 patients with FTD (12 with behavioral variant FTD (bvFTD), 8 with semantic variant primary progressive aphasia (svPPA), and 5 with nonfluent variant primary progressive aphasia (nfvPPA)) and in 17 healthy controls. Odor identification was assessed using a modified UPSIT, and flavor was assessed by cross-modal matching of flavors to words and pictures. Relative to the controls, all three FTD subgroups exhibited deficits in both odor and flavor identification. The performance decrement was associated with atrophy in the anteromedial temporal lobe network in the combined FTD cohort.
Lewy body disease After AD, Lewy body disease (LBD; also known as “diffuse” Lewy body disease), is the most common dementing neurodegenerative disorder. The syndrome is termed Dementia with Lewy bodies (DLB) if the dementia occurs before, during, or within a year of the motor symptoms (Lippa et al., 2007). Among the features of this disorder are progressive and fluctuating cognitive decline, visual hallucinations, spontaneous parkinsonism, and sleep disturbances. Decreased smell function is also common in LBD, albeit rarely appreciated clinically, and appears to be
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unrelated to disease duration or severity (Liberini et al., 2000; McShane et al., 2001; Olichney et al., 2005; Williams et al., 2009; Wilson et al., 2011). In one study, anosmia was noted in 41% of 22 autopsy-confirmed cases, 16% of 43 autopsy-confirmed AD patients, and 6% of 94 age-matched controls (McShane et al., 2001). Unfortunately, differing degrees of dysfunction could not be determined since the olfactory testing consisted of simply sniffing a bottle of lavender water and asking whether it could be smelled or not. Using the 12-item B-SIT, Westervelt et al. (2003) found 5 of 9 LBD patients to be anosmic patients (56%), compared to only 1 AD patient (11%). The two groups were matched to one another on the basis of age, gender, and dementia level. The average B-SIT scores were significantly lower in the LBD than in the AD group. Their study was repeated in a further 26 subjects suffering from LBD and confirmed the severe and greater olfactory defect on B-SIT compared to AD (Westervelt et al., 2016). The pathologic basis of the olfactory loss is not clear, although several studies suggest that the Lewy pathology is relevant. Ross et al. (2006), in the Honolulu-Asian aging study, found an association between postmortem incidental Lewy bodies and premortem B-SIT scores in persons without parkinsonism or dementia during life. The age-adjusted relative odds of incidental Lewy bodies in the lowest vs the highest B-SIT tertile was 11.0 (95% confidence interval ¼ 1.3–536, P ¼ 0.02). Wilson et al. (2011) identified 26 LBD cases from 201 autopsied brains of older persons who had been administered the B-SIT at some point before death [mean (SD) age at death ¼ 88.0 (6.54)]. Those with Lewy bodies exhibited B-SIT scores similar to those expected from older patients with PD (Aden et al., 2011), whereas those without Lewy bodies exhibited B-SIT scores expected for someone of their chronologic age. The smell deficit was present only in those whose Lewy bodies were present within limbic or cortical regions, not solely within the substantia nigra. Although no assessment of OB pathology was made, others have reported Lewy pathology, NFTs, and aberrant tau within the bulbs of both LBD and PD patients (Tsuboi et al., 2003; Mundinano et al., 2011). Since modest correlations do not define causality, other possible reasons for the smell loss of LBD must be considered. The involvement of neurotransmitter deficiencies, particularly that of acetylcholine, would seem most obvious (Doty, 2017). Cholinesterase inhibitors have been found useful for treating the neuropsychiatric and cognitive elements of this disease (McKeith et al., 1996) and the daytime sleepiness of this disorder correlates with the neuronal depletion of the cholinergic nucleus basalis of Meynert (Kasanuki et al., 2018).
Semantic dementia Semantic dementia (SD) is a multimodal disorder in which patients have difficulty recognizing the significance of words, objects, faces, nonverbal sounds, and tastes, despite their normal perception of such stimuli. SD is potentially a very important test case for understanding the cognitive organization of chemosensory processing, as it is the paradigmatic disorder of human semantic memory. In SD, one might expect a parallel loss of meaning for odors but no impairment in their detection and discrimination. Pathologically, SD is associated with severe atrophy of the amygdala, middle, and inferior temporal gyri. There is relative sparing of the posterior hippocampal formation, distinguishing SD from AD where major pathology is within the posterior hippocampus. One study compared the olfactory test scores of patients with mild AD (14 cases) to SD (eight cases), FTD (11 cases), and corticobasal syndrome (CBS; 7 cases, described later in this chapter)—all defined by clinical, rather than pathologic, criteria (Luzzi et al., 2007). In this study, patients of Italian and British origin were evaluated by a specially designed test battery. As expected, the AD group performed poorly on odor discrimination, naming, and odor picture-matching tasks. The SD group had particularly low scores on odor naming in the presence of normal discrimination, in keeping with the concept of olfactory agnosia. Piwnica-Worms et al. (2010) administered a modified UPSIT, in which words and pictures were simultaneously presented for the response alternatives to 3 patients with probable SD and 1 patient with the logopenic variant of primary progressive aphasia. They also administered tests of flavor perception, flavor identification, and congruency of flavor combinations. Impairment in the ability to identify flavors or to determine congruence of flavor combinations was found. The ability to classify flavors according to affective valence did not differ from controls. However, a perceptual deficit was found in the single patient with logopenic variant of primary progressive aphasia; while relatively preserved identification of flavors was evident, the ability to determine flavor congruence was impaired. It was proposed that SD induces a true deficit of flavor knowledge (associative agnosia).
Vascular dementia Vascular Dementia (VD) is accompanied by gradual cognitive decline, pseudobulbar palsy, and a relatively late onset of memory impairment. A step-wise decrease in motor function is common. VD typically occurs in elderly hypertensive ateriopaths and is viewed by many as a questionable entity. In many cases it may simply be AD with coincidental infarcts.
CHEMOSENSORY DYSFUNCTION IN NEURODEGENERATIVE DISEASES Knupfer and Spiegel (1986) found moderate impairment of olfactory threshold, recognition, identification, and naming tasks in 18 patients with presumed VD, but the deficit was less than that observed for AD. Similarly, Duff et al. (2002), in their study of 20 patients with VD, found scores on a basic 3-odor test (termed the Pocket Smell Test or PST) to be superior to scores of those with AD or depression. In contrast, Gray et al. (2001) found no significant difference in UPSIT scores between 13 patients with AD and 13 with VD.
MOTOR DISORDERS Amyotrophic lateral sclerosis (ALS) The most common form of motor neuron disease is ALS. Its primary features are degeneration of neurons within the anterior horn of the spinal cord and the cortical neurons of the pyramidal tract, resulting in rapidly progressive weakness and muscle wasting, twitching (fasciculation), and cramps. Death usually occurs within 3 years of symptom onset, with the condition spreading to the bulbar muscles (i.e. those concerned with chewing, swallowing and breathing). In 1991, Elian reported that the average UPSIT score of 9 male and 6 female ALS patients was significantly but modestly lower than that of age-matched controls, being around 30 (compared to 20 typically observed for AD and PD patients) (Elian, 1991). A similar bilateral UPSIT decrement was observed 3 years later by Sajjadian et al. (1994) in 17 female and 20 male ALS patients. Although nearly half of the group had scores falling within the normal range, three quarters scored below their individually matched controls. Only 11% had scores reflecting total or near total anosmia. No left/right differences were observed in 14 subjects whose nostrils were tested separately. Remarkably, significant correlations between UPSIT scores and both the sural sensory nerve conduction velocities (r ¼ 0.73) and latencies (r ¼ 0.70) were observed. These UPSIT findings were replicated in a large study of 58 ALS and 135 controls by Hawkes et al. (1998), although only bulbar patients exhibited statistically significant decrements implying that impaired sniffing might be confounding the results. These investigators measured the olfactory event-related potential (OERP) to H2S in 15 patients. In nine, the amplitude and latency responses were normal; in one, the P2 latency was significantly delayed; in two, the responses were absent; and in three, technical problems precluded assessment. In common with other neurodegenerative diseases, the physiologic basis for the olfactory dysfunction of ALS is not clear. Most forms appear to be sporadic, although early-onset forms have an A4V mutation of the superoxide dismutase SOD1 gene and FUS positive basophilic inclusions (Juneja et al., 1997; Aksoy et al., 2003;
Baumer et al., 2010). There is a case study report of ALS and smell loss that developed in a 44-year-old man who had been exposed occupationally to high concentrations of cadmium in a battery factory (Bar-Sela et al., 1992). Cadmium can reduce brain copper-zinc superoxide dismutase levels and can enhance the excitotoxicity of glutamate. Lipofuscin accumulation has been found in the AON and the mitral and tufted cells of the OB of patients with this disease (Hawkes et al., 1998). The aforementioned finding of a significant correlation between UPSIT scores and sural nerve latencies and amplitudes suggests the possibility of an association with cholinergic dysfunction (Sajjadian et al., 1994).
Dystonia Dystonia is a syndrome of sustained or intermittent muscle contractions resulting in abnormal, often repetitive, movements and postures, that affect one or more sites of the body. Ten percent of those with adult-onset primary dystonia have one or more affected first- or second-degree relatives demonstrating a genetic pathogenesis. Where a mutation is known, the dystonia is given the prefix “DYT” followed by a number that relates to the order of discovery. Some dystonias have parkinsonian features and are responsive to levodopa therapy, notably DYT5 (Dopa-responsive dystonia; DRD; Segawa syndrome). DYT5 exhibits mutations in tyrosine hydroxylase (TH) or the GTP cyclohydrolase 1 gene. Parkinsonian features present later. As noted in the following sections, only mild to moderate loss of smell function is found in most cases of dystonia. In one study of 16 patients with idiopathic adult-onset dystonia (mostly cervical), UPSIT scores were well within the normal range (Silveira-Moriyama et al., 2009c). DYT3 is a common X-linked recessive dystonia with parkinsonism, also termed “Lubag.” DYT3 is caused by a gene mutation at Xq13.1 that codes for TATA-binding protein-associated factor-1 (TAF1), which is expressed in the striatum. The average age of onset is approximately 40 years, and the disorder commences with progressive dystonia, mainly affecting the jaw, neck, and trunk, followed by parkinsonism. Filipino adult males with maternal roots from the Philippine Island of Panay are predominantly affected, although people born outside of the Philippines also have this disorder. Infrequently, a milder form of disease has been identified in females. A single study of 20 affected males, using a culturally modified UPSIT, showed olfaction to be mildly impaired (29 vs 32 on the UPSIT 40-point scale), even in the early stages (Evidente et al., 2004). The smell loss was independent of the degree of dystonia, rigidity, severity, and disease duration. Olfactory function also appears to be adversely altered in DYT25 (Vemula et al., 2013). Whole exome
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sequencing revealed a missense mutation (V228F) in GNAL (guanine nucleotide-binding protein; Golf) (Vemula et al., 2013). Golf is known to play a role in olfaction, coupling G-protein receptors to adenylyl cyclase. Since it is expressed in the olfactory neuroepithelium and striatum, its distribution provides a plausible explanation for an association between dystonia and olfactory dysfunction. Six members of one family who harbored the p.V228F mutation had lower UPSIT scores than 5 noncarrier family members (respective means ¼ 25.5 & 33.0, P < 0.026) (Vemula et al., 2013). Apparently none of the family members complained of the dysfunction. Vemula et al. also mention that two Iranian families with isolated congenital anosmia showed linkage to 18p11.23-q12.2 (Ghadami et al., 2004), an area that is close to the GNAL coding region and point out that mice deficient in Ga(olf ) are anosmic (Belluscio et al., 1998). A single limited autopsy of a patient with DYT12, a rapid onset dystonia-parkinsonism syndrome that does not respond to levodopa, found no Lewy pathology or cell loss in the substantia nigra (Rajput et al., 1994). Other studies have similarly failed to find Lewy body pathology in dystonia cases (Inoue et al., 2001; Mennella et al., 2001).
Essential tremor Essential tremor (ET), unlike PD, is accompanied by postural and action tremor, not at rest, with the involuntary movement more likely to involve the hands, voice, and head. Unlike PD, ET is not accompanied by slow movement, a stooped posture, or a shuffling gait. Nonetheless, ET can be confused with benign tremulous PD where cogwheeling is absent or equivocal. ET patients are allegedly at a higher risk than the general population for future development of AD and PD (Louis, 2009; Laroia and Louis, 2011). A family history is often evident in keeping with autosomal dominant inheritance, although onset is bimodal with peaks in young and late adult life. Unlike PD, ET is not associated with meaningful olfactory dysfunction, making smell testing of some use in aiding the differential diagnosis of these two disorders. Busenbark and colleagues were the first to report that patients with ET scored normally on the UPSIT (Busenbark et al., 1992). Despite a study by Louis et al. (2002) claiming that ET is associated with mild UPSIT impairment, this has not been observed in any other published study (Adler et al., 2005; Shah et al., 2005; Quagliato et al., 2009; McKinnon et al., 2010). For example, Shah et al. (2008) compared UPSIT scores of 59 ET patients, 64 tremor-dominant PD patients, and 245 healthy controls. The scores of the ET patients were
indistinguishable from those of the controls. A surprising finding was that those who had a first-degree relative with tremor actually scored significantly better than age- and gender-matched controls. Djaldetti et al. (2008) did not find a relation with the extent of dopaminergic innervation measured by DATScan, and ET patients with and without rest tremor did not have abnormal smell tests. Finally, a study by Louis et al. (2008) suggested a correlation between the cerebellar neurotoxin Harmane (methylpyridoindole) and scores on the UPSIT in ET patients, although no difference in the mean UPSIT scores between the ET patients and controls were found. There have been no detailed pathologic studies of the olfactory pathways in ET, and only a few on the rest of the brain (Louis et al., 2006b). The major pathology is in the cerebellum, where Purkinje cell axonal swelling (‘torpedoes’) are found more frequently than in control brains (Louis et al., 2006a).
Huntington’s disease Huntington’s disease is a late-onset autosomal dominant disorder with high penetrance, characterized by progressive involuntary motor symptoms, notably chorea, dementia, and, in rare cases, PD-like muscular rigidity (Westphal variant) (Shoulson, 1986). Approximately half of at-risk offspring have the mutation that will ultimately result in HD. This disease is accompanied by marked deficits in odor identification, discrimination, detection, and odor memory similar to those observed in AD, PD, and DS (Moberg et al., 1987; Nordin et al., 1995b; Bylsma et al., 1997; Moberg and Doty, 1997; Hamilton et al., 1999; Lazic et al., 2007). For example, in one study the average UPSIT score for 25 HD patients (mean age ¼ 46.7 yr) was 24.8 (SD ¼ 8.7) (Moberg and Doty, 1997) and in another study of 12 HD patients, the average was 21.2 (SD ¼ 7.0) (mean age ¼ 42.0 (3.6) (Barrios et al., 2007). A delay in the P3 odor event related potential has been reported, as well as a negative correlation between amplitude and both the Unified Huntington’s Disease Rating Scale (UHDRS) movement scores and the number of CAG repeats (Wetter et al., 2005). One study found that HD patients performed worse than controls on visual and olfactory measures of “source memory” (i.e., whether a male or female had presented a given stimulus on earlier trials) but not for the memory of the smell or pictured item itself (item memory) (P < 0.05) (Pirogovsky et al., 2007). The point in time where olfactory dysfunction is first measurable in HD is not known with accuracy. In one study of 25 HD probands, 12 at-risk offspring, and 37 unrelated controls, significant UPSIT and threshold
CHEMOSENSORY DYSFUNCTION IN NEURODEGENERATIVE DISEASES deficits were only apparent in the HD group (Moberg and Doty, 1997). A similar study of 20 HD patients, 20 at-risk offspring carrying the HD mutation, and 20 mutationnegative adults also found that only the HD patients exhibited olfactory dysfunction (Bylsma et al., 1997). In both cases HD had been present for at least 2 years. Others have similarly seen no odor identification or detection deficits in nonsymptomatic HD gene carriers (Larsson et al., 2006; Pirogovsky et al., 2007). Although Larsson et al. (2006) found that 10 gene carriers performed similarly to 10 controls on odor identification and threshold tests, they did find that the carriers underperformed controls on a match-to-sample odor quality discrimination test employing 12 different combinations of four fruit-like odors (P < 0.03). UPSIT data from the PREDICT-HD study, in which a subject’s current age and CAG expansion lengths were employed to model the theoretical time of olfactory dysfunction onset, suggest that the dysfunction may occur some 15–20 years earlier (Paulsen et al., 2008). However, longitudinal follow-up is needed to determine the validity of this study’s projections since it is based on a model of cross-sectional data and its findings do not concur with those of studies suggesting that olfactory deficits occur near the time of symptom onset, as detailed earlier. The physiologic basis for the olfactory loss of HD is unclear. In a study of 12 HD patients, Barrios et al. (2007) found UPSIT scores correlated significantly with reductions in entorhinal cortex, thalamus, parahippocampal gyrus, and caudate nucleus volumes. A study employing diffusion tensor MRI found negative correlations between UPSIT scores and mean diffusivity in multiple subcortical and cortical brain regions, including the insula, anterior caudate, and medial temporal cortex (Delmaire et al., 2013). A more recent study of 120 asymptomatic gene-positive subjects and 119 early HD patients found UPSIT scores to be inversely related to gray matter volume of the superior right hippocampus and the left insula and white matter volume bilaterally in the temporal stems and in the right parietal and frontal lobe regions (Scahill et al., 2013). Such studies infer that neural circuits related to central olfactory processes are involved. It is noteworthy that dysfunctional cholinergic circuits are key elements of HD, although the neurotransmitter deficits of this disease are region specific and complex (D’Souza and Waldvogel, 2016). Transgenic rodent models of HD also exhibit olfactionrelated anomalies. Thus, the huntingtin (HTT) CAG heterozygous knock-in mouse exhibits impairments in olfactory discrimination in addition to hypoactivity, decreased anxiety, and motor learning/coordination deficits (Holter et al., 2013). In the R6/2 knockin HD rat model, reduced cell proliferation was documented within the subventricular zone and OB (Kandasamy et al., 2015).
Although survival of OB cells was reduced, the frequency of neuronal differentiation was unaltered in the granule cell layer even though increased dopaminergic neuronal differentiation was present in the glomerular layer. In humans, there are widespread pathologic changes particularly in the cerebral cortex (deep layers), globus pallidus, thalamus, subthalamic nucleus, substantia nigra, and cerebellum.
Idiopathic rapid eye movement sleep behavior disorder The major symptoms of idiopathic rapid eye movement (REM) sleep behavior disorder (RBD) are loss of muscle tone and the acting out of dream-related behavior during REM sleep. RBD is a strong risk factor for PD and other synucleinopathies, such as multiple system atrophy (MSA) and Lewy Body Disease (LBD). Olfactory dysfunction is common in RBD (Miyamoto et al., 2010; Postuma et al., 2011, 2013). In a 5-year prospective follow-up study of 62 patients with idiopathic RBD, impaired olfaction at baseline was related to a 65% 5-year risk of developing a defined neurodegenerative disease, compared to a 14% risk for those with normal olfaction (Postuma et al., 2011). The olfactory loss is similar to that of AD, PD, DS, and HD, with UPSIT scores falling around 20 (Aguirre-Mardones et al., 2015). In one study, the three most common clinical presentations were RBD followed by hyposmia, hyposmia followed by RBD, and hyposmia followed by RBD and constipation occurring around the same time (Aguirre-Mardones et al., 2015). Characteristically, olfactory dysfunction appears up to 5 years before the RBD diagnosis. In one large study of olfaction and sleep, nearly all of 30 patients with RBD had significantly increased olfactory thresholds, and there was evidence of Parkinsonism in eight, implying that olfaction and RBD are early features of PD (Stiasny-Kolster et al., 2005). Similar findings were documented by Iranzo et al. (2006). In keeping with many sleep studies, no pathologic confirmation was available, and where such confirmation was done, e.g. Boeve et al. (2003), the changes in RBD were more in keeping with parkinsonism than classic PD. Interestingly, acute sleep deprivation per se has a specific but mild adverse influence on the ability to identify odors—an influence that cannot be explained on the basis of task difficulty (Killgore and McBride, 2006). As yet, it is not clear whether this phenomenon is the cause or is otherwise related to the RBD findings described earlier. The pathophysiology of the olfactory loss of RBD is unknown. This disorder exhibits pontine and medullary degeneration, such as the sublaterodorsal nucleus and their glutaminergic projections to the medullary or magnocellular reticular formation (Iranzo, 2018). In PD, PET studies have found that the symptoms of RBD are closely
R.L. DOTY AND C.H. HAWKES
associated with cholinergic denervation within cortical, limbic, and thalamic brain regions (Kotagal et al., 2012). Recently, punch biopsies from the leg of RBD patients revealed a reduction in intraepidermal nerve fiber density reflecting small fiber neuropathy (Schrempf et al., 2016). Since small fiber neuropathy is associated with nicotinic cholinergic processes (Kyte et al., 2018), this raises the possibility that such pathology is a marker for cholinergic dysfunction associated with smell loss comparable to sural nerve latencies noted in ALS (Sajjadian et al., 1994).
PD and variants CLASSIC PARKINSON’S DISEASE Smell dysfunction is a major component of so-called classic, sporadic, or idiopathic PD, along with several nonmotor symptoms, including constipation, weight change, cognitive dysfunction, and dysautonomia. Unlike AD, in well-established PD, the dysfunction is relatively stable over time and typically unrelated to disease stage or duration (Doty et al., 1988a, 1992b; Barz et al., 1997; Hawkes et al., 1997; Oka et al., 2010), although exceptions may
UPSIT score (± SEM)
occur (Hawkes, 2008; Sharma and Turton, 2012; Cavaco et al., 2015). However, the dysfunction is essentially equivalent to that of AD (Fig. 20.2), and like AD, the smell loss often appears years before the definitive clinical PD motor signs (Ponsen et al., 2004; Ross et al., 2005; Haehner et al., 2007). The dysfunction is marked, bilateral, and occurs in over 90% of patients (Doty et al., 1984; Hawkes and Doty, 2018). Most investigators find that the PD-related olfactory defect is not confined to any specific set of odors and exhibits high sensitivity and sensitivity in differentiating PD from normal controls (0.91 and 0.88, respectively, in males 60 years of age) (Doty et al., 1995) and from a number of commonly-confused diseases (e.g., progressive supranuclear palsy: PSP, MSA, ET) (Busenbark et al., 1992; Doty et al., 1993; Wenning et al., 1995; Ondo and Lai, 2005). A few studies suggest that there may be a degree of odor specificity in PD, whether using the UPSIT or other tests such as the Sniffin’ Sticks (SS) test (Hawkes and Doty, 2018, p. 318). If so, a shortened smell test battery could be used. Like AD, the dysfunction is detected by all types of olfactory tests (Doty et al., 2015), and
Log concentration (± SEM)
–2.00 –3.00 –4.00 –5.00
Fig. 20.2. Mean (SEM) scores on the University of Pennsylvania Smell Identification Test (UPSIT) and a single ascending staircase detection threshold test using phenyl ethyl alcohol for patients with Alzheimer’s disease (n ¼ 34) or Parkinson’s disease (n ¼ 81) and age-, gender-, and race-matched controls (respective n’s ¼ 34 and 81). Data from Doty, R.L., Reyes, P.F., Gregor, T. 1987. Presence of both odor identification and detection deficits in Alzheimer’s disease. Brain Res Bull 18, 597–600 and Doty, R.L., Deems, D.A., Stellar, S. 1988a. Olfactory dysfunction in parkinsonism: a general deficit unrelated to neurologic signs, disease stage, or disease duration. Neurology 38, 1237–1244. Copyright © 2017 Richard L. Doty.
CHEMOSENSORY DYSFUNCTION IN NEURODEGENERATIVE DISEASES complete anosmia is not the norm. In one study, only about a third (38%) of 81 PD patients were anosmic on an odor identification test as defined by a score less than 17 out of 40 on the UPSIT. Only 87% reliably detected the highest concentration of phenyl ethanol that was presented in a detection threshold test (Doty et al., 1988a). In another study, 40 of 41 (98%) of PD patients reported that 35 or more of the 40 UPSIT items had some olfactory sensation even though such odors did not correspond to any of the response alternatives (Doty et al., 1992b). As in AD, some asymptomatic first-degree relatives of PD patients exhibit olfactory dysfunction. In PD, this predicts, to some degree, future development of PD (Montgomery Jr. et al., 1999, 2000; Ponsen et al., 2004). Ponsen et al. (2004) studied the olfactory function of 361 asymptomatic relatives of PD patients. Those who performed in the top 10% and bottom 10% were then scanned for dopamine transporter function within the striatum using the [123I]b-CIT labeled DA transporter. A number of those in the bottom 10% exhibited substantial reduction in DA transporter uptake, whereas none of those in the top 10% did so. When assessed 2 years later, none of the 38 relatives who scored in the top 10% had developed clinically defined PD or exhibited DA transporter dysfunction. All of those in the bottom 10% exhibited DA transporter dysfunction and four had developed clinically defined PD. Reflecting AD, longitudinal studies suggest that olfactory dysfunction in PD is associated with a much higher risk of subsequent development of dementia (Baba et al., 2012). Similarly, olfactory test scores are weakly correlated with some cognitive measures, most notably those involving verbal memory and executive function (Bohnen et al., 2010; Parrao et al., 2012), although strong relationships are generally lacking (Doty et al., 1989).
OLFACTORY SYSTEM PATHOLOGY IN CLASSIC PD The pathologic basis of the smell loss of PD remains enigmatic, although numerous studies have assessed correlations between olfactory test scores and measures of brain pathology. Interestingly, a number of risk factors for PD are associated with smell loss, including age (Doty et al., 1984), head trauma (Doty et al., 1997), exposures to toxins, and in a protective sense, lifetime intake of caffeinated beverages (Siderowf et al., 2007). To what degree these risk factors play a role in the expression of the olfactory loss of PD is not clear. Olfactory epithelium In general, Lewy bodies—the hallmark a-synucleinrelated pathology of PD—have not been found within olfactory epithelium of PD cases at autopsy, although dystrophic neurites without Lewy bodies have been documented, as well as accumulated amyloid precursor protein fragments analogous to those found in AD
(Crino et al., 1995). Duda et al. (1999) found no differences in the expression of abnormal a-synuclein within the olfactory mucosa of PD patients relative to that observed in healthy older controls, as well as in patients with LBD, AD, and MSA. Moreover, Witt et al. (2009) found no differences in the olfactory epithelium between 7 PD patients and 16 age-matched controls (9 of whom who had microsmia) for antibodies against a-synuclein, olfactory marker protein (OMP), protein gene product 9.5 (PGP 9.5), b-tubulin (BT), proliferation-associated antigen (Ki 67), the stem cell marker nestin, cytokeratin, and p75NGFr. The latter investigators concluded that the PD-related olfactory dysfunction was more likely due to central than to epithelial pathology. This issue was addressed further in a study of the olfactory pathways in 105 autopsied Japanese subjects (Funabe et al., 2013). There were 39 with Lewy-related a-synucleinopathy (LBAS, Lewy neurites) in the central or peripheral nervous system, of whom 7 showed Lewy neurites in the olfactory mucosa and bulb. There were 6 of 8 cases with LBAS in olfactory neurons of the lamina propria (the layer just deep to the olfactory epithelium) in those with clinically or pathologically confirmed PD (4 cases) and one instance of LBAS with incidental LBD. As noted earlier, no studies have found Lewy bodies, only dystrophic neurites, in the olfactory epithelium. Whether this is a sampling issue is not clear since the Lewy body is composed of clumps of phosphorylated a-synuclein. It remains conceivable that healthy subjects, coincidentally found to have a-synuclein-containing dystrophic neurites in the nasal receptor zone by Duda et al. (1999), were in the preclinical stage of PD and that the changes actually represent a disease-related, if not disease-specific, finding. A major difficulty is that, with age, the olfactory neuroepithelium is replaced progressively by respiratory epithelium and, for safety reasons, many have sampled from the more accessible anterior part of the middle turbinate where olfactory receptor neurons are less numerous. At present, the presence of specific PD related Lewy pathology in the nasal olfactory epithelium is possible but not proven. Central olfactory structures PD-related pathology is more readily demonstrable in the OBs and tracts of patients with PD. As with the case of AD and many older persons, MRI studies find that OB volume is decreased in patients with PD (Pearce et al., 1995; Yousem et al., 1998; Thomann et al., 2009a; Wang et al., 2011; Brodoehl et al., 2012), In an early neuropathologic study of the OBs of 8 PD patients and 8 controls, all PD cases contained Lewy bodies within the mitral cells and cells within the AON (Daniel and Hawkes, 1992). The Lewy body morphology at these sites resembled that observed in the cortex, although inclusions showing a classic trilaminar structure were rarely present. Within
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the AON, neuronal loss correlated with the number of Lewy bodies, as well as with disease duration (Pearce et al., 1995). Beach et al. (2009) found that 55 of 58 OBs from patients with PD contained Lewy bodies, achieving a sensitivity of 95% and specificity of 91% vs elderly controls, an observation echoed in a smaller study by Jellinger (2009). The bulbar a-synucleinopathy density score correlated well with such density scores in other brain regions, together with measures on the Mini-mental State Examination (MMSE) and Unified PD Rating Scale (UPDRS). A recent quantitative postmortem analysis of the glomeruli within the OBs of PD patients and controls found a predominantly ventral deficit in the glomerular layers (Zapiec et al., 2017). This was interpreted as being consistent with the olfactory vector hypothesis, i.e., damage from invasion of xenobiotics through the olfactory receptor cells (Doty, 2008). In a study of PD central olfactory structures, deposits of abnormal a-synuclein were found predominantly in the temporal division of the piriform cortex, olfactory tubercle, or anterior portions of the entorhinal cortex (Ubeda-Banon et al., 2010a), in keeping with Braak staging (Braak et al., 2004). Ubeda-Banon et al. (2012) explored the distribution of abnormal a-synuclein within the AON, olfactory tubercle, piriform cortex, posterolateral cortical amygdala, and lateral entorhinal cortex of homozygous transgenic mice that overexpressed the human A53T variant of a-synuclein. A significant increase of a-synuclein expression in the transgenic strain was found in the piriform cortex at 8 months compared to other brain structures. Double-labeling experiments using neural tracers showed axonal collaterals of mitral cells entering layer II of the piriform cortex in close proximity to a-synuclein-positive cells. No changes were observed in the substantia nigra (up to age 8 months), but the OB and piriform cortex were both affected at 2 months of age. This is in keeping with the concept of olfactory damage preceding motor changes. The potential importance of central a-synuclein pathology in explaining the anosmia of PD was highlighted in experiments involving Thy1-aSyn transgenic mice that overexpressed a-synuclein under the Thy1 promoter (Chesselet et al., 2012). These mice have high levels of a-synuclein expression throughout the brain but no loss of nigrostriatal dopamine neurons up to 8 months. Compared with wild-type littermates, Thy1-aSyn mice could still detect and habituate to odors but showed olfactory impairments in aspects of all three testing paradigms they a
employed, i.e., latency to find an exposed or hidden odorant, a block test centered on exposure to self and nonself odors, and a habituation/dishabituation test based on exposure to nonsocial odors. Neurotransmitter/neuromodulator systems A largely overlooked possibility is that the olfactory deficits of PD relate to altered levels of specific neurotransmitters or neuromodulators (NT/NM) intimately involved in modulating or shaping the olfactory percept (Doty, 2017). NT/NM decrements may occur before the presence of obvious neuron degeneration, although such degeneration can also result in such decrements. The human OB contains at least 20 different neurotransmitters, including dopamine. Acetylcholine. One possible explanation of the olfactory deficits observed in PD and to some other neurodegenerative diseases accompanied by smell loss relates to cell damage within the forebrain cholinergic system. Acetylcholine plays an important role in the innate immune system and when cholinergic cells are damaged, resistance to pathogens decreases (Boeckxstaens, 2013). Antiinflammatory pathways within the basal forebrain are regulated by nicotinic ACh receptors (nAChRs) found on macrophages and microglia (Egea et al., 2015). The differentiation of myelin-forming oligodendrocytes are enhanced in the CNS by ACh via increased myelin gene expression, an important point, given that myelinated nerve fibers are less susceptible to PD as well as AD pathology. It is noteworthy that cholinergic neurons within the basal forebrain are much more sensitive than most other neurons to pathogenic agents and ischemic damage (McKinney and Jacksonville, 2005). Acetylcholinesterase inhibitors such as donepezil and galantamine have been shown to protect neuronal cells from glutamate neurotoxicity (Takada-Takatori et al., 2006). PET studies have shown that AChE activity within the ascending cholinergic pathways are markedly depressed in PD, but not PSP, a disorder with relatively little olfactory dysfunction (Shinotoh et al., 1999). Positive correlations have been demonstrated between odor identification test scores and AChE activity measured by PET in PD within the hippocampal formation (r ¼ 0.63, P ¼ 0.0001, amygdala r ¼ 0.55, P ¼ 0.0001), and neocortex r ¼ 0.57, P ¼ 0.0003) (Bohnen et al., 2010).a Interestingly, like most psychophysical studies of olfactory function, PET studies find that the cholinergic dysfunction is similar in early and late-stage PD, i.e., does
Based on data after scores of 0 were omitted on the University of Pennsylvania Smell Identification Test (UPSIT). Because the UPSIT is a 4-alternative 40-odorant forced-choice test, chance performance would be around 10, not 0, the latter of which the authors had used in a few cases where clear anosmia was evident (Nicolas Bohnen, personal communication, August 30, 2011). The original cholinergic correlations with UPSITscores were 0.56 for the hippocampus, 0.50 for the amygdala, and 0.46 for the neocortex. After the 0 omissions, dopamine-related associations, as measured by monoamine transporter type 2, became nonsignificant (Ps > 0.05).
CHEMOSENSORY DYSFUNCTION IN NEURODEGENERATIVE DISEASES not progress with disease severity (Shimada et al., 2009). However, if the PD-associated alteration in smell function is related mainly to ACh deficiency, one might expect the deficit to be evident when centrally acting anticholinergic drugs are used. They affect memory, but not movement, whereas the older centrally acting dopaminergic blockers can cause severe parkinsonism, e.g., Haloperidol, Stelazine tetrabenazine. The latest antipsychotic drugs mainly block the D3 receptors. Dopamine. Associations have been noted between olfactory test scores and the degree of damage to dopaminergic brain regions, as inferred from functional imaging of the dopamine transporter within the caudate and putamen (Siderowf et al., 2005; Bohnen and Frey, 2007; Berendse et al., 2011; Deeb et al., 2010). However, the strength of these associations is variable, and the olfactory dysfunction is unresponsive to L-DOPA and dopamine agonists (Quinn et al., 1987; Doty et al., 1992b; Roth et al., 1998). If dopamine is involved, the dopamine receptors in the olfactory pathways are so dysfunctional or severely depleted that they cannot respond. Interestingly, dopamine deficiency has not been observed in the OBs of PD patients at autopsy. Indeed, a significant increase in the number of periglomerular dopaminergic neurons was reported in an initial study of the human OB (Huisman et al., 2004), as well as upregulation of TH expression. As TH is the precursor of dopamine synthesis, such upregulation was a proposed mechanism for the microsmia of PD. A subsequent study by the same group, which adjusted for gender, failed to confirm the initial findings, although a trend was still apparent (Huisman et al., 2008). An elevation of TH expression relative to three controls was also reported in the OBs of three Macaca monkeys who had been injected with proneurotoxin methyl-phenyl-tetrahydropyridine (MPTP) (Belzunegui et al., 2007). Increased bulbar TH expression has also been noted in transgenic rats and mice bearing the common PD a-synuclein mutations, A30P and A53T (Ubeda-Banon et al., 2010b; Lelan et al., 2011). In the MPTP mouse model of PD, a fourfold increase of dopamine expression in the OB has also been reported (Yamada et al., 2004). Such dopamine increase may reflect attempts to compensate for loss of a dopamine-responsive substrate, conceivably via increased migration of dopamine secreting cells from the subventricular zone/rostral migratory stream into the OB (Bedard and Parent, 2004). Norepinephrine and serotonin. Although alterations in CNS norepinephrine (NE) and serotonin (5-HT) cannot be totally ruled out as having some effect on olfactory function of patients with PD, a major influence seems unlikely. Thus, most studies suggest that olfactory function is largely spared in patients with depression (Khil et al., 2016), a disorder commonly accompanied by
decreased levels of NE and serotonin (5-HT). Intact olfaction also has been demonstrated in patients with dopamine b-hydroxylase deficiency, an inherited recessive autosomal disorder in which NE synthesis is diminished (Garland et al., 2011). Interestingly, such patients are also spared neurocognitive dysfunction (Jepma et al., 2011). While, in rats, pharmacologic blocking of a- and b-adrenergic receptors impairs learning of an odor discrimination task, once the task is learned, such disruption has no effect (Doucette et al., 2007). A similar phenomenon is also evident when bulbar NE is locally depleted by 6-hydroxydopamine (Doty et al., 1988b). It should be emphasized that the locus coeruleus, which is affected in Braak stage II (prodromal phase), secretes noradrenaline and has a strong serotinergic input. In rodents, there are noradrenergic connections between the locus coeruleus and the olfactory bulb (Shipley et al., 1985).
DRUG-INDUCED PARKINSONISM Drug-induced parkinsonism, also termed drug-induced PD (DPD), is often caused by neuroleptic medications, including wide-spectrum dopamine antagonists such as Haloperidol and trifluoperazine. The clinical features of DPD are commonly indistinguishable from idiopathic PD. In recent years, the prevalence of DPD has declined, largely due to the introduction of selective D2 dopamine receptor and 5-hydroxytryptamine (5HT) antagonists. In a pioneering study of 10 patients with DPD, five had abnormal UPSIT scores and none made a complete recovery from DPD even when the offending medication was changed or stopped (Hensiek et al., 2000). Of the remaining five who did regain motor function after drug cessation or adjustment, all but one had normal smell function. Unfortunately, several of these patients had a psychotic disorder, which may have contributed or even caused their smell problem. Nonetheless, it is possible that some individuals with DIPD are predisposed to develop PD and that exposure to a dopamine depleting drug unmasks underlying disease and its associated olfactory dysfunction. Thus, their clinician without realizing it may have been treating a patient with prodromal features of PD. In a subsequent DPD study of 15 patients that had received selective or nonselective dopamine-blocking medication for depression (Haloperidol, Flupenthixol, and Risperidone), Kruger et al. (2008) found impaired identification and detection, but not discrimination SS test scores. Depression, per se, was not the cause of the olfactory dysfunction since both unmedicated depressed patients and depressed patients who received similar medications without developing DPD had normal olfactory test scores. Bovi et al. (2010) administered SS to 16 DPD patients (7 haloperidol, 5 amisulpride, 2 perphenazine, 1 fluphenazine, 1 clomipramine), 13 PD patients,
R.L. DOTY AND C.H. HAWKES least, one nonmotor measure of MPTP-treated monkeys, which correlates with olfactory dysfunction in humans (i.e., cardiac denervation) (Elsworth et al., 2000; Goldstein et al., 2003). MPTP-treated mice exhibit intrabulbar inflammatory microgliosis and increased expression of cytokines associated with apoptosis such as interleukin-1a (IL-1a) and IL-1b (Vroon et al., 2007). Cholinergic associations appear possible. In accord with epidemiologic studies that suggest cigarette smoking protects against the development of PD, current and previous cigarette smokers with PD tend to outperform their nonsmoking counterparts on the UPSIT (Sharer et al., 2015). This phenomenon is similar to the finding that smokers exposed to workplace solvents and acrylates perform better on the UPSIT than nonsmokers (Schwartz et al., 1989, 1990). Strong correlations have been noted between PD odor identification test scores and cardiac 123I-metaiodobenzylguanidine (MIBG) uptake (Goldstein et al., 2008), implying an association with autonomic nervous system processes. Such associations appear to be independent of disease duration and clinical ratings of motor function (Lee et al., 2006).
and 19 age- and sex-matched normal controls. Only those with abnormal SPECT dopamine transporter binding in the putamen (n ¼ 7) evidenced olfactory dysfunction, suggesting that central DA damage rather than with druginduced DA receptor blockade may be the cause. However, another study using the B-SIT found no identification deficits in 15 DPD patients whose DPD had been induced by levosulpiride, haloperidone, flunarizine, perphenazine, metoclopramide, or risperidone (Lee et al., 2007). The most widely publicized cases of DPD appeared in northern California in the early 1980s. DPD developed after a small number of young drug addicts injected a heroin-like substance, methyl-phenyl-tetrahydropyridine 1(MPTP). MPTP is metabolically converted, mainly in CNS glial cells, to the toxic ion 1-methyl-4-phenyl-piperidinium (MPP+) by monoamine oxidase B. MPP+ readily enters dopaminergic terminals, binding to the dopamine transporter and damaging DA neurons by interfering with complex 1 of the electron transport chain. Interestingly, mice lacking the DA transporter are protected from MPTP toxicity (Bezard et al., 1999). In 1992, six of the original young MPTP-induced parkinsonism patients, along with 13 young PD patients and 10 normal controls, undertook the UPSIT (Doty et al., 1992a). The MPTP-related test scores did not differ significantly from those of the controls, although those of the young PD subjects did so (Fig. 20.3). It is conceivable that olfactory dysfunction would have been detected in the MPTP patients had the testing occurred sooner after the MPTP exposure or if there had been more frequent exposures to or higher doses of MPTP. Thus, the olfactory dysfunction of mice who receive intranasal MPTP recovers over time (Prediger et al., 2006) like, at
Considerable heterogeneity in olfactory function occurs in inherited forms of PD, although in many cases the olfactory dysfunction cannot be distinguished from that of classic PD. Even though PD-related genes are relatively rare in the general population, there are clear exceptions. The primary olfactory findings from studies of various familial forms of PD are presented in Table 20.1 from Hawkes and Doty (2018).
20 n = 13
Log concentration (vol/vol) (± SEM)
Number of items correct (± SEM)
n = 10
Parkinson’s MPTPControls disease induced parkinsonism
–4.0 –5.0 ns (p=.26)
–6.0 –7.0 –8.0 n = 13
n = 10
Parkinson’s MPTPControls disease induced parkinsonism
Fig. 20.3. Mean (SEM) University of Pennsylvania Smell Identification Test (UPSIT) and phenyl ethyl alcohol detection threshold test scores for persons with MPTP-induced parkinsonism, young patients with idiopathic Parkinson’s disease, and matched normal controls. From Doty et al. (1992a), with permission from John Wiley and Sons.
Table 20.1 Currently proposed genic forms of parkinsonism with some associated pathologic features and olfactory deficits where known
Gene and common mutations
A synuclein (SNCA). G209A. Missense mutations: A53T, A30P and E46K. Also duplications and triplications.
Inheritance pattern and locus
Function or effect of mutation
Parkin Over 200 mutations
Mitochondrial disorder. UPS, E3-ubiquitin ligase
Early onset. Good response to levodopa. Impaired olfaction in 1 case (Markopoulou et al., 1997). Abnormal in 2/7 Greek cases (Bostantjopoulou et al., 2001) and in 6 Japanese cases (Nishioka et al., 2009). Severe olfactory defect in two cases from Germany (Kertelge et al., 2010). Abnormal identification in 14 or 16 cases (Koros et al., 2018). Duplications resemble classic PD. Dementia prominent in duplications and triplications. No evidence of smell loss was observed by Tijero et al. (2010) in an asymptomatic carrier of the E46K substitution in the a-synuclein gene Early onset, slow progression. Good response to levodopa. No dementia. Normal/mild impairment of olfaction in manifesting and nonmanifesting carriers, heterozygotes but not compound heterozygotes (Khan et al., 2004; Alcalay et al., 2011). Susceptibility to glioma, lung cancer, possibly leprosy, and TB
3 and 5 6
Not confirmed PINK1 Over 60 mutations
Mitochondrial kinase. Defective mitophagy
DJ-1 10 mutations LRRK2/Dardarin G2019S; N1437H
AR 1p36 AD 12q12
Oxidative stress. Defective mitophagy Membrane trafficking, kinase
Early onset and slow progression. Good response to levodopa. Dementia. Moderate impairment of olfaction in all cases and some asymptomatic heterozygotes (Ferraris et al., 2009; Eggers et al., 2010). One autopsy showed LB but sparing of locus coeruleus and amygdala. OB not examined (Samaranch et al., 2010) Good response to levodopa. Normal olfaction based on 1 patient (Verbaan et al., 2008) Moderate to severe olfactory impairment in manifesting patients from London, New York, Lisbon, Brazil, and Germany (Berg et al., 2005; Khan et al., 2005; Lin et al., 2008; Kertelge et al., 2010; Silveira-Moriyama et al., 2010b; Saunders-Pullman et al., 2011). Variable or no impairment in nonmanifesting carriers (SilveiraMoriyama et al., 2008; Johansen et al., 2011; SaundersPullman et al., 2011). Dementia and tremor common. Good response to levodopa. Susceptibility to leprosy and TB Continued
Table 20.1 Continued PARK number
Gene and common mutations
Inheritance pattern and locus
ATP13A2 10 mutations
Not confirmed PLA2G6 Karak syndrome
Not confirmed Heterozygous mutation (D620 N) in VPS35 gene
Function or effect of mutation
Kufor-Rakeb disease. Based on four subjects (Kertelge et al., 2010). Similar to Hallervorden-Spatz disease. Levodopa-responsive PD with pyramidal signs, supranuclear gaze palsy, and dementia (Klein et al., 2009)
Ubiquitin protein ligase
Karak syndrome. Adult onset dystonia-parkinsonism. Temporary response to levodopa. Dementia. Cortical LB in four autopsies. No OB data but hippocampus involved in some (Paisan-Ruiz et al., 2012) Early onset levodopa-responsive parkinsonism with dystonia and spasticity
0 (One limited autopsy)
Modified from Hawkes, C.H., Doty, R.L. 2018. Smell and taste disorders. Cambridge University Press, Cambridge. AD ¼ autosomal dominant; AR ¼ autosomal recessive; LB ¼ Lewy bodies; OLF ¼ olfactory defect.
Indistinguishable from tremor-dominant PD. Dementia uncommon. Good response to levodopa
CHEMOSENSORY DYSFUNCTION IN NEURODEGENERATIVE DISEASES To identify possible familial PD, some investigators have administered olfactory tests and other PD-related measures to first degree relatives of PD patients. Lower UPSIT scores have been found in sons and daughters, in particular, where the affected parent was the father (Montgomery Jr. et al., 1999, 2000). One study evaluated olfaction and dopamine striatal transporter activity (DATScan) in 78 asymptomatic first-degree relatives of nonfamilial PD patients (Ponsen et al., 2004). Forty were hyposmia patients at baseline. 2 years later, four had abnormal DATScans and displayed clinical evidence of PD. In the remaining 36 individuals with hyposmia who displayed no sign of PD, the rate of decline of dopamine transporter binding was higher than in normosmic relatives. The impact of familial PD on olfactory function is perhaps best exemplified by studies of patients with PARK 8. The leucine-rich repeat kinase 2 gene (LRRK2) at the PARK 8 locus on chromosome 12p11.2-q13.1 is one of the most prevalent causes of familial PD. While only around 1% of North American PD patients carry this mutation (Correia et al., 2010), over 40% of Arab-Berbers of North Africa with PD do so (Lesage et al., 2005). This condition gives rise to late onset benign tremor and may be indistinguishable from sporadic PD. Penetrance of the most common LRRK2 mutation (G2019S) is incomplete and age dependent (Lesage et al., 2007). Limited pathologic studies show Lewy and tau pathology in olfactory pathways at all levels (Silveira-Moriyama et al., 2009a). UPSIT scores typical of classic PD were found in five PARK 8 patients with the G2019S mutation from London (Silveira-Moriyama et al., 2008) and 16 PARK 8 patients with this mutation from Lisbon (Ferreira et al., 2007). Unaffected relatives at 50% risk of PARK 8 were not similarly impacted. In another preliminary study from Brazil that used SS, impaired olfaction was found in 22 LRRK2 patients carrying the G2019S mutation, but it was less severe than those with classic PD (Silveira-Moriyama et al., 2010b). In a German study, seven PARK 8 patients, three of whom were symptomatic and four of whom were nonsymptomatic, exhibited low UPSIT scores relative to controls (Kertelge et al., 2010). Less clear-cut results were documented in a large French pedigree that carried the G2019S mutation (Lohmann et al., 2009). A US-based investigation that used UPSIT in a study of 126 G2019S mutation carriers found no significant olfactory dysfunction in nonmanifesting carriers, suggesting to the authors that microsmia is not predictive of LRRK2related parkinsonism (Saunders-Pullman et al., 2014). Another group from Spain assessed UPSIT scores in (a) 29 subjects with parkinsonism due to the G2019S mutation, (b) 49 asymptomatic mutation carriers,
(c) 47 noncarrier relatives, (d) 50 subjects with idiopathic PD and (e) 50 community-based controls (Sierra et al., 2013). In the G2019S manifesting carrier group, 50% were hyposmia patients compared to 82% in the IPD group, and there was no significant difference between these two. Hyposmia was less frequent in the asymptomatic carrier group (26%) and asymptomatic noncarriers (28%), suggesting that olfactory dysfunction is not found in asymptomatic carriers of the G2019S mutation. Normal B-SIT scores were found in a Norwegian study of 47 nonsymptomatic family members of LRRK2 PD patients, of whom 32 were positive and 15 negative for either the G2019S or the N1437H mutation (Johansen et al., 2011). In summary, PD patients with LRRK2 mutations appear, on average, to have a decreased sense of smell, but the severity is less than that of idiopathic PD. Nonmanifesting carriers appear to have no olfactory impairment. Before it is concluded that hyposmia is not a premotor feature in this monogenetic disorder, much larger populations need to be tested.
GLUCOCEREBROSIDASE-RELATED PARKINSONISM Parkinsonism can be a presenting feature of Gaucher’s disease (GD), the most prevalent autosomal recessive lysosomal disorder. Other distinguishing features of this disorder are bone, hematologic, and pulmonary abnormalities (Saunders-Pullman et al., 2010). GD is caused by mutations in the glucocerebrosidase (GBA) gene. In one study of six carriers of the GBA mutation, three were anosmic, two severely microsmic, and one moderately microsmic, with the mean UPSIT score falling within the range expected for patients with sporadic PD (Goker-Alpan et al., 2008). In another study, borderline lower scores on a 12-item odor-identification test (P ¼ 0.08) were observed in 20 PD patients, heterozygous for one of the 2 GBA mutations (N370S, L444P) (Brockmann et al., 2011). In still another study, one of two GBA cases, both of whom were anosmic, was a 54-year-old man who reported that the smell dysfunction appeared when he was a teenager (Saunders-Pullman et al., 2010). The initial PD sign was tremor of the right hand appearing at 48 years of age. Soon thereafter he experienced the onset of symptoms such as anxiety, depression, low blood pressure, urinary urgency, and medication sensitivity. McNeill and colleagues studied 30 patients with Gaucher parkinsonism, their heterozygous GBA mutation carriers, and 30 mutation negative controls matched for age, gender, and race (McNeill et al., 2012). It was found that olfactory scores on the UPSIT were significantly lower in the Gaucher patients and heterozygous carriers. In a subsequent paper it was shown that odor identification scores declined slightly from baseline over
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a 2-year period with respective UPSIT means ¼ 31.85 vs 30.71 (Beavan et al., 2015). It is not clear from either paper whether any carriers free of clinical evidence of parkinsonism, as measured by the UPDRS, had abnormal UPSIT or whether any carrier with normal olfaction had an abnormal UPDRS score.
MULTIPLE SYSTEM ATROPHY MSA is a rapidly progressive type of parkinsonism accompanied by autonomic and cerebellar dysfunction. MSA-Parkinsonism (MSA-P), the most common form of MSA (80% of cases), is defined by akinesia and rigidity. MSA-Cerebellar (MSA-C) is a form in which cerebellar ataxia is dominant. Salient clinical features are dysarthria, stridor, contractures, dystonia, altered orthostatic blood pressure, constipation, bladder control issues, sexual dysfunction, and RBD (Kaufmann and Biaggioni, 2003). Its pathology is found within the basal ganglia, cortex, and spinal cord, as well as within the OBs, but peripheral autonomic neurons are spared (Kovacs et al., 2003). The discovery of glial cytoplasmic inclusions (GCIs) in MSA brains confirmed beliefs that striatonigral degeneration, sporadic olivopontocerebellar atrophy, and the Shy-Drager syndrome are, in fact, different clinical expressions of MSA (Papp et al., 1989). In a pioneering study, the UPSIT was administered to 29 patients with MSA and 123 controls (Wenning et al., 1995). Moderate dysfunction was evident in the MSA patients relative to the controls (respective means ¼ 26.7 and 33.5). The test scores of the MSA-P and MSA-C types did not differ. Others have similarly observed olfactory deficits in MSA patients (Muller et al., 2002; Abele et al., 2003; Goldstein et al., 2008; Garland et al., 2011). Unlike PD, no meaningful correlations have been observed between UPSIT scores and measures of cardiac 123I-metaiodobenzylguanidine (MIBG) uptake (Lee et al., 2006).
PARKINSON DEMENTIA COMPLEX OF GUAM The Parkinson dementia complex of Guam (PDG), also known as the ALS/parkinsonism-dementia complex of Guam (ALS/PDG), exhibits variable combinations of the features and pathology of atypical parkinsonism, dementia, and ALS. This progressive neurodegenerative disorder is found mainly among the residents of Guam, the Mariana islands, the Kii peninsula of Japan, and the coastal plain of West New Guinea (McGeer and Steele, 2011). Between 1957 and 1965, PDG accounted for at least 15% of adult deaths in the indigenous Chamorro population of Guam (Reed et al., 1966; Reed and Brody, 1975). Since that time, its prevalence has markedly decreased, and by 1999 its ALS component has been absent (Plato et al., 2003).
Doty et al. (1991) administered the UPSIT to 24 PDG patients. Their test scores were significantly depressed, being equivalent to those from 24 AD and 24 PD North American patients matched on smoking behavior, gender, and age. Subsequently, Ahlskog et al. (1998) administered an abbreviated version of the UPSIT to 9 Guamanians with symptoms of ALS, 9 with symptoms of pure parkinsonism, 11 patients with pure dementia, 31 patients with PDG, 53 neurologically normal Guamanians and 25 neurologically normal North American controls. The UPSIT scores were markedly and equally depressed in the four disease groups. It is debated how much PDG reflects environmental or genetic factors. The decrease in prevalence since 1970 suggests an environmental toxin could be involved, such as the plant excitotoxins derived from Cycad nuts, high aluminum, or low calcium and magnesium level in drinking water (Oyanagi, 2005). Pathologically, it is classed as a tauopathy with NFTs and no Lewy bodies, unlike idiopathic PD. In keeping with PD, the number of cells within the AON are significantly decreased (Doty, 1991). A retinopathy with an appearance similar to larval migration has been noted in a significant number of PDG patients and several nonsymptomatic cohorts (Cox et al., 1989; Kato et al., 1992; Kokubo et al., 2006). This unique retinopathy has not been found in any other part of the world or in any other neurodegenerative disease, although on the surface it resembles the well-documented “snail-track” degeneration of the retina. No larva, however, has ever been found and the observation may well be coincidental.
VASCULAR PARKINSONISM Vascular parkinsonism (VP) differs from PD in that it is predominantly of the rigid type and rarely accompanied by rest tremor. It is usually associated with normal striatal dopamine transporter PETor SPECT imaging (Tzen et al., 2001). Moreover, it exhibits more variable responses to L-DOPA than PD and is most common in patients with extensive cerebrovascular disease involving the basal ganglia. Insidious onset cases tend to have more scattered lesions than acute onset cases, who have comparatively more abnormalities in the subcortical gray nuclei (thalamus, striatum, globus pallidus) (Zijlmans et al., 1995). Katzenschlager et al. (2004) administered the UPSIT to 14 VP patients, 18 PD patients, and 27 normal controls of similar age. The scores of the VP patients did not differ significantly from those of healthy controls (respective means ¼ 26.1 and 27.6), both of which differed from those of the PD patients (mean ¼ 17.1). In contrast, Navarro-Otano et al. (2014) found severe impairment of odor identification (mean UPSIT ¼ 18.3) in a study of 15 cases of clinically diagnosed VP. This measurement did not differ significantly from the mean of their PD
CHEMOSENSORY DYSFUNCTION IN NEURODEGENERATIVE DISEASES patients (mean ¼ 15.3). Both were much lower than the control mean (30.7). Given these disparate results, more research is clearly needed to determine whether olfactory testing may be useful, at least in some cases, in differentiating VP from PD.
Progressive supranuclear palsy Patients with progressive supranuclear palsy (PSP), also known as the Steele–Richardson syndrome, exhibit failure in voluntary vertical gaze, a rapid progression of motor dysfunction, marked imbalance, and advancing cognitive decline. Its characteristic pathology is widespread deposit of aberrant tau protein in degenerating neurons. However, the OBs appear to be spared (Tsuboi et al., 2003). Williams et al. (2005) have proposed that PSP be divided into two varieties based on a clinicopathologic study of 103 cases—“Richardson syndrome,” characterized by early onset of falls and postural instability, and “PSP-P,” characterized by a tremor with asymmetric onset with moderate initial therapeutic response to L-DOPA. In the first substantial olfactory study of PSP, the UPSIT was administered to 21 PSP patients, 21 PD patients, and 21 healthy controls matched by age gender and smoking habit (Doty et al., 1993). Seventeen of each group also received an odor detection threshold test. Subjects were included only if they performed well on the picture identification test (PIT) (Vollmecke and Doty, 1985) to ensure that any UPSIT differences in test scores were not related to cognitive problems. The olfactory test scores of the PSP patients did not differ significantly from those of the controls on either test, although the PSP group trended towards less sensitivity on the threshold measure (P ¼ 0.085). The olfactory function of PSP patients was markedly superior to that of the PD group (ps < 0.001). No meaningful associations were found in either patient group between the olfactory test scores and measures of motor symptom severity, disease stage, or medication usage. A subsequent study of 15 PSP cases and 123 healthy controls was in support of these findings (Wenning et al., 1995). Evidence for some degree of smell dysfunction in this disease comes from a study of 36 PSP patients (six of whom were pathologically confirmed), 140 PD patients, and 124 healthy controls (Silveira-Moriyama et al., 2010a). The UPSIT scores of the PSP patients were lower than those of the controls and higher than those of the PD patients. Although the PSP scores may have been impacted in some instances by coexisting dementia, this was not true in all cases. NFTs and tau accumulation was present in the rhinencephalon of six brains that were analyzed, although the OBs were largely spared and in half of these cases, antemortem function was normal.
In another study, a more complex picture has emerged (Baker and Montgomery Jr., 2001). These investigators found that of 23 first-degree relatives of PSP patients, nine (39%) scored in the abnormal range on the UPSIT. This is remarkably high, posing the question whether other factors intervened to impact the test scores since the familial risk of PSP is much lower than 39%. While additional pathologically confirmed studies are needed, the weight of the evidence is that olfaction is normal or affected only mildly in the commoner, Richardson variant, which is the easier of the two syndromes to diagnose. The fact that the PSP-P variant may simulate PD might explain why some patients diagnosed with apparent classic PD have normal olfactory function.
Prion-related diseases Prion diseases, also known as transmissible spongiform encephalopathies, are a family of rare neurodegenerative diseases of which Creutzfeldt–Jakob disease (CJD) is the classic example. To our knowledge, olfactory testing has been performed in only a single patient with a prion disease, a 54-year-old ceramic tiler with a pathologically confirmed variant of CJD (Reuber et al., 2001). Over the course of 12 months, this man became unable to distinguish the taste of beer from tea and developed an unusual craving for vanilla ice cream, along with irritability, excess drowsiness, imbalance, and tremor. Crude olfactory testing found impaired odor detection and recognition. Taste measurement was not performed. At autopsy, widespread prion staining was evident in the cerebral cortex and basal ganglia. The staining was particularly strong within the olfactory tracts, which were vacuolated. There is evidence from both human and animal studies that the olfactory mucosa can serve as a reservoir for pathogenic prions (PrPSc). In the sporadic form of CJD, one study found PrPSc in the olfactory cilia and central olfactory pathway of all nine patients that were examined (Zanusso et al., 2003). PrPSc was not found in the respiratory mucosa or in control tissue. These investigators suggested that olfactory pathway involvement is an early feature in all varieties of CJD and that, in MV2 and VV2 variants, olfactory pathology is accompanied by damage in the dorsal motor nucleus of the vagus, solitary tract, and perihypoglossal nuclei (Zanusso et al., 2009). These observations are supported by a case report of a 59-year-old woman who had a nasal olfactory epithelial biopsy 45 days after initial CJD symptoms (Tabaton et al., 2004). In this case, prion protein (PrPc) immunostaining was observed in the olfactory cilia and olfactory mucosa. The finding of PrPSc in the olfactory epithelium at an early stage in human and animal studies supports
R.L. DOTY AND C.H. HAWKES
the concept of centrifugal spread of PrPSc along olfactory pathways and implies that prions shed into nasal secretions may spread to other individuals (Hamir et al., 2008; Bessen et al., 2010, 2012). There is also evidence that the nonpathogenic cellular prion protein (PrPc) is involved in the normal processing of olfactory sensory information (Le Pichon et al., 2009). Thus, in prion protein knockout mice, olfaction-related behavior and oscillatory activity in the deep layers of the main OB are disrupted (Le Pichon et al., 2009). Indeed, there is evidence that expression of PrPc can reflect a general response to cellular stress which, in turn, plays a role in neuroprotection and neurogenesis of cells within the olfactory neuroepithelium (Parrie et al., 2018).
Spinocerebellar ataxias The human cerebellum is structurally connected with all major subdivisions of the brain, including the brainstem, cerebrum, basal ganglia, diencephalon, limbic system, and spinal cord. Although classically viewed as a motor coordinating center, the cerebellum has been implicated in information processing of many sensory systems, including olfaction. Indeed, since the pioneering functional imaging study of Yousem et al. (1997), it has become apparent that the cerebellum is somehow involved in associations between the olfactory system and both motor and sensory processes (Sobel et al., 1998). Thus, many studies have focused on the olfactory function of spinocerebellar ataxias (SCAs), a heterogeneous group of diseases of the cerebellum, its afferent and efferent connections. Although typical symptoms include progressive incoordination of limb movements, gait, and speech, in most cases, a more diffuse neurodegenerative process is present. Thus, autonomic dysfunction, extrapyramidal signs, sleep disturbances, visual attentional deficits, and impairment of saccadic and smooth pursuit movements are often present (Rub et al., 2008). All SCAs are, by definition, autosomal dominant, with over 40 abnormal genes identified to date. Friedreich’s ataxia is autosomal recessive and the main variety of the recessive ataxias. Inherited ataxias for which olfactory data are available are described later.
FRIEDREICH’S ATAXIA Friedreich’s ataxia (FRDA), a recessively inherited ataxia with progressive corticospinal tract damage, peripheral neuropathy, diabetes, and cardiac abnormalities, has been associated with both threshold and identification deficits. In a pioneering study, Satya-Murti and Crisostomo (1988) found elevated pyridine thresholds in 7 FRDA patients relative to those of 20 age-matched normal controls. Modest decrease in mean UPSIT scores was reported by Connelly et al. (2003) in 23 patients with
FRDA. The scores did not differ from a group of 12 individuals with other types of SCAs, including SCA2 (n ¼ 2), SCA3 (n ¼ 5), SCA7 (n ¼ 1), and unidentified SCAs (n ¼ 4), suggesting similar dysfunction among SCA types. The scores did not correlate with GAA trinucleotide repeat length, disease duration, or walking disability. A more recent study, available only in abstract form, compared SS odor identification test scores from 17 FRDA patients to 34 healthy controls (Branco Germiniani et al., 2014). Significant hyposmia was noted in 8 patients. No correlation was evident between disease duration, ataxia severity, or number of GAA repeats, as found in the study by Connelly et al. Age of onset was similarly unrelated.
SPINOCEREBELLAR ATAXIA TYPE 2 In addition to coordination and balance problems, Spinocerebellar ataxia type 2 (SCA2) is associated with speech and swallowing difficulties, rigidity, tremor, and ophthalmoplegia. In one study, 12 patients with this mutation exhibited low UPSIT scores relative to controls, a decrement not observed in patients they tested with Machado– Joseph Syndrome (SCA3) (Fernandez-Ruiz et al., 2003). In a small study, Hentschel et al. (2005) observed normal UPSIT scores in seven individuals with the SCA2 mutation and one at-risk patient. In a more definitive study, Velazquez-Perez et al. (2006) evaluated UPSIT, olfactory threshold, and discrimination test scores in 53 genetically verified cases of SCA2. Mild to moderate olfactory impairment was found in about half of the subjects tested.
SPINOCEREBELLAR ATAXIA TYPE 3 (MACHADO–JOSEPH SYNDROME) Olfactory function is normal or only slightly compromised in Spinocerebellar Ataxia Type 3 (SCA3; the Machado–Joseph Syndrome). Fernandez-Ruiz et al. (2003) reported that their 5 SCA3 patients had normal UPSIT scores. In a comparison of 41 SCA3 patients with 46 controls, Braga-Neto et al. (2011) found slightly lower scores in the SCA3 on the 16 odor SS identification test (11.5 2.4 vs 12.8 1.5, P ¼ 0.003). However, a more recent study by Moscovich et al. (2012) found no significant difference between the SS scores of 17 SCA3 patients and 17 controls after adjusting for age and cognitive function (11.5 2.0 vs 11.9 2.3). The little or no smell dysfunction of a patient with Machado–Joseph Syndrome might be useful in distinguishing patients with this disorder from those with SCA2 or classic PD.
SPINOCEREBELLAR ATAXIA TYPE 7 SCA7 is associated with poor balance and loss of vision. Galvez et al. (2014) administered the UPSIT and SS tests
CHEMOSENSORY DYSFUNCTION IN NEURODEGENERATIVE DISEASES to 28 SCA7 patients and 28 controls. A significant deficit was observed for the UPSIT and for the identification and discrimination components of the SS tests, but not the threshold test, suggesting to the authors (p. 499) that “SCA7 neurological damage affects olfactory perception but spares the patients’ olfactory sensory capabilities.” However, such distinction is questionable since it is well established that odor thresholds are also impacted by central lesions such as those of AD and epilepsy (Doty et al., 1987, 2018). The physiologic basis of the olfactory losses of various SCAs is unknown. Because their neurologic dysfunction goes far beyond the cerebellum, the involvement of the cerebellum, per se, is presently enigmatic.
Corticobasal syndrome The original term corticobasal degeneration has been renamed CBS because of the very high rate of diagnostic errors prior to autopsy. In the classic disorder, parkinsonian features are compounded by limb dystonia, ideomotor apraxia, myoclonus, and ultimately, cognitive decline. The condition is classed as a tauopathy because there is accumulation of tau protein typically in the frontoparietal cortex and basal ganglia. In a large pathologic survey of 93 OBs, there were three cases of CBS (Tsuboi et al., 2003), but none of these displayed tau pathology. Most CBS patients seem to have relatively normal smell function, although exceptions occur. In a landmark study of seven older patients with clinically suspected CBS (Wenning et al., 1995), UPSIT scores, while low (mean ¼ 27), did not differ significantly from age-matched controls. In a larger study of 25 patients, only 8 exhibited normal UPSIT scores, with a mean percentile score of 31.6% (Pardini et al., 2009). Two patients with autopsy confirmation of CBS were both anosmic. Another study of seven clinically defined CBS patients reported mild impairment of odor naming and odor picture-matching but normal odor discrimination (Luzzi et al., 2007).
OTHER DISORDERS Depression Even though depression is not a neurodegenerative disease, it often accompanies such conditions and may be misdiagnosed as dementia. The weight of the evidence is that depression, per se (also known as major affective disorder), does not cause meaningful smell dysfunction. Nevertheless, subtle olfactory changes may be present in some instances, and medication used in its treatment may alter the sense of smell. Since olfactory dysfunction itself
can lead to depression, cause and effect associations are often confounded by comorbidities. For example, AD is commonly accompanied by both depression and smell dysfunction, but depression is not the cause of the smell dysfunction. Depression may alter how odors are perceived along a hedonic dimension (Naudin et al., 2012, 2014). The first empirical study on this topic compared UPSIT scores of 19 nondepressed controls to those of 51 patients with moderate to severe depression (Hamilton Depression Rating Scale scores ranging from 18 to 37). All met DSM-III criteria for major depressive disorder, with or without melancholic features or atypical (bipolar II) depressive disorder (Amsterdam et al., 1987). No differences in test scores were found between the test groups (P ¼ 0.41) or between the melancholic and nonmelancholic depression subtypes (P ¼ 0.85). Most subsequent studies have also reported no impact of depression on olfactory function (e.g., Warner et al., 1990; Gross-Isseroff et al., 1994; Thomas et al., 2002; Pentzek et al., 2007; Scinska et al., 2008; Swiecicki et al., 2009; Hardy et al., 2012). Although Gross-Isseroff et al. (1994) found no differences in detection threshold sensitivity to either androstenone or amyl acetate between 9 unmedicated patients with major depressive disorder and 9 healthy controls, the depressed group exhibited lower amyl acetate thresholds than did the controls 42 days after initiation of antidepressant drug therapy (3 on 150 mg/day maprotyline, 4 on 150–200 mg/day imipramine, 2 on 20 mg/day fluoxetine) (P ¼ 0.009). This questions whether antidepressants, per se, alter olfactory function. Even though Postolache et al. (1999) found no UPSIT or PEA threshold differences between 24 patients with seasonal affective disorder (SAD) and 24 controls on either side of the nose, right, but not left-side, UPSIT scores were negatively correlated with “typical,” in contrast to “atypical,” depression scores (r ¼ 0.56, P ¼ 0.006). While Hardy et al. (2012) found no UPSIT or PEA detection threshold differences between 20 patients with DSMIV bipolar disorder and 44 controls, threshold sensitivity was inversely related to clinical ratings of depression on the Positive and Negative Syndrome Scale (PANSS; Kay et al., 1987). Manic symptoms were inversely related to the olfactory sensitivity scores. Croy et al. (2014) found no significant differences between 27 depressed female inpatients and 28 controls on SS tests of odor identification, detection, and discrimination. However, prolonged olfactory event-related potential latencies were noted in 17 participants; 14 exhibited reduced fMRI activation in the thalamus, insula, and left middle orbitofrontal cortex. All measures were said to show some improvement following psychotherapy.
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In contrast to most studies finding no or little effect of depression on olfaction, a few reports have suggested that depression decreases ability to identify (Serby et al., 1990; Clepce et al., 2010; Zucco and Bollini, 2011; Kamath et al., 2018) or detect (Pause et al., 2001; Lombion-Pouthier et al., 2006) odorants. Relative to 21 healthy controls, Negoias et al. (2010) found elevated thresholds and smaller OB volumes on each side of the nose in 18 patients with acute major depressive disorder. Although no significant left/right differences were apparent, a significant negative correlation between OB volume and depression scores was observed for threshold and bulb volumes on the right, but not the left. Neither odor identification nor discrimination was altered by the disease. Conversely some describe enhanced smell function. In contrast to their 1999 study, Postolache et al. (2002) reported that patients with winter SAD (n ¼ 14) were more sensitive to PEA than controls (n ¼ 16). Tests were performed twice, once during the winter and once during the summer. During both seasons, the SAD thresholds were significantly lower in the patients. Although each nostril was tested separately, no left/right data were presented, making it unclear what component was actually being evaluated. Four years later Kruger et al. (2006) compared bipolar disorder euthymic patients in those with (n ¼ 7) and without (n ¼ 9) histories of eventtriggered episodes. Those with event-triggered episodes exhibited lower PEA thresholds and shorter latency event-related potentials, although tests of odor identification and detection were not altered. No comparison against controls was made. In aggregate, the studies mentioned earlier strongly suggest that depression, per se, has little or no influence on most measures of olfaction, although exceptions may occur. The basis of the few discrepant findings is not clear, but may reflect differences in test procedures, employed odorants, or the types or degree of depression being tested.
Pure autonomic failure Pure Autonomic Failure (PAF) is typified by neurogenic orthostatic hypotension probably due to reduction of norepinephrine (noradrenalin) secretion in sympathetic nerves, without other neurologic features. Lewy bodies are present in the brain stem, the pre- and postganglionic autonomic neurons, the peripheral sympathetic and parasympathetic nerves (Hague et al., 1997). Although parkinsonism is absent in PAF, it shares pathologic features and some consider PAF belongs to the spectrum of Lewy Body disorders and that PAF may be a precursor of PD. An early example concerns a patient who underwent lumbar sympathectomy for peripheral vascular disease.
Biopsy showed Lewy bodies in the sympathetic ganglia, and 3 years thereafter, the patient developed typical PD (Stadlan et al., 1965). Kaufmann et al. (2004) described 1 patient with PAF who appeared to progress to PD after 20 years and another subject with marked dysautonomia who developed DLB after 18 months. Goldstein and Sewell (2009) studied olfaction in 8 patients with PAF, 23 with PD, and 20 with MSA. The PAF group had a low UPSIT score (mean of 22) similar to PD and significantly worse than MSA (mean of 31). Individual UPSIT scores correlated positively with cardiac fluorodopamine radioactivity in the septum but not fluorodopamine brain PET scans, implying that the olfactory dysfunction was independent of striatal dopamine deficiency. A similar approach was taken by Silveira-Moriyama et al. (2009b) in a group of 16 subjects with PAF, 14 with MSA, and 191 with PD. After adjustment for age, gender, and smoking behavior, they found the lowest UPSIT score in PD and equal impairment in MSA and PAF, suggesting that the olfactory defect in PAF occupied a position intermediate between classic PD and healthy controls. Another study evaluated the UPSIT in 12 patients with PAF, 10 with MSA, and 4 with dopamine b hydroxylase deficiency (Garland et al., 2011). Severe olfactory impairment was noted in the PAF group with little or no change in the other two groups.
Wilson’s disease This autosomal recessive disorder of copper metabolism, also known as hepatolenticular degeneration, is an autosomal recessive disorder caused by an ATP7B gene mutation on the long arm of chromosome 13. Copper accumulation occurs in the liver and basal ganglia and can lead, if not treated, to progressively severe dystonia and parkinsonism. Mueller et al. (2006), used the SS test battery to assess olfactory function in 24 Wilson’s disease patients. There were 11 with just liver disease and a further 13 with additional neurologic symptoms. Those in the neurologic group were compared to the hepatic group and found to have mild to moderate olfactory impairment. Olfactory function was unrelated to longterm penicillamine treatment. The olfactory scores correlated with neither MRI nor fluorodeoxyglucose PET scans. The authors suggested that the microsmia related to “specific functions of the basal ganglia in the processing of odorous stimuli.” Although pathologic studies of the OB in Wilson’s disease appear to be lacking, there is evidence of amygdala pathology, suggesting a potential limbic cause of the disorder (Shimoji et al., 1987). There is one report of “olfactory paranoid syndrome” (possibly similar to the olfactory reference syndrome) in a Japanese patient with Wilson’s disease associated with idiopathic thrombocytopenic purpura. The psychiatric and
CHEMOSENSORY DYSFUNCTION IN NEURODEGENERATIVE DISEASES physical symptoms recovered after treatment with penicillamine (Sagawa et al., 2003).
TASTE DYSFUNCTION As noted in the introduction, taste is often confused with smell. Thus, most people who complain of ‘taste’ disorders during eating are really reporting loss of flavor secondary to damage of the olfactory receptors. During deglutition, volatiles from foodstuffs enter the nasopharynx to activate the olfactory receptors. When such receptors are compromised, the flavor of such foodstuffs is diminished. Compared to olfaction, measures of taste function are available only for a few neurodegenerative diseases.
COGNITIVE DISORDERS Alzheimer’s disease The majority of studies that have assessed taste in patients with dementia have focused on AD. Although findings are mixed, there is evidence that AD impacts taste function although the effects are modest, and controls for nontaste task-related elements of such testing are generally lacking. In a pioneering study, Waldton (1974) assessed taste function in 66 women who had a diagnosis of “senile dementia” verified at autopsy. Taste dysfunction was noted early in the disease course and progressed over a 3-year follow-up period. Since this early study, several reports of decreased taste function have appeared in connection with AD or its precursor, minor cognitive impairment (MCI). Schiffman et al. (1990) measured quinine and glutamic acid thresholds on 30 patients with probable AD, 8 with possible AD, 16 with dementia due not to AD, and 12 healthy controls of similar age. Although thresholds for quinine (bitter) did not differ among the groups, glutamic acid thresholds were elevated in all groups relative to controls, suggesting lack of specificity to AD. This same phenomenon was noted 12 years later by this same group in 33 subjects from multiplex families who were genetically at risk for AD (Schiffman et al., 2002). Moreover, the at-risk subjects performed worse than the controls on a measure of taste memory—an index that declined over the next 18 months. Lang et al. (2006a) found lower taste identification scores in 52 demented (24 AD) than in 52 nondemented older persons, with no differences between the AD and non-AD demented subjects, again suggesting lack of specificity. The nonAD demented group comprised 2 persons with Pick’s disease, 10 with cerebrovascular disease, 3 with Lewy body dementia, 3 with hydrocephalus, 6 with PD, and one each with multiple system atrophy, cardiovascular degeneration, tick-borne encephalitis, and multiple sclerosis. The severity of dementia correlated with the taste
test results. More recently, Steinbach et al. (2010) assessed taste of each side of the tongue in 29 subjects with MCI, 30 with AD, and 29 healthy controls. Taste was assessed using filter paper strips impregnated with various concentrations of sucrose, citric acid, sodium chloride, and quinine. Relative to controls, the MCI and AD patients exhibited significant reduction in taste function, but the MCI and AD test scores did not differ. Reflecting other studies on this topic, it is not clear whether the dementia-related deficit represents a true taste effect or confounds by the taste procedure itself. In contrast to the above are two negative reports in AD. Using a whole-mouth swish and spit tests, Koss et al. (1988) found no evidence of taste (or olfactory) detection threshold deficits in 10 AD patients relative to 10 healthy controls. Similarly, Murphy et al. (1990) found no difference in whole-mouth sucrose taste detection threshold scores between 20 AD patients and 20 elderly controls. Despite some conflicting reports the evidence overall favors a mild and slowly progressive disorder of taste in AD.
MOTOR DISORDERS Amyotrophic lateral sclerosis Altered taste is sometimes mentioned by patients with ALS, in some cases before symptom onset. In a case study, two ALS patients reported initial symptoms of a persistent bitter or metallic taste. In one case, this was primarily affecting the posterior tongue (Petzold et al., 2003). Spatial gustatory testing using sucrose, sodium chloride, citric acid, and quinine did not reveal hypogeusia for any quality, although both patients noted a bitter dysgeusia throughout the testing. The dysgeusia antedated the diagnosis and neither subject was taking Riluzole, a standard ALS medication that may impair taste function. In one study, taste loss was reported by three of four middle-aged male patients with a novel form of ALS, Facial onset sensori–motor neuropathy (FOSMN) (Vucic et al., 2006). In one of these cases, trigeminal sensory loss occurred 5 years before the disease with spread of sensory loss over the face, head, upper limbs, and trunk. At autopsy, there was neuronal loss in the solitary tract nucleus. In another study, “complete loss of taste and smell” was noted in an individual with FOSMN, but involvement of the solitary tract nucleus at postmortem was not mentioned (Ziso et al., 2015). No chemosensory measurements appear to have been undertaken in any patient. In one personal case of FOSMN (CHH), symptomatic taste impairment preceded facial sensory symptoms by about a decade, suggesting that ageusia might be a useful biomarker of future disease.
R.L. DOTY AND C.H. HAWKES
PD and variants CLASSIC PD The impact of PD on taste appears to be less salient than its effect on olfaction, and some question whether taste deficits, per se, are even present in PD. Lewy body changes can be demonstrated in the submandibular glands (Del Tredici et al., 2010), a process that might influence the consistency of saliva and thereby taste appreciation. There is no strong evidence that Lewy body pathology exists within brainstem regions involved with taste, i.e., the nucleus tractus solitarius (Braak and Del, 2009), although such pathology does occur in the anterior insular / operculum region, which is an important relay station for fibres travelling to the orbitofrontal cortex. These are animal and fish studies! Paper is not concerned with taste. In theory, taste impairment infers pathology in the anterior insular zone, an area that is affected only in the later stages of disease (Braak stage 5). Sienkiewicz-Jarosz et al. (2005) examined taste identification ability, and both taste intensity and pleasantness ratings to citric acid, NaCl, quinine, and sucrose in 30 medicated PD patients and 33 healthy controls. The tastants were presented to the tip of the tongue on filter paper strips. Electrogustometric thresholds were also obtained from the same tongue region. Relative to the controls, the PD patients found a 0.025% concentration of quinine to be more intense (P < 0.04) and exhibited lower electrogustometric taste thresholds (P < 0.001). In a subsequent study, these investigators found a 1% solution of sucrose presented by syringe to the anterior tongue was rated as more intense by the PD patients than by the controls in a manner similar to that previously observed for quinine (SienkiewiczJarosz et al., 2013). The electrical threshold finding was not replicated. In contrast to the work of Sienkiewicz-Jarosz et al., other studies report decreased taste function in PD patients. In one investigation, 25 PD patients and 16 normal controls rated the pleasantness of six ascending suprathreshold concentrations of sucrose on a rating scale (Travers et al., 1993). The average PD preference curve was a monotonically increasing function, unlike that of the controls, which was an inverted U-shape. It is conceivable that the U-shape occurred because the higher sucrose concentrations were perceived as weaker and therefore not perceived as less pleasant. Lang et al. (2006b) compared 10 individuals with a Parkinson syndrome with 42 assorted patients without dementia. The PD group had more difficulty in identifying sour and salty sensations from citric acid and NaCl embedded on filter paper strips. This work had two limitations. First, the comparisons were confounded by varying degrees of dementia
within the Parkinson syndrome group, which comprised six subjects with PD, one with PD and AD, and three with LBD. Second, the controls were also heterogeneous, with some having had prior “minor strokes” and others having vascular risk factors for stroke. More recent reports also suggest PD-related decrements are present in taste function. Moberg et al. (2007) found only 24% of 56 PD patients were phenylthiocarbamide (PTC) tasters, as compared to 75% of 20 healthy controls, suggesting a decrement in bitter taste function. Shah et al. (2009), using electrogustometry, found that 27% of 75 PD patients had, relative to 74 age- and sex-matched controls, elevated taste thresholds on both the front and back of the tongue. The thresholds were not impacted by PD-related medications. Kim et al. (2011) noted a decrease in the ability to identify tastants in 15 women with PD relative to 14 female controls. However, the magnitude was not large and the deficit was only significant when data were combined across sweet, sour, bitter, and salty tastant trials. Cecchini et al. (2014) reported that 61 PD patients were less able, on average, than 66 controls to identify accurately the salty taste of NaCl presented on a piece of filter paper. This was not the case for sweet, sour, and bitter tasting stimuli, and no deficit was evident when the NaCl was sprayed into the mouth. In the most comprehensive study to date, Doty et al. (2014) administered both whole mouth and regional taste tests to 29 early-stage PD patients and 29 age-, sex- and race-matched controls. The tests employed multiple concentrations of sucrose, citric acid, caffeine, and sodium chloride. The left and right sides of the anterior tongue were also tested using electrogustometry. The PD patients were tested twice in counterbalanced order— once while on and once while off dopamine-related medications. While the whole-mouth taste identification test scores were nominally lower in the PD group than in the controls (for all four taste stimuli), the intensity ratings for the weaker concentrations of all stimuli, except caffeine, tended to be higher in the PD patients than in the controls. In accord with the findings of SienkiewiczJarosz and associates, the PD subjects tended to rate the stimuli as more intense on the anterior tongue and less intense on the posterior tongue relative to the controls. No meaningful relations were found between taste test scores and UPDRS scores, L-DOPA medication equivalency values, or [99mTc]TRODAT-1 SPECT imaging of dopamine transporter uptake within the striatum and associated regions. The authors speculated that PD-related damage to CN IX may release central inhibition on CN VII at the level of the brainstem, resulting in the observed enhancement of taste intensity on the anterior tongue.
CHEMOSENSORY DYSFUNCTION IN NEURODEGENERATIVE DISEASES
This review examined the influences of a range of neurodegenerative diseases on the abilities to smell and taste. Additionally, it evaluated the extant literature regarding the pathophysiology responsible for the chemosensory deficits. It is apparent that olfaction is markedly affected by several neurodegenerative conditions. Although many investigations highlight altered taste function, in terms of sweet, sour, bitter, and salty perception, the breadth of taste studies is severely limited, chiefly because practical taste tests applicable in the clinic have not been widely available. For both chemosensory modalities, not all studies are in agreement. Interactions between environmental and genetic factors appear to be at play for the sense of smell, although the underlying causes or their relative degrees of impact are still not well understood. Recent reports that some pathologic proteins may move across synapses leads to new concepts of olfactory chemosensory system involvement, particularly in light of evidence that viruses and nanoparticles may induce neurodegenerative disease pathologies. Despite the shortcomings of current studies, they represent a major revolution in quantifying chemosensation. Undoubtedly a better understanding of the chemosensory deficits of neurodegenerative diseases will be forthcoming.
Familial dysautonomia (FD), also known as Riley-Day syndrome, Hereditary Sensory and Autonomic Neuropathy type 3, is a rare autosomal recessive disorder due to mutations in the IKBKAP gene located on 9q. In addition to defective lacrimation, vasomotor instability, and altered pain and temperature perception, features of FD include impaired taste and lack of, or poorly formed, fungiform and circumvallate papillae (Henkin and Kopin, 1964; Smith and Dancis, 1964; Pearson et al., 1970). Filiform papillae are present (Henkin and Kopin, 1964). Among the first to assess taste function in FD were Smith and Dancis (1964). They presented 3 different concentrations of sucrose and 3 different concentrations of hydrochloric acid (HCl) to 11 FD subjects ranging in age from 7 to 13 years. The FD patients were only able to discern the highest of the three concentrations of each tastant. However, it is not clear whether this was based on taste or other properties of the stimuli (e.g., viscosity, stringency). A more sophisticated study of taste in FD was performed by Henkin and Kopin (1964). These investigators assessed detection and recognition thresholds for sucrose, NaCl, HCl, and urea, in six FD patients over an 18-month period. Markedly elevated detection and recognition thresholds were observed in their six subjects for all four taste stimuli. Interestingly, subcutaneous, but not topical, application of methacholine brought the taste thresholds for NaCl back into the normal range in two subjects who were tested. Apparently, other tastants were not similarly evaluated. This suggested to the authors that the gustatory deficit of FD may involve cholinergic processes in accord with a FD-related heightened pupillary response to local application of methacholine and other excessive cholinergic responses to this drug (e.g., sweating). Subsequently, Gadoth et al. (1997) reported that 9 FD patients had less ability than 15 healthy controls to identify the quality of each of two concentrations of sucrose, NaCl, and quinine (bitter). The rate of recognition of sour stimuli (citric acid) was similar in the two groups. Negative facial responses were made to higher concentrations of nonsugar stimuli in both groups, with somewhat more attenuation in the FD patients. Based on these findings, the authors proposed that FD was associated with a specific rather than general dysgeusia. They noted considerable variability in their test measures, which may reflect such factors as nongustatory elements of the taste stimuli, the involvement of foliate papillae, and the nature of their test procedures.
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