Prevalence of Olfactory Loss in Parkinson Disease

The association between olfactory dysfunction and PD was noted more than 30 years ago.9 Virtually all studies performed since then have shown olfactory disturbances in patients with PD. The reported prevalence of olfactory dysfunction in PD, however, ranges from 45 and 49% in the pioneering studies of Ansari and Johnson9 and Ward et al,2 respectively, up to 74% in the work of Hawkes et al,3 or as high as 90% in a study published by Doty et al.1 In a recent multicenter study10 using a comprehensive testing method in a large sample of patients with PD (n = 400) from three independent populations, the prevalence of olfactory dysfunction in people with PD was greater than previously reported. More than 96% of patients with PD were found to present with significant olfactory dysfunction compared with young, normosmic patients. When using age-dependent normative criteria, 74.5% of this study population was diagnosed with olfactory loss ( Fig. 11.1 ). Furthermore, of the patients with PD with smell loss, more than 80% were functionally anosmic or severely hyposmic regardless of the olfactory test being used for diagnosis. These data also confirmed numerous previous studies regarding a lack of correlation between olfactory loss and both duration of disease1,3,11 and the clinical severity of PD, as measured by means of the Hoehn and Yahr scale and the Unified Parkinson Disease Rating Scale (compare with ref. 12)—although some studies found a correlation between the severity of PD and certain measures of olfactory function (namely latencies of olfactory event-related potentials13 or results from an odor discrimination task).14 However, this inability to demonstrate a relationship between disease duration and olfactory loss may be partially owing to a “basement effect” of olfactory dysfunction in patients with PD with moderate-to-severe disease, and if only patients with early PD are assessed it might be possible to demonstrate a worsening function with disease duration. With regard to olfactory function, no major differences were found among subtypes of PD (tremor-dominant PD, akinetic-rigid PD, or mixed-type PD). While this confirms previous observations in small sample sizes,15,16 the present findings are in contrast to reports by Stern and colleagues,11 who reported significantly better odor identification scores in patients with tremor-predominant PD (n = 40) than in patients with postural instabilitygait disorder–predominant PD (n = 23). While differences among studies may be due to the type of olfactory test used, sample size, normative data, and age distribution (which varied among these investigations), available data allow the conclusion that olfactory dysfunction is a highly reliable symptom of the disease. This concurs with the results of a case–control study of 90 patients with PD and healthy controls by Bohnen et al,17 who found that the accuracy of smell testing in PD diagnosis outweighs the accuracy of motor test batteries and nonmotor tests of depression, and anxiety.

Olfactory Dysfunction in Early Parkison Disease Diagnosis

Patients with PD frequently report a reduction in their sense of smell that occurs a few years prior to the onset of motor symptoms. Support for the existence of a prodromal phase of PD, including a long premotor phase, comes from imaging, neuropathology, and various clinical or epidemiological surveys. The best evidence for a long premotor phase is derived from large prospective studies examining olfaction, constipation, rapid eye movement (REM) sleep behavior disorder, and depression.18–20 Estimates for the duration of the prodrome range from 2 to 50 years depending on the symptom, duration of follow-up, accuracy of diagnosis, and individual variation.

However, patients’ lack of awareness of smell deficits may account for the inconsistent results described in retrospective surveys. In two small studies,21,22 upon questioning prior to olfactory testing, 24 and 39% of respondents indicated an awareness of decreased olfactory function which actually preceded their diagnosis of PD. Several studies could show evidence of olfactory dysfunction in untreated, newly diagnosed patients.1 A plethora of evidence from recent studies supports the view that deficits in the sense of smell may precede clinical motor symptoms by years. A study by Ponsen et al23 of 361 asymptomatic relatives of patients with PD selected 40 relatives with the lowest olfactory performance. Within 2 years of follow-up, 10% of these first-degree relatives of patients with PD with significant olfactory loss developed clinical PD. In a follow-up study 5 years from baseline testing, five relatives had developed clinical PD as defined by the United Kingdom Parkinson′s Disease Society Brain Bank Diagnostic Criteria for Parkinson′s Disease. Initial clinical (motor) symptoms appeared 9 to 52 months (median 15 months) after baseline testing. Poorer performance on each of three olfactory processing tasks was associated with an increased risk of developing PD within 5 years.

In 2007, Haehner et al24 published data on a clinical follow-up of 30 patients diagnosed with idiopathic olfactory loss. Four years from baseline, 7% (n = 2) of the individuals with idiopathic olfactory loss who were available for follow-up examination (n = 24) had newly developed clinical PD symptoms. Altogether, 13% (n = 4) of the patients presented with PD-relevant abnormalities of the motor system. The results indicated that unexplained olfactory loss may be associated with an increased risk of developing PD-relevant motor symptoms.

By contrast, authors of a twin study25 concluded that smell identification ability may not be a sensitive indicator of future PD, even in a theoretically at-risk population. This was based on the fact that patients who subsequently developed PD had no evidence of significant smell loss when they were initially tested. However, as pointed out by the authors themselves, the reason for this negative finding might lie in the very long delay of 7 years between baseline assessment and follow-up visit. The initial test may have been too early for their subjects to have developed signs of smell dysfunction.

This is in accordance with the results of a large longitudinal study by Ross and colleagues.26 They assessed olfactory function in 2,267 elderly men in the Honolulu Heart Program and found an association between smell loss and future development of PD. They came to the conclusion that impaired olfaction can predate PD by at least 4 years and may be a useful screening tool to detect those at high risk for development of PD in later life. However, this relationship appears to weaken beyond the 4-year period.

Along with quantitative smell loss, idiopathic phantosmia has also been proposed to herald PD. Several case reports show that some patients have experienced phantosmia very early in the course of the disease.27,28 According to a recent study by Landis et al,29 however, idiopathic phantosmia as an early sign of PD probably remains a rather exceptional presentation and the overwhelming majority of people with idiopathic phantosmia will not develop PD.

Recent data on olfactory loss as an early PD symptom are compatible with predictions made on the basis of neuropathological investigations. Braak et al30 ( Fig. 11.2 ) describe involvement of olfactory pathways and lower brainstem regions before nigrostriatal pathways are affected, which might cause early nonmotor symptoms. Documented pathological alterations in the olfactory bulb (OB) include neuronal loss and the accumulation of Lewy bodies and Lewy neurites within the intrabulbar portions of the anterior olfactory nucleus ( Fig. 11.3 ). Other layers of the OB also exhibit accumulation of Lewy bodies and Lewy neurites to a lesser degree. Indeed, it has been suggested that the olfactory system is an ideal location to try to better understand the pathophysiology of Lewy neurodegeneration.31 In another attempt to understand the etiology of olfactory dysfunction in PD, Huisman et al32 found an increase of periglomerular dopaminergic neurons in the OB in patients with PD ( Fig. 11.3 ). They interpreted their finding within the context of a possible compensatory mechanism in response to the loss of dopaminergic neurons in the basal ganglia. This concurs with their observation that dopaminergic neurogenesis in the glomerular layer tripled after nigrostriatal lesioning and, consistent with this finding, the total number of tyrosine hydroxylase positive cells increased.33 However, results of a follow-up study34 indicated a gender-related change, namely that the number of dopaminergic cells in the OB of both male and female patients with PD equals that of healthy males of the same age group. The authors therefore concluded that the hyposmia in patients with PD cannot simply be ascribed to dopamine in the OB. In another attempt to explain the mechanism of olfactory dysfunction in PD, Sobel and colleagues demonstrated a deficit in the magnitude of sniffing in patients with PD and reported small improvements in odor identification performance with forced vigorous sniffing.35

Several prospective studies currently underway will help to determine if olfactory loss may become a useful biomarker of PD development within populations at risk for PD. For instance, the current Parkinson-associated risk syndrome study,36 which is examining the use of olfactory dysfunction and dopaminergic functional imaging as predictors of risk in first-degree relatives of patients with PD, will advance our understanding of early PD presentation.

Olfactory Dysfunction in the Differential Diagnosis of Parkinsonian Syndromes

Numerous studies suggest that olfactory disturbances in PD may have diagnostic utility for the differentiation of PD from other movement disorders. Wenning et al37 presented data suggesting that olfactory function is differentially impaired in distinct parkinsonian syndromes. They reported a preserved or mildly impaired olfactory function to be more likely in atypical parkinsonism such as multiple system atrophy (MSA), progressive supranuclear palsy (PSP), or corticobasal degeneration (CBD), whereas pronounced olfactory loss appeared to suggest PD. In a study on 50 patients with parkinsonian syndromes, Müller et al21 also found evidence for olfactory loss in MSA, but little or no olfactory loss in (the few investigated) patients with PSP and CBD. With regard to the differentiation between MSA and PD, a combined odor thresholds, odor discrimination, and odor identification (TDI) score cut-off of 19.5 had a sensitivity of 78% and a specificity of 100%. When the TDI score cut-off was increased to 24.8, sensitivity in this sample was 100% while specificity fell to 63%. This moderate specificity seems to be the limiting parameter for diagnostic purposes. A recent American Academy of Neurology practice parameter on the diagnosis and prognosis of PD concluded that olfactory testing “should be considered” to differentiate PD from PSP and CBD but not from MSA.38 Furthermore, Liberini et al39 reported a significant olfactory impairment in Lewy body disease (LBD), which does not allow differentiation from PD. In a sample of 116 patients with mild LBD, mild AD, and mild cognitive impairment and controls, Williams et al40 describe even more marked olfactory impairment in patients with mild dementia with Lewy bodies than in those with mild AD. This lends significance to the role of Lewy body pathology in olfactory dysfunction, which would be in line with the observation that patients with nondegenerative causes of parkinsonism, such as vascular parkinsonism,41 present with preserved smell function. There is also evidence for less olfactory disturbance in familial parkinsonism. In PARK2 PD, the olfactory sense is relatively well preserved, whereas PARK1 PD subjects are hyposmic ( Table 11.1 ; reviewed in ref. 4). Two studies examined olfactory dysfunction in autosomal recessive PARK6 PD and found impaired olfactory function in symptomatic homozygotes as well as asymptomatic heterozygotes.42,43 Recent data44 suggest that patients with PARK8 PD present with impaired olfactory identification while asymptomatic carriers show normal olfactory performance, although the studies have included relatively few subjects (reviewed in ref. 45).

Results from studies of secondary parkinsonism also indicate a relationship between parkinsonian symptoms and olfactory dysfunction. Krüger et al46 found an association between medication-induced parkinsonism and olfactory dysfunction in patients with psychotic depression treated with dopamine D2 receptor–blocking neuroleptic drugs. Here, the severity of motor symptoms positively correlated with the degree of olfactory dysfunction, which might indicate patients with latent basal ganglia dysfunction of neurodegenerative etiology. Similar to the results seen in drug-induced parkinsonism, a recent study of patients with Wilson disease revealed that those with neurological symptoms showed significant olfactory dysfunction compared with those with hepatic symptoms.47 Individuals who were more severely neurologically affected also presented with more pronounced olfactory deficits. Based on these observations, olfactory testing should not be considered to differentiate PD from these specific conditions by itself. However, olfactory testing can inform the differential diagnosis of parkinsonism in the same way that many other examinations, including deep tendon reflex, extraocular movement, and cerebellar function assessments, cannot distinguish parkinsonian disorders in isolation, but can be helpful in the context of a complete history and physical examination. In particular, olfactory dysfunction assessment can be important in cases where patients present with parkinsonian features but preserved olfaction, when it appears to be valid to question a diagnosis of PD.