Antje Hähner

Clinical Significance of Results from Olfactory Testing

Background: Although widely used in healthy subjects and patients with olfactory loss, the significance of changes of scores from validated olfactory tests is unknown.

Biopsies of olfactory epithelium in patients with Parkinson's disease.

Parkinsons disease (PD) is a neurodegenerative disorder involving several neuronal systems. Impaired olfactory function may constitute one of the earliest symptoms of PD. However, it is still unclear to what degree changes of the olfactory epithelium may contribute to dysosmia and if these changes are different from those of other hyposmic or anosmic patients. This study aimed to investigate the hypothesis that olfactory loss in PD is a consequence of specific PD‐related damage of olfactory epithelium. Biopsies of 7 patients diagnosed with PD were taken. Six patients with PD were hyposmic, one anosmic. As non‐PD controls served 9 patients with hyposmia, 9 with anosmia, and 7 normosmic individuals. Further, nasal mucosa of 4 postmortem individuals was investigated. Immunohistochemical examinations were performed with antibodies against olfactory marker protein (OMP), protein gene product 9.5 (PGP 9.5), beta‐tubulin, (BT), proliferation‐associated antigen (Ki 67), the stem cell marker nestin, cytokeratin, p75NGFr, and α‐synuclein. Most of the biopsy specimens exhibited irregular areas of olfactory‐like, dysplastic epithelium positive for either PGP 9.5 or BT, but negative for OMP. No major histochemical differences in either the expression or distribution of these proteins were observed in the olfactory epithelium of patients with PD compared with controls. Reverse transcription PCR (RT‐PCR) data indicated mRNA for OMP in almost all subjects, independently of their olfactory performance. These data support the idea that olfactory loss in Parkinsons disease is not a consequence of damage to the olfactory epithelium but rather results from distinct central‐nervous abnormalities.

Olfactory Dysfunction: Common in Later Life and Early Warning of Neurodegenerative Disease

BACKGROUND Disturbances of smell and taste are common. About 5% of the general population have anosmia (absence of the sense of smell). Olfactory dysfunction can markedly impair the quality of life. METHODS Review of pertinent literature retrieved by a selective search. RESULTS In recent years, simple and reliable tests of the sense of smell have been introduced in otorhinolaryngology. Olfactory testing has become a new focus of attention in neurology as well, mainly because many patients with neurodegenerative diseases-including the majority of those with Parkinsons or Alzheimers disease-have olfactory loss early on in the course of their disorder. Olfactory dysfunction is thus regarded as an early sign of neurodegenerative disease that may allow a tentative diagnosis to be made years before the motor or cognitive disturbances become evident. As for the treatment of olfactory loss, anti-inflammatory drugs and surgery can help in some cases, and olfactory training can lead to significant improvement of post-viral olfactory deficits. CONCLUSION Olfactory dysfunction is common and becomes more common with advancing age. It is increasingly receiving attention as an important sign for the early diagnosis and the differential diagnosis of neurodegenerative disorders.

Background sound modulates the performance of odor discrimination task.

Even though we often perceive odors in the presence of various background sounds, surprisingly little is known about the effects of background sound on odor perception. This study aimed to investigate the question whether background sound can modulate performance in an odor discrimination task. In Experiment 1, participants were asked to perform the odor discrimination task while listening to either background noise (e.g., verbal or non-verbal noise) or no additional sound (i.e., silent condition). Participants’ performance in the odor discrimination task was significantly deteriorated in the presence of background noise compared with in the silent condition. Rather, the detrimental effect of verbal noise on the task performance was significantly higher than that of non-verbal noise. In Experiment 2, participants were asked to conduct the odor discrimination task while listening to either background music (Mozart’s sonata for two pianos in D major, K448) or no additional sound (silent condition). Background music relative to silent condition did not significantly alter the task performance. In conclusion, our findings provide new empirical evidence that background sound modulates the performance in an odor discrimination task.

Influence of background noise on the performance in the odor sensitivity task: effects of noise type and extraversion.

Recent research demonstrated that background noise relative to silence impaired subjects’ performance in a cognitively driven odor discrimination test. The current study aimed to investigate whether the background noise can also modulate performance in an odor sensitivity task that is less cognitively loaded. Previous studies have shown that the effect of background noise on task performance can be different in relation to degree of extraversion and/or type of noise. Accordingly, we wanted to examine whether the influence of background noise on the odor sensitivity task can be altered as a function of the type of background noise (i.e., nonverbal vs. verbal noise) and the degree of extraversion (i.e., introvert vs. extrovert group). Subjects were asked to conduct an odor sensitivity task in the presence of either nonverbal noise (e.g., party sound) or verbal noise (e.g., audio book), or silence. Overall, the subjects’ mean performance in the odor sensitivity task was not significantly different across three auditory conditions. However, with regard to the odor sensitivity task, a significant interaction emerged between the type of background noise and the degree of extraversion. Specifically, verbal noise relative to silence significantly impaired or improved the performance of the odor sensitivity task in the introvert or extrovert group, respectively; the differential effect of introversion/extraversion was not observed in the nonverbal noise-induced task performance. In conclusion, our findings provide new empirical evidence that type of background noise and degree of extraversion play an important role in modulating the effect of background noise on subjects’ performance in an odor sensitivity task.

A brain-lesion pattern based algorithm for the diagnosis of posttraumatic olfactory loss.

BACKGROUND Brain areas processing olfactory information exhibit functionally relevant morphological dynamics. This suggests the exploitation of anatomical information in the diagnosis of an olfactory dysfunction. Following previous identifications of olfactory eloquent areas such as the olfactory bulbs and tracts, we focused at a brain-morphology based algorithm for establishing the diagnosis of olfactory loss following brain injury. METHODOLOGY Forty-one patients with a history of head trauma dated back 40 ± 39 months, and additional 23 patients without head trauma, were assessed for damages in 11 olfaction-relevant brain areas using magnetic resonance imaging (MRI). Olfactory function was derived from the use of a standardized, reliable and validated olfactory test. An olfactory diagnostic algorithm was derived following classification and regression tree analysis of the brain lesion pattern. RESULTS Subjects were assigned to olfactory diagnoses of anosmia, hyposmia or normosmia. These diagnoses were predictable at an accuracy of 62.3 % from the degree of damage in the olfactory bulb and in the left temporal lobe pole. The main diagnosis algorithm addressed the presence of anosmia, which could be predicted from the degree of damage in these brain areas at an accuracy of 81.3 %. CONCLUSIONS We independently reproduced previously identified brain regions in which morphological damage is associated with olfactory loss. Based on this reproduction, an algorithm was developed for the diagnosis of anosmia from central-nervous damage. Thus, we introduce a morphological component to the olfactory diagnosis that specifically addresses clinical cases of olfactory loss following head trauma.

Selective hyposmia in Parkinson's disease?

Dear Sirs,In 1993 Hawkes and Shephard [1] presented data onrelative selectivity of the smell defect in Parkinson’sdisease (PD). By using the University of Pennsylvaniasmell identification test (UPSIT) they demonstrated themost significant result for pizza and wintergreen in dis-criminating PD patients from healthy controls, with a90 % sensitivity and 86 % specifity. They discussed thepossibility of a congenital or acquired selective hyposmiain PD and recommended selective olfactory testing for PDdiagnosis. Currently, the practical benefits of selectivetesting results are disputed. Whereas Hawkes reported ontwo UPSIT odours, Double et al. [2] found that fivespecific odors (gasoline, banana, pineapple, smoke, andcinnamon) of the short version of the UPSIT, the B-SIT,discriminate PD patients most effectively, while pizza,mint, and licorice were optimal in the study by Silveira-Moriyama et al. [3]. In a German study [4], however,cinnamon was found to be ineffective for PDdiscrimination. In the work by Doty et al. [5], no evi-dence of a pattern of PD-related smell loss to specificUPSIT items was found. These data suggest that selectivetesting results mainly rely on the olfactory test anddescriptor items used as well as the study population andcultural differences, but no systematic studies are avail-able comparing odour identification in PD with hyposmiadue to other causes.We investigated 35 PD patients (mean age 64 years,range 44–82 years, 22/13 male/female) in comparison to35 patients with post-viral (n = 16), posttraumatic(n = 5), sinonasal (n = 7), or idiopathic (n = 7) olfactoryloss (mean age 59 years, range 24–81 years, 18/17 male/female) to determine whether odour identification in PDdiffers from that in non-Parkinsonian hyposmia. With asample size of 35 in each group, a Chi square test with a0.05, two-sided significance level had an 80 % power todetect a sufficient difference between the two patientgroups. For overall olfactory assessment, we used thevalidated 16-item ‘‘Sniffin

Olfactory function in patients with hyposmia compared to healthy subjects - An fMRI study.

BACKGROUND Individuals with hyposmia, or the partial loss of smell, represent a large sector (15 %) of the population that is likely to grow with the current aging population; however, our understanding to how hyposmics centrally process odors is still not clear. One popular non-invasive tool for in vivo imaging of biological activity among human brains has been function magnetic resonance imaging (fMRI) which uses blood-oxygenation level dependent (BOLD) signal as an indirect measurement. Therefore, the aim of this study was to understand differences in olfaction processing between patients with hyposmia and healthy controls using functional magnetic resonance imaging (fMRI). METHODOLOGY Eleven hyposmic and 12 healthy, normosmic subjects were exposed to two different food-related odors (coffee and peach) during a block-designed fMRI session. Additionally, odor perception qualities were rated for each odor throughout the scanning session. RESULTS The activations of the normosmic group were localized in typical olfactory areas (insula, orbitofrontal cortex [OFC], limbic system and amygdala). The hyposmic group showed similar regions of activation (insula, OFC, limbic system), however, less activation was found in the amygdala, left anterior cingulate and right OFC, but higher activation was shown in the right parahippocampal and both the left and right posterior cingulate gyrus which are assumed to play an important role in the processing and remembrance of memories. CONCLUSIONS These results indicate similar central olfactory processing among groups, yet subjects with partial loss may attempt to compensate smell impairment with odor memory or higher motivation to smell.

Drug-target based cross-sectional analysis of olfactory drug effects

BackgroundDrug effects on the human sense of smell attract increasing interest, yet systematic evidence from controlled studies is sparse. The present cross-sectional approach to olfactory drug effects made use of the recent developments in informatics, knowledge discovery, and data mining allowing connecting drug-related information from humans with underlying molecular drug targets.MethodsIn this prospective cross-sectional study, n = 1008 outpatients at a general practitioner were enrolled. All currently taken medications were obtained, and olfactory function was assessed by means of a clinically established 12-item odor identification test. The association between the patients’ sense of smell and the administered medications was based (i) on the active pharmacological substances and (ii) on the molecular targets queried from the publicly accessible DrugBank database.ResultsOf the 168 different substances, six were taken sufficiently often to be analyzed. The administration of levothyroxine was associated with a higher olfactory score (p = 0.033). For the 168 drugs, 323 different targets could be queried. Thirty-one gene products were addressed sufficiently often to be analyzed. Besides agonistic targeting of thyroid hormone receptors (genes THRA1, THRB1) agreeing with the above result, antagonistically targeting the adrenoceptor alpha 1A (gene ADRA1A) by several unrelated medications was associated with a significantly higher olfactory score (p = 0.012).ConclusionsThe identified drug effects on olfaction are both biologically plausible based on supportive information from basic science studies. The novel molecular target-based approach suggested clear advantages over the classical drug or drug class-based approach. It increased the analyzable data volume fivefold and provided plausible hypotheses about mechanistic drug effects opening possibilities for drug discovery and repurposing.

Olfaction in People with Down Syndrome: A Comprehensive Assessment across Four Decades of Age

Background Down syndrome (DS) shows neuropathology similar to Alzheimer disease, which presents olfactory impairment. Previous work showed olfactory impairment in DS, but a comprehensive evaluation of olfactory function in DS is lacking. Methods We investigated a large number (n = 56; M = 31, F = 25) DS participants (age range18-57y) using the “Sniffin’ Sticks” Extended test. This comprises three subtests (threshold, discrimination, and identification) yielding a global score (TDI) defining normosmia, hyposmia, and functional anosmia. To the best of our knowledge, this is the second largest group of DS people investigated for olfactory function ever. Age- and sex matched euploid individuals (n = 53) were the control. Results In DS, TDI was lower (16.7±5.13 vs. 35.4±3.74; P<0.001), with DS people performing worse in any subtests (P<0.001 for all); 27 DS participants showed functional anosmia (i.e., TDI<16). In DS, age was weakly and negatively correlated with TDI (r = -0.28, P = 0.036) and identification (r = -0.34, P = 0.012). When participants were stratified in young adults (18-29y) and older adults (30-61y), a significant effect of age was found for identification in both DS (young adults, 8.3±2.58; older adults, 6.9±2.99; P = 0.031) and control (young-adult, 14.3±1.18, older adult, 13.0±1.54; P = 0.016). Conclusion Olfactory function is overall severely impaired in DS people and may be globally impaired at relatively young age, despite of reportedly normal smell. However, specificity of this olfactory profile to DS should be considered with some caution because cognition was not evaluated in all DS participants and comparison with a control group of non-DS individuals having cognitive disabilities was lacking. Further study is required to longitudinally assess olfactory dysfunction in DS and to correlate it with brain pathology.