Spinocerebellar ataxia type 2 olfactory impairment shows a pattern similar to other major neurodegenerative diseases
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- Velázquez-Pérez, L., Fernandez-Ruiz, J., Díaz, R. et al. J Neurol (2006) 253: 1165. doi:10.1007/s00415-006-0183-2
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Olfactory function is affected in different neurodegenerative diseases. Recently, it has been found that some hereditary ataxias are also associated with significant olfactory impairment. However, the initial findings did not examine the nature of the olfactory impairment associated with these ataxias. In the present article the effect of spinocerebellar ataxia type 2 (SCA2) on olfactory function was studied in 53 SCA2 patients and 53 healthy control subjects from Holguín, Cuba. Several tests were applied to evaluate olfactory threshold, description, identification and discrimination. The results show significant impairment in SCA2 patients on all olfactory measurements, and the pattern of olfactory deficits found suggests that they have much in common with those reported for other neurodegenerative diseases such as Parkinson’s and Alzheimer’s diseases.
Keywordsspinocerebellar ataxiaolfactory functionolfactory impairmentneurodegenerative diseases
One of the most prevalent deficits among different neurodegenerative disorders is a deterioration in olfactory function. [7, 13, 15, 17]. However, olfactory integrity in the hereditary ataxias had not been evaluated until several reports studying the neural pathways of the olfactory system showed a distinct cerebellar participation in olfaction [20, 25]. The convergence of these two fields led to a quick succession of reports showing a significant olfactory impairment in patients with different kinds of cerebellar ataxias [1, 4, 11].
We investigated spinocerebellar ataxia type 2 (SCA2) olfactory deficits . In general, the dominantly-inherited autosomal ataxias are a heterogeneous group of neurodegenerative disorders characterized by progressive ataxia that results from degeneration of the cerebellum and its afferent and efferent connections. SCA2 patients manifest a lack of coordination in gait, limb movements and speech, an early slowing of horizontal eye movements and an early neuropathy [18, 23, 29]. Clinical onset is usually in midlife . Neuropathological analysis has demonstrated severe olivopontocerebellar atrophy early in the course of the disease, progressing to the involvement of the anterior horn, substantia nigra, thalamus and somatosensory pathways[10, 21].
In the present report we address the nature of the olfactory deficit in a large number of Cuban SCA2 patients [18, 22]. We tested olfactory threshold, identification and discrimination and analyzed their relation to the motor and cognitive impairment, the number of CAG trinucleotide repetitions, the age of onset and the years of disease duration.
Subjects and methods
The diagnosis of SCA2 was based on genealogical descent from the founder population, on the disease manifestation with cerebellar ataxia and dysarthria, and on molecular genetic determination of the repeat expansions described elsewhere .
Fifty three patients (28 men and 25 women) ranging in age from 26 to 70 years (mean, 41.8; standard deviation [SD], 11.51), age at onset from 14 to 53 years (mean, 29.56; SD, 10.23), disease duration from 4 to 30 years (mean, 12.54; SD, 6.06), and polyglutamine repeat sizes from 34 to 53 repetitions (mean, 40.38; SD, 3.49) were admitted to the Center for the Research and Rehabilitation of Hereditary Ataxias in Holguín for this study. The clinical assessment was conducted using the International Cooperative Ataxia Rating Scale (ICARS). The Mini-Mental State Examination (MMSE) was also administered to all subjects. A group of 53 healthy unpaid volunteers from Holguín Province (28 men and 25 women) ranging in age from 25 to 72 years (mean, 41.94; SD, 11.6) matched with the patients for gender, age, and smoking history served as controls. Although nasal endoscopy was not performed, subjects with a history of sinus or nasal surgery, head trauma, diabetes, sinusitis, nasal difficulties or any other major disorder that could have affected their olfactory performance, were excluded from the study. The procedures followed were in accordance with the ethical standards of the committees on human experimentation of both the Center for the Research and Rehabilitation of Hereditary Ataxias in Holguín and the Universidad Nacional Autónoma de México. In addition, all subjects gave their informed consent prior to the experiments in accordance with the Helsinki Declaration of 1975, as revised in 1989.
Smell identification test
In order to assess the general odor identification capabilities of subjects, the Spanish version of the University of Pennsylvania smell identification test (UPSIT) was used (Sensonics Inc. Haddon Height, NJ, USA). This test consists of 40 scratch-and- sniff presentations of odorants in a four- alternative forced-choice identification paradigm. The UPSIT has been used to evaluate other populations with neurodegenerative disorders, and it enables comparison with published standardized scores based on large normative data sets . To reduce potential sources of variance, rather than permitting self-administration, the UPSIT was administered to the subjects (both SCA2 and control) by the experimenters. The odorant was scratched by the experimenter and then held to the subject’s nose for smelling.
Two common beverages (instant coffee, Nescafé Clasico, Nestlé; and an orange drink, Clight, Kraft) were presented in 250 ml polyethylene squeeze bottles equipped with a flip-up spout . These odorants were chosen in preference to monomolecular substances to maximize the ecological validity of the stimuli and the ability of the subjects to accurately name them . Ten concentrations of the odorants were prepared in distilled de-ionized water. Pairs consisting of the odorant and the diluent were presented to subjects in a randomized two- alternative forced- choice ascending staircase procedure, and subjects asked to identify the bottle containing the odorant. Five consecutive hits were taken as the criterion for threshold. Subjects could sample each bottle twice, and approximately 10 s elapsed between them giving their response to one pair of stimuli and presentation of the next. Substances were renewed before each session .
Once the threshold was established, testing continued by presenting the target bottles singly in ascending concentration and asking subjects to describe or to try to name the odorant. The lowest concentration which the subject gave a descriptor or name was registered as the perception of odor quality regardless of accuracy.
The lowest concentration at which subjects could then correctly name the odorant was taken as their olfactory recognition capability.
Finally, to determine subjects’ ability to distinguish between suprathreshold concentrations of two similar-smelling odorants, they were given 10 trials in which they were asked to distinguish between the similar-smelling odors of horchata (a drink made of rice, milk and sugar; Frescogary, D’gari) and atole de cajeta (a caramel-flavored, maize-based drink; Maizena). Subjects were presented with three bottles, one of which contained the target (five times horchata and five times atole in randomized order) and were asked to identify the bottle that smelled differently. Again, these substances were chosen to maximize ecological validity and their usefulness in discriminating between different populations .
Simple regression analysis was conducted within the SCA2 patients. Among the 40 UPSIT odorants there were some that were identified in the same proportion by both subject groups, like solvent, leather and pine, which were identified on average by 92% and 91% of the controls and SCA2 patients, respectively. There were other odorants, however, that were disproportionately identified by the two groups, such as orange, chocolate and coconut, that were identified in average by 89% and 58% of the control and SCA2 subjects, respectively. There were no odorants or combinations of odorants that could be used to discriminate reliably between the two populations.
In the patient group there were no significant correlations between UPSIT score and age (r = −0.16, p = 0.13), disease duration (r = 0.01, p = 0.46), or polyglutamine expansion size (r = 01, p = 0.45). Significant UPSIT correlations were found with ataxia score (r = 0.26, p = 0.03), MMSE (r = 0.27, p = 0.03) and smoking history (r = −0.27, p = 0.02). However, after excluding 13 patients with MMSE below 25, the only correlation found in the 40 remaining patients was between UPSIT score and age (r = −0.3, p = 0.03). Excluding the demented subjects did not change the significant difference in UPSIT scores (Mann-Whitney test, Z = −3.72, p < 0.001) between control (with the corresponding 13 subjects excluded) and SCA2 subjects (mean = 31.6; SD = 2.4 and mean = 27.7; SD = 5, respectively). All subsequent analyses were done in the remaining 40 patients and their respective controls.
In the olfactory discrimination task (Fig. 2B) there was a marked impairment in SCA2 patients compared with the control group (Z = −4.44, p<0.01). Whereas control subjects identified the target odorant significantly above chance (≥ 7 trials correct) the SCA2 patients failed to do so. There were no correlations, however, between olfactory discrimination and the other non-olfactory variables.
The present results show a significant impairment in a large population of SCA2 patients in olfactory threshold, quality, identification and discrimination when compared with matched control subjects. These results not only provide a robust corroboration of an initial report on an olfactory deficit in a small SCA2 population of Mexican patients , but more importantly, they investigate more closely the nature of the olfactory deficit of these patients.
There have been three previous studies testing olfactory function in cerebellar ataxic patients. One of these studies reported that eight patients with multiple system atrophy of cerebellar type (MSA-C) and 11 patients with sporadic cerebellar ataxia of unknown etiology had impairments in odor discrimination and identification . The second study tested two patient populations, one Friedreich ataxia group (FRDA) and a combined CNS ataxic group (two SCA2, five SCA3, one SCA7 and five with unidentified cerebral degeneration). Both groups had olfactory deficits measured with UPSIT. The authors suggested that the olfactory problems of the FRDA group could be due to global loss of sensory pathways, while the deficits observed in the CNS ataxic group could reflect cerebellar damage. The third study compared hereditary ataxia patients with Parkinson’s disease and Huntington’s disease patients and reported the olfactory impairment of the former group to be less severe than in the basal ganglia disorders group. Furthermore, the authors analyzed different groups of ataxia patients and found that SCA2, autosomal recessive ataxia and sporadic ataxia patients all showed olfactory impairments, while SCA3 patients were spared. However, the subdivided population was small so further confirmation is needed. Unfortunately, the second study  did not report individual scores for the mixed patient group that included 5 SCA3 patients. The present study follows from the previous studies that tested small numbers of mixed patient populations, and provides compelling confirmation that SCA2 patients have an olfactory impairment.
In general, olfactory capabilities can be measured in three main but not necessarily mutually exclusive domains; sensitivity (threshold), identification and discrimination . Whereas sensitivity depends, at least in part, on the peripheral olfactory system, olfactory identification and discrimination require the participation of central olfactory structures and are considered to be more cognitive tasks . SCA2 patients seem to be affected in all three domains, since they show a significant impairment in olfactory threshold, identification and discrimination. In a comprehensive meta-analysis of olfactory function in Alzheimer’s and Parkinson’s disease , it was found that both patient populations show severe deficits in the three olfactory domains, with no differential olfactory deficits between populations. Although SCA2 patients show a milder deterioration, we found the same pattern of olfactory deficits as in the other two major neurodegenerative diseases, suggesting an intriguing resemblance between the three disorders.
We were especially interested in trying to ascertain if the olfactory deficits correlated with any other variable shown by these patients. Analysis of the whole patient population showed a positive correlation between UPSIT and MMSE scores, which is a general index of cognitive performance. As expected, demented subjects had low UPSIT scores, resulting in a significant correlation between these two measures. When dementia was discarded as a factor, the only UPSIT correlation found was with age, a finding that is consistent with previous reports [9, 24]
Previous findings suggest that damage to the cerebellar circuitry may be responsible for the olfactory impairment in SCA2 patients. Recently, it has been demonstrated that unilateral cerebellar lesions lead to olfactory impairments selective to input from the contralesional nostril , providing further support for a cerebellar role in olfaction. However, since SCA2 is a complex neurodegenerative disease as stated in the introduction, further studies are needed on the integrity of SCA2 patients´ olfactory system. An important finding is the lack of correlation between olfactory impairment and the different disease-related variables. This finding suggests another similarity with the Parkinson’s disease olfactory deficit that also seems to be independent of neurological signs, disease stage or duration . To our knowledge, there has been no report describing the condition of the primary olfactory pathway, including the olfactory bulb or nasal epithelium, in SCA2 patients. Our group, however, is currently working on trying to identify pathological damage to these structures in SCA2 postmortem preparations.
The finding of an olfactory deficit in spinocerebellar ataxia patients adds to a larger picture of olfactory deficits in different neurodegenerative diseases. Other studies have suggested that olfactory dysfunction is an early indicator that could signify the onset of some of these disorders [3, 5, 19].
We believe that the evidence for olfactory dysfunction in the main neurodegenerative diseases has attained a level that deserves special attention, since its study could shed important light on disease mechanisms currently not known, and to which the olfactory system is especially susceptible.
This study was partially supported by Fideicomiso UNAM to RDC and an Agreement between CIRAH and Coordinación de la Investigación Científica, UNAM.
We are grateful to the patients, control subjects, and to the Cuban Ministry of Health for the cooperation given. We also thank Rafael Ojeda for his help during this study.