Olfactory dysfunction is commonly observed in various neurodegenerative diseases, and our clinical observations indicate that patients with SCA exhibit olfactory impairment to a certain extent. Several studies have highlighted the close relationship between the cerebellum and olfactory function. Ivanka Savic et al. [1] used functional magnetic resonance imaging (fMRI) to reveal the activation of the cerebellum during olfactory stimulation. Juan Fernandez-Ruiz et al. [2] were the first to confirm olfactory dysfunction in patients with cerebellar damage. However, notably, the degree of olfactory impairment in patients with SCA is not as severe as those with Parkinson’s disease (PD) or Alzheimer’s disease (AD). Furthermore, studies have revealed a close relationship between olfaction and cognitive function in patients with SCA. Vázquez-Pérez et al. [3] investigated olfactory function in 53 patients with SCA2 and 53 healthy controls and revealed significantly lower olfactory scores in the SCA2 group compared with the healthy control group. Moreover, a significant correlation was observed between the olfactory scores and Mini-Mental State Examination (MMSE) scores (p = 0.03). In this study, we evaluated the olfactory function of 30 patients with SCA (primarily SCA1 and SCA3 subtypes) and analyzed its correlation with motor impairment, anxiety and depression status, and sleep quality.
The results of this study suggest that, compared with the control group, patients in the SCA group exhibit decreased olfactory threshold, discrimination, and identification, consistent with the findings from previous studies. Galvez et al. [4] demonstrated that olfactory discrimination and identification abilities were significantly impaired in patients with SCA7 while their olfactory threshold remained within normal levels, suggesting that neurological damage in patients with SCA7 affects olfaction but preserves olfactory perception ability. Similarly, Braga-Neto et al. [5] found a significant decrease in the olfactory ability of patients having SCA3, with the degree of olfactory dysfunction correlating with patient age, education level, smoking status, and MMSE scores. Additionally, significant differences in olfactory function have been observed among different subtypes of SCA. Mariana Moscovich et al. [6] conducted olfactory tests on patients with SCA10 and SCA2, and the results indicated olfactory impairments in patients with SCA2 but no significant olfactory defects in patients with SCA10 [7].
The mechanism underlying olfactory dysfunction remains unclear, but the decrease in olfactory threshold is typically associated with damage to the olfactory epithelium and olfactory sensory neurons [8]. This damage is most commonly attributed to chronic rhinitis [8]. Therefore, it is crucial that studies evaluating olfaction in patients with SCA exclude the influence of peripheral olfactory system damage. Numerous studies have found olfactory dysfunction in various neurological disorders, including idiopathic PD [9, 10], AD, schizophrenia, and multiple sclerosis (MS).
Olfaction and movement disorders share a close relationship, with olfactory dysfunction serving as an early indicator for the onset of certain diseases. In PD, the prevalence of olfactory loss exceeds that of tremor. In patients with MS, olfactory dysfunction is significantly negatively correlated with the number of active lesions in the primary and secondary olfactory cortices [11, 12]. Traditionally, the human cerebellum is the center for motor coordination; it contains more neurons than other parts of the brain and is structurally connected to all major branches of the central nervous system, including the cerebrum, basal ganglia, diencephalon, limbic system, brainstem, and the spinal cord [11, 12]. The cerebellum also plays a role in olfactory function [13], and the evidence supporting its involvement in olfactory processing includes the following: (A) reports of olfactory defects in patients with cerebellar or near-cerebellar tumors [14, 15]; (B) signs of cerebellar abnormalities in patients with olfactory loss-related disorders, such as schizophrenia [16]; and (C) fMRI demonstrating cerebellar activation during olfactory processes [2]. fMRI studies revealed activation in the posterior lateral hemisphere of the cerebellum following odor induction, activation of the uvula and posterior quadrangular lobes following odor recognition tasks, and activation of the right central lobule and vermis solely evoked through olfaction [17]. (D) T Connelly et al. conducted the University of Pennsylvania Smell Identification Test on patients with ataxia, primarily caused by cerebellar pathology (SCA and related disorders) and Friedrich’s ataxia (a condition primarily associated with loss of input cerebellar pathways). The results showed that olfactory test scores were significantly lower in patients with cerebellar disease compared with the control group [18].
The olfactory dysfunction in SCA may be related to disruptions in brain network function associated with olfaction. fMRI conducted on the central olfactory system revealed that patients with PD who possess olfactory dysfunction exhibit a significant decrease in regional homogeneity in traditional olfactory regions, such as the amygdala, olfactory gyrus, orbitofrontal gyrus, parahippocampal gyrus, and insula, and few nontraditional olfactory centers, such as the prefrontal gyrus and temporal pole, suggesting that besides traditional olfactory core regions, other brain regions also participate in olfaction [19]. For example, the decrease in olfactory threshold is correlated with the left primary olfactory cortex [20]; odor discrimination tasks are associated with the frontal and temporal lobes and the limbic system such as the orbitofrontal cortex and hippocampus [21]; odor recognition tasks activate the cerebellum, temporal lobe, and parietal lobe cortex [22]; and the cerebellum receives olfactory inputs from the piriform cortex via the ventral striatum [23]. The basal ganglia, as a core component of the neural circuitry hypothesis, can receive signal inputs from the primary olfactory cortex, including the olfactory tubercle, during olfactory tasks [24], and patients with PD having olfactory dysfunction exhibit a significant decrease in dopamine transporter uptake in the bilateral caudate nucleus and the left anterior and posterior putamen [25].
In this study, the age of the patients with SCA was negatively correlated with various olfactory scores, indicating that age is an important risk factor for olfactory dysfunction [26]. The HAMA, HAMD, and PSQI scores were higher in the SCA group than the control group, suggesting that most patients with SCA have anxiety, depression, and sleep disorders. However, no correlations between the scores of HAMA, HAMD, and PSQI and olfactory function were observed in the SCA group in this study.
The olfactory sticks used in this study were developed by the Institute of Psychology, Chinese Academy of Sciences. The sticks offer the advantages of convenience, accuracy, and high sensitivity. The selected odors are familiar to the Chinese population; nonirritable; and enable the assessment of the sensitivity level of odor detection and odor perception and the ability to perceive odor characteristics to determine their association with odor concepts in the memory system. These sticks meet the requirements for scientific research and clinical examinations.
In conclusion, this study demonstrates a high prevalence of olfactory dysfunction in patients with SCA, characterized by a comprehensive decrease in olfactory threshold, discrimination, and identification functions. No correlation is observed between olfactory dysfunction in SCA and motor symptoms, pain, anxiety, depression, or sleep disturbances. However, this study has certain limitations. First, the sample size was relatively small, which may lead to biased results. Second, fMRI examinations were not conducted to further explore the neurobiological mechanisms underlying olfactory dysfunction in SCA. Lastly, no follow-up investigation was conducted to determine the relationship between olfactory dysfunction and treatment outcomes.