The autosomal dominant spinocerebellar ataxias (SCA) are a heterogeneous group of disorders that differ in the extent of neuropathological involvement of cerebellum, brainstem, and basal ganglia. It is well established that these disorders can be manifested in neuropsychiatric symptoms,¹ but it is less understood how frequently these symptoms occur on presentation and the extent to which they differ among SCA subtypes. Moreover, the differences in presenting neuropsychiatric symptoms between SCA types may reflect differences in the underlying neuropathology of the disorder. We report the frequency depressive and memory symptom complaints, the two most common neuropsychiatric symptoms in SCA,¹ among a large cohort of SCA patients presenting to a large university-based ataxia center. We reviewed the intake neuropsychiatric assessments for the four common SCA subtypes with distinctive underlying differences in neuropathology. The findings of this study highlight the importance of a neuropsychiatric evaluation of patients who present with a potentially inheritable ataxic disorder.

This study reviewed 76 subjects presenting to a large university-based ataxia program. The patients underwent extensive initial evaluations, including intake neurological and psychiatric assessment, neurological examinations, laboratory tests (routine tests and thyroid function tests, B12 level, and VDRL), and magnetic resonance imaging (MRI) of the brain. If the patients met clinical criteria for a spinocerebellar ataxia, further genetic testing was obtained. All patients diagnosed with SCA1, SCA2, SCA3, or SCA6, the common SCA subtypes, were included in this study. An intake neuropsychiatric assessment identified memory and depressive complaints. These two symptoms are the most common neuropsychiatric symptoms in SCA. An ataxia specialist screened the patients and their caregivers for neuropsychiatric symptoms, especially depressive and memory problems. The patients were screened for the following symptoms of depression: depressed mood, anhedonia, and lack of interest in usual activities.² They were screened for the following symptoms of memory difficulty: difficulty remembering recent events or problems incorporating new information.

This study included a total of 12 SCA1, 22 SCA2, 20 SCA3, and 22 SCA6 patients (Table 1). Depressive symptoms were significantly greater in SCA3 (60%) compared to the other SCA types (SCA1 [25%], SCA2 [23%], and SCA6 [27%]) (Figure 1). In contrast, memory symptoms were less frequent, although not at significance level, in SCA6 (23%) compared to the other SCA subtypes (SCA1 [42%], SCA2 [45%], and SCA3 [50%]; χ2=3.63, df=3, p=0.057).

We performed an additional analysis comparing the presence of initial neuropsychiatric symptoms with two measures of disease severity, disease duration, and CAG repeat length (Table 1). No significant associations occurred after Bonferroni correction for multiple comparisons.

Patients with a spinocerebellar ataxia may have depression or memory difficulty on initial presentation with their disorder.³,⁴ In this large series of patients evaluated in a university-based ataxia center, depressive symptoms were significantly more frequent in those with SCA3 compared with all other SCA patients. The greater depressive complaints in SCA3 may be due to dysfunction of frontal-subcortical circuits in the basal ganglia, structures that are uniquely involved in SCA3 as opposed to the other subtypes. The presence of early neuropsychiatric features in SCA emphasizes the need for careful behavioral screening and assessment of these patients. Patients with SCA are usually seen in neurological programs where their disturbances in gait, coordination, and movements may take precedence over evaluations for depression or memory difficulty. The patients in this study were initially screened for these difficulties, resulting in subsequent referrals for treatment of depression or for neuropsychological testing, as indicated. This study further indicates that the presence of early neuropsychiatric symptoms can be diagnostic clues to the particular subtype of SCA. In addition to cerebellar degeneration, differences in other neuropathological involvement between SCA subtypes may account for differences in neuropsychiatric manifestations. In SCA1 there is variable olivopontocerebellar atrophy (OPCA), with more prominent involvement of the dentate nuclei.⁵—⁷ In SCA2 there is OPCA with nigral degeneration and less prominent involvement of the dentate nuclei.¹ In SCA3 there is a lack of OPCA, but significant pathology in the dentate nuclei, substantia nigra, subthalamic nuclei, striatum and globus pallidus.⁸ Finally, in SCA6 the pathology is uniquely restricted to the cerebellum.⁹

The involvement of the basal ganglia in SCA3 may account for the increased frequency of depressive symptoms in this subtype. A number of neurological disorders that involve the basal ganglia and its connections, such as Huntington's disease and Parkinson's disease, also result in similar depressive symptoms. The greater frequency of depressive complaints in SCA3 patients, as in these other neurological disorders, may result from disruption of reciprocal connections between the frontal lobes and the striatum within the basal ganglia.¹

This study is a preliminary report of screening for initial neuropsychiatric symptoms in spinocerebellar ataxia. One limitation of this study is the focus on initial symptoms. This report, however, emphasizes the importance of patient or caregiver report of the experience of neuropsychiatric difficulty; experiences which may lead them to seek clinical consultation. Second, the study is limited to the common neuropsychiatric symptoms, rather than a more extensive survey of behavioral symptoms. Finally, there is no comparison group consisting of patients diagnosed with a non-SCA chronic movement disorder. This report, however, focuses on a comparison across different subtypes of SCA. In sum, early neuropsychiatric symptoms are common in SCA, particularly depressive symptoms in SCA3. This preliminary report shows that the likelihood of presentation with neuropsychiatric symptoms varies depending on the SCA type and its underlying neuropathology. Neuropsychiatric symptoms, such as depressive and memory symptoms, are common presenting symptoms in SCA and should be evaluated in all patients presenting with a progressive ataxia.

*Significantly higher rate of depressive complaints than found in other spinocerebellar ataxia subtypes (χ2=8.02, df=3, p<0.005)

This research was supported in part by the National Ataxia Foundation, the Carmen and Louis Warschaw Endowment in neurology, and NIH grant R01-NS33123