Cognitive, emotional and other non-motor symptoms of spinocerebellar ataxias

Abstract

Purpose of review:

Spinocerebellar ataxias (SCAs) are autosomal dominant degenerative syndromes that present with ataxia and brain stem abnormalities. This review describes the cognitive and behavioral symptoms of SCAs in the context of recent knowledge of the role of the cerebellum in higher intellectual function.

Recent findings:

Recent studies suggest that patients with spinocerebellar ataxia can display cognitive deficits even early in the disease. These have been given the term: Cerebellar Cognitive Affective Syndrome (CCAS). CCAS can be tracked using newly developed rating scales. In addition, patients with spinocerebellar ataxia also display impulsive and compulsive behavior, depression, anxiety, fatigue, and sleep disturbances.

Summary:

This review stresses the importance of recognizing non-motor symptoms in SCAs. There is a pressing need for novel therapeutic interventions to address these symptoms given their deleterious impact on patients’ quality of life.

Introduction

Spinocerebellar ataxias (SCAs) are autosomal dominant ataxic degenerative syndromes. The genetic causes of spinocerebellar ataxia syndromes are complex with close to 50 types of SCAs described [1]. The most common SCAs are caused by microsatellite repeats, of which eight are CAG trinucleotide expansions in the coding region of the gene (SCA1, 2, 3, 6, 7, 8, and 17). Since CAG encodes glutamine, these ataxias are also called polyglutamine ataxias.

This classification of autosomal dominant ataxias in the molecular era has superseded the previous Harding classification. In the prior classification, which was clinical, the autosomal dominant cerebellar ataxias (ADCAs) were divided into three groups —ADCA 1, 2 and 3 [2]. While all ADCAs had cerebellar ataxia, ADCA1 had additional neurological features of pyramidal, extrapyramidal involvement or amyotrophy while ADCA2 displayed retinal degeneration. ADCA3 was a term used to autosomal dominant ataxia presenting as relatively pure cerebellar disease. This classification already anticipated that the distinct SCAs are caused by cerebellar degeneration with additional aspects of the nervous system involved [8–16] (Table 1). This includes myoclonus, seizures and spasticity from cortical involvement and chorea as well as parkinsonism because of involvement of the basal ganglia. Many patients also have urinary symptoms and bladder instability as determined by urodynamic studies [3]. Bowel symptoms are less common and a milder complaint [4]. Likewise, reduced sense of smell, often abnormal in neurodegenerative syndromes, is only rarely seen in the SCAs [5–7].

Table 1:

Spinocerebellar ataxia with cognitive impairment likely originating from extra-cerebellar pathways.

SCA type	Non-ataxic clinical features
SCA2	Dementia, parkinsonism, myoclonus
SCA12	Dementia
SCA17	Dementia, chorea
SCA19/22	Cognitive impairment, myoclonus
SCA21	Cognitive impairment
SCA27	Cognitive impairment, orofacial dyskinesia
SCA32	Cognitive impairment, testicular atrophy and azoospermia in males
SCA48	Cognitive impairment in adulthood
ATX-ATN1 (DRPLA)	Dementia, myoclonus, chorea, seizures
ATX-DN	Dementia, hearing loss, narcolepsy

ATX: ataxia; DRPLA: dentatorubral pallidoluysian atrophy; DN: deafness and narcolepsy; SCA: spinocerebellar ataxia.

But beyond the role of degeneration in other parts of the CNS affecting the disease phenotype, it is becoming increasingly clear that the cerebellum itself is involved in tasks beyond sensorimotor integration. These aspects of cerebellar function include contributions to higher intellectual processing, such as cognition, executive function, affect and verbal fluency. Disturbances in these domains in ataxic patients have been termed the cerebellar cognitive affective syndrome (CCAS) [17–20]. CCAS is thought to result from dysmetria in the cognitive domains and is rooted in the same modular architecture of the cerebellum required for sensorimotor integration.

Cerebellar anatomy

The cerebellar cortex is organized in three layers: molecular layer, Purkinje cell layer and granule cell layer. The cellular diversity and connections of the cerebellar cortex are complex [21]. Purkinje cells are the sole output neurons of the cerebellar cortex. They receive two excitatory inputs from the climbing fibers and mossy fibers. Climbing fibers arise from the inferior olive of the contralateral medulla oblongata. Mossy fibers originate from spinal cord, pons and reticular formation and relay onto granule cells; these send their dendritic connections as parallel fibers that form synapses with Purkinje cells. Parallel fibers also excite GABAergic molecular layer interneurons (basket cells and stellate cells) that inhibit Purkinje cells. In the granule cell layer, there are several additional types of interneurons which do not project on Purkinje cells directly, but indirectly modulate the Purkinje cell output. The final integration of Purkinje cell output is to modulate deep cerebellar nuclei signaling.

The modular processing of information occurs in distinct cerebellar lobules which are connected to the cerebellar cortex and the rest of the brain in a specific manner [22]. A subset of the lobules in the cerebellum, including all the lobules in the anterior lobe and part of lobule VI and VIII in the posterior lobe, are involved in sensorimotor integration. These lobules receive sensory input from the spinocerebellar tracts; the inputs are integrated at the cerebellar cortex in deep cerebellar nuclei (globose, emboliform and the dorsal part of the dentate. The lobules are reciprocally connected with the motor cortices via the corticopontine-pontocerebellar projections, and cerebellothalamic-thalamocortical projections. The cerebellar flocculonodular lobe, vermis and fastigial nucleus are interconnected with the vestibular and brainstem nuclei that are also associated with gait and equilibrium.

The remainder of lobule VI and all of lobule VII of the cerebellum are not connected to the cortical sensorimotor areas and do not receive input from the spinocerebellar tracts or from the inferior olive nucleus. Instead, they receive input from the principle olivary nucleus which has little spinal cord input and are linked to the association areas of the cerebral cortex via the ventral and lateral parts of the dentate nucleus. It is these lobules that are thought to play a role in cognitive and affective processing [22]. Functional neuroimaging studies have contributed to our knowledge of these non-motor functions of the cerebellum [23].

Current understanding of the cognitive and behavioral cerebellum

Cerebellar cognitive affective syndrome

Cerebellar cognitive affective syndrome (CCAS), as mentioned earlier, is the term given to the constellation of cognitive deficits from cerebellar circuit disruption [17, 19, 20, 24–26]. The CCAS includes but is not limited to executive dysfunction, visuo-spatial deficits, emotion-affect dysregulation and verbal memory and word finding difficulties [17, 19, 20, 26]. In patients with SCAs, these cognitive symptoms manifest early or can even precede ataxia [27, 28].

To evaluate the broad range of cognitive impairments and behavioral abnormalities associated with cerebellar disorders, the CCAS rating scale was developed in 2018 [26]. This assessment tool encompasses domains such as language, execution, memory, attention, visuospatial abilities, abstract thinking, and affect. Each item within the scale has a diagnostic cut-off score, differentiating patients from controls. The diagnosis of CCAS is determined by the number of failed test items: one failure suggests possible CCAS, two failures indicate probable CCAS, and three failures signify definite CCAS. The total score of the scale is useful for tracking an individual patient’s longitudinal performance and has been translated in several languages for broad applicability [26][29, 30].

Cerebellum and reward: animals and humans

Animal studies have provided insights into the role of the cerebellum in reward processing [31–39]. Cerebellar neurons have distinct roles. In rodents, granule cell neuronal firing encodes reward anticipation and delivery. Different groups of granule cells respond to different reward settings [39]. The activation of reward-anticipation in granule cells is independent of sensory encoding and is not triggered by unexpected rewards, demonstrating specificity [39]. In monkeys, climbing fibers encode the size of reward expectation [34]. In addition, climbing fiber firing pattern in mice conveys reward prediction error signals to the process of reinforcement learning [37]. Finally, deactivation of the dentate nucleus impairs the effort-based decision-making ability [36], which is also linked to reward processing. In summary, each component of cerebellar circuit appears to be related to different processes of reward and decision-making.

Purkinje cells have recently been found to express dopamine D2 receptors. These receptors regulate the social behaviors and preferences in mice [32]. Cerebellar activity also influences dopamine release from other brain regions such as the nucleus accumbens and the forebrain [40, 41]. The cerebellum also is connected to the ventral tegmental area (VTA) which also modulates social behavior [31, 41–43]; [44–48].

Most of these studies have been performed on experimental animals. To investigate the impact of cerebellar dysfunction on reward processing in humans, studies have focused on impulse and compulsive behaviors (ICBs), common outcomes of abnormal reward processing [49–52][53]. Patients with cerebellar ataxia exhibit increased ICBs compared to controls, specifically in gambling, hobbyism, punding, and compulsive medication use [49]. Patients also have more impulsivity traits as measured by the Barratt impulsiveness scale-11. Interestingly impulsivity traits in patients with cerebellar ataxia are distinct from those with Parkinson disease. Patients with cerebellar ataxia have impulsivity driven by mainly the non-planning personality trait, whereas Parkinson disease patients’ display impulsivity traits across multiple domains, which include attentional, non-planning and motor domains [50]. These findings suggest that the cerebellum may contribute to impulsivity in a domain-specific manner. Additionally, studies on the gambling behaviors in cerebellar ataxia, using Iowa gambling tests, demonstrated these patients are making riskier decisions, consistent with impaired reward processing [51]. To measure the diverse presentation of ICBs in cerebellar disorders, the cerebellar impulsivity-compulsivity assessment (CIA) scale was developed. The CIA scale, consisting of 10 questions, effectively captures and monitors cerebellar ICBs. [52].

Non-motor symptoms in SCA patients

SCA patients are only recently being studied with these insights into the role of the cerebellum in higher order functions. In addition, there is also a growing appreciation for other non-motors symptoms— such as fatigue and sleep dysfunction— that significantly worsen quality of life.

Cognitive deficits

The degree of cognitive involvement varies among the SCAs [27]. SCA3 is the most prevalent SCA with cognitive decline that can lead to dementia. Some of the less common causes of SCA, such as SCA17, can have a higher proportion of patients with cognitive decline and dementia. Within SCA3, cognitive impairment is consistently observed and effectively assessed by the CCAS, which not only differentiates SCA3 patients from controls but also detects early neuropsychological deficits, correlating with ataxia severity [27]. Studies on SCA1, SCA2, and SCA3 most usually reveal mild executive dysfunction across these subtypes, with additional verbal fluency and word memory deficits in SCA2 and SCA3 [54]. Based on cognitive severity, neuropathological patterns, and MRI findings, a study categorized SCAs as three groups: mild dysexecutive syndrome related to cerebello-cortical circuit disruption (such as SCA 6 and 8), more extensive deficits due to striato-cortical and cerebello-cerebral circuit disruptions (SCAs 1, 2, 3, and 7), and dementia (seen in SCA17 and rarely the common SCAs, such as SCA3) [55]. There is a need for a more comprehensive understanding of cognitive dysfunction in all the SCAs, with an emphasis on uncovering deficits that impair the quality of life.

Depression

Among the non-motor symptoms of SCAs, depression has been particularly well studied (Table 2). Regardless of the type of SCA, patients have more depressive symptoms compared to controls [56–67]. A study of 526 SCA patients from the European spinocerebellar ataxia consortium, EUROSCA, demonstrated clinically relevant depression in 25% SCA1 patients, 20% SCA2 patients, 25% SCA3 patients, and 18% SCA6 patients [67]. Another study of 300 SCA patients from the Clinical Research Consortium for Studying Cerebellar Ataxia (CRC-SCA) in the United States showed clinically relevant depression in 25% SCA1 patients, 22% SCA2 patients, 31% SCA3 patients, and 22% SCA6 patients [63, 68]. Both studies measured the severity of depression using Patient Health Questionnaire [63, 67]; therefore, the study results are comparable. The prevalence of depression does not appear to be statistically different among SCA1, SCA2, SCA3, and SCA6 patients [63, 67].

Table 2:

Studies on depression in spinocerebellar ataxias

Study	Participant	SCA type	Assessment measures	Key findings
Cecchin et al. 2006	79	SCA3	Beck Depression Inventory	34% SCA3 patients have moderate to severe depression
Klinke et al. 2010	32	SCA1, SCA2, SCA3, SCA6	Beck Depression Inventory	Mild depression in 50% SCA1, 33% SCA2, 13% SCA3, and 75% SCA6
Schmitz-Hübsch et al. 2011	526	SCA1, SCA2, SCA3, SCA6	Patient Health Questionnaire	Clinically relevant depression in 25% SCA1, 20% SCA2, 25% SCA3, 18% SCA6
Braga-Neto Pedro et al. 2012a	29	SCA3	Beck Depression Inventory	SCA3 patients have higher depression scores than controls
Braga-Neto Pedro et al. 2012b	38	SCA3	Beck Depression Inventory	SCA3 patients have higher depression scores than controls
Lopes et al. 2013	32	SCA3	Beck Depression Inventory	SCA3 patients have higher depression scores than controls
Fancellu et al. 2013	42	SCA1, SCA2	Hamilton Depression Scale	More depression in both SCA1 and SCA2 patients when compared to controls
Lo et al. 2016	300	SCA1, SCA2, SCA3, SCA6	Patient Health Questionnaire	Clinically relevant depression in 25% SCA1, 22% SCA2, 31% SCA3, 22% SCA6
Pedroso et al. 2017	33	SCA2	Beck Depression Inventory	SCA2 patients have higher depression scores than controls
Moro et al. 2017	56	SCA3 SCA10	Beck Depression Inventory	SCA3 and SCA10 patients have higher depression scores than controls
Lin et al. 2018	104	SCA3	Beck Depression Inventory	58% SCA3 patients have depression
Hengel et al. 2023	227	SCA3	Patient Health Questionnaire	SCA3 patients have a higher depression scores than controls

SCA: spinocerebellar ataxia

A study from Asia on SCA3, the most common SCA, showed that 58% of 104 patients have depression [62]. Similarly, a recent study from the European SCA3 consortium, European Spinocerebellar Ataxia Type-3/Machado-Joseph Disease Initiative (ESMI), with 227 SCA3 patients also demonstrated depressive symptoms are more common among SCA3 patients than controls [60]. These studies reinforce the notion that depression is a major non-motor symptom of SCAs. Moreover, a study also showed that depression could precede motor symptom onset and thus could be an early symptom for SCAs [60].

What are the factors that contribute to depression in SCAs? Female sex appears to be a risk factor for depression in SCAs [62, 67]. In addition, ethnicity appears to play a role. Caucasian SCA3 patients are more likely to have depressive symptoms than their African American counterparts [69]. Other genetic factors may also modulate depression in SCAs. A study showed 40% of SCA patients also carry the intermediate repeat expansions of C9orf72 [70], a risk factor gene for amyotrophic lateral sclerosis [71]. Interestingly, SCA1, SCA2, and SCA6 patients with intermediate repeats of C9orf72 have different rates of progression of depressive symptoms [70], suggesting a potential role of the interactions between repeat expansion genes. Since depression has a significant impact on patient quality of life in SCAs, early identification and treatment of depression in SCA patients is crucial [63], Depression in SCAs is often associated with other non-motor symptoms such as anxiety and impulsivity, and clinicians should also pay special attention to these comorbid symptoms [49,56,57,59,64,66].

Anxiety

Anxiety is another common symptom in SCA patients. Studies of anxiety in SCAs consistently showed that SCA1, SCA2, and SCA3 patients have higher anxiety scores than controls (Table 3) [56,57,59,64,66]. However, studies have yet to investigate the associated factors that modulate anxiety symptoms in SCAs.

Table 3:

Studies on anxiety in spinocerebellar ataxias

Study	Participant	SCA type	Assessment measures	Key findings
Braga-Neto Pedro et al. 2012a	29	SCA3	Hamilton Anxiety Scale	SCA3 patients have higher anxiety scores than controls
Braga-Neto Pedro et al. 2012b	38	SCA3	Hamilton Anxiety Scale	SCA3 patients have higher anxiety scores than controls
Lopes et al. 2013	32	SCA3	Beck Anxiety Inventory	SCA3 patients have higher anxiety scores than controls
Fancellu et al. 2013	42	SCA1, SCA2	Hamilton Anxiety Scale	No statistical significant higher anxiety scores in SCA1 and SCA2 patients when compared to controls, but numerically SCA1 and SCA2 patients have higher anxiety scores.
Pedroso et al. 2017	33	SCA2	Hospital Anxiety and Depression Scale	SCA2 patients have higher anxiety scores than controls

SCA: spinocerebellar ataxia

Other neuropsychiatric symptoms that can occur in SCAs are irritability, apathy, and personality changes [72]. In a study comparing neuropsychiatric symptoms of cerebellar degeneration, which includes SCAs, and Huntington’s disease, 77% patients of cerebellar degeneration have neuropsychiatric symptoms, which are comparable to Huntington’s disease [73]. Personality changes were identified in 26% of patients with cerebellar degeneration whereas comorbid psychotic disorder occurs in 10% of patients [73]. These studies underscore the diverse neuropsychiatric symptoms that could occur in SCA patients.

Fatigue

Fatigue is a disabling symptom in SCA patients since it further limits physical activity. The prevalence of fatigue in SCA3 is between 53%−64% with sample sizes of 20–93 [74–78]. One study demonstrated that 100% of 12 SCA1 patients suffer from fatigue [79]. Depression is a contributing factor to fatigue in SCA3 patients and fatigue in SCA3 is associated with excessive daytime sleepiness [74,75,77,78]. Fatigue is associated with more severe ataxia symptoms in most SCA patients. Differences in fatigue could arise from other variable including social and ethnic differences [75, 77]. Regardless, fatigue negatively impacts the quality of life in SCA3 patients [75]. Since studies of fatigue have focused on SCA3, we know little about fatigue in other SCAs.

Sleep disturbance

Sleep disturbance is also common in patients with SCA [80]. The specific sleep disturbances in these patients are REM sleep behavior disorder (RBD), restless legs syndrome, excessive daytime sleepiness, insomnia, and sleep apnea [80]. Restless leg syndrome occurs more frequently in SCA patients (28% in patients versus 10% in controls) [81]. Among SCAs, SCA3 appears to have a higher incidence of restless leg syndrome, and up to 45% of SCA3 patients suffer from restless leg syndrome [82]. The contributing factors to restless leg syndrome in SCA3 patients include female gender, age of ataxia onset (onset after age 30), presence of peripheral neuropathy, and documented iron deficiency [83]. Whether restless leg syndrome is directly caused by the pathological repeat expansions of ATXN3 or is secondary to peripheral neuropathy and/or iron deficiency in SCA3 patients remains controversial [82, 83]. There is also the possibility that extrapyramidal involvement or involvement of dopamine circuitry could lead to RLS in SCA3. In this context, RBD and excessive daytime sleepiness also typically seen in parkinsonian syndrome are reported to occur in 49% and 42% of SCA2 patients, respectively [66]. Another study of a small sample size also reported 50% SCA2 patients have RBD [84]. Interestingly, SCA3 patients have reduced REM sleep but RBD still can occur.⁸⁵ These studies indicate that RBD could be a non-motor symptom of SCAs. In addition to RBD, sleep apnea and excessive daytime sleepiness are also part of the constellation of sleep disturbance in SCAs. A study showed that 34% and 43% of SCA3 patients have sleep apnea and excessive daytime sleepiness, respectively [86].

In summary, SCA patients have diverse non-motor symptoms. Therefore, clinicians should pay special attention to these often under-recognized symptoms and to offer treatment accordingly.

Conclusion

Spinocerebellar ataxias are distinguished from the rest of the neurodegenerative diseases by their motor features of ataxia resulting from degeneration of the cerebellum. There is, however, a growing recognition of the broader spectrum of symptoms, particularly in the non-motor realm. Some of these symptoms arise from degeneration in other parts of the brain, including the cortex and brainstem. The cerebellum itself is increasingly implicated in non-motor functions, such as cognition, mood, and affect. Functional and structural imaging studies, utilizing advanced MRI and spectroscopic techniques, have further expanded our knowledge of the neural circuits responsible for cognitive and behavioral symptoms in SCAs. These advances are crucial given that non-motor symptoms impact the quality of life for both patients and their caregivers.

Currently, the non-motor symptoms are managed with medications proven effective in other neuropsychiatric disorders. In the future, dedicated clinical studies will need to be conducted to test and optimize their efficacy in SCAs or find novel pharmacological agents. Additionally, we envision non-pharmacological strategies such as neurostimulation techniques, including Transcranial Magnetic Stimulation and Transcranial Direct Current Stimulation to address both motor and non-motor symptoms at a circuit level.