Neural Correlates of Apathy in Multiple System Atrophy: A Clinical and Perfusion Imaging Study

ABSTRACT

Background

Apathy is a frequent nonmotor symptom of multiple system atrophy (MSA) that worsens quality of life. Although frontostriatal dysfunction has been implicated in apathy, its neural basis in MSA remains insufficiently characterized.

Objectives

To identify the neural substrates of apathy associated with MSA‐specific neurodegenerative processes.

Methods

This retrospective cross‐sectional study included 76 patients with cognitively preserved clinically established/probable MSA who underwent clinical and neuropsychological assessments, including the Apathy Scale and a separate depression measure, magnetic resonance imaging, and cerebral blood flow single‐photon emission computed tomography. Clinical variables, gray matter volume, and voxel‐wise perfusion were compared between apathy and non‐apathy groups. Multivariate logistic regression was used to analyze the independent association of the significant perfusion cluster with apathy, and seed‐based covariance analysis was used to explore network alterations.

Results

Apathy was present in 55.3% of patients and did not differ between motor subtypes. Compared with the non‐apathy group, the apathy group showed lower visuospatial scores and frequency of neurogenic orthostatic hypotension, similar depression scores and gray matter volume, and reduced perfusion in the medial prefrontal cortex on voxel‐wise perfusion analysis. These findings remained independently associated with apathy after adjustment for clinical variables. Seed‐based covariance analysis suggested reduced positive covariance between the medial prefrontal cortex and cerebellar regions, predominantly in the posterior lobe.

Conclusions

Apathy was common in MSA even with relatively preserved global cognition and distinct from depression. In addition to medial frontostriatal dysfunction, exploratory findings suggested that mechanisms related to cerebellar cognitive affective syndrome may contribute to its pathophysiology.

In 76 patients with multiple system atrophy (MSA) and relatively preserved global cognition, apathy was present in 55.3%, with no association with motor severity or depressive symptoms. Reduced medial prefrontal cortex (mPFC) perfusion was independently associated with apathy after adjustment for clinical variables, while exploratory covariance analysis suggested reduced positive covariance between the mPFC and posterior cerebellar regions. These findings suggest that apathy may reflect MSA‐related neurodegenerative processes involving medial frontostriatal dysfunction and possibly cerebellar cognitive affective syndrome (CCAS)‐related mechanisms.

Abbreviations

AAL

Automated Anatomical Labeling

ACE‐III

Addenbrooke's Cognitive Examination III

CBF

cerebral blood flow

CCAS

cerebellar cognitive affective syndrome

CI

confidence interval

CT

computed tomography

DARTEL

Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra

FAB

Frontal Assessment Battery

FWE

family‐wise error

FWHM

full width at half maximum

HAM‐D

Hamilton Depression Rating Scale

MDS

Movement Disorder Society

MMSE

Mini‐Mental State Examination

MNI

Montreal Neurological Institute

mPFC

medial prefrontal cortex

MRI

magnetic resonance imaging

MSA

multiple system atrophy

MSA‐C

cerebellar variant of multiple system atrophy

MSA‐P

parkinsonian variant of multiple system atrophy

nOH

neurogenic orthostatic hypotension

OR

odds ratio

QOL

quality of life

SPECT

single‐photon emission computed tomography

UMSARS

Unified Multiple System Atrophy Rating Scale

VOI

volume of interest

1. Introduction

Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by progressive neuronal loss associated with α‐synuclein accumulation in the central nervous system. Clinically, it presents with a combination of parkinsonism, cerebellar ataxia, and autonomic failure. MSA is classified according to the predominant motor phenotype as a parkinsonian variant (MSA‐P) or a cerebellar variant (MSA‐C) [1]. Traditionally, cognitive impairment has been regarded as a diagnostic red flag in MSA. However, increasing evidence has shown that patients with MSA frequently exhibit frontal lobe dysfunction, particularly executive dysfunction, as well as behavioral disturbances, such as depression and apathy [2].

Apathy is a syndrome characterized by reduced goal‐directed behavior resulting from lack of motivation. It interferes with physical activity and social participation, leading to reduced activities of daily living and cognitive function, thereby further increasing caregiver burden [3, 4]. Although apathy and depression often coexist, the two are considered distinct neuropsychiatric syndromes with different core features and neural substrates; therefore, they should be evaluated separately when investigating disease mechanisms [5]. In MSA, apathy has been identified as an independent determinant of worse quality of life (QOL) [6] and reportedly follows a course independent of depression, motor severity, and cognitive impairment [7, 8]. These findings suggest that apathy in MSA may arise not merely as a secondary psychological reaction to physical disability or depression but rather in association with disease‐specific neurodegenerative processes.

In general, apathy is thought to arise from frontostriatal circuit dysfunction, although the pattern of impairment is not uniform among diseases [9]. In MSA, however, the neural mechanisms of apathy remain poorly understood, and neuroimaging studies that directly address apathy are scarce. Previous reports have suggested similar frontostriatal involvement, based on the association between apathy and frontal lobe impairment [7, 10]. However, apathy has been reported to be common in both MSA‐C and MSA‐P [11], raising the possible contribution of neural mechanisms beyond frontostriatal circuit dysfunction to apathy in MSA.

Clarifying the neural basis of apathy in MSA is important for advancing our understanding of its disease‐specific pathophysiology. Moreover, given that no established disease‐modifying therapy is currently available for MSA, such insights may help inform symptomatic management. Therefore, this study aimed to identify the neural substrates of apathy that are associated with MSA‐specific degenerative processes. To this end, we limited the study population to patients with MSA and relatively preserved global cognitive function in order to reduce potential confounding by broader cognitive impairment. We evaluated apathy and depression using separate measures and examined differences in clinical characteristics and cerebral blood flow (CBF) single‐photon emission computed tomography (SPECT) findings between patients with and without apathy.

2. Methods

2.1. Study Design and Ethics

This retrospective study was performed in line with the principles of the Declaration of Helsinki and approved by the institutional review board of Chiba University Graduate School of Medicine (approval no. 2052). The requirement for written informed consent was waived because this study used clinical and imaging data obtained during routine clinical practice.

2.2. Participants

We retrospectively identified consecutive patients who met the following criteria: (1) underwent comprehensive inpatient evaluation for suspected MSA at Chiba University Hospital between September 2017 and November 2024 and (2) were diagnosed as clinically established or clinically probable MSA, according to the 2022 Movement Disorder Society (MDS) criteria [1]. The diagnosis and subtype were determined by movement disorder specialists. Patients were classified as having MSA‐C or MSA‐P based on the predominant motor syndrome upon admission. Patients were excluded if they met any of the following criteria: (1) missing data for the Apathy Scale, Hamilton Depression Rating Scale (HAM‐D), brain magnetic resonance imaging (MRI), or CBF SPECT; (2) history of structural brain disease other than MSA or major depression; and (3) a Mini‐Mental State Examination (MMSE) score of < 27, which has been used in Japan as the cutoff suggestive of mild cognitive impairment [12].

A total of 125 patients were initially identified. After excluding patients with missing Apathy Scale (n = 3), HAM‐D (n = 1), and MRI (n = 1); those with cerebral infarction (n = 3), depression (n = 3), and polymicrogyria (n = 1); and those with MMSE of < 27 (n = 37), 76 patients were included in the final analysis.

2.3. Clinical Assessments

Sex, years of education, age at symptom onset, age at admission, and disease duration were collected from the medical records. Disease severity was assessed using the Unified Multiple System Atrophy Rating Scale (UMSARS) parts I and II, International Cooperative Ataxia Rating Scale, and MDS Unified Parkinson's Disease Rating Scale part III [13, 14, 15]. Neuropsychological assessment tools included the Addenbrooke's Cognitive Examination III (ACE‐III), Frontal Assessment Battery (FAB), MMSE, Wechsler Memory Scale‐Revised, Starkstein's Apathy Scale, HAM‐D, and the Japanese version of the REM Sleep Behavior Disorder Screening Questionnaire [16, 17, 18, 19, 20, 21, 22]. Autonomic function was assessed by averaging post‐void residual urine volumes measured once daily over three consecutive days with a portable ultrasound bladder scanner and by determining the presence of neurogenic orthostatic hypotension (nOH) on head‐up tilt test, according to the MDS criteria [1]. The presence of apathy was defined as an Apathy Scale score of ≥ 16, based on a validation study of the Japanese version of the scale [20].

2.4. MRI and SPECT Acquisition

All participants underwent brain MRI and CBF SPECT/computed tomography (CT) in close temporal proximity as part of the diagnostic evaluation. Brain MRI was performed using a single 3.0‐T scanner (DISCOVERY MR750, GE HealthCare, Chicago, IL, USA), including three‐dimensional T1‐weighted imaging. N‐isopropyl‐p‐[¹²³I] iodoamphetamine CBF SPECT/CT was performed using one of two hybrid SPECT/CT systems (GE Infinia Hawkeye 4 system before December 2020 and NM/CT 870 DR system from January 2021 onward; GE HealthCare, Chicago, IL, USA). SPECT images were reconstructed with attenuation correction based on low‐dose CT. Details of the MRI and SPECT acquisition and reconstruction parameters are provided in Table S1.

2.5. Image Preprocessing

Images were preprocessed using SPM12 (Wellcome Centre for Human Neuroimaging, UCL Queen Square Institute of Neurology, London, UK) running on MATLAB R2024a (The MathWorks Inc., Natick, MA, USA). T1‐weighted images were segmented into gray matter, white matter, and cerebrospinal fluid and normalized to Montreal Neurological Institute (MNI) space using a study‐specific DARTEL template. Jacobian modulation was applied to the gray matter images, which were then smoothed with an 8‐mm full width at half maximum (FWHM) Gaussian kernel. Total intracranial volume was calculated as the sum of gray matter, white matter, and cerebrospinal fluid volumes.

CBF SPECT images were coregistered with each participant's gray matter image, normalized to MNI space using the same transformation parameters as those applied to MRI, and smoothed with a 14‐mm FWHM Gaussian kernel.

2.6. Statistical Analysis

Statistical analyses were performed using SPSS version 27.0 (IBM Japan, Tokyo, Japan). Patients with and without apathy were compared using Student's t‐test, Welch's t‐test, or Mann–Whitney U test for continuous variables, as appropriate for the data distribution, with effect size reported as mean difference or Hodges–Lehmann estimate, and using chi‐square test and odds ratio (OR) for categorical variables. To assess the potential influence of the cognitive selection criterion, demographic and clinical characteristics were additionally compared between patients included in the final analysis and those excluded because of MMSE scores < 27 using the same statistical methods. A two‐sided p value of < 0.05 was considered statistically significant.

Voxel‐based morphometry was used to compare gray matter volume between groups, with age, sex, and total intracranial volume as covariates. For voxel‐wise SPECT analysis, CBF SPECT images were compared between groups, with age, sex, SPECT/CT system type, and global mean CBF as covariates. In both analyses, a gray matter mask was applied, and significance was defined as a voxel‐level threshold of p < 0.001 (uncorrected) together with a cluster‐level threshold of p < 0.05 corrected for family‐wise error (FWE). Anatomical labeling was performed using the Automated Anatomical Labeling (AAL) atlas [23].

For the cluster that was significant on SPECT analysis, standardized residuals were calculated from the cluster mean value after removing the effects of age, sex, SPECT/CT system type, and global mean CBF. The resulting values were used as the adjusted cluster z score, which was then entered into a multivariate logistic regression model using the presence of apathy as the dependent variable. Independent variables included the adjusted cluster z score, UMSARS part I score, HAM‐D score, ACE‐III visuospatial score, and nOH. A two‐sided p value of < 0.05 was considered statistically significant.

In addition, seed‐based covariance analysis was performed using the AAL volume of interest (VOI), which contained the significant peak voxel on SPECT analysis as the seed. Mean values for the 116 AAL VOIs were extracted using PETPVE12 [24]. Within each group, partial correlation coefficients between the seed VOI and each of the other VOIs were calculated after adjustment for age, sex, global mean CBF, and SPECT/CT system type. Multiple‐comparison correction was performed using R version 4.5.2 (R Foundation for Statistical Computing, Vienna, Austria) and the Benjamini–Yekutieli false discovery rate procedure [25]. A q value < 0.05 was considered statistically significant, and a q value < 0.1 was considered exploratory.

In a post hoc analysis, we examined whether FAB score modified the relationship between the medial prefrontal cortex (mPFC) seed and the eight cerebellar VOIs identified in the exploratory covariance analysis. We performed linear regression analyses for each cerebellar VOI as the dependent variable, including the mPFC seed and FAB main effects and the mPFC seed × FAB interaction as the term of interest, adjusting for age, sex, global mean CBF, SPECT/CT system type, presence of apathy, and the mPFC seed × apathy interaction. The mPFC seed, cerebellar VOI, and FAB values were standardized before analysis. The p values for the mPFC seed × FAB interactions were corrected using the Benjamini–Yekutieli procedure, with q < 0.05 considered statistically significant.

3. Results

3.1. Patient Characteristics

The demographic and clinical characteristics of the study participants are summarized in Table 1. Among the 76 patients included in the analysis, the diagnosis was clinically established MSA in 54 (71%) and clinically probable MSA in 22 (29%). Based on the predominant motor features, 44 patients (58%) were classified as having MSA‐C and 32 (42%) as having MSA‐P. The median disease duration was 2.2 years (interquartile range, 1.3–3.1).

TABLE 1.

Demographic and clinical characteristics of the study participants.

Group	MSA			p
	Total (n = 76)	With apathy (n = 42)	Without apathy (n = 34)
Age at onset, years a	60.5 (51–67)	61.0 (52–67)	60.0 (51–68)	0.908
Sex b				0.356
Male	38 (50%)	19 (45%)	19 (56%)
Female	38 (50%)	23 (55%)	15 (44%)
Education, years a	12.0 (12–16)	12.0 (12–16)	13.0 (12–16)	0.582
Age at admission, years a	62.0 (53–70)	62.0 (53–71)	62.5 (53–70)	0.904
Disease duration, years a	2.2 (1.3–3.1)	2.2 (1.3–2.9)	2.3 (1.4–3.2)	0.468
Disease subtype b				0.210
MSA‐C	44 (58%)	27 (64%)	17 (50%)
MSA‐P	32 (42%)	15 (36%)	17 (50%)
Diagnostic criteria b				0.349
Clinically established	54 (71%)	28 (67%)	26 (76%)
Clinically probable	22 (29%)	14 (33%)	8 (24%)
SPECT/CT system b				0.785
Infinia Hawkeye 4	46 (61%)	26 (62%)	20 (59%)
NM/CT 870 DR	30 (39%)	16 (38%)	14 (41%)
Apathy Scale score a	16.0 (13–20)	20.0 (17–22)	12.0 (11–14)	—

Abbreviations: MSA, multiple system atrophy; MSA‐C, cerebellar variant of multiple system atrophy; MSA‐P, parkinsonian variant of multiple system atrophy; SPECT/CT, single‐photon emission computed tomography/computed tomography.

^a Median (IQR), Mann–Whitney U test.

^b n (%), chi‐square test.

According to the Apathy Scale, 42 patients (55.3%) were classified as having apathy. There were no significant differences in age, sex, and disease duration between patients with and without apathy. By subtype, apathy was present in 27 of 44 patients (61%) with MSA‐C and 15 of 32 patients (47%) with MSA‐P, with no significant difference between subtypes (p = 0.210).

The 76 included patients were additionally compared with the 37 patients excluded because of MMSE scores < 27 (Table S2). Compared with included patients, excluded patients were older at symptom onset and admission, had fewer years of education, had higher Apathy Scale scores, and were more frequently classified as having apathy (29/37 [78.4%] vs. 42/76 [55.3%], p = 0.017). The distribution of clinically established and clinically probable MSA also differed between the groups. In contrast, no significant differences were observed in sex, disease duration, MSA subtype, or UMSARS parts I and II scores.

3.2. Comparison of Clinical Characteristics

As shown in Table 2, compared with the non‐apathy group, the apathy group had significantly lower ACE‐III visuospatial subscores [Hodges–Lehmann estimate −1.0, 95% confidence interval (CI) −1.0 to 0.0; p = 0.002] and less frequent nOH (OR 0.27, 95% CI 0.10–0.69; p = 0.006) but similar HAM‐D scores (Hodges–Lehmann estimate 1.0, 95% CI −1.0 to 3.0; p = 0.211).

TABLE 2.

Comparison of clinical characteristics between patients with and without apathy.

Clinical characteristics	With apathy (n = 42)	Without apathy (n = 34)	Effect estimates (95% CI)	p
Disease severity scores
UMSARS part I score a	12.0 (9–16)	14 (11–17)	−2.0 (−4.0 to 1.0)	0.104
UMSARS part II score a	13.0 (11–17)	14.5 (10–18)	0.0 (−3.0 to 2.0)	0.867
ICARS score a	24.0 (19–31)	26.5 (18–31)	−1.0 (−6.0 to 4.0)	0.718
MDS‐UPDRS part III score a	25.0 (13–38)	23.0 (14–40)	1.0 (−6.0 to 6.0)	0.900
Neuropsychiatric assessments
FAB score a	15.0 (14–16)	15.0 (13–16)	0.0 (−1.0 to 1.0)	0.824
MMSE score a	29.0 (28–30)	29.0 (28–30)	0.0 (−1.0 to 0.0)	0.221
ACE‐III total score a	91.5 (87–93)	92.0 (88–95)	−1.0 (−4.0 to 1.0)	0.172
Attention/orientation a	17.0 (16–18)	18.0 (17–18)	0.0 (−1.0 to 0.0)	0.069
Memory a	23.0 (22–25)	23.0 (22–24)	0.0 (−1.0 to 1.0)	0.866
Fluency b	9.6 ± 2.2	10.1 ± 2.3	−0.6 (−1.6 to 0.4)	0.253
Language a	26.0 (25–26)	26.0 (25–26)	0.0 (0.0 to 0.0)	0.745
Visuospatial a	15.0 (14–16)	16.0 (15–16)	−1.0 (−1.0 to 0.0)	0.002 c
WMS‐R indices
Attention and concentration b	99.1 ± 11.8	100.8 ± 13.7	−1.6 (−7.5 to 4.2)	0.580
General memory a	93.0 (86–100)	93.0 (87–104)	−2.0 (−8.0 to 3.0)	0.436
Verbal memory b	89.1 ± 11.7	91.4 ± 13.6	−2.3 (−8.1 to 3.5)	0.427
Visual memory a	105.5 (90–113)	105.0 (96–113)	−2.0 (−7.0 to 4.0)	0.541
Delayed recall b	92.2 ± 13.2	94.6 ± 12.6	−2.4 (−8.3 to 3.6)	0.429
HAM‐D scores a	5.0 (4–7)	5.0 (3–8)	1.0 (−1.0 to 3.0)	0.211
RBDSQ‐J scores a	5.0 (4–7)	4.0 (3–8)	0.0 (−1.0 to 2.0)	0.566
Autonomic functions
PVR volume, mL a	58.4 (34–111)	73.2 (40–151)	−12.5 (−39.0 to 12.4)	0.305
nOH c	15 (35.7%)	23 (67.6%)	0.27 (0.10 to 0.69)	0.006*

Abbreviations: ACE‐III, Addenbrooke's Cognitive Examination III; FAB, Frontal Assessment Battery; HAM‐D, Hamilton Depression Rating Scale; ICARS, International Cooperative Ataxia Rating Scale; MDS‐UPDRS, Movement Disorder Society's Unified Parkinson's Disease Rating Scale; MMSE, Mini‐Mental State Examination; nOH, neurogenic orthostatic hypotension; PVR, post‐void residual; RBDSQ‐J, Japanese version of the REM Sleep Behavior Disorder Screening Questionnaire; UMSARS, Unified Multiple System Atrophy Rating Scale; WMS‐R, Wechsler Memory Scale‐Revised.

^a Median (IQR), Hodges–Lehmann estimate, Mann–Whitney U test.

^b Mean ± SD, mean difference, Student's or Welch's t‐test.

^c n (%), odds ratio, chi‐square test.

^* p < 0.05.

3.3. MRI and CBF SPECT Findings

Compared with the non‐apathy group, the apathy group did not show significant changes in the gray matter volume in all brain regions but demonstrated a significant cluster of reduced perfusion on voxel‐wise CBF SPECT analysis, with the peak voxel located in the left medial superior frontal gyrus [peak MNI coordinates x = −4, y = 70, z = 8; maximum t value = 4.31; cluster size = 1894 voxels; p(FWE) = 0.041; Figure 1]. This cluster extended across the bilateral medial superior frontal cortex, medial orbitofrontal cortex, and anterior cingulate cortex, which broadly corresponded to the medial prefrontal cortex (mPFC). No regions showed significantly increased perfusion.

FIGURE 1.

Reduced cerebral blood flow in patients with apathy than in those without apathy. Cortical surface rendering (A) and sagittal (B) views show a significant cluster in the medial prefrontal cortex involving the medial superior frontal, orbitofrontal, and anterior cingulate cortices.

3.4. Multivariate Analysis of the Significant SPECT Cluster

On multivariate logistic regression analysis, the adjusted cluster z score remained significantly associated with apathy after adjustment for the other clinical variables (adjusted OR 0.27, 95% CI 0.13–0.58; p = 0.001). Moreover, apathy was independently associated with ACE‐III visuospatial score (adjusted OR 0.59, 95% CI 0.36–0.95; p = 0.029) and nOH (adjusted OR 0.17, 95% CI 0.05–0.59; p = 0.006) but not with UMSARS part I score (adjusted OR 0.93, 95% CI 0.83–1.05; p = 0.230) and HAM‐D score (adjusted OR 0.98, 95% CI 0.85–1.14; p = 0.794).

3.5. Seed‐Based Covariance Analysis

Figure 2 and Table S3 show the results of seed‐based covariance analysis using the left medial superior frontal gyrus VOI as the seed. After excluding VOIs that overlapped with the significant cluster identified on voxel‐wise SPECT analysis, no correlations survived multiple‐comparison correction in the apathy group, although an exploratory positive correlation was observed with the left superior frontal gyrus (r = 0.536, q = 0.064).

FIGURE 2.

Positive seed‐based covariance networks of the left medial superior frontal gyrus. Images from patients with apathy (A) and without apathy (B) are shown. Blue nodes indicate the seed; red and pink nodes indicate significant and exploratory positive correlations. Positive cerebellar correlations in the non‐apathy group were not observed in the apathy group.

In the non‐apathy group, there was a significant positive correlation with the left superior frontal gyrus (r = 0.636, q = 0.043) and a significant negative correlation with the right amygdala (r = −0.617, q = 0.043). In addition, exploratory positive correlations were identified with the left supplementary motor area (r = 0.589, q = 0.058) and multiple cerebellar regions, predominantly in the posterior lobe (right Crus II/VIIb/VIII, bilateral lobule IX, vermis IX/X, and left lobule III; r = 0.543–0.591, q = 0.058–0.091). In the apathy group, the correlation coefficients for these cerebellar VOIs ranged from −0.143 to 0.001, and all corresponding q values were 1.000.

In a post hoc analysis, the mPFC seed × FAB interaction coefficients were positive across all eight cerebellar VOIs (B = 0.085–0.207). Six of the eight interactions were nominally significant (p = 0.013–0.037); however, none remained significant after Benjamini–Yekutieli correction (q = 0.134–0.508; Table S4).

4. Discussion

In this study, we evaluated apathy in patients with MSA and preserved cognitive function using a self‐reported scale and assessed depression using a specific measure. Approximately half of the patients had apathy, and they showed relatively less frequent nOH and low visuospatial cognitive scores. Voxel‐based analysis revealed no significant difference in gray matter volume between patients with apathy and those without apathy, whereas voxel‐wise CBF SPECT demonstrated reduced mPFC perfusion in the apathy group, and seed‐based covariance analysis further suggested reduced positive covariance between this region and the cerebellum.

In MSA, apathy is a frequent behavioral disturbance that is distinct from depression, even at a cognitively preserved stage. In this cohort, apathy was identified in 55.3% of patients and tended to be slightly more frequent in MSA‐C than in MSA‐P. In addition, depression scores were not independently associated with apathy. The reported frequencies of apathy in MSA have varied across studies, likely reflecting differences in patient selection and assessment methods. Studies that used comprehensive informant‐based assessment tools, such as the Neuropsychiatric Inventory and Frontal Behavioral Inventory, have generally reported prevalence rates of approximately 40%–50% [8, 11, 26, 27, 28, 29]. Self‐rated nonmotor symptom scales have yielded substantially higher estimates of 80%–90% [6, 30], and apathy‐specific tools have reported approximately 50% [7, 10]. Among these approaches, informant‐based assessments have been suggested to be less sensitive to subtle internal changes in the early phase of apathy [26]. In this study, we used a self‐reported scale to enable more accurate identification of apathy in patients with preserved cognitive function [31] and found that apathy was already present in approximately half of patients. Notably, disease duration and UMSARS parts I and II scores did not significantly differ between included patients and those excluded because of MMSE scores < 27, indicating that this selection did not simply reflect differences in disease duration or motor severity. Although previous reports have yielded inconsistent findings on subtype differences [7, 11, 27], our findings indicated that apathy was also common in MSA‐C.

Medial frontostriatal circuit dysfunction is likely to play a central role in the pathophysiology of apathy in MSA. In this study, reduced perfusion in the mPFC, including the medial orbitofrontal cortex and anterior cingulate cortex, was independently associated with apathy after adjustment for other clinical variables. The ventromedial prefrontal cortex is thought to contribute to valuation based on reward and cost, whereas the anterior cingulate cortex is involved in linking such value signals to the initiation and maintenance of goal‐directed behavior; both regions are considered key neural substrates of apathy [32]. Neuropathological studies on MSA have shown that the disease process extends to the frontal cortex, including the anterior cingulate cortex [33]. In MSA‐P, longitudinal voxel‐based morphometry studies have demonstrated progressive atrophy of the medial frontal and orbitofrontal cortices [34], and neuropathological evidence suggested that frontal cortical involvement can occur relatively early in the disease course [33]. On the other hand, neocortical pathological spread in MSA‐C had been thought to occur relatively late [35]. In this study, the finding of mPFC hypoperfusion supported the importance of medial frontostriatal circuit dysfunction as a neural substrate of apathy in MSA. At the same time, given that our cohort was at a relatively early disease stage and included several patients with MSA‐C, attributing this finding solely to direct pathological involvement of the mPFC may not be plausible. This suggests that a broader network dysfunction affecting the mPFC may also contribute to apathy in MSA.

The mechanisms related to cerebellar cognitive affective syndrome (CCAS) may also contribute to apathy in MSA. In this study, patients with apathy showed mild visuospatial impairment, and covariance analysis suggested reduced positive covariance between the mPFC and cerebellar regions, predominantly in the posterior lobe. The posterior cerebellum is thought to contribute to cognitive and affective regulation by forming cerebello‐cortical loops with the prefrontal cortex, parietal association cortex, and limbic system [36]. Disruption of this network gives rise to CCAS, which is characterized by deficits in executive function, visuospatial cognition, language, and emotion–affect, and apathy has also been described as one of its manifestations [36, 37]. In MSA, degeneration of pontocerebellar pathways has been associated with impairments in language, visuospatial function, and processing speed [38, 39], and visuospatial dysfunction has also been linked to reduced cerebellar metabolism [40]. Taken together, these observations suggest the possible involvement of CCAS‐related mechanisms in apathy in MSA. However, visuospatial performance was the only cognitive domain that differed between the groups. Although post hoc analysis showed positive mPFC × FAB interactions across all eight cerebellar regions, none remained significant after multiple‐comparison correction. Accordingly, the observed covariance pattern may also reflect visuospatial or broader cognitive network dysfunction and should therefore be regarded as exploratory and hypothesis‐generating. Nevertheless, the possibility of CCAS‐related network involvement may provide one theoretical explanation for the high frequency of apathy not only in MSA‐P, which is more directly related to frontostriatal dysfunction, but also in MSA‐C.

Furthermore, this study found that nOH was relatively infrequent in the apathy group. In MSA, nOH is thought to result from degeneration of the central orthostatic regulatory network, which includes the hypothalamus, brainstem autonomic nuclei, and intermediolateral cell column of the spinal cord [41]. The relationship between nOH and apathy in MSA remains poorly understood. In a previous longitudinal study, patients with and without orthostatic hypotension showed no significant difference in apathy severity at baseline or in its longitudinal change [42]. One possible explanation for the inverse association observed in our cohort is heterogeneous involvement of neural systems underlying orthostatic regulation and motivation during the course of MSA. However, given the cross‐sectional and single‐center design, the mechanisms underlying this association remain unclear. Selection or referral bias, incomplete characterization of the severity and temporal evolution of nOH, and residual confounding by unmeasured clinical or treatment‐related factors cannot be excluded.

Several limitations of this study should be acknowledged. First, the study cohort was based on clinical rather than neuropathological diagnoses, and diagnostic misclassification cannot be completely excluded. However, approximately 70% of our patients met the clinically established MSA criteria, which have high specificity against neuropathological diagnosis [43, 44]. Second, considering its retrospective cross‐sectional design at a single center, this study was subject to selection bias and limited generalizability, and the temporal and causal relationships among the observed findings could not be determined. Although we restricted the analysis to patients with MMSE scores ≥ 27, the MMSE may not fully capture the frontal‐executive dysfunction characteristic of MSA [2]. Patients excluded because of MMSE scores < 27 were more frequently classified as having apathy based on a self‐report apathy scale; however, the absence of informant‐based assessments limited reliable evaluation of apathy and its imaging correlates in these patients. Therefore, our findings are primarily applicable to patients with MSA and relatively preserved global cognitive function. Further studies using apathy assessments appropriate to cognitive status are needed to determine whether these findings extend to patients with more pronounced cognitive impairment. Third, although our findings suggested an association between apathy and CCAS in MSA, we could not specifically assess executive function as a core domain of this syndrome. Future longitudinal studies using tools that more comprehensively assess each CCAS domain will be needed to clarify the relationship between apathy and CCAS, as well as their impact on functional outcomes and QOL.

In conclusion, in patients with MSA and relatively preserved global cognitive function, apathy was common in both motor subtypes, even at a relatively early stage, and was strongly associated with mPFC dysfunction. Furthermore, our findings suggested the possible contribution of CCAS‐related mechanisms to its pathophysiology. Taken together, these findings indicated that apathy is an important nonmotor feature of MSA from its early stages and may exert a long‐term impact on the QOL of both patients and caregivers.

Author Contributions

Yuki Nakagawa: methodology, software, data curation, investigation, formal analysis, visualization, writing – original draft. Atsuhiko Sugiyama: conceptualization, methodology, software, data curation, validation, funding acquisition, project administration, writing – review and editing. Yoshikazu Nakano: methodology, software, visualization, writing – review and editing. Hajime Yokota: writing – review and editing. Shigeki Hirano: writing – review and editing. Masahiro Namiki: writing – review and editing. Tatsuya Yamamoto: writing – review and editing. Yoshitaka Yamanaka: writing – review and editing. Shoichi Ito: writing – review and editing. Masahiro Mori: supervision, writing – review and editing.

Funding

This work was partly supported by grants‐in‐aid from the Research Committee of Ataxia, Health Labor Sciences Research Grant, and the Ministry of Health, Labor and Welfare, Japan (grant number: JPMH20FC1041), and the Japan Agency for Medical Research and Development (grant number: JP25wm0625520).

Conflicts of Interest

S.H. received honoraria for lectures from Eli Lilly Japan K.K., Daiichi Sankyo Co. Ltd., and Kowa Company Ltd. YO.N. received honoraria for lectures from Kowa Company Ltd., Eisai Co. Ltd., and Eli Lilly Japan K.K., and grant support from Japan Society for the Promotion of Science KAKENHI and the Miyata Yukihiko Memorial ALS Research Grant. All other authors report no financial disclosures within the last 12 months.

Supporting information

Table S1: Imaging acquisition and reconstruction parameters.

Table S2: Comparison of clinical characteristics between included patients and patients excluded based on the cognitive criterion.

Table S3: Results of seed‐based covariance analysis in the apathy and non‐apathy groups.

Table S4: Post hoc analysis of mPFC–cerebellar perfusion relationships according to FAB score.

Data Availability Statement

The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.