GRAPHICAL ABSTRACT

INTRODUCTION

Reduced uptake of ¹²³I-meta-iodobenzylguanidine (¹²³I-MIBG) in the heart among patients with Parkinson’s disease (PD) reflects myocardial postganglionic sympathetic dysfunction, which occurs in the neurodegenerative process of PD. Decreased ¹²³I-MIBG uptake is frequently observed in patients with Lewy body (LB) diseases (LBDs), including PD and dementia with Lewy bodies (DLBs), and its severity typically increases as the disease progresses. Cardiac sympathetic denervation (CSD), as assessed by ¹²³I-MIBG scintigraphy, has been incorporated into the diagnostic criteria for PD and DLB [1,2]. Previous single-center and meta-analysis studies, which analyzed myocardial ¹²³I-MIBG scintigraphy in a single imaging session, have demonstrated low sensitivity but high specificity in distinguishing PD from atypical Parkinsonian syndromes (APS) [3,4]. EFNS/MDS-ES suggest that this imaging modality can aid in the differential diagnosis of PD versus APS with level A and class II evidence [5].

However, approximately 30% of PD patients show normal ¹²³I-MIBG uptake in the initial scan [6]. Recent studies using sequential ¹²³I-MIBG scintigraphy have demonstrated progressive CSD in PD patients [7]. Moreover, longitudinal ¹²³I-MIBG imaging has proven to be more effective than initial imaging in differentiating PD from APS [8].

In patients with PD, myocardial ¹²³I-MIBG uptake is inversely correlated with bradykinesia, rigidity, speech impairment, postural instability, gait disturbance, and falls [9,10]. Additionally, PD patients with normal ¹²³I-MIBG uptake in the early stage tend to exhibit slower progression of motor symptoms [11,12]. In contrast, those with reduced ¹²³I-MIBG uptake experience greater nonmotor burdens, including cognitive impairment, constipation, orthostatic hypotension, hyposmia, depression, anxiety, psychosis, and rapid eye movement (REM) sleep behavior disorder (RBD) [13,14]. Furthermore, reduced ¹²³I-MIBG uptake is associated with a greater incidence of motor complications [15]. These findings suggest that variability in CSD, as assessed by ¹²³I-MIBG uptake, may reflect distinct patterns of disease progression in PD patients.

Recently, the α-synuclein origin site and connectome (SOC) model has been proposed to classify PD on the basis of the initial site of misfolded α-synuclein (α-syn) deposition and its propagation pathway. This model is based on the premise that α-syn pathology originates at a specific site and subsequently spreads in a sequential manner. The propagation is bidirectional through neuronal connections, and differences in the site of origin and direction of spread may account for variations in clinical presentation and disease progression. According to the SOC model, PD can be categorized into body-first and brain-first subtypes. In body-first PD, α-syn pathology originates in the peripheral autonomic or enteric nervous system and ascends via the vagus nerve and sympathetic connections through the midbrain, eventually reaching the substantia nigra and striatum (bottom-up propagation). In contrast, brain-first PD begins in the olfactory bulb or amygdala, where it spreads to the striatum and midbrain before propagating retrogradely to the peripheral nervous system (top-down propagation). Recent multimodal imaging studies have provided supporting evidence for these subtypes [16]. In body-first PD and isolated REM sleep behavior disorder (iRBD), CSD, cholinergic denervation, and delayed colon transition time were observed as early findings. Conversely, in brain-first PD, although dopaminergic degeneration is evident, nonmotor symptoms are relatively preserved. Body-first and brain-first PD may represent two distinct pathological processes, corresponding to midbrain-predominant and amygdala-olfactory-predominant patterns in Braak’s staging system.

There are distinct clinical differences between body-first PD and brain-first PD, particularly in the early stages of disease. In body-first PD, nonmotor symptoms, such as RBD, constipation, olfactory dysfunction, and orthostatic hypotension, often precede the onset of motor symptoms. Compared with that in brain-first PD, dopaminergic neuronal degeneration in the brain tends to progress symmetrically in body-first PD [17]. Additionally, motor and cognitive symptoms are typically more severe and progress more rapidly [18,19]. In contrast, brain-first PD is characterized by asymmetrical dopaminergic degeneration, leading to asymmetrical motor symptoms. Moreover, the progression of cognitive and motor symptoms tends to be slower compared to body-first PD. A recent review summarized key updates on this evolving topic [20].

To distinguish between body-first PD and brain-first PD, it is essential to determine the regional sequence of pathological α-syn deposition. However, in clinical practice, directly assessing the distribution of α-syn pathology is challenging, and temporal discrepancies may exist between pathological involvement, neurodegeneration, and symptom onset. Given that bidirectional propagation can ultimately lead to a convergent disease state, the presence of pathological changes in both the peripheral and nigrostriatal systems complicates the determination of the temporal sequence of disease progression. Therefore, the most feasible approach for distinguishing these two subtypes is to identify differences in pathological involvement at the prodromal or early disease stage and to monitor the direction of pathological progression over time.

reduction in myocardial ¹²³I-MIBG uptake suggests the presence of LB pathology in the heart [21]. Therefore, reduced ¹²³IMIBG uptake in the prodromal or early stages of PD may indicate a body-first phenotype. In this review, we aim to provide evidence that CSD, as visualized via myocardial ¹²³I-MIBG scintigraphy, can be used to distinguish brain-first and body-first phenotypes within the framework of the SOC model.

MULTIMODAL EVIDENCE FOR CSD INDICATING BODY-FIRST PD

In body-first PD, the heart often shows early signs of LB pathology before motor symptoms appear. Previous studies have demonstrated reduced myocardial ¹²³I-MIBG uptake in individuals with iRBD and in patients with PD presenting with premotor RBD, suggesting that CSD precedes nigrostriatal degeneration in body-first PD. Postmortem studies have revealed that LBs are frequently found in cardiac sympathetic ganglia and nerve fibers in patients with PD [22,23]. In PD, α-syn deposition appears earlier in the distal axons of the cardiac sympathetic nerves than in the paravertebral sympathetic ganglia [24]. This centripetal progression suggests that the pathology originates in the peripheral autonomic nerves and progresses toward the brain, aligning with the body-first PD trajectory in which peripheral nerves are affected first, with the heart being a significant early target.

The accumulation of misfolded α-syn in the heart can lead to CSD. A decrease in tyrosine hydroxylase (TH)-immunoreactive sympathetic fibers and abundant α-syn accumulation in the epicardium have been observed in patients with reduced ¹²³IMIBG uptake, supporting the presence of LBD [21]. Patients with CSD may experience orthostatic hypotension even before the onset of tremors or stiffness [25]. In prospective studies, reduced ¹²³I-MIBG uptake in patients with PD and those with iRBD was independent of dopaminergic degeneration but was associated with autonomic dysfunction and olfactory impairment, both of which are more prevalent in body-first PD [14,26]. Additionally, a recent imaging study demonstrated that patients with PD could be clustered into cardio-cortical impairment and dopaminergic-dominant dysfunction subtypes on the basis of differences in ¹²³I-MIBG uptake, dopaminergic degeneration, and disease duration [27]. Compared with the dopaminergic-dominant dysfunction cluster, the cardiac-cortical impairment cluster presented early CSD and greater gray matter atrophy. Notably, early myocardial ¹²³I-MIBG uptake has emerged as a key indicator for distinguishing pathological and clinical subtypes of PD. Therefore, ¹²³I-MIBG uptake may reflect differences in peripheral involvement between body-first PD and brain-first PD and may help identify their distinct trajectories. Interestingly, CSD frequently overlaps with nonmotor symptoms such as constipation and RBD, further supporting the notion that body-first PD involves extensive autonomic and brainstem structures prior to nigrostriatal degeneration [28].

The α-syn seed amplification assay (SAA) is a diagnostic technique that amplifies and visualizes phosphorylated α-syn. This method has been validated for diagnosing LBD and differentiating between synucleinopathies. The detection of α-syn SAA in PD patients may be associated with pathological myocardial ¹²³IMIBG uptake and may reflect disease burden. A recent study reported that 85.2% of patients with PD and reduced ¹²³I-MIBG uptake were positive for cerebrospinal fluid (CSF) α-syn SAA, whereas only 14.3% of those with normal ¹²³I-MIBG uptake were positive [29]. Reduced ¹²³I-MIBG uptake associated with body-first PD may thus indicate a high α-syn burden. Positive skin α-syn SAA results in PD have been linked to the presence of RBD, constipation, mild cognitive impairment, and a greater number of nonmotor symptoms [30]. Additionally, CSF α-syn SAA positivity has been associated with a higher Braak stage [31].

Cohort studies have demonstrated that CSF α-syn SAA is positive in 93% of individuals with iRBD, and dermal α-syn SAA has a 79.1% positivity rate [32,33]. Another study revealed that α-syn can be detected using SAA up to 10 years before the onset of PD [34]. Similar to CSD, positive α-syn SAA findings suggest a high risk of phenoconversion in prodromal PD [35]. Therefore, the presence of α-syn in peripheral tissues during the prodromal stage may be indicative of body-first PD. A recent study classified PD subtypes on the basis of α-syn SAA profiles, identifying dermal SAA+/nasal SAA− as indicative of body-first PD and dermal SAA−/nasal SAA+ as characteristic of brain-first PD [36]. Although the diagnostic accuracy of α-syn SAA requires further evaluation, regional differences in α-syn distribution could serve as another biomarker for distinguishing body-first PD from brain-first PD.

EVIDENCE RELATED TO INCIDENTAL LBD

Incidental Lewy body disease (ILBD) is a condition in which LBs—abnormal aggregates of α-syn that develop within nerve cells—are found in the brains of individuals at autopsy who presented no clinical signs of PD or DLB during life. The presence of LBs is a hallmark pathological feature of these disorders, and their detection in ILBD suggests that LB presence may represent a preclinical stage of PD or DLB. The observation of brainstem LBs in iRBD patients, which are strongly indicative of prodromal PD, further supports this possibility [37].

Autopsy studies in individuals with ILBD have revealed that neuronal degeneration in the substantia nigra is comparable to that observed in patients with clinically manifested PD [38,39]. Additionally, α-syn SAA has been detected in the CSF and skin of subjects with ILBD [40]. Individuals with ILBD also exhibit impaired olfactory function and various nonmotor symptoms [41]. Furthermore, an electrophysiological study revealed that the resting tremor frequency in ILBD patients fell between that of healthy individuals and patients with PD [42]. These diverse clinical, electrophysiological, and pathological findings support the hypothesis that ILBD represents a prodromal stage of PD.

In individuals with ILBD, reduced myocardial ¹²³I-MIBG uptake has been observed, along with α-syn deposition in TH-immunoreactive cells within the epicardium [22,43]. Autopsy studies have demonstrated that CSD precedes neuronal cell loss in the dorsal vagal nucleus and sympathetic ganglia, as well as LB deposition in the midbrain [23,44]. These findings support a peripheral origin of early PD pathology, following a bottom-up spreading mechanism.

In ILBD, α-syn deposition has been observed not only in the heart but also in the submandibular gland, basal ganglia, cervical spinal ganglia, intestines, and stomach [39]. Notably, neuronal cell loss in the substantia nigra in individuals with ILBD did not correlate with nigral LB deposition but rather preceded it and was associated with the local α-syn burden [45]. These findings suggest that reduced myocardial ¹²³I-MIBG uptake, potentially resulting from α-syn deposition, may serve as an indicator of prodromal PD and support the hypothesis that the peripheral onset of α-syn pathology is consistent with the progression pattern of body-first PD.

Future research into ¹²³I-MIBG uptake in ILBD may help clarify the temporal relationship between CSD and the onset of clinical symptoms of LBDs. This finding also underscores the potential of myocardial ¹²³I-MIBG scintigraphy not only as a diagnostic tool in symptomatic PD and DLB, but also for identifying individuals in preclinical stages.

EVIDENCE RELATED TO IDIOPATHIC RBD

RBD is a characteristic symptom of synucleinopathies, including PD, DLB, and MSA, and indicates pathological involvement of the midbrain. iRBD is considered a prodromal state of PD, and the progression from iRBD to PD typically reflects the body-first PD subtype. Accordingly, in many clinical studies investigating brain-first and body-first PD subtypes, premotor RBD has been used primarily as a criterion to differentiate between the two phenotypes.

iRBD is associated with various autonomic dysfunctions and nonmotor manifestations commonly observed in patients with PD. Pathological analyses have demonstrated that patients with iRBD exhibit brainstem-predominant PD pathology, with more pronounced LB deposition and neuronal loss in the dorsal motor nucleus of the vagus nerve and the medullary tegmentum than in the locus ceruleus and the substantia nigra [46]. A considerable proportion of patients with iRBD demonstrate reduced myocardial ¹²³I-MIBG uptake, often accompanied by decreased heart rate variability, indicating cardiac autonomic dysfunction [47]. While autonomic impairment in iRBD patients may serve as a potential predictor of phenoconversion to PD, its predictive accuracy remains limited [48]. In contrast, myocardial ¹²³I-MIBG uptake has emerged as a more reliable predictor of phenoconversion in iRBD patients, demonstrating high sensitivity and specificity [49].

In patients with iRBD, myocardial ¹²³I-MIBG uptake is typically reduced [50-52]. Cross-sectional studies have shown that the heart-to-mediastinum (H/M) ratio in patients with iRBD is even lower than that in patients with PD [51,52]. In one Japanese study, 29 out of 31 patients with iRBD presented reduced ¹²³I-MIBG uptake, with a delayed H/M ratio of 1.49±0.39 [51]. In comparison, 21 out of 26 patients with PD presented reduced uptake, with a delayed H/M ratio of 1.80±0.68. In another study, the delayed H/M ratio in iRBD patients was 1.39±0.40, whereas in patients with PD, it was 1.55±0.45 [52]. The H/M ratio decreased as the Hoehn and Yahr stage advanced, and no significant difference was detected between the groups at stage 3 or above. Given that iRBD is considered a prodromal stage of PD and that ¹²³I-MIBG uptake generally decreases with disease progression, the relatively high H/M ratio observed in PD patients may reflect a heterogeneous group comprising both individuals who progressed from iRBD (body-first PD) and those with preserved ¹²³I-MIBG uptake (brain-first PD). This implies that both bodyfirst and brain-first subtypes of PD may coexist and that ¹²³IMIBG uptake may serve as a useful biomarker for differentiating body-first and brain-first PD.

Therefore, reduced myocardial ¹²³I-MIBG uptake in early PD frequently overlaps with premotor RBD, and early ¹²³I-MIBG reduction strongly suggests disease progression along the bodyfirst PD subtype trajectory that progresses from iRBD.

EVIDENCE RELATED TO PURE AUTONOMIC FAILURE

Pure autonomic failure (PAF) is a neurodegenerative disorder characterized primarily by autonomic dysfunction without the motor symptoms observed in other synucleinopathies. A significant proportion of patients with PAF later progress to PD or DLB, suggesting that PAF may represent a prodromal phase of LBDs (Figure 1) [53].

Pathology studies have shown that these patients exhibit neurodegeneration accompanied by LB deposition in the autonomic nervous system [54]. Notably, myocardial ¹²³I-MIBG uptake is reduced in the majority of patients with PAF, making it one of the most sensitive biomarkers for detecting autonomic failure [55]. A cohort study demonstrated that myocardial ¹²³I-MIBG uptake is an effective tool not only for identifying prodromal PD in patients with RBD, but also in those with PAF [53]. These findings suggest that myocardial ¹²³I-MIBG uptake could play a crucial role in the early detection of body-first PD.

However, not all cases of PAF progress to LBD. Some may convert to multiple system atrophy (MSA) or may be associated with conditions such as amyloid neuropathy. Interestingly, in certain patients with normal ¹²³I-MIBG uptake, PAF was later converted to MSA, suggesting that ¹²³I-MIBG imaging may be a valuable tool for differentiating LBD from MSA [56]. In a recent study, all 13 patients with PAF exhibited reduced ¹²³I-MIBG uptake, and phosphorylated α-syn deposition was observed in skin biopsies, closely resembling the pathological features of PD and DLB [57]. In contrast, among the 13 patients with MSA, although 11 had phosphorylated α-syn in the skin, all had normal ¹²³I-MIBG uptake. Notably, phosphorylated α-syn deposition in autonomic nerves was observed in PAF and LBD but was largely absent in MSA, reinforcing the potential of ¹²³I-MIBG imaging and skin biopsies as differential diagnostic tools.

Reduced ¹²³I-MIBG uptake in the heart is a common finding in PAF, supporting its role as evidence of prodromal LBD (Figure 1). This reduction implies the presence of LB pathology within peripheral autonomic nerves. The early involvement of peripheral LB pathology in PAF and its subsequent progression to PD aligns with the body-first PD progression model. Thus, myocardial ¹²³I-MIBG imaging holds promise as a diagnostic and predictive biomarker for both prodromal and body-first PD.

BIOMARKERS FOR DIFFERENTIATING BETWEEN BODY-FIRST AND BRAIN-FIRST PD SUBTYPES

Within the SOC model, differentiating body-first from brain-first PD subtypes necessitates identifying both the primary site of pathological onset and the subsequent direction of propagation. However, by the time PD manifests clinically, pathological involvement often exists in both the peripheral autonomic nervous system and the central nervous system, limiting the ability to clearly distinguish between these two phenotypes.

Various biomarkers have been explored to aid in this differentiation and can be broadly categorized into two approaches. The first involves retrospective inference of the disease trajectory on the basis of prodromal features suggestive of a peripheral origin and bottom-up propagation, which are characteristic of body-first PD. Key prodromal indicators include premotor RBD and early autonomic dysfunctions. The second approach focuses on the early clinical phase of PD, when phenotypic differences between body-first and brain-first subtypes may be more distinct. Biomarkers commonly used in this context include CSD assessed via ¹²³I-MIBG myocardial scintigraphy, asymmetry in striatal dopamine transporter (DAT) uptake, and peripheral α-syn deposition detected through skin or gastrointestinal biopsies. The diagnostic utility of each biomarker may vary depending on the timing of assessment, methodological accuracy, and clinical context. Therefore, appropriate selection and interpretation of these markers are essential. Table 1 summarizes the characteristics, advantages, and limitations of these tools.

Although the SOC model remains hypothetical and requires further empirical validation, several studies have employed premotor RBD through retrospective assessment to distinguish between body-first PD and brain-first PD. These studies have identified clinical and imaging features that are consistent with the hypothesized patterns of pathological spread [16,17]. The phenoconversion from iRBD to PD strongly supports the bottom-up propagation of α-syn pathology. iRBD is also associated with pathological LB deposition in the midbrain and is widely recognized as a robust prodromal indicator of PD. Consequently, premotor RBD serves as a strong clinical marker of body-first PD.

RBD is a highly distinctive symptom and can be assessed through detailed interviews with patients and caregivers. Although polysomnography remains the gold standard for diagnosis, its high cost and limited accessibility are notable barriers. Reliance solely on clinical questionnaires yields suboptimal diagnostic accuracy. Prior studies have reported specificity values of RBD questionnaires ranging from 48.1% to 67.4%, with sensitivity between 80% and 92% [58]. Moreover, the possibility of early MSA cannot be entirely excluded. The lack of a reliable quantitative measure further limits the utility of RBD in assessing disease onset and progression.

Premotor autonomic dysfunction, similar to premotor RBD, may indicate phenoconversion and has the advantage of being clinically accessible through symptom evaluation. However, autonomic dysfunction can arise from multiple etiologies, and its diagnostic accuracy may be limited. The current lack of standardized diagnostic criteria restricts the utility of premotor autonomic impairments as a standalone biomarker for prodromal PD.

Striatal DAT uptake asymmetry may reflect distinct pathological progression patterns between body-first PD and brain-first PD and has been explored as a potential imaging biomarker for distinction. This imaging-based approach can be applied at the time of diagnosis and allows for concurrent evaluation of cognitive and motor symptoms. However, a clearly defined cutoff value for DAT asymmetry has yet to be established, which limits its utility at the individual level. Furthermore, DAT imaging is not suitable for assessing the prodromal phase or advanced stages and may be confounded by concomitant brain lesions.

Pathological confirmation of peripheral α-syn involvement during the early or prodromal stage could support the body-first PD hypothesis. However, low sensitivity limits its use as a standalone biomarker. Additionally, the need for tissue biopsy or α-syn SAA constrains its clinical applicability.

UTILIZATION OF CSD DIFFERENTIATING BODY-FIRST PD FROM BRAIN-FIRST PD

CSD is a distinctive feature of LBD and serves as an effective biomarker for differentiating body-first PD from brain-first PD. In particular, myocardial ¹²³I-MIBG scintigraphy enables both highly accurate diagnosis and quantitative assessment of CSD. CSD indicates peripheral α-syn involvement, and the presence of CSD in the early stages of PD strongly supports the body-first subtype. Among patients with PD, CSD frequently overlaps with RBD [16,59]. However, unlike RBD, CSD is not typically observed in MSA, offering a clear differential advantage. Furthermore, the anatomical separation between the heart and the brain supports the plausibility of temporal dissociation in the pathological involvement between the two regions.

However, the absence of specific clinical symptoms directly attributable to CSD limits its utility in identifying prodromal PD. In most cases, CSD is only assessed after the clinical diagnosis of PD has been made, making it difficult to establish its temporal precedence. Additionally, ¹²³I-MIBG scintigraphy involves substantial costs and requires specialized equipment and facilities. Comorbid cardiac conditions—such as ischemic heart disease, arrhythmia, idiopathic dilated cardiomyopathy, hypertrophic cardiomyopathy, and cardiomyopathies—may confound ¹²³I-MIBG measurements [60]. Notably, reduced ¹²³I-MIBG uptake has been reported in approximately 37% of patients with heart failure [61]. Given the high prevalence of cardiac disease in elderly individuals and the difficulty in detecting asymptomatic cardiac conditions, it is essential to consider potential cardiac influences when interpreting ¹²³I-MIBG scintigraphy results. Moreover, CSD can eventually develop in brain-first PD as the disease progresses, underscoring the importance of utilizing this marker as early in the disease course as possible. Previous studies have shown that ¹²³I-MIBG values may decrease in patients who initially present normal uptake, typically within approximately 2 to 3 years of follow-up [8,62]. Therefore, performing ¹²³I-MIBG scintigraphy within 2 years of symptom onset may enhance its diagnostic utility. Compared with those with early deficits, patients with initially preserved uptake tended to maintain normal H/M ratios over time, supporting the value of longitudinal quantitative comparisons.

Within the SOC model, patient classification on the basis of CSD status allows useful clinical interpretation. Among PD patients, the absence of CSD may suggest a brain-first PD subtype or atypical parkinsonism. Follow-up assessments confirming the subsequent development of CSD can improve the accuracy of brain-first PD identification. Given the high sensitivity of ¹²³IMIBG imaging for detecting CSD, the likelihood of false-negatives is relatively low, making ¹²³I-MIBG imaging a reliable tool for early PD phenotyping.

Conversely, the presence of CSD may indicate either bodyfirst PD or an advanced stage of brain-first PD. However, distinguishing between these two groups remains challenging and represents a significant limitation of using CSD alone to differentiate the two PD subtypes. Figure 2 summarizes the key factors supporting the interpretation of CSD as indicative of body-first PD. Crucially, ¹²³I-MIBG scanning must be performed early, and clearly reduced ¹²³I-MIBG uptake must be observed. Additional supporting features may include the presence of premotor RBD, peripheral α-syn detection, and symmetric reduction in DAT uptake on neuroimaging. Quantitative measures of the degree of the H/M ratio of ¹²³I-MIBG uptake and CSF α-syn SAA levels may also provide supportive evidence, although further detailed studies are needed to define reliable thresholds for these markers.

Importantly, reduced ¹²³I-MIBG uptake is not specific to PD and should also increase the possibility of DLB. The body-first phenotype is more commonly observed in DLB than in PD, and because PD and DLB are often indistinguishable, ongoing monitoring of cognitive function and disease progression is essential for accurate clinical interpretation.

Distinguishing between body-first and brain-first PD subtypes is essential for understanding disease initiation and pathologic propagation mechanisms, promoting a more homogeneous classification of PD. Body-first PD may allow for the identification of prodromal PD patients, making them potential candidates for future disease-modifying therapies, whereas brain-first PD may be associated with lower α-syn burden and relatively favorable prognosis. These subtype directions also provide valuable insights into disease progression patterns, enabling more precise disease staging and therapeutic targeting by clarifying progression patterns and facilitating earlier intervention.

However, there are currently no definitive biomarkers capable of clearly distinguishing between body-first PD and brain-first PD, and research in this area remains limited. The most effective strategy likely involves a multimodal approach, incorporating CSD, premotor RBD, DAT asymmetry, and other markers. Further extended pathological and clinical research is urgently needed to develop and validate more robust diagnostic frameworks.

A major limitation of current evidence linking reduced ¹²³I-MIBG uptake to PD subtypes lies in its reliance on cross-sectional studies. Longitudinal studies tracking ¹²³I-MIBG uptake and both central and peripheral pathology in the prodromal and early PD stages are needed to clarify disease trajectories.

Recently, counterarguments have been raised regarding the SOC model, which underpins the brain-first and body-first hypothesis [63]. These critiques target several unverified assumptions within the model, including whether PD pathology originates from a single site, whether cell-to-cell transmission occurs exclusively through neural pathways, and whether α-syn alone is sufficient to drive disease propagation. Alternative hypotheses have been proposed, including the possibility that the cardiac sympathetic nervous system may represent an additional site of α-syn pathology initiation. Nonetheless, the SOC model should be viewed as a conceptual framework designed to enhance our understanding of body-first and brain-first phenotypes rather than as a literal representation of the complex human pathological environment. This method likely has limitations in fully capturing the pathogenesis of PD.

In this context, recent pathological studies have suggested a possible distinction between two types of PD initiation: a sympathetic type, originating in the heart and sympathetic trunk, and a parasympathetic type, beginning in the dorsal motor nucleus of the vagus and the locus coeruleus [64]. This classification may help explain some of the inconsistencies observed within the SOC model. However, these proposals remain incomplete and currently lack sufficient empirical validation. Despite the controversy and the need for further refinement, the brain-first and body-first framework continues to provide insights into PD progression. In particular, cardiac involvement remains a hallmark of the body-first phenotype, and myocardial ¹²³I-MIBG scintigraphy offers a reliable and accessible tool for assessing this pathological process.

In conclusion, CSD represents a promising biomarker for distinguishing between body-first PD and brain-first PD within the SOC framework. However, it should not be used in isolation, but rather as part of a comprehensive assessment that includes RBD, autonomic dysfunctions, and other biomarkers for optimal phenotyping. Further research is needed to refine the role of CSD in early detection, define quantitative thresholds, and improve its reliability as a phenotyping tool for PD subtypes. Through such an approach, CSD may be used to identify prodromal PD, monitor disease progression, and enhance therapeutic strategies by improving our understanding of the pathophysiological heterogeneity of PD.

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (NRF-2017R1D1A1B06028086).

Acknowledgments

The authors would like to thank Sayoon Kim (University of Toronto, Ontario, Canada) for her excellent editing the manuscript for non-intellectual content.

Author Contributions

Conceptualization: Dong-Woo Ryu, Joong-Seok Kim. Data curation: Dong-Woo Ryu, Joong-Seok Kim. Funding acquisition: Joong-Seok Kim. Investigation: all authors. Project administration: Dong-Woo Ryu, Joong-Seok Kim. Resources: all authors. Software: Dong-Woo Ryu. Supervision: Joong-Seok Kim. Validation: Joong-Seok Kim. Visualization: Dong-Woo Ryu, Joong-Seok Kim. Writing—original draft: Dong-Woo Ryu. Writing—review & editing: Sang-Won Yoo, Yoonsang Oh, Joong-Seok Kim.

Figure 1.

Schematic chart showing the pathophysiology and phenoconversion of pure autonomic failure. REM, rapid eye movement; PD, Parkinson’s disease; DLB, dementia with Lewy body; MSA, multiple system atrophy; PAF, pure autonomic failure; ¹²³I-MIBG, ¹²³I-meta-iodobenzylguanidine; PET, positron emission tomography.

Figure 2.

Factors supporting cardiac sympathetic denervation as an indicator of body-first Parkinson’s disease. ¹²³I-MIBG, ¹²³I-meta-iodobenzylguanidine; REM, rapid eye movement; SAA, seed amplification assay.

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