GRAPHICAL ABSTRACT

INTRODUCTION

Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease [1] and poses an oncoming socioeconomic burden in ageing societies. The classic motor symptoms of PD are bradykinesia, rigidity, and resting tremor [2] which result from dopaminergic nigrostriatal degeneration and the subsequent disruption of the basal ganglia–thalamo–cortical loops. PD is diagnosed based on clinical symptoms [3]. In clinical practice, neuroimaging techniques are frequently needed to rule out structural pathology utilizing conventional magnetic resonance imaging (MRI) and dopaminergic positron emission tomography (PET) or to visualize degeneration in the presynaptic dopaminergic system utilizing single-photon emission computed tomography [4]. Research on functional MRI (fMRI) provides insight into the pathophysiology of PD by highlighting the changes that occur as the disease progresses and leads to complications [5].

Blood-oxygen Level Dependent (BOLD) fMRI examines variations in deoxyhemoglobin levels, which reflects spontaneous fluctuations during the resting state or neural metabolism changes triggered by tasks [6]. BOLD-contrast imaging fMRI provides adequate spatial resolution to localize activated brain areas and distinguish them from adjacent regions. This facilitates the measurement of neuronal activation based on the paramagnetic properties of blood. Furthermore, BOLD response delays occur 1–2 seconds after the stimulus, reaching a peak approximately 5 seconds later as the vascular system reacts [7].

We utilized resting-state fMRI (RS-fMRI) to examine spontaneous low-frequency fluctuations in the BOLD signal, ranging from 0.01 to 0.08 Hz, and investigated the functional architecture of the brain [8]. Various patterns of functional connectivity coactivation can be observed in the RS environment. The “RS” functional networks consist of the default mode network (DMN), sensorimotor network (SMN), visual network, executive control network (CEN), dorsal attention network (DAN), salience network (SAL), and auditory network [9].

Functional connectivity is defined by the temporal coherence of neuronal activity patterns emerging from anatomically separated regions [9], thus expressing functional interplay between separate areas. Several studies have shown the presence of functional reorganization within RS networks in patients with PD [10] and demonstrated how each network interacts with the others and various approaches to analyzing RS-fMRI, such as the traditional a priori seed-based region of interest [8]. Additionally, regional homogeneity (ReHo) and the amplitude of low-frequency fluctuation (ALFF) fluctuations are two RS-fMRI metrics that indicate local brain activity [11,12].

An alternative analytical approach for RS-fMRI data is graph theoretical analysis. This technique considers anatomical brain regions as nodes linked by edges that represent the connectivity shown by the temporal correlation of BOLD fluctuations among these nodes [13].

Recently, several cross-sectional RS-fMRI studies [10] have demonstrated that alterations in the cerebello–thalamo-cortical circuit are an essential hallmark in PD, with further decreased posterior putaminal activation associated with motor impairment [14]. The development of cognitive impairment is associated with network disruption at the DMN, salience, and associated visual and frontoparietal levels [15,16], with further within-network DMN connectivity predicting cognitive decline in PD patients without cognitive impairment [17,18].

In a recent large-scale network meta-analysis, Tang and colleagues [15] analyzed 72 RS-fMRI studies of alpha-synucleophaties. Examinations of patients with PD, Lewy body dementia (LBD), or multiple system atrophy have confirmed that motor control is influenced by connectivity among the subcortical network and SMN, particularly within the cortico–basal ganglia–thalamo–cortical pathways. Moreover, the severity of motor dysfunction is correlated with diminished connectivity between the cerebellum and the frontoparietal network. The authors also noted decreased connectivity between the subcortical network, CEN, and posterior DMN linked to cognitive impairment. Finally, the authors demonstrated diminished connectivity within attentional control networks, particularly the ventral attention network and DMN, and an imbalance in networks related to emotion processing.

In conclusion, RS-fMRI is a widely accessible, cost-effective, noninvasive, and nonionizing imaging method employed in numerous cross-sectional studies of PD. It aids in comprehending pathophysiological irregularities at various stages of the disease.

This literature review highlights critical functional studies conducted in longitudinal cohorts and multimodal prospective functional approaches to PD as promising tools for tracking disease progression.

Search strategy

This literature review examined articles published on PubMed up to June 2024. Keywords such as “longitudinal,” “multimodal,” “functional magnetic resonance imaging”, and “Parkinson’s disease” were cross-referenced following a thorough assessment of abstracts, elimination of duplicates, and filtering out papers not written in English.

LONGITUDINAL RESTING STATE IMAGING STUDIES IN PARKINSON’S DISEASE

Tuovinen et al. [19] performed a longitudinal graph-based RSfMRI study over a one-and-a-half years in an early-stage cohort of PD patients. They reported an increase in cerebellar connectivity with itself and a decrease in connectivity between the cerebellum and the caudate, thalamus, and amygdala in PD patients compared with controls over time. Furthermore, longitudinal cerebellar connectivity is linked to changes in motor severity, as measured by the Movement Disorders Society Unified Parkinson’s disease rating motor scale (MDS-UPDRS-III). The authors concluded that during the early stages of PD, increased cerebellar connectivity attempts to compensate for the decline in motor function caused by the hypofunction of the striatal–thalamocortical circuit [20].

Notably, longitudinal cerebellar connectivity is linked to the rate of change in the motor MDS-UPDRS-III score for PD patients with a longer disease duration (>10 years), according to a prospective RS-fMRI study conducted by Zeng and colleagues [21] using ReHo methodology. Reduced functional connectivity was observed in the DMN and SMN. Conversely, PD patients had greater connectivity in the supplementary motor area, temporal gyrus, and hippocampus than did controls. Overall, longitudinal RS functional studies with varying follow-up durations in PD patients have shown compensatory cerebellar hyperfunction, which is correlated with motor deterioration [19,21,22]. Importantly, chronic dopaminergic therapy may also influence increased functional connectivity in the cerebellum [23].

In an interesting seed-based RS-fMRI study, Manza and colleagues [24] assessed the functional connectivity pattern of the putamen and caudate nucleus in a small cohort of 11 PD participants. The authors noted that functional decoupling between the anterior putamen and midbrain is linked to long-term motor decline, reinforcing findings from prior cross-sectional functional studies [25]. Moreover, diminished cognition was linked to enhanced connectivity between the dorsal caudate nucleus and the anterior cingulate cortex. Their longitudinal functional data highlighted the intricate roles of the striatum, highlighting hyper and hypofunction within the striatal–thalamo–cortical circuit [26]. Nevertheless, the absence of a control group and the limited sample size should be contextualized.

A few prospective RS functional studies have focused on cognitive impairment in PD patients [27-29]. A whole-brain RS-fMRI study by Olde Dubbelink and colleagues [28] assessed 36 patients with PD over 3 years. Notably, 6 patients presented with dementia. They reported reduced functional connectivity in posterior cortical areas compared with controls, particularly in the cuneus, occipital gyrus, calcarine cortex, and postcentral gyrus, which was related to a decrease in cognitive scores. With respect to network analysis, in RS-fMRI studies, Klobušiaková et al. [29] studied 39 PD patients, 22 of whom had PD-mild cognitive impairment (PD-MCI) for 1 year. The authors observed an increase in functional connectivity between the frontoparietal network, DMN, and SAL over time in individuals with PD-MCI compared with controls, indicating compensatory changes. Finally, as part of a longitudinal independent component analysis-based RS-fMRI study [27], executive function was assessed in 31 patients with PD over 3 years. The authors showed that diminished executive function correlated with heightened connectivity between the frontoparietal network and deep grey matter structures and alterations in connectivity within the DAN.

Hou et al. [30] performed ALFF fMRI analysis in a prospective cohort of drug-naïve PD patients. They presented a classification model highlighting the hyperconnectivity and hypoconnectivity of the precentral gyrus in the putamen over time, differentiating between PD patients and controls. Moreover, the authors outlined a prediction model that correlated the extent of motor deterioration in PD patients with heightened connectivity in the superior occipital gyrus and diminished connectivity in the caudate nucleus.

Finally, Filippi and colleagues [31] assessed 146 patients with PD over 4 years. They performed a cluster analysis based on the disease subtypes, classifying them into mild and moderate-to-severe PD groups. The authors revealed that variations in functional connectivity over time varied among disease subtypes, showing both hyperconnectivity and hypoconnectivity in all individuals with PD. They identified four distinct patterns of functional connectivity trends. Patients with moderate-to-severe PD exhibited global network changes compared with those with mild PD. Furthermore, longitudinal changes in functional connectivity correlated with shifts in motor, nonmotor, and cognitive decline in PD patients.

In summary, several RS functional studies conducted in longitudinal cohorts of PD patients (Table 1, Figure 1A) revealed heightened cerebellar activation linked to motor severity as time progressed. Furthermore, reduced connectivity in the posterior cortical regions and associated networks is correlated with cognitive dysfunction in PD patients. Finally, a decrease in the functional connectivity of the caudate nucleus may predict motor decline in the early phases of the disease.

LONGITUDINAL TASK-BASED IMAGING STUDIES IN PD

Various cross-sectional task-based fMRI studies have utilized motor experimental paradigms to uncover the mechanisms behind motor decline in PD patients. A motor-task meta-analysis [14] demonstrated that decreased connectivity of the posterior putamen is associated with motor impairment, in contrast to variable findings across connectivity studies in frontoparietal motor areas. These findings indicate a complicated interaction between nigrostriatal dopaminergic denervation and cortical pathology in PD patients.

Only three prospective motor task-based fMRI studies in PD cohorts exist in the literature [32-34]. In a unimanual grip force task, Burciu and colleagues [32] assessed a cohort of 46 patients in 1 year with an a priori region of interest in the basal ganglia, motor cortex, and cerebellum. The authors described longitudinally decreased connectivity in the putamen and motor cortex in PD patients compared with controls, highlighting the motorrelated pattern of cerebello-thalamo-cortical loops and the basal ganglia in PD patients. In a joystick motor task, Hannaway and colleagues [33] assessed a prospective cohort of patients with PD at baseline, 18 months, and 36 months. The authors demonstrated longitudinal increased cerebellar hyperconnectivity over time from baseline visits, which may be compensatory, as task-related activity, such as response time, is associated with hyperconnectivity in the contralateral motor, parietal, and temporal areas.

Working memory (WM) impairment frequently affects cognitive domains in PD patients with MCI. Multiple studies have evaluated brain activation during WM tasks in PD patients, revealing decreased functional activation in the caudate nucleus and anterior cingulate cortex in patients with executive dysfunction or PD-MCI (with single or multiple domains) compared with patients with PD and no cognitive impairment [35,36]. Despite these previous findings, a recent meta-analysis revealed insufficient evidence to link a specific type of neural injury to executive dysfunction, partly because few studies have focused on this topic [37].

In a prospective WM task using a verbal two-back WM paradigm [35], 28 patients with PD (11 with PD-MCI) were assessed over 1 year. The authors reported diminished longitudinal connectivity in the fusiform gyrus and caudate nucleus in PD-MCI patients compared with cognitively unimpaired PD patients. This finding suggests a posterior cortical alteration in the progression of cognitive impairment, as opposed to the frontostriatal changes observed during an earlier cross-sectional study [38].

Given the limited number of longitudinal task-based fMRI studies in PD patients (Table 2, Figure 1B), it is challenging to reach definitive conclusions, as more prospective studies are needed.

LONGITUDINAL MULTIMODAL IMAGING STUDIES IN PD

Only two longitudinal multimodal studies have combined RS-fMRI with presynaptic dopaminergic markers [39,40]. Li and colleagues [39] studied 20 PD patients over 20 months and assessed the RS connectivity of the putamen, caudate, and substantia nigra subdivisions and the dopamine transporter (DAT) using ¹⁸C-PE2I PET. This high-affinity radioligand binds selectively and reversibly to the DAT in vivo. Reduced connectivity between the posterior putamen and the midbrain, thalamus, sensorimotor cortex, and supplementary motor area was linked to changes in DAT density over time. These findings indicated that as PD progresses, the functional connectivity within the basal ganglia correlates with the integrity of dopaminergic pathways; however, the study lacked a control group.

In their longitudinal trimodal study, Steidel and colleagues [40] assessed 17 patients with early-stage PD and 14 controls over a follow-up interval of 14 months with ¹⁸F-DOPA PET, ¹⁸FDG PET, and RS-fMRI. The authors analyzed the midbrain and striatum using metabolic and dopaminergic markers. They subsequently conducted seed-based functional connectivity analysis. Compared with control subjects, PD patients presented decreased FDG metabolism in the left midbrain and reduced FDOPA uptake in the caudate nucleus. FDG metabolism in the left midbrain decreased compared with that at baseline, as did the FDOPA uptake of the caudate nucleus. Furthermore, lower FDOPA uptake in the putamen correlated with diminished longitudinal striato-cortical connectivity and worsening MDS-UPDRS-III scores. These findings support the hypothesis that striato-cortical dysfunction occurs in PD patients along an anterior‒posterior gradient and can occur over a short period; however, this was the first trimodal study [24].

Another potential combination of functional multimodality is plasma or cerebrospinal protein markers. Campbell et al. [41] longitudinally assessed 64 patients with PD and no cognitive impairment versus 27 controls over 2–6 years. They studied resting-state networks, focusing on the DMN, DAN, frontoparietal control network (FPCN), SAL, and SMN, along with cerebrospinal fluid (CSF) protein levels of α-synuclein, β-amyloid, and tau. The authors discovered decreased connectivity within the SMN and between the frontoparietal network and DAN over time in PD patients compared with healthy controls. Additionally, baseline levels of CSF α-synuclein protein were found to predict a reduction in connectivity of the SMN, which is present in cross-sectional studies [42] and even in patients without cognitive impairment. This study revealed that network-level RS functional connectivity decreases over time and may be related to the levels of CSF α-synuclein, with no significant associations with tau or β-amyloid. Moreover, the longitudinal decline in connectivity between the DAN and the FPCN correlates with cognitive decline, suggesting a potential marker for the development of dementia.

Rapid-eye-movement behavioral sleep disorder (RBD) is characterized by a lack of muscular tone (atonia) and dream enactment behaviors during REM sleep [43]. RBD may indicate an early sign of PD, with estimates suggesting a neurodegeneration phase lasting approximately 10 years before classic motor symptoms appear. This has fueled interest in researching idiopathic RBD (iRBD) and its possible connection to PD. In a prospective study involved 40 patients with iRBD [44], including 21 with MCI, alongside 24 healthy controls studied over 4 years using RS-fMRI and ¹⁸FDG PET. Patients with iRBD-MCI exhibited reduced metabolism in the bilateral inferior parietal lobule and occipital and temporal cortices compared with those with iRBD with normal cognition and healthy controls. Furthermore, seed-based functional connectivity analysis of previous hypometabolic regions revealed decreased connectivity between the left angular gyrus and occipital gyrus in iRBD-MCI patients relative to iRBD patients with normal cognition. Finally, the ratio of phenoconversion to PD (or LBD) after 4 years occurred in 30% (12/40) of healthy subjects, highlighting the significant functional and metabolic dysfunction in the posterior brain regions, particularly in the occipital cortex, which is crucial for the phenoconversion process from iRBD to PD/LBD.

Furthermore, Woo et al. [45] assessed structural and functional connectivity patterns of brain olfactory-related structures in iRBD patients over 4 years with voxel-based morphometry, RSfMRI and DAT ¹⁸F-FP-CIT uptake; among 22 patients, 20 converted to synucleinopathy. A morphometric study revealed progressive longitudinal atrophy in the olfactory cortex, gyrus rectus, and amygdala of iRBD patients compared with controls. Moreover, the exploratory functional prospective analysis revealed various functional clusters originating from the olfactory cortex and amygdala, which did not align with the pattern of structural atrophy. This discrepancy may be attributed to the sequential progression of the pathology and, in part, to compensatory mechanism responses.

To conclude, an intriguing but limited array of multimodal methods that integrate functional fMRI with other molecular imaging techniques and fluid markers exist within longitudinal cohorts in PD patients (Table 3, Figure 2).

FUTURE DIRECTIONS FOR MULTIMODAL FUNCTIONAL IMAGING IN PD

Future multimodal strategies that integrate functional and structural imaging techniques may provide fresh insights into visualizing pathological progression in PD patients. Research on dopaminergic degeneration utilizing magnetic structural methods [4]—including neuromelanin-sensitive MRI, iron-sensitive susceptibility imaging and diffusion-weighted imaging—are helpful diagnostic biomarkers for patients with early-stage PD. Furthermore, combining nigral imaging markers may increase diagnostic performance [46] when iron and neuromelanin volumes are considered. In terms of diffusion-weighted imaging, two multimodal longitudinal studies combining water fractional volume imaging of the substantia nigra and DAT imaging revealed that increased free water in the posterior nigral areas correlated with a reduction in ipsilateral putamen DAT rates over time [47,48]. However, it is crucial to recognize that this diffusional measure rises sharply during the initial 2 years (compared with the years after that). This finding indicates that this progression biomarker notably increases in the early disease stages.

Few cross-sectional multimodal functional imaging studies on PD have been reported in the literature [49-52]. In a recent multimodal study, Su and colleagues [52] combined neuromelanin-sensitive MRI, quantitative susceptibility mapping, multishell diffusion MRI, and RS-fMRI in a cohort of 37 patients with PD and 28 controls to determine the pathological basis of levodopa-induced dyskinesias (LIDs). The authors observed enhanced connectivity between the substantia nigra and putamen in PD patients with LID compared with those without LID. Furthermore, PD-LID patients presented higher iron levels, reduced neuromelanin content, and increased volume fraction in the substantia nigra than PD patients lacking LID. To monitor the progression of PD effectively and predict outcomes for clinical subtypes on the basis of motor and nonmotor symptoms, implementing multimodal functional methods alongside diffusional metrics such as free water imaging or neuromelanin-sensitive MRI in longitudinal studies is essential. Additionally, prospective imaging techniques could assist in assessing the impacts of neuroprotective and neurorestorative treatments and focused ultrasound therapies.

A reduction in serotonergic neurons can lead to nonmotor symptoms such as depression, anxiety, cognitive decline, and sleep issues, with some symptoms appearing before motor symptoms. In a comprehensive functional study, Li and colleagues [39] (in submission) evaluated 15 PD patients with RS-fMRI and the distribution of serotonin transporters with 11C-DASB PET after 20 months. Over time, PET uptake changes tended to cluster within highly functionally connected regions, suggesting a significant correspondence between functional connectivity patterns and the spatial distribution of serotonin. Furthermore, a multimodal longitudinal functional approach should be considered combing additional molecular imaging non-dopaminergic markers especially relevant in the pathophysiology of PD including noradrenergic [53] and cholinergic [54] tracers. In addition, combination with molecular imaging markers of neuroinflammation, including microglial [55] and astroglial [56] activation, as well as protein deposition, such as β-amyloid [57] and tau [58] imaging, could open new windows in multimodal longitudinal functional approaches.

In recent years, the quantification of fluid proteins—including α-synuclein, tau, and β-amyloid in plasma and CSF—has opened a window into PD biomarker studies [59,60]. Furthermore, longitudinal CSF studies demonstrated that α-synuclein levels decline during the early stages of the disease preceding the onset of motor symptoms [61]; however, this decline does not seem to be correlated with classic dopaminergic neurodegeneration. Interestingly, a cross-sectional fMRI study combined with CSF protein analysis revealed a correlation between reduced SMN connectivity and the lowest CSF α-synuclein levels in PD patients [42]. Although the latter was replicated in a longitudinal study [41], future studies should consider multimodal imaging that combines functional and structural imaging measures and molecular imaging with fluid biomarkers, including lysosomal and synaptic dysfunction markers, multiomics methods (including DNA methylation, single-nucleotide polymorphism and RNA expression) [62], endothelial dysfunction [63], and neuroinflammation markers [64] among others.

Patients with PD display a different microbiome than healthy controls do [65], with at least two bacterial species related to disease severity. PD is a multisystem disorder; therefore, according to the multimodal imaging evidence of brain-first and bodyfirst pathological disease progression [66], the gut microbiome should also be included in future longitudinal functional imaging studies for clinical stratification and progression of the disease. Furthermore, the gut microbiota is considered a promising therapeutic target for PD [67], with some evidence of RS neural correlates [68]; hence, a multimodal functional approach with microbiota in longitudinal settings based on novel therapies focused on gut dysbiosis will be needed soon.

A significant drawback within the literature is the variability in sample sizes across PD studies and the need for more healthy controls in certain longitudinal studies. Only a handful of functional studies have involved longitudinal cohorts with PD, and even fewer have employed multimodal designs. These small sample sizes hinder the validation of models, necessitating the division of the sample into training and testing group sets. Artificial intelligence methods promise to overcome these limitations [69]. Specifically, resampling methods such as cross-validation and bootstrapping enable the estimation of a model’s performance on new, unseen data, and their accessibility has grown significantly owing to the enhanced computational capabilities of today’s computers [69].

A significant limitation of the present review is the lack of a control group in some studies [24,33,39,45]. Therefore, they cannot be directly compared with the prospective PD group. A significant recruitment initiative must target healthy controls, as longitudinal multimodal functional studies in PD patients require a robust control group for comparison; this remains a crucial bias.

In conclusion, previous research opens a promising avenue for future multimodal functional integrations in prospective PD studies (Figure 3).

CONCLUSIONS

This literature review examines functional MRI studies conducted in a resting state or during experimental tasks within longitudinal cohorts of PD patients. We specifically emphasize multimodal functional approaches that integrate other imaging biomarkers, such as structural or radionuclide imaging techniques, alongside CSF protein concentrations in prospective studies to track PD progression. While it is important to acknowledge several limitations of these studies, their findings still illuminate the potential value of multimodal imaging in monitoring PD progression. However, there is an ongoing need for longitudinal multimodal functional studies that incorporate additional structural markers (e.g., neuromelanin MRI, water fractional volume MRI, and quantitative susceptibility mapping), molecular imaging markers (such as amyloid and tau imaging), and fluid markers (including CSF and plasma) in large, well-defined early PD patient cohorts to increase our understanding of pathophysiology and foster novel therapeutic interventions to improve patient outcome care.

Notes

Conflicts of Interest

The authors have no financial conflicts of interest.

Funding Statement

None

Acknowledgments

We would like to thank Dr. Fernando Guillen and Dr. Victor Suárez from Departments of Nuclear Medicine and Radiology from Clínica Universidad de Navarra for providing graphical support of PET and MRI images.

Author Contributions

Conceptualization: Antonio Martín-Bastida. Data curation: Antonio Martín-Bastida. Formal analysis: Antonio Martín-Bastida. Methodology: Antonio Martín-Bastida, María Cruz Rodríguez-Oroz. Project administration: Antonio Martín-Bastida. Resources: Antonio Martín-Bastida. Software: Antonio Martín-Bastida. Supervision: María Cruz Rodríguez-Oroz. Writing—original draft: Antonio Martín-Bastida. Writing—review & editing: Antonio Martín-Bastida, María Cruz Rodríguez-Oroz.

Figure 1.

Resting-state longitudinal functional studies in PD. A: Resting-state longitudinal functional studies in PD. B: Task-based longitudinal functional studies in PD. PD, Parkinson’s disease; FC, functional connectivity; FP, frontoparietal; DMN, default mode network; MCI, mild cognitive impairment; FPN, fronto-parietal network; DGN, deep grey matter network; DAN, dorsal attention network; MDS-UPDRS-III, Movement Disorders Society Unified Parkinson’s disease rating motor scale; M1, primary motor cortex.

Figure 2.

Multimodal longitudinal functional studies in Parkinson’s disease. PET, positron emission tomography; FC, functional connectivity; SMA, supplementary motor cortex; DAT, dopamine transporter; MDS-UPDRS-III, Movement Disorders Society Unified Parkinson’s disease rating motor scale; CSF, cerebrospinal fluid; iRBD, idiopathic rapid-eye-movement behavioral sleep disorder; MCI, mild cognitive impairment; VBM, voxel-based morphometry.

Figure 3.

Future directions. MRI, magnetic resonance imaging; Ach, acetylcholine; CSF, cerebrospinal fluid.

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