Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer‘s dementia [1,2]. Initially perceived as a condition affecting the motor system by α-synuclein-mediated loss of dopaminergic neurons in the substantia nigra , current knowledge about associated cognitive, neuropsychiatric and nonmotor symptoms has led to increased interest in cholinergic, serotoninergic, noradrenergic and other neurotransmitter systems [3,4]. For some time, advanced neuroimaging has been an invaluable tool to investigate in-vivo changes in Parkinson's disease . But although voxel-based morphometry MRI has previously detected volume changes in cortical and subcortical areas , state of the art neuroimaging nowadays provides a window into the (micro-) structure and function of neuronal networks and surrounding glia [7,8▪].
The aim of this review therefore is to summarize the most relevant recent developments in both structural and functional neuroimaging in Parkinson's disease pertaining to certain aspects: the detection of underpinning neurobiological processes, the use of different neuroimaging techniques as biomarkers of disease progression and the application of imaging to guide and monitor therapeutic interventions.
DETECTION OF UNDERLYING NEUROBIOLOGICAL PROCESSES
Neuroimaging continues to be a powerful tool for the in-vivo study of disease-related pathophysiology and recent developments in Parkinson's disease corroborate this.
It has been apparent for some time that the degeneration of neurons in Parkinson's disease is not limited to the Substantia nigra, but only recent developments of respective tracers allow the detailed in-vivo study of additional neurotransmitter systems (see Table 1).
Although quantification of presynaptic dopaminergic function is part of daily clinical practice , the exact anatomical pattern and longitudinal dynamics of signal changes are increasingly described: a substantial meta-analysis of 142 studies using PET or single photon emission computed tomography (SPECT) to assess presynaptic dopaminergic function confirmed consistently larger decreases in binding in posterior > anterior putamen > caudate nucleus across ligands for aromatic L-amino-acid decarboxylase (AADC), dopamine transporter (DaT) and vesicular monoamine transporter 2 (VMAT2); overall, disease severity correlated closest with dopaminergic terminal loss in the caudate nucleus [10▪▪,11]. Focusing on the physiological equivalent of SPECT signalling, a large study reported postmortem numbers of nigral neurons in Parkinson's disease and atypical parkinsonian conditions not to correlate with [123I]FP-CIT or [123I]b-CIT tracer binding [12▪], which contrasts with previous observations . This suggests that these tracers actually reflect striatal changes such as axonal dysfunction or reduced DaT expression, rather than the number of intact nigral neurons.
Similarly, the dynamics of changes among tracer targets are increasingly studied: a substantial meta-analysis reported a consistently smaller reduction in 6-[18F]fluoro-L-dopa measuring AADC in both caudate nucleus and putamen compared with DaT and VMAT2 levels, suggesting either less severe loss or even compensatory upregulation of AADC in Parkinson's disease [10▪▪]. An analysis of a large number (n = 210) of healthy control DaTSCANs indicated a relatively higher DaT concentration in women, as female striatal volumes are slightly lower, but DaT quantification similar between sexes .
Nigro-striatal dopaminergic loss, as quantified by DaT, has also been used to study pathophysiological changes only accessible to advanced imaging techniques by means of correlation analysis: one study on the basis of diffusion tensor imaging (DTI) reported a negative correlation between fractional anisotropy of the substantia nigra and putaminal dopamine transporter signal over time [15▪], while another cross-sectional study described that on neuromelanin-sensitive sequences, substantia nigra volume correlated best with nigro-striatal innervation loss . Both studies detected microstructural changes based on correlations with established DaT quantification. Similarly, the severity of dopaminergic degeneration correlated with changes in diffusion measurements in the striatum in a primate MPTP model .
Today, the in-vivo study of dopaminergic degeneration is able to detect the temporal and spatial dynamics of tracer changes and serves as a basis for the explorative study of novel imaging approaches.
Although serotoninergic dysfunction is known to occur in Parkinson's disease, in-vivo quantification has been achieved only recently. [123I]FP-CIT exhibits nonspecific, extrastriatal binding for presynaptic serotonergic transporters [18,19▪] and hence has been used to assess its involvement in the pathogenesis of nonmotor symptoms. One study found significant differences in hypothalamic binding between Parkinson's disease and atypical parkinsonism, suggesting a different pattern of serotonergic presynaptic receptor involvement between these conditions . More specifically, the same team reported a negative association of levels of anxiety with low [123I]FP-CIT binding in the thalamus in a large sample of de-novo Parkinson's disease patients [19▪]. A similar negative correlation between right caudate nucleus [123I]FP-CIT SPECT tracer binding and anxiety has been reported in a large, controlled cohort of de-novo Parkinson's disease patients , confirming an earlier observation .
Although the above-mentioned results are in line with the hypothesis of anxiety mainly being linked to a serotoninergic dysfunction in earlier and a dopaminergic dysfunction in later disease stages , this remains to be proven in larger, and ideally longitudinal samples.
Noradrenergic projections almost exclusively originate from the locus coeruleus, playing a role in cognitive attention, sleep cycle regulation and autonomic function. The application of neuromelanin-sensitive MRI sequences to identify pigmented cells of the locus coeruleus [23▪] and [11C]MeNER PET to characterize noradrenalin transporters  allowed a study comparing Parkinson's disease patients with and without rapid eye movement sleep behaviour disorder (RBD) and controls, revealing most pronounced reductions for both signals in the PD+RBD group [23▪], supporting an earlier neuromelanin-based study  (see Fig. 1). In terms of dynamics, first evidence indicates that the reduction in neuromelanin-content might be greater in the locus coeruleus than substantia nigra , possibly reflecting the progression of neuropathology according to the Braak hypothesis . Although of minuscule anatomical size, the noradrenergic system and the implications of changes to it, is now accessible to state-of the art imaging.
There has been a debate over the anatomical and functional cause of cognitive symptoms in Parkinson's disease, which present most frequently as executive, and in later stages more widespread dysfunction including memory impairment . A noticeable PET-based contribution is the finding that it might be the interaction between caudate nucleus dopaminergic and cortical cholinergic denervation to explain Parkinson's disease cognitive decline and dementia [28,29]. The data seem to suggest a possible compensatory overactivity of the cortical cholinergic system for caudate nucleus dopaminergic degeneration in early disease stages, before cognitive symptoms become apparent with cholinergic decline. This challenges the previously proposed dual syndrome hypothesis, which distinguishes dopaminergically mediated fronto-striatal executive impairments and cholinergically mediated memory symptoms .
Parkinson's disease neuropathology is dominated by the presence of α-synuclein deposits, although β-amyloid and tau have been implicated in cognitive impairment in Parkinson's disease [30,31▪]. Recent publications seem to support a role for both tau and β-amyloid only in advanced stages of cognitive impairment [30,31▪,32], most noticeably in dementia with lewy bodies . Anatomically, precuneus and inferior temporal gyrus tau tracer uptake has been reported to be associated with this , adding to our understanding of mixed pathology in Parkinson's disease.
White matter involvement
Overt white matter lesions have been implicated with the development of both cognitive symptoms and gait disorder in Parkinson's disease. The reported observation of an association between white matter lesions and neurogenic orthostatic hypotension  supports the notion that extreme blood pressure changes might contribute to the development of cognitive symptoms through white matter lesions . Small vessel involvement, defined as lacunes or white matter hyperintensities, have equally been linked to cortical thinning and cognitive impairment . Overall, greater white matter lesion load is reported among patients presenting with postural instability and gait difficulty compared with a tremor-dominant phenotype [37,38].
Computational and theoretical advances allow for a more comprehensive assessment of microstructural changes and network disruptions: a meta-analysis of 39 DTI studies comparing data from 1087 PD patients and 768 healthy controls identified consistent changes within subcortical (substantia nigra) and cortical areas (cingulate and temporal cortices) as well as white matter fibre tracts (corpus callosum and corticospinal tract) . In a cohort of treatment-naive patients, prospective high-resolution 3-Tesla DTI imaging and graph theory detected reduced connectivity in mesolimbic–striatal pathways, within the basal ganglia, the sensorimotor circuits and also the limbic system . Another study suggested more prominent white matter lesions along the cerebello-thalamo-cortical pathway in tremor-dominant Parkinson's disease patients . A large study of advanced Parkinson's disease patients also identified DTI changes in diffuse basal ganglia and fronto-parietal networks among Parkinson's disease patients with mild cognitive impairment . Taken together, these findings point towards early, progressive and widespread damage to white matter connections, initially evident only at a microstructural level .
A number of findings suggest a role of the immune system in Parkinson's disease pathoaetiology . Activation of microglia may be evaluated through novel PET radioligands, such as [18F]FEPPA, although first, moderately sized studies in Parkinson's disease were not able to show signal differences in comparison to healthy controls [44,45]. [11C]PBR28 imaging, however, revealed a reduction in microglia activation after treatment with a selective myeloperoxidase inhibitor in Parkinson's disease, although this study included no controls for comparison . Indirect indications of inflammation have also been detected by signs of blood– brain barrier breakdown, evident as microbleeds and gadolinium leakage .
Phosphodiesterases are enzymes highly expressed on striatal medium spiny neurons, metabolizing cAMP and cGMP, the second messengers of dopamine receptors. First studies employing specific radioligands, such as [11C]IMA107 binding to phosphodiesterase 10A , showed lower binding activity in the basal ganglia of Parkinson's disease patients compared with controls, and a negative correlation with disease duration and severity . The same group adopted [11C]rolipram, assessing phosphodiesterase 4 levels, and reported lower binding in caudate, putamen, hypothalamus and cortex to correlate with spatial working memory deterioration [50▪▪]. Positing phosphodiesterase expression as a marker of striatal dopaminergic terminal loss, it would be interesting to study its decline longitudinally and compare its dynamics with DaT and other markers of dopaminergic degeneration in the future.
The application of functional MRI (fMRI) studies in Parkinson's disease is still an evolving field, with a considerable heterogeneity of paradigms and patient subgroups being studied. Nevertheless, a methodologically sound, recent meta-analysis of resting state fMRI studies indicated reproducible, increased functional connectivity in the left postcentral gyrus . Although this might highlight this area to be explored further, the conclusive interpretation of results of task-dependent fMRI studies  remains challenging, still.
IMAGING MODALITIES AS A BIOMARKER OF DISEASE PROGRESSION
Monitoring disease progression is a prime aim in Parkinson's disease imaging research, but although there have been some developments, it remains to be seen which modality might emerge as the most suitable measure.
Brain tissue physiologically contains iron, more than 90% of which is stored in the form of ferritin, and the basal ganglia (Globus Pallidus > Putamen > Caudate) are particularly rich in iron. Imaging studies have shown that ferritin accumulates throughout the basal ganglia in a linear fashion as a function of age . Iron-sensitive MRI sequences, including SWI, 3D FLAIR, T2*, R2 and R2* relaxation, as well as quantitative susceptibility mapping (QSM) or adiabatic T1rho have been increasingly applied to study iron-content and iron metabolism in Parkinson's disease . Overall, QSM has been suggested to be more sensitive than R2* to detect deep cerebral nuclei iron quantity [54,55], allowing the visualization of the dorsolateral nigral hyperintesity or nigrosome-1 within the substantia nigra. A meta-analysis of 16 studies suggested this assessment to be the most sensitive and specific imaging protocol to date to differentiate Parkinson's disease patients from controls and possibly suitable to differentiate degenerative from nondegenerative parkinsonism [56▪]. Nigral hyperintensity has also been correlated with disease progression and not only reported to predict DaTSCAN measures in Parkinson's disease [57,58] but also idiopathic RBD .
Disease severity, as measured by clinical characteristics ranging from UPDRS-III, H&Y stage, depression and anxiety to levodopa equivalent daily dose, has been reported to correlate with iron load in Parkinson's disease on SWI [60▪], R2* sequences  and QSM [54,62]. Iron load, especially in the caudal region of the substantia nigra (R2*), has been reported to be particularly higher in patients with freezing of gait in both cross-sectional  and longitudinal samples . Taken together, as an epiphenomenon of the underpinning neuropathological process, iron accumulation seems to be a good candidate to follow disease progression in Parkinson's disease.
Regarding extranigral tissue in Parkinson's disease in comparison to controls, iron load was found increased in GP and putamen on SWI-weighted sequences [60▪], and red nucleus, GP and thalamus on QSM quantification . A QSM-based study described iron signal changes only in SNc in early disease stages, whereas more prominent involvement of red nucleus and GP were apparent in more advanced patients . Only one study reported whole brain iron level assessments; using a cross-sectional protocol, it reported higher QSM values in dorsal pons and a number of cortical areas, arguably following the topographical progression of α-synuclein deposition .
Iron content therefore seems to emerge as a powerful imaging tool with high diagnostic accuracy (nigral hyperintensity), good correlation with clinical characteristics and good spatial as well as longitudinal temporal resolution.
Neuromelanin is an insoluble pigment and by-product of catecholamine-synthesis. Its production is Fe3+-mediated and appears to be governed by cytosolic content of dopamine or other catecholamines and is therefore predominantly located in substantia nigra and locus coeruleus. Quantification of neuromelanin to follow disease progression has been investigated widely. The histologically known pattern of substantia nigra neuronal changes affecting postero-lateral aspects of SNc earlier/more than anterior-medial ones has been replicated with neuromelanin imaging [65–67]. Similarly, the progressive loss of SWI-hyperintensity from nigrosome-1 to nigrosome-4 seems to follow disease progression . Neuromelanin loss has also been correlated with UPDRS [65,66] and MDS-UPDRS scores , H&Y stages  and disease duration .
Hence, neuromelanin appears to be a promising imaging biomarker for Parkinson's disease progression, if confirmed prospectively.
Substantia nigra free water
Free water measurements are an advanced diffusion-based modelling approach, measuring the fractional volume of unconstrained diffusion. The recent development of a bitensor modelling technique allows to acquire the fractional signal of water from a single voxel. The detection of posterior substantia nigra free water was able to distinguish Parkinson's disease patients from controls [70,71▪▪] and in a multisite study showed to correlate with H&Y stages, MDS-UPDRS part III and cognitive performance . This appeared to be independent of acute dopaminergic medication . First longitudinal data indicated that posterior substantia nigra free water increases over time and can predict bradykinesia severity and MOCA scores , which was validated in a larger, international study [71▪▪] (see Fig. 2). By and large, all of the above suggest that substantia nigra free water might become a valuable tool to monitor Parkinson's disease progression.
It is generally accepted that DaT measurements correlate with the degree of dopaminergic cell loss; however, its exact dynamics across disease stages has not been clear. A recent study implied different velocities of midbrain neuromelanin-signal loss measured via [18F]AV-1451 PET [75▪], versus striatal dopaminergic loss ([123I]FP-CIT SPECT) in early Parkinson's disease . Together with further evidence [77▪], this has been interpreted to indicate that in humans nigral cell loss and striatal tracer uptake in vivo correlate closely only up to a nigral cell loss of 50%. Beyond this, the dynamics of neurodegeneration and tracer uptake seem to follow a more lose correlation, as also observed in MPTP-treated monkeys . Accordingly, the majority of longitudinal PET studies [10▪▪] point to a negative exponential dopaminergic loss in Parkinson's disease, consistent with the nonlinear pattern previously described for the progression of motor symptoms, with faster progression in the first symptomatic disease phase [10▪▪]. This is in keeping with the ‘dying back’ concept, describing axonal and terminal degeneration in the striatum before neuronal cell loss in substantia nigra .
GUIDING AND MONITORING THERAPEUTIC INTERVENTIONS
We have noted some developments in the application of imaging used for therapeutic interventions in Parkinson's disease.
Both deep brain stimulating and advanced lesioning  rely on the correct presurgical identification of target structures. One report proposed STN visualization to benefit from using QSM over T2*-weighted images  (see Fig. 3). Similarly, advanced high angular resolution diffusion-based imaging has been proposed to improve VIM nucleus targeting in tremor patients [82▪]. Probably, the most innovative addition to functional stereotactic neurosurgery has been the development of the publicly available ‘DBS Intrinsic Template Atlas’ [83▪▪] – this combination of subcortical brain manual segmentation, automatic multimodal probabilistic maps, coregistration with histology as well as STN and GP internus functional subsegmentation according to structural connectivity, offers potential advantages for future functional neurosurgical trials [83▪▪].
Another set of studies investigated the effect of both anatomical and functional connectivity after STN-DBS and validated the findings in a second, independent data set [84▪▪]: apart from replicating that STN-DBS has an effect on supplementary motor area and medial prefrontal cortex activity, authors reported that both types of connectivity explained 26.2% of clinical variance in intervention outcome. They concluded that their findings support the idea of focusing surgical treatment not only on specific brain regions but also on network nodes [84▪▪].
Finally, of more practical relevance, the development of a new coil system able to reduce DBS lead absorption might alleviate safety concerns for post-DBS MRI monitoring .
Levodopa/carbidopa intestinal gel
Continuous delivery of levodopa via levodopa/carbidopa intestinal gel (LCIG) provides more stable levodopa levels in blood with respective clinical advantages over pulsatile oral intake, which is advantageous in advanced Parkinson's disease cases. A small pilot study documented a sustained significant reduction in striatal [11C]raclopride binding, suggesting sustained higher dopamine levels during LCIG infusion .
One study examined the effect of apomorphine infusions as add-on therapy using resting state PET over a 6-month period: induced changes in this relatively small sample (n = 12) were documented throughout motor, cognitive and limbic networks and appear compatible with the notion that metabolic changes in Parkinson's disease could be reversed by continuous dopaminergic treatment .
A randomized trial of cognitive rehabilitative approaches documented improved executive function, visual memory and functional but no structural changes on functional MRI after 3 months of integrative cognitive rehabilitation [88▪], persisting at 18 months .
In this review, we provide an update on current applications of state-of-the-art neuroimaging in Parkinson's disease. The expansion of the current in-vivo imaging armamentarium increasingly allows the comparison and cross-validation of different imaging modalities. It seems that the increasing number of radionuclide-based protocols assessing microglia activation, protein accumulation and receptor density as well as the combination of established and novel approaches drive developments in this field of movement disorder research. Providing distinct and complementary information, in particular the combination of these techniques will most likely advance our understanding of the pathophysiology of Parkinson's disease processes in the future. Among others, future work should focus on identifying the ideal marker to monitor disease progression.
Financial support and sponsorship
This work has received no dedicated support.
Conflicts of interest
VR declares received travel grants from AbbVie, Boston Scientific and Italian Neurological Society. SRS has received grant support by the Swiss Science Foundation, the Swiss Neurological Society and the European Academy of Neurology. KPB has received grant support from welcome/MRC, NIHR, Parkinson's UK and EU horizon 2020. He has received royalties from publication of the Oxford Specialist Handbook Parkinson's Disease and Other Movement Disorders (Oxford University Press, 2008, 2016) and of Marsden's Book of Movement Disorders (Oxford University Press, 2013). He has received honoraria/personal compensation for participating as consultant/scientific board member from Ipsen, Allergan, Merz and honoraria for speaking at meetings and from Allergan, Ipsen, Merz, Sun Pharma, Teva, UCB Pharmaceuticals and from the American Academy of Neurology and movement disorders society.
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* Both Vittorio Rispoli and Sebastian R. Schreglmann contributed equally to this article.