Presynaptic dopaminergic terminal imaging and non-motor symptoms assessment of Parkinson’s disease: evidence for dopaminergic basis?

Parkinson’s disease (PD) is now considered to be a multisystemic disorder consequent on multineuropeptide dysfunction including dopaminergic, serotonergic, cholinergic, and noradrenergic systems. This multipeptide dysfunction leads to expression of a range of non-motor symptoms now known to be integral to the concept of PD and preceding the diagnosis of motor PD. Some non-motor symptoms in PD may have a dopaminergic basis and in this review, we investigate the evidence for this based on imaging techniques using dopamine-based radioligands. To discuss non-motor symptoms we follow the classification as outlined by the validated PD non-motor symptoms scale.


INTRODUCTION
Contrary to previous perceptions, Parkinson's disease (PD) is recognised as a multisystem disorder. Besides dopamine (DA), three further key neurotransmitters have been described to be involved in the pathogenesis of PD; namely noradrenaline (NA), acetylcholine (ACh), and serotonin (5HT). 1,2 Consequentially, nonmotor symptoms (NMS) in PD can potentially be related to dopaminergic, non-dopaminergic pathogenesis or a combination of both. 1,3 Individual studies indicate that apathy, 4 anxiety 5 as well as aspects of sleep disturbances 6 appear to be linked to striatal dopaminergic deficiency as measured by dopamine transporters (DaT) scans. However, NMS such as depression, 7 fatigue, 8 weight changes, 9 and visual hallucinations (VH) 10 may be driven by deficiency in non-dopaminergic transmitters.
The NMS Scale (NMSS) was validated as the first comprehensive and holistic health-professional completed measure of NMS in PD and has now been used as a primary or secondary outcome measure in a number of clinical trials and epidemiological studies. 11 The NMSS allows for calculation and grading of the burden (severity multiplied by frequency) of 30 different NMS, which are covered in nine different domains. 12,13 These are cardiovascular, sleep/fatigue, mood/cognition, perceptual problems/hallucinations, attention/ memory, the gastrointestinal tract, urinary system, sexual function, and miscellaneous containing olfactory dysfunction.
In this review we primarily address the relationship of dopaminergic radioligands and the individual NMS covered by NMSS domains to examine a possible underlying dopaminergic basis of these varying NMS (Fig. 1).
To conduct this review, we gathered articles, which used dopaminergic imaging to explore the pathophysiology of different NMS, Fig. 2 summarises our methodology. We had three possible terms; Term A had an asterisk allowing for several terms with the same beginning being considered. Term B covered neuroimaging words, whilst Term C were the possible NMS that could have been used. We initially found 8734 articles, which then left us with 42 studies to include once we removed duplicated and referred to our exclusion criteria.

NMSS DOMAIN 1: CARDIOVASCULAR DYSFUNCTION
Cardiovascular dysfunction is a key autonomic feature of PD and patients often present with orthostatic hypotension (OH). There are currently no studies reporting cardiovascular dysfunction in PD to have a dopaminergic basis. However, using the 123 I-metaiodobenzyl guanidine (MIBG) radiotracer, a NA analogue, studies have shown there to be a reduction in the postganglionic presynaptic cardiac sympathetic innervation, suggestive of cardiac sympathetic dysfunction early in PD patients, giving rise to symptoms such as OH. [14][15][16][17][18][19] Several studies have shown reduction in cardiac uptake regardless of using MIBG or 18 F-DOPA cardiac positron emission tomography (PET) in PD patients with OH when compared to those without. [14][15][16]20,21 These results suggest that there might be a decrease in catecholamine uptake (that being DA or NA) in PD patients with OH, but not all studies agree. 22,23 NMSS cardiovascular dysfunction: summary statement There is evidence of sympathetic neuronal defect, specifically focusing on noradrenergic depletion in PD. [23][24][25][26][27] However, there are no dopaminergic imaging studies exploring a dopaminergic defect as the basis of cardiovascular dysfunction. In line with the assumption of initial lower brainstem involvement, 28 noradrenergic dysfunction likely occurs prior to dopaminergic dysfunction, prompting suggestions that PD may be partly a noradrenergic disorder. 29 Further research is needed to explore dopaminergic involvement and noradrenergic dysfunction in early PD patients.
There are amendments to this paper NMSS DOMAIN 2: SLEEP DISORDERS AND FATIGUE Sleep disturbance occurs in 60-90% of all PD patients 30 with symptoms ranging from insomnia, sleep apnoea, restless legs syndrome (RLS), rapid eye movement (REM) behaviour disorder (RBD) to excessive daytime somnolence (EDS). It represents one of the most frequent complaints by the patients. 31 Two aspects of sleep dysfunction, EDS and RBD, have been studied with dopaminergic imaging and are discussed below.
• Excessive daytime somnolence EDS is the tendency to drift off to sleep quickly and more frequently than usual during the day. 32 EDS can be assessed by the Epworth sleepiness scale (ESS). 33 The link between EDS and dopaminergic dysfunction is unclear. Pavese and colleagues conducted a multi-modal PET study, using 18 F-DOPA and 11 C-DASB tracers in PD patients with EDS, and reported both dopaminergic and serotonergic dysfunction (Table 1). 34 Happe    38 and 80% of iRBD patients progressing to PD in 10-12 years. 3 Hence, RBD is now recognised as the most robust marker of prodromal PD. 39 RBD has been shown, at least in part, to be associated with dopaminergic defect, which is consistent with Braak stage 2 pathophysiology. 28 Reduction in DaT uptake in iRBD patients has been shown, specifically in the putamen. 40,41 Using 123 I-FP-CIT, 123 I-IBZM, and 11 C-dihydrotetrabenazine (DTBZ) radiotracers, several studies have suggested the nigrostriatal dopaminergic pathway as being implicated in RBD pathogenesis. [42][43][44][45] However, Kim and colleagues reported their idiopathic RBD patients had a reduced DaT uptake in the putamen, yet when assessing DaT density in the putamen, the levels remained within normal ranges, leaving them to conclude there may likely be an additional pathogenic pathway implicated in RBD (see Table 1). Studies exploring REM sleep duration, using PET and SPECT imaging, have yielding interesting results whereby the upper brainstem is found to be suppressing REM sleep in early-PD causing uncertainty as to a dopaminergic or non-dopaminergic involvement in the pathophysiology of REMsleep in PD itself. 46,47 Investigating non-dopaminergic nuclei has led to assumptions of RBD pathophysiology to include the pedunculopontine nucleus and laterodorsal tegmental nuclei (cholinergic nuclei), raphe nucleus (serotoninergic), pre-coeruleus (glutaminergic) and locus coeruleus (noradrenergic). 48 RLS and PLM are common in PD patients. 50 The precise pathophysiology of both conditions is still unknown and, to our knowledge, there are currently no specific studies investigating RLS-PD pathophysiology using dopaminergic imaging. Nonetheless, studies in idiopathic RLS have suggested a dopaminergic mechanism central to its pathophysiology, which is made evident by the effectiveness of dopaminergic treatment. 51 Studies have shown there to be hypo-dopaminergic activity in idiopathic RLS patients either through reduction in DaT uptake, densities or receptor availability. [52][53][54][55][56] However, others have shown no such change, 57-59 while some have even reported an increase in DaT densities. 60 Furthermore, it has been hypothesised that compared to PD patients, idiopathic RLS patients may have a mishandling of DA rather than a decrease of dopaminergic cells, as seen in PD.

Fatigue
Fatigue is a specific NMS in PD with considerable negative impact on the quality of life of patients. 61 Some studies reported fatigue and dopaminergic dysfunction as not being significantly associated when assessed using neuroimaging. 8,62,63 Both, Schifitto and colleagues and Pavese and colleagues found no significant reduction in striatal dopaminergic uptake between fatigued and Table 1 continued However, Pavese also used 11 C-DASB PET and reported a significant reduction in serotonergic transporter (SERT) binding particularly in the caudate, putamen, ventral striatum and thalamus (Table 1). Hence, Pavese suggests, not only the involvement of extra-striatal pathways, but also a non-dopaminergic involvement in the form of serotonergic dysfunction underpinning central fatigue.
Supplementary to the notion of a non-dopaminergic involvement, Chou and colleagues recently hypothesised cholinergic dysfunction to also be involved by using 11 C-methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) and 11 C-DTBZ monoaminergic PET imaging. 63 However, their results found no significant evidence to support this hypothesis. Nonetheless, clinical experience dictates that dopaminergic therapies can be effective in treating fatigue-PD patient groups, which has led many to conclude that dopaminergic dysfunction might have a partial role. 62,63 NMSS sleep disorders and fatigue: summary statement Sleep disorders in PD, particularly EDS and RBD, may both have a dopaminergic basis, at least in part. Complex pathway interactions underpin RBD where cholinergic mechanisms are also implicated, while raphe serotonergic dysfunction may underlie EDS. DaTscan imaging, such as using 18 F-DOPA, has provided little evidence to support a dopaminergic basis to fatigue in PD, instead a nondopaminergic pathway (such as limbic serotonergic deficit) seems more plausible.

NMSS DOMAIN 3: MOOD AND APATHY
Neuropsychiatric problems are a common manifestation in PD 64 with depression being the most prevalent with up to 45% of patients affected. 65 Here, we explore the most commonly discussed mood and apathetic problems PD patients face and examine its potential pathophysiology using different radiotracers with a focus on DA.

Depression
The pathophysiology of depression has been associated with dopaminergic defect by several studies ( Table 2) reporting an inverse correlation of depression with dopaminergic availability. [66][67][68][69][70] However, as Braak hypothesis suggests, early lower brainstem pathophysiology may involve several other nuclei and thus other neurotransmitters, 28 specifically serotonin. 71 When investigating this association, studies have found there to be an inverse correlation between SERT binding within areas such as the dorsal midbrain, suggestive of a serotonergic dysfunction. 72,73 Politis and colleagues conducted a large in vivo study, using 11 C-DASB PET in antidepressant-naïve PD patients. Their results show an altered serotonergic function associated with higher depression levels in these patients, which suggests abnormal serotonergic neurotransmission in PD depression pathophysiology. Further probing into alternative neurotransmitter involvement has found there to also be noradrenergic dysfunction in the locus coeruleus. 69,74 • Anxiety Anxiety composes a range of disorders, which can be classified into three categories (anxiety disorder, obsessive-compulsive disorder, and trauma and stressor-related disorder). 75 Being a disorder, which can coexist with depression, 76 the pathophysiology of anxiety is thought to be dopaminergic in part. Anxiety has also been shown to be a dopaminergic medication-related phenomenon evident in the dominant relationship with nonmotor fluctuations in PD. 77 Studies from Weintraub and colleagues, Erro and colleagues, and others (Table 2) have reported a reduction in dopaminergic uptake in the right striatum of anxious PD patients. However, when assessing different forms of anxiety, studies have not reported the same trend. Moriyama and colleagues, and Kaasinen and colleagues reported a positive correlation between dopaminergic DaT uptake within the striatum and social anxiety or personality traits and anxiety in patients, respectively. 78,79 The variation found here, suggests anxiety to be heterogeneous in origin with a partial dopaminergic basis. Remy and colleagues demonstrated a negative correlation between the severity of anxiety with binding at the locus coeruleus and bilateral amygdala using 11 C-RTI32, forging the concept of a DAnoradrenergic system involvement in PD-anxiety. 69 This is supported by the understanding that both noradrenergic and dopaminergic pathways project from the locus coeruleus to sites including the amygdala and striatum. 80,81 • Apathy One third of PD patients experience apathy, 82 characterized by a state of emotion with reduced motivation and a sense of reduced goal-directed behaviour, and ambition. 83 Several types of apathy have been described and there is recognition that at least in part, apathy has a dopaminergic origin possibly through the involvement of the mesocorticolimbic circuit. [84][85][86] Thobois and colleagues used [ 11 C]-raclopride, a DA D2/D3 receptor ligand, and reported that PD-apathy patients had reduced synaptic DA release in the mesocorticolimbic system. 87 In pure apathy (non-demented and non-depressed) PD patients, there has been a demonstration of reduced dopaminergic uptake in the striatum. 4,69 However recently, Chung and colleagues have demonstrated there to be no association of striatal dopaminergic binding in early PD with apathy. 88 Unfortunately, currently there is little evidence exploring the association of PD-apathy with dopaminergic dysfunction independent of other neuropsychiatric conditions. However, the reduced caudate uptake is mirrored in other neurodegenerative studies such as Dementia with Lewy bodies, 89 Alzheimer's disease, 90 and frontotemporal dementia. 91 The use of subthalamic nucleus deep brain stimulation (STN-DBS) in PD has itself been identified as being associated with inducing postoperative apathy. 92 However, evidence exists showing there to be some predisposition to this risk factor in these patients including DA agonist withdrawal syndrome. [93][94][95] Studies have explored mesolimbic dopaminergic dysfunction in STN-DBS induced apathy in PD patients 54,96,97 finding there to be different mechanisms at play between early and late PD. Therefore, initially the dopaminergic mesocortical system is involved due to the relative sparing of the nigrostriatal dopaminergic system.
• Cognitive Impairment (CI) CI and dementia have been associated with PD. Around 40% of patients have CI 98 at early-stage of PD, 99 and around 80% of patients may experience PD-related dementia (PDD) at a latestage. 100,101 Mild CI in PD (MCI) is also somewhat prevalent, where a recent review from the Movement Disorders Society (MDS) task force reports a prevalence of 27% (range 19-38%). 102 A dopaminergic basis of cognitive impairment is possible and using 18 F-DOPA PET, studies have demonstrated reduced dopaminergic uptake in PD patients at different stages of their condition with CI or PDD 99,[103][104][105][106][107][108][109] (Table 3), especially in the caudate nucleus. [110][111][112] PDD is known to be a late-manifestation in PD. 113 However, conversely some patients have been shown to present with early dopaminergic uptake changes within frontal structures critical to cognitive and executive function 99 ; thus cognitive impairment can be an early-manifestation in PD. Three SPECT studies have shown there to be an association between reduced dopaminergic uptake and cognitive impairment in PD and CI as well as PD Table 2. There seems to be both dopaminergic and noradrenergic defect in the limbic system of dPD, as suggested by the results. The study's sample is small and their PD patient's disease duration ranges from 0.5 to 9 years, which is very broad. However, this is an important study and a      and MCI, [114][115][116] however the authors do not use a uniform cognitive function test making their clinical definition of CI vary slightly. Nonetheless, they all report a significant correlation between striatal dopaminergic defect (more commonly unilateral and contralateral to the most affected side) and cognitive impairment existing in these PD patients ( Table 3). The pathophysiology of cognitive impairment in PD may also involve the brainstem and corticostriatal pathway with cholinergic dysfunction. 117-121 Using 2-18 F-FA-85380 PET, studies have shown there to be cholinergic dysfunction of not just the striatum, but also the cerebellum, pons, and thalamus. 122,123 In PDD, studies using N-11 C-methyl-4-piperidyl-acetate ( 11 C-PMP) acetylcholinesterase (AChE) PET have reported cholinergic degeneration. 124,125 Bohnen and colleagues used 11 C-PMP AChE PET on PDD patients finding a strong correlation of reduced radiotracer uptake with performances on working memory, attentional, and executive function tests suggesting a dominant cholinergic basis to these functions. 126,127 NMSS mood and apathy: summary statement Depression, apathy, and anxiety are often grouped together despite their heterogeneity in presentation and clearly apathy is a distinct NMS in its own right with several subtypes. 83 Depression, anxiety, and aspects of apathy appear to have partial dopaminergic dysfunction, as per evidence from dopaminergic imaging (Fig. 3). The role of dopaminergic pathology in PD depression is far from clear and as such, in this review we have demonstrated the knowledge so far (see Table 3). Vast evidence is emerging to support serotonergic pathology as having clearer implications in PD depression, 7 this is further supported by reduction in the midbrain FP-CIT SPECT DaT binding most likely reflecting serotonergic pathology rather than dopaminergic. Whilst serotonergic pathology may be at fault in PD depression, the spectrum of anxiety disorders may have noradrenergic, as well as dopaminergic involvement. By means of dopaminergic imaging, apathy has been demonstrated to have a mesocorticolimbic dysfunction. Nonetheless, the need to explore these nondopaminergic bases is required to further understand the spectrum of conditions such as apathy, where specific PD research is lacking.
DaT imaging has shown supportive evidence for a dopaminergic dysfunction in PD cognitive impairment. With the complexity that cognition presents with and the level of neurotransmitters involved, an expectation of both dopaminergic and cholinergic dysfunction seems possible.

NMSS DOMAIN 4: PERCEPTIONAL DISORDERS
Perceptional disorders in PD, ranging from VH to delusions, are particularly prevalent with one-in-four PD patients experiencing VH. [128][129][130][131][132] A dopaminergic basis of VH and other perceptional disorders is being researched. A cortico-striato-thalamocortical dysfunction has been suggested, 89,133,134 however at present, work is required to determine and distinguish the differing forms of hallucinations. Recent data provides evidence of a dopaminergic basis in VH 135 (Table 4), but not auditory hallucinations. 136 Several studies also support non-dopaminergic involvement through both serotonergic 10 and cholinergic 129,130,[137][138][139][140] means.
Lower DaT binding in the striatum in early PD measured by [ 123 I] [ß]-CIT tracer (DaTscan) is associated with increased prospective risk of psychosis spectrum at 5 years. 134 It is unclear whether this binding reduction is the underlying mechanism of the psychosis spectrum or, whether an indirect association, for example reflecting more extensive neurodegenerative involvement in the psychosis spectrum, is present. A serotonergic imaging study using the 5HT 2A receptor ligand setoperone-F 18 identified increased binding in patients with VH in ventral Table 3 continued There's some suggestions of striatal DA depletion contributing to cognitive defect in PD. This is an interesting study in drug naïve PD and addressing MCI vs. non-MCI PD. Supports a subtype concept and also a nondopaminergic origin of MCI even in early PD. occipito-temporal regions and bilateral frontal cortex. 10 In contrast, a 5HT 1A receptor binding study in post-mortem tissue found no association with psychosis spectrum, although 5HT 1A binding was elevated in PD irrespective of hallucination status in sublayers of orbito-frontal, ventral temporal, and motor cortex. 141 NMSS perceptional disorders: summary statement Currently, DaT imaging has not supported perceptional disorders as having a dopaminergic basis. Rather, recent studies suggest a multifactorial origin of hallucinations including alterations in dopaminergic, serotonergic, and cholinergic systems. Further longitudinal imaging studies involving the aforementioned neurotransmitters and pathways are required.

NMSS DOMAIN 5: ATTENTION DEFECTS
PD patients have been noted to experience various attentional function deficits, including visuospatial 142 and during performance of tasks requiring a switch of behaviour. 143,144 The evidence thus far supports a dopaminergic pathology underlying attention deficits in PD. Work from Rinne and colleagues (Table 5) find correlation between reduced 18 F-DOPA uptake in the caudate and frontal cortex with attentional and working memory deficit. Further evidence supports dopaminergic deficit within the frontal cortex (more specifically the medial portion), alongside the anterior cingulate and the dorsolateral prefrontal cortex. 99 However, Bohnen and collegues showed a robust correlation with cortical AChE activity with attention and working memory; suggestive of cholinergic involvement. 124 NMSS attention defects: summary statement Attention defects in PD are likely to be mediated through cholinergic dysfunction although a dopaminergic pathophysiology is also suggested by dopaminergic imaging studies. This is supported by the concept of frontal lobe and basal ganglia disturbances, which over the course of time may progressively worsen.

NMSS DOMAIN 6: GASTROINTESTINAL TRACT
Gastric dysfunction in PD is a prevalent issue with symptoms ranging from drooling, dysphagia, and constipation to gastroparesis 145,146 with constipation being suggested as a pre-motor marker in a recent Danish study. 147 There is currently no evidence that supports a dominant dopaminergic pathogenesis for gastric symptoms, whereas cholinergic dysfunction has been suggested by Gjerloff and colleagues who investigated the parasympathetic involvement of AChE binding using 11 C-donepezil PET. They report a significant decrease in 11 C-donepezil uptake in the small intestines and pancreas, proposing cholinergic dysfunction of the enteric nervous system in PD. 148 NMSS gastrointestinal tract: summary statement Dopaminergic imaging studies supporting a dopaminergic basis to the pathophysiology of gastric dysfunction in PD are currently not explored. The use of 11 C-donepezil PET however has suggested there to be an early enteric cholinergic dysfunction in PD.

NMSS DOMAIN 7: URINARY DYSFUNCTION
Referred to collectively as lower urinary tract symptoms (LUTS), one of the key and most frequent autonomic problems in PD is bladder dysfunction. 149 PD patients experience elevated urinary frequency, urgency, nocturia, incontinence, and voiding. 150 There is evidence for an underlying dopaminergic basis in the pathophysiology of LUTS (Table 6). Dopaminergic influences in the micturition reflex are present in inhibitory pathways arising from dopaminergic Substantia Nigra pars Compacta fibres, whilst the stimulatory affect arises from dopaminergic ventral tegmental area (VTA) fibres. 151,152 Work from Winge and colleagues further supports a dopaminergic dysfunction (Table 6). 201 However, the micturition reflex and LUTS are controlled by a number of neurotransmitters including DA, serotonin, NA, and ACh. 153 Moreover, PD-LUTS patients do not necessarily respond to levodopa or dopaminergic treatment but may instead require anticholinergic treatment suggesting a dominant underlying cholinergic basis. 152,154 NMSS urinary dysfunction: summary statement There is evidence for a dopaminergic association with urinary dysfunction in PD patients particularly D1 receptor activity. 150 However, urinary dysfunction in PD is likely to have a mixture of dopaminergic and cholinergic mechanisms.

NMSS DOMAIN 8: SEXUAL DYSFUNCTION
Sexual dysfunction is a common problem for many PD patients 155,156 and erectile dysfunction (ED), hyper-sexuality, loss of lubrication, loss of libido, and involuntary urination during sex are just some such symptoms. 149,[157][158][159][160][161] There is poor evidence that dopaminergic dysfunction may underlie sexual dysfunction.

Olfactory changes
Braak and colleagues proposed the idea that PD-pathology begins in extra-nigral structures, hence why olfactory dysfunction is a common initial prodromal symptom for many PD patients. 28 There is some evidence that dopaminergic dysfunction is responsible for olfactory symptoms (Table 7). Using SPECT imaging, several studies now have found there to be supporting evidence of DaT uptake reduction in hyposmic patients. [173][174][175][176][177][178][179][180] Scherfler and colleagues offer concordant evidence that both nigral and olfactory tract degeneration parallels that of putaminal dopaminergic dysfunction in PD patients, 202 although not all studies agree. [181][182][183] In contrast, two studies present evidence that DA agonists are ineffective in treating hyposmic symptoms however, this may be because the damage is simply too excessive. 184,185 • Weight changes PD patients characteristically undergo diet/metabolism-unassociated weight loss starting early in the course of the disease. 186,187 Based on available evidence, a dopaminergic basis for weight change in PD patients is not unexpected, however only one study by Lee and colleagues explores this (Table 7). DA is involved in modulating the reward and motivational properties of food intake 188 causing problems in weight gain and loss. 189 Weight gain is commonly associated with DA agonist treatment due to the side effects of ICD, specifically compulsive binge eating. [190][191][192][193] However, evidence suggests a prominent serotonergic involvement, and weak potential for noradrenergic action 194 as serotonin is thought to play a crucial role in modulation of appetite. 195 In a study using 11 C-DASB, a marker for SERT, Politis and colleagues demonstrated increased tracer binding in the rostral raphe nuclei, hypothalamus, caudate nucleus, and ventral striatum in PD patients with abnormal BMI changes. 9 Interestingly, gain in BMI was associated with raised 11 C-DASB binding in the anterior cingulate cortex when compared to those with reduced BMI. These findings imply that decreased levels of serotonin, due to elevated clearance, could lead to abnormal BMI changes. Furthermore, Sharma and colleagues propose introduction of a Park-weight subtype following observation, using standardized olfactory assessments, reporting PD patients with severe olfactory dysfunction correlate with having an increased risk of weight loss. 196,197 NMSS miscellaneous: summary statement The pathophysiology of olfactory dysfunction in PD may have a dopaminergic basis, and in part clinical data supports this observation. 198 However, involvement of the cholinergic system is also likely given the recent definition of the olfactory-limbic pathway. 199,200 Abnormal weight change is a common symptom in PD, affecting patients early. Recent imaging studies suggest that alterations in dopaminergic as well as serotonergic systems give rise to pathological changes in weight. Areas identified to be involved comprise the striatum for dopaminergic changes and

CONCLUSION
To our knowledge, this is the first review that has summarised available evidence exploring the possible dopaminergic basis of NMS pathophysiology using the domains integral to the NMSS, a widely used validated measure of holistic NMS assessment. Hence, it also addresses an unmet need in this regard. We have found there to be 12 NMS with imaging based evidence for at least in part, a dopaminergic pathophysiological basis ( Table 8). The use of radiotracers has certainly evolved and as such tracers such as, 99m Tc-TRODAT-1 SPECT is not regularly used in research now due to its low unreliability and low specificity in comparison to other imaging modalities. Furthermore, we have highlighted key NMS which have non-dopaminergic pathophysiologic involvement (Table 9).
Our review findings are summarised in Table 10, where we have classified evidence for the neurotransmitters involved in the pathophysiology of NMS into four arbitrary categories (strong, moderate, weak, and conflicting evidence). We have catogorised stronger evidence as having open-label trials, or more than 3 publications demonstrating neuroimaging based evidence. Moderate evidence; as having clinical trials, or 2-3 studies presenting neuroimaging based evidence, while weak evidence is defined as having some clinical cases, or 1 study reporting neuroimaging based evidence. Finally, conflicting evidence is defined having 2 or more conflicting studies. This table presents the first summary of NMS in relation to the potential neurotransmitters involved in their pathology. It also shows how some NMS such as insomnia, anhedonia, and delusions have had no or very little exploratory research conducted.