Vascular Parkinsonism (VP) is a clinical syndrome characterized by parkinsonian features associated with cerebrovascular disease, as highlighted in Zijlmans' diagnostic criteria (52). Two presentations are recognized: an acute onset (VPa) typically occurring within a year after a strategic infarct affecting the basal ganglia, thalamus, or frontal lobe, or a more insidious, progressive onset (VPi) on a background of diffuse subcortical white matter lesions, leading to symmetrical lower-body parkinsonism and cognitive dysfunction (52). Clinical clues favoring VP include stepwise progression (53), prominent gait impairment with leg predominant symptoms (52, 54–58) and co-occurrence of pyramidal signs, pseudobulbar palsy and urinary incontinence (52, 57, 59, 60). Furthermore, VP patients are generally older at the onset of motor symptoms (53, 56, 57, 61), have shorter disease duration compared to PD (56, 57, 61), and often present with more symmetric motor involvement (52, 59, 60). PD is suggested by pill rolling resting tremor (52, 56, 57), typical non motor symptoms like hyposmia, rapid eye movement (REM) sleep behavior disorder (RBD) and a significant levodopa responsiveness. The fact that parkinsonism is required in both VP and PD and vascular changes are a common finding in older people including those with PD, explains the diagnostic dilemma, where a specific surrogate marker would be highly needed.

Subcortical and periventricular white matter hyperintensities (WMH) and lacunar infarctions are frequently observed in VP, correlating with the severity of motor symptoms, postural instability and falls (56, 62). While total or deep WMH are associated with aging and cerebrovascular risk factors, periventricular WMH appear more specifically linked to the severity of parkinsonism, particularly gait disturbances (55, 63, 64). Other cohorts, however, found no association between the burden of periventricular WMH or dopaminergic imaging findings and the motor severity (55, 65, 66), cognitive functions or depression (65). Moreover, 10%−30% of asymptomatic elderly individuals with vascular risk factors show subcortical lesions, further complicating the relationship between imaging findings and clinical symptoms (67).

In VP, ischemic damage disrupts motor circuits, particularly thalamocortical fibers to the supplementary motor area and cerebellar fibers controlling leg movement, due to lesions in the basal ganglia, thalamus, and subcortical white matter (52, 59, 62). Although some VP patients exhibit cell loss in the substantia nigra with a similar pattern to PD, the damage is generally less severe as shown in histopathological studies, suggesting that dopaminergic depletion is less prominent or absent in VP (52, 68, 69).

Dopaminergic imaging reveals distinct patterns that help differentiate VP from PD. Across larger cohorts, 60 to 70% of VP patients exhibit an abnormal striatal DAT uptake (56, 58, 63), but reductions are generally milder and more symmetric than in PD (53, 56, 58, 66, 70, 71). Quantitatively, age corrected striatal reduction averages 1.2% in VP compared to the 40.8% in PD (70). Compared with PD's posterior putamen-dominant asymmetry, VP often shows balanced involvement of both the anterior caudate and posterior putamen with a lower caudate/putamen (C/P) ratio (54–56, 58, 70). Striatal-to-background ratios (SNBRs) and striatal asymmetry indices (SAI) are useful metrics. Posterior putamen SNBRs at a cut-off of 1.85 yielded 100% sensitivity and 52.2% specificity for distinguishing PD from VP in one study (55). SAI also differentiates PD from VP, achieving 100% specificity for PD at a cut-off value of 14.08, though sensitivity is lower (54). Advanced techniques, such a machine learning approach with statistical parametric mapping, achieve over 90% accuracy for PD/VP discrimination (71). While abnormal dopaminergic imaging is highly predictive of PD, normal scan cannot reliably exclude PD due to its lower negative predictive value (12, 72). Approximately 30%−40% of VP patients, particularly in cases with WMH rather than basal ganglia involvement, show normal dopaminergic imaging indicating non-dopaminergic mechanisms such as disruptions in thalamocortical pathways (56, 58, 63). Conversely, asymptomatic individuals, such as those with NOTCH3 mutations, may show nigrostriatal denervation, reflecting a presymptomatic disease phase (73). The findings in dopaminergic imaging in VP are heterogeneous (see Table 3) (61, 74), with some studies showing a normal uptake in all VP patients (72), in contrast with the significant reduction observed in other studies (54, 66, 75).

Dopaminergic imaging findings seem to correlate with other clinical markers of VP. Higher vascular load (periventricular and hemispheric WMH) has been reported more often in VP patients with normal DAT binding (63), whereas Lee et al. (55) found that reduced SNBRs in VP patients correlated with the severity of periventricular white matter hyperintensities. Imaging characteristics may differ between VPa and VPi, with higher asymmetry indices in cases of unilateral ischemic lesions affecting the nigrostriatal pathway (76).

The relationship between dopaminergic imaging findings and levodopa response in VP is highly variable. Patients with normal striatal binding rarely benefit from dopaminergic therapy, with over 90% non-responder in one study with 76 VP patients (63), suggesting a non-dopaminergic cause for their symptoms (74, 77, 78). Among those with reduced DAT uptake, levodopa responsiveness varies widely, ranging from 20 to 50% (56, 57), nearly half may still fail to respond despite evidence of presynaptic dopaminergic deficits (63). Some cohorts report better motor improvement when dopaminergic imaging is abnormal (52, 53, 63, 74, 76, 78), whereas others find no clear levodopa benefit even in the presence of presynaptic deficits (53, 56, 71, 73, 75, 79). Overall, lesion topology seems influential: midbrain lesions disrupting the nigrostriatal pathway respond more often than striatal lesions or territorial infarctions (56, 74, 76). In practice, extent of vascular lesions, disease severity, and hypertension predict poor levodopa response more robustly than dopaminergic imaging alone (63). An imaging-guided pathway for selecting patients for DAT imaging and action on PD-like vs. VP-like patterns is provided in Figure 3.

While presynaptic dopaminergic imaging can aid distinguishing VP from PD, especially when combined with semi-quantitave metrics and clinical context, it cannot reliably confirm or exclude VP on its own. Given the frequent coexistence of VP and PD, assessing potential co-pathology is essential. The role of imaging in guiding levodopa therapy remains limited (61), as non-dopaminergic mechanisms contribute significantly to VP symptomatology (53, 79). However, in patients with a DAT deficit, we suggest a pragmatic levodopa trial, as some degree of responsiveness has been observed. Moreover, this trial can aid in distinguishing VP from PD, particularly in cases where postural instability and gait disorder (PIGD) subtype of PD is suspected. Given these complexities, VP management requires a broader approach, addressing vascular risk factors and tailoring treatment strategies based on the individual patient's imaging findings and clinical presentation (12). See Table 3 for study-level details and Figure 3 for a suggested imaging-guided algorithm.

Dural arteriovenous fistulas (DAVFs) are acquired vascular malformations with abnormal shunting between arteries and veins in the dura mater. The clinical symptoms vary depending on the location of the DAVF and on whether the lesion is solely dural or has a prominent drainage pattern (80).

First described by Matsuda et al. (81), the occurrence of parkinsonism with or without progressive cognitive dysfunction caused by DAVF has been rarely reported. Venous hypertension, which results from increased blood flow through the draining veins or from obstruction to drainage, has been associated with the neurological deficits (81–85). When the DAVF lead to a venous congestion of the galenic system, patients may present with parkinsonism (84, 85).

The decreased regional cerebral blood flow in the basal ganglia for patients with DAVF and parkinsonism has been demonstrated by a few authors (81, 84–88) but to our knowledge there are only two case reports of presynaptic dopaminergic imaging findings in DAVF-associated parkinsonism. Kim et al. (87) reported a patient with presynaptic dopaminergic deficit, which was not related to hemodynamic changes induced by DAVF. Previous symptoms with RBD, constipation and visual hallucinations, suggested underlying nigrostriatal degeneration unmasked or exacerbated by venous congestion. The patient's symptoms, except for the RBD, improved after DAVF occlusion without medication, suporting a hemodynamic aggravation of a pre-existing dopaminergic deficit (87). Kawasaki et al. (88) showed decreased dopamine transporter activity in the bilateral striatum in dopaminergic imaging with an improvement of the clinical symptoms after the treatment of the DAVF. Presynaptic dopaminergic imaging remains rarely documented, and no prevalence estimates are possible.

The response to dopaminergic treatment seems inconsistent in DAVF-associated parkinsonism. While some authors report at least a transient response to dopaminergic treatment (85, 86), others could not observe any benefit (84). The lack of response to dopamine has been interpreted for some authors as a sign of impaired postsynaptic striatal function due to venous congestion (88), but this remains hypothesis-level given the paucity of presynaptic data. In contrast, patients seem to have a clear benefit regarding their motor and cognitive symptoms after embolization of the DAVF, emphasizing the correlation between basal ganglia perfusion deficits and DAVF-related parkinsonism (84, 86, 87).

When DAVF-related parkinsonism is suspected, treat the fistula first. Reversing parkinsonism through successful DAVF treatment highlights the importance of addressing underlying vascular abnormalities to restore normal cerebral function and alleviate symptoms. Consider presynaptic dopaminergic imaging if the clinical picture suggests possible co-pathology (e.g., prodromal PD geatures) or if imaging would alter management.

Toxoplasma gondii can infect any nucleated cell, including within the central nervous system (CNS), crossing the blood-brain barrier during acute infection. During chronic infection, parasite cysts persist in the CNS, while being cleared from other organs (89). In mice, Toxoplasma cysts are found in various brain regions. However, it has a tropism for the basal ganglia, especially thalamus and striatum, as well as the amygdala, likely due to blood transport by the middle cerebral artery (89).

Clinically, movement disorders are uncommon in cerebral toxoplasmosis (CTx) and tend to be hyperkinetic, parkinsonism is rare. To our knowledge, there is only one case report documenting a (unilateral) presynaptic dopaminergic striatal deficit (90). Parkinsonism improved with levodopa after other treatments failed (90). CTx-related parkinsonism is likely due to direct damage to the substantia nigra rather than the basal ganglia, which would rather cause a postsynaptic dopaminergic deficit, as evidenced in this case by Magnetic resonance imaging (MRI) and dopaminergic imaging (90). Given the case-level nature of the evidence, the prevalence of presynaptic dopaminergic imaging abnormalities in CTx cannot be estimated, and presynaptic imaging should be considered selectively for atypical presentations or when a co-pathology is in the differential.

Studies on HIV-related parkinsonism have shown variable prevalence rates and contributing factors. Mattos et al. (91) reported a 2.7% frequency of involuntary movements in patients with acquired immunodeficiency syndrome (AIDS), while half of them exhibited parkinsonian features. The most common causes of parkinsonism in these patients were HIV itself (12 patients), toxoplasmosis of the midbrain (3), and metoclopramide (3) (91). Recent observations suggest a decrease in HIV-related parkinsonism cases, possibly due to the introduction of highly active antiretroviral therapy (HAART) (91).

Presynaptic dopaminergic imaging evidence is limited and heterogeneous. A case study detailed a patient initially misdiagnosed with PD. Dopaminergic imaging showed bilaterally reduced putaminal uptake, with relatively preserved uptake in the caudate nucleus. The patient responded well to dopaminergic therapy and showed a complete clinical remission following HAART. A bilateral onset and rapid progression are common in HIV-associated parkinsonism but uncommon in PD. In this case the patient's presentation including levodopa-induced dyskinesia, which is uncommon in HIV-related cases, lead to the misdiagnosis of PD (92).

Another case, however, described a normal dopaminergic imaging in a patient experiencing rapid cognitive decline and parkinsonism, with only partial improvement after HAART, remaining care-dependent until death from pneumonia (93).

Because presynaptic imaging evidence in HIV-associated parkinsonism is limited to two case reports, no firm conclusions can be drawn.

Although movement disorders in COVID-19 are rare, there have been a few reports of parkinsonism following severe COVID-19 infection. To our knowledge, only two studies have described the results of dopaminergic imaging in COVID-19 infection.

The mechanisms linking COVID-19 to parkinsonism remain unclear, but several hypotheses have been proposed. One possibility is direct viral invasion, as coronaviruses can access the CNS via the olfactory bulb, triggering neuroinflammation and microglial activation that may contribute to dopaminergic dysfunction (94). Supporting this, coronavirus antibodies have been detected in the CSF of PD patients, suggesting a potential immune-mediated mechanism (95). Alternatively, systemic inflammation and hypoxic-ischemic injury could exacerbate neurodegeneration. Severe COVID-19 leads to prolonged hypoxia, oxidative stress, and cytokine release, all of which have been linked to dopaminergic neuron vulnerability (96, 97). Infections also alter dopamine metabolism, reducing vesicular dopamine storage and increasing DAT activity, which may further impair striatal function (98). Another possibility is that COVID-19 may unmask preclinical PD in individuals with pre-existing but subclinical nigrostriatal deficits. Systemic infections have been associated with acute worsening of PD symptoms and in some cases, a faster disease progression (99). While this hypothesis remains speculative, it aligns with previous observations that systemic inflammation and metabolic stress can accelerate symptom onset in individuals already at risk for PD (100).

Dulski et al. reviewed 24 post-COVID-19 parkinsonism patients, noting that brain MRI was often normal while dopaminergic imaging showed impaired uptake in all eight patients in whom scans were performed. Levodopa responsiveness was reported in 12/15 treated patients; however, clinical improvement sometimes occurred without therapy or with immunomodulatory treatment, indicating a secondary etiology rather than primary neurodegeneration. Dopaminergic imaging patterns were asymmetric, paralleling findings from other viral infections linked to parkinsonism (97).

A case report described a 58-year-old man, who developed a hypokinetic-rigid syndrome with ocular abnormalities and opsoclonus following a severe SARS-CoV-2 infection. Dopaminergic imaging revealed an asymmetrical bilateral decrease in presynaptic dopamine uptake, particularly in the putamina. Significant spontaneous improvement in parkinsonian symptoms was observed without specific treatment. The authors discuss the similarities of this case with encephalitis lethargica, with similar acute symptoms like myoclonus and ocular motility disorders as well as fluctuating and transient changes in level of consciousness (96).

In the few post-COVID parkinsonism cases with presynaptic imaging, dopaminergic imaging confirms nigrostriatal dysfunction in those selected patients; however, the available evidence is limited to these case-level observations, so no firm conclusions can be drawn about prevalence, characteristic patterns, or prognosis. Further research is needed to determine whether these cases represent a distinct, virus-induced form of parkinsonism, the unmasking of pre-existing PD, or simply a coincidental onset of disease. The variability in clinical outcomes, including cases with spontaneous recovery, suggests that multiple mechanisms may be at play.

Subacute Sclerosing Panencephalitis (SSPE) is a progressive, fatal encephalitis caused by a persistent mutated measles virus infection, usually emerging after a 4–10 year latency (101). The estimated incidence ranges between 6.5 and 11 per 100 000 measles cases annually (102), with the highest risk observed in individuals infected before age 5 (101, 102). Although the disease burden has declined due to widespread vaccination (101), cases persist in low-coverage regions (102), and reemergence has been noted in developed countries (103).

SSPE commonly begins during childhood or adolescence, but adult-onset cases have been reported, typically with atypical features (104). The clinical trajectory is classically divided into four stages (105):

Movement disorders are present in up to 50% of the patients and are increasingly recognized as core features (106, 107). While myoclonus is most prominent (92% in some cohorts), other manifestations include dystonia (up to 48%), chorea (up to 14%), tremor (6.7%−39.1%), parkinsonism (5%−26%), ataxia (up to 18%), and rarely, tics and stereotypies (106, 107).

MRI abnormalities in SSPE may include periventricular white matter hyperintensities -more accentuated in the parieto-occipital cortex than the frontal cortex- cerebral atrophy, and basal ganglia involvement (104, 108).

Only limited data exist on dopaminergic imaging in SSPE. Hsieh et al. (109) reported combined FDG and FDOPA PET scans in a 19-year-old woman with stage II SSPE. FDG PET showed diffusely reduced cortical metabolism across both hemispheres, cerebellum, and thalami, while FDOPA PET showed preserved uptake in the striatum. The caudate showed slightly decreased glucose uptake relative to dopaminergic activity. The discrepancy suggests that dopaminergic terminals in the striatum are relatively spared early in the disease, despite extensive cortical and subcortical dysfunction. Singer et al. (104) described a 26-year-old woman with progressive visual loss, cognitive impairment and parkinsonism. [¹⁸F]fluoro-DOPA PET imaging showed preserved uptake in both caudate nuclei and the left putamen, but a slight reduction in the right putamen. This suggested relatively intact presynaptic dopaminergic function in early stages, despite profound extrapyramidal symptoms. The patient progressed to a state of myoclonus, retrocollis, and postural instability. At autopsy, extensive pathology was noted in cortical areas and the putamen, with notable neuronal loss in the substantia nigra—providing histological evidence for dopaminergic involvement in later disease stages.

To date, no curative therapy exists. Disease-modifying agents like intraventricular or intrathecal interferon-α and oral isoprinosine show mild effect at best (110). Symptomatic treatments like valproate, carbamazepine, clonazepam, or clobazam may alleviate myoclonus and movement disorders. However, most cases progress inexorably. Notably, adult-onset cases occasionally show a slower trajectory, transient stabilization or even spontaneous remission (104).

Dopaminergic imaging in SSPE is limited to anecdotal reports, yet provides valuable insights. The preservation of FDOPA uptake despite cortical hypometabolism aligns with clinical observations: hyperkinetic disorders, cognitive impairment and neuropsychiatric symptoms emerge earlier, while hypokinetic features like parkinsonism tend to appear later. This supports the hypothesis that basal ganglia circuits—particularly those involving dopaminergic terminals—may be relatively resilient until advanced disease stages. Given this selective vulnerability and only mild tracer uptake reduction in patients with clinical parkinsonism, further dopaminergic imaging studies could delineate dopaminergic dysfunction across disease stages and phenotypes. This would also clarify whether parkinsonism in SSPE results from presynaptic dopaminergic failure, or secondary network disruption.

Japanese Encephalitis is a mosquito-borne viral CNS infection, which is endemic in Asia and western Pacific regions (111). The clinical spectrum ranges from asymptomatic infections to non-specific febrile illness, aseptic meningitis and acute encephalitis, which is the most common presentation (111, 112).

Even though most of the infections are clinically inapparent it is a severe, potentially lethal illness, with case fatality rate up to 30% (111). The disease course can be subdivided into a prodromal stage with fever, headache, fatigue, nausea and vomiting; the acute stage with changes in the mental status, confusion, encephalopathy, possible parkinsonian syndrome and/or upper and lower paralysis followed by the late stage with gradual recovery and possible persistence of CNS signs in up to 30%−50% of cases (111, 112). About one in four patients presents with a movement disorder, usually parkinsonism (113). The involvement of the basal ganglia has been described earlier from imaging studies with MRI (114, 115).

Our search of dopaminergic imaging retrieved only case-level evidence. There was one small case series with three patients aged 20–28 and two case reports of individuals aged 65–67. Despite the large age gap, the clinical presentation was similar with signs of acute infectious encephalitis and parkinsonian symptoms. A decreased striatal uptake in all patients was detected via ¹²³I-FP-CIT and ⁹⁹mTc-TRODAT-1. While Liao et al. and Tadokoro et al. showed an asymmetric striatal uptake, the patient observed by Lin et al. had a symmetric decreased striatal uptake (113, 116, 117). A longitudinal imaging study proposed an initial unilateral invasion of the thalamus with expansion throughout the disease course with the presentation of cytotoxic edema, as a possible explanation for these findings (118), although this remains hypothesis-level.

Available reports indicate acute striatal presynaptic reduction during encephalitic presentations. However, the limited evidence does not allow us to drawn any firm conclusion.

Creutzfeldt-Jakob disease (CJD) is a rare and fatal prion disease, characterized by rapidly progressive neurodegeneration, with myoclonus, ataxia, rapid progressively dementia, akinetic mutism, and visual disturbances as presenting symptoms (14, 119, 120). Parkinsonism, dystonia and chorea are also possible clinical manifestations, strongly suggesting the involvement of the dopaminergic system (121). Parkinsonism can be an initial symptom of CJD, although it is relatively rare, sometimes leading to wrong diagnosis in the initial disease stage. However, the prevalence of extrapyramidal symptoms increases with longer disease duration and parkinsonism is frequently observed in the terminal stages of CJD, commonly in the form of akinetic mutism (14).

Multiple case studies have highlighted the relevance of dopaminergic imaging in CJD. A presynaptic dopaminergic deficit in CJD, typically with greater putaminal than caudate reduction, has been described by many authors, supporting the hypothesis of nigrostriatal dysfunction in this disease (121–127). This also holds true for familial CJD, where parkinsonism is more commonly observed compared to sporadic or variant forms of CJD (125, 128). Further supporting the link between CJD and nigrostriatal dysfunction, Vital et al. (14) conducted a neuropathological study revealing both pre- and post-synaptic cell loss in the nigrostriatal system of CJD patients, with the presynaptic dopaminergic loss being more accentuated in the cases of CJD presenting with parkinsonism than in those dominated by chorea or myoclonus. The loss of dopaminergic neurons in the substantia nigra correlated with the loss of neurons in the caudate and putamen, suggesting a parallel pre- and postsynaptic degeneration of the nigrostriatal pathway in CJD. Those cases underscore the importance of considering CJD in rapidly progressing atypical parkinsonism cases, as it may mimic an atypical parkinsonism, especially in the initial disease stage (123, 126, 128).

Park et al. (129) in contrast, presented a case of probable sporadic CJD with extrapyramidal symptoms as the main feature, where ¹⁸F-FP-CIT PET imaging showed no dopaminergic deficits. This finding has been supported by other authors, who described normal tracer uptake or only mildly decreased uptake on the caudate tail despite a marked parkinsonism in a patient with CJD (15, 130). This suggests that postsynaptic alterations may contribute to parkinsonism in CJD (129, 130).

Collectively, most of the published cases reveal significant dopaminergic deficits that correlate with clinical symptoms and neuropathological findings. Thus, while not diagnostic, it can provide supportive evidence of nigrostriatal dysfunction or indicate preserved presynaptic activity, suggesting a predominant postsynaptic pathology. Given the rapid progression and poor response to dopaminergic therapy, an early distinction from other parkinsonian syndromes can help guide diagnostic workup, patient counseling, and treatment decisions.

Diabetic uremic syndrome typically manifests as uremic encephalopathy with cortical involvement, resulting in seizures, asterixis, and myoclonus (132). A less common phenotype involves basal ganglia dysfunction, leading to parkinsonism, more unfrequently dyskinesia, chorea, and loss of consciousness (133). Pathophysiological factors include uremic neurotoxicity that impair mitochondrial function and disrupt the balance between excitatory and inhibitory amino acids, as well as microvascular and nutritive components (134).

Presynaptic dopaminergic imaging is limited to two case reports with divergent findings. Suzuki et al. (135) reported a 57-year-old man with diabetic renal failure, who presented with parkinsonism and loss of consciousness. His dopamine transporter imaging was normal, and his symptoms and MRI changes improved rapidly after hemodialysis, pointing to a reversible, non-nigrostriatal mechanism. Conversely, Ishii et al. (136) described a patient with sub-acute parkinsonian symptoms and a marked presynaptic dopaminergic impairment with no clinical improvement after hemodialysis or after levodopa administration. MRI showed vacuolated changes following focal necrosis, suggesting irreversible basal ganglia injury (136).

With only two presynaptic imaging cases, no firm conclusions can be drawn about prevalence or typical DAT patterns. Available reports suggest that normal DAT in this context aligns with dialysis-responsive and secondary parkinsonism.

A subset of patients with chronic liver dysfunction may develop cirrhosis-related parkinsonism, regardless of the cause of liver failure (137, 138). Burkhard et al. (137) studied 51 patients eligible for liver transplantation over 1 year, finding that 11 (21.6%) had moderate to severe parkinsonism, with motor UPDRS ranging from 20.5 to 61. This condition differs from PD, presenting with rapidly evolving and symmetric akinetic-rigid syndrome, dysarthria, early gait and postural impairment, focal dystonia, and a prominent resting tremor (137, 139, 140).

Increased manganese (Mn) deposition, due to impaired Mn excretion via the bile duct (140), is a suggested cause, but it remains unclear why only a few patients develop parkinsonism since increased Mn is present in all cirrhotic patients (141). Chronic Mn accumulation is however not the only pathomechanism in cirrhotic disease. Synergistic effects of other toxic products like ammonium, neuroinflammation, and nitrosative stress are also contributing factors (131).

Yang et al. (142) reviewed 21 cases and proposed a classification into three categories: levodopa-resistant atypical parkinsonism without a dopaminergic deficit, coincidental PD with superimposed cirrhosis, and a subgroup of undetermined cases.

Pooling the presynaptic imaging reports we included (two case series, two case reports, one prospective cohort; total n = 17), 10/17 (~59%) showed preserved DAT/FDOPA uptake and typically a symmetric, rapidly evolving akinetic–rigid phenotype with limited levodopa benefit, consistent with secondary, cirrhosis-related parkinsonism, 6/17 (~35%) showed reduced presynaptic uptake, usually asymmetric with a posterior-putaminal (rostrocaudal) gradient, and levodopa responsiveness, compatible with coexistent degenerative PD/dual pathology, and 1/17 (~6%) had reduced uptake without levodopa response (undetermined) (139–143). Notably, MRI T1 basal-ganglia hyperintensity may occur regardless of presynaptic status. These proportions are exploratory and derived from case-level evidence, but they are practical for counseling: selective DAT SPECT/¹⁸F-DOPA PET helps set expectations (secondary vs. degenerative mechanisms) and identify the minority likely to benefit from dopaminergic therapy.

Mn is an essential trace metal primarily entering the body through diet. 98% of these Mn load is cleared by the liver, which explains the MRI and clinical findings resembling Mn intoxication in patients with chronic liver disease (144). A characteristic “manganism” phenotype is also seen with continuous consume of ephedrone (methcathinone), a CNS stimulant producing amphetamine-like effects, which is synthesized from pseudoephedrine, KMnO4, vinegar, and water (145–148). While exposure levels to Mn required to cause disease are unclear, serum Mn levels poorly correlate with neurological symptoms, with individual susceptibility influenced by factors like liver dysfunction, iron deficiency and genetic predisposition (149).

Mn-induced parkinsonism often presents with behavioral changes before parkinsonian features. The parkinsonism induced by Mn presents some features that helps differentiate this one from PD as a more symmetric presentation, kinetic tremor, dystonia, a characteristic gait known as “cock-walk” and early cognitive, balance, and speech issue. Some patients may show pyramidal signs. Patients are often younger at onset and unresponsive to levodopa therapy (145, 148–152). Parkinsonian features may progress after the cessation of Mn exposure (145, 150).

Mn toxicity damages GABAergic neurons in the globus pallidus, increases synaptic glutamate, reduces striatal dopamine, and disrupts iron regulation, causing oxidative stress and neuronal injury (145). MRI often reveals symmetrical T1 hyperintense signals in the globus pallidus, most severe in its medial part, the subthalamic nucleus and substantia nigra reticulata as well as putamen (145, 153, 154).

The dopaminergic imaging findings in manganism are heterogeneous. Although there are numerous studies documenting an intact nigrostriatal dopaminergic system (145–148, 151, 152), suggesting a predominant involvement of the postsynaptic dopaminergic pathway. There are a few reports of pathological dopaminergic imaging findings. The presynaptic dopamine deficit in those patients tends to be milder than in PD (155) and some patients may show an affection of the caudate, which is not so severely affected in PD (150).

Three non-exclusive explanations have been proposed for the presynaptic dopamine deficit observed in manganism: (i) an incidental Mn exposure in patients with PD, (ii) a degeneration in the presynaptic dopaminergic neurons caused by manganism, or (iii) Mn exposure as a risk factor for developing PD (156). Given the small, heterogeneous literature, no prevalence estimates can be made for presynaptic abnormalities or dual pathology.

In suspected manganism, preserved uptake in dopaminergic imaging is common and aligns with poor levodopa response and suggest a postsynaptic/network dysfunction. Abnormal DAT uptake should prompt consideration of PD co-pathology and may justify a levodopa trial with longitudinal follow-up. Dopaminergic imaging is therefore best used selectively to exclude degenerative nigrostriatal loss when clinical or MRI features suggest manganism, and to guide patient counseling about expected dopaminergic benefit.

Osmotic demyelination syndrome (ODS) is a rare condition typically triggered by the rapid correction of hyponatremia, among other conditions, leading to central pontine myelinolysis (CPM) and extrapontine myelinolysis (EPM) due to degeneration and loss of oligodendrocytes (157, 158). Clinically, it presents with a biphasic course starting with encephalopathy or seizures due to hyponatremia, followed by mild improvement after correction of hyponatremia, and then a few days later deterioration due to myelinolysis (157, 158).

CPM primarily affects the corticobulbar and corticospinal tracts, resulting in dysarthria, dysphagia, quadriparesis, and potentially a locked-in syndrome, while EPM involves various brain regions leading to a wider spectrum of symptoms (158). MRI of patients with EPM show symmetric T2 hyperintensities and T1 hypointensities predominantly in the striatum and thalamus (159, 160), but the substantia nigra may also be affected (161). Some case reports have documented a putaminal atrophy in the chronic phase of ODS (162).

A study involving 11 patients revealed various movement disorders in ODS, including generalized dystonia (27.3%), parkinsonism (36.4%), or both (36.4%). Postural tremor was observed in 45.5% of the patients. Other movement disorders such as myoclonus, chorea, pseudochoreoathetosis, belly dancer dyskinesia, tics and ataxia can also be observed in ODS (157). The disruption of the frontal subcortical networks running through the striatum can lead to neurobehavioral symptoms (158). Patients commonly show features of both CPM and EPM (157, 158).

Evidence in ODS is limited to four case reports (n = 4). Across these, severe reduction in presynaptic striatal dopamine transporter density in patients with ODS-induced parkinsonism was demonstrated, suggesting damage to the nigrostriatal pathway (159–162), The asymmetry of clinical signs correlated well with asymmetric reduction in uptake of the radiotracer ligand (159–161). In two cases, recovery of clinical symptoms correlated with normalization of radiotracer uptake in follow-up studies, suggesting potential reversibility of nigrostriatal dysfunction (159, 162).

Cases have shown improvement with dopaminergic treatment (159–161), although responses can vary (157).

Overall, ODS can manifest as a complex array of neurological symptoms due to its diverse regional brain involvement, with movement disorders being prominent. These disorders can resolve (159, 160, 162), persist, or evolve over time (157, 161), necessitating tailored symptomatic treatment and close monitoring for long-term management (157, 159, 160, 162).

Although presynaptic evidence in ODS is limited to four single-patient reports, the findings are concordant. These case-level data suggest that presynaptic dysfunction in ODS-related parkinsonism is typically present and may be reversible, but numbers remain too small to infer prevalence or prognostic accuracy.

Secondary chorea encompasses a group of hyperkinetic movement disorders arising from non-genetic systemic conditions, including infectious causes, drug-related chorea, autoimmune, metabolic or hematologic derangements (163). Although rare, these conditions provide a unique window into the vulnerability of the basal ganglia to systemic disturbances, highlighting complex interactions between vascular, metabolic, and neurotransmitter-related mechanisms.

In polycythemia vera (PV), chorea occurs in ~0.5%−5% of patients, with a striking female predominance (female:male ratio = 4:1) (164). Typically manifesting after age 50, the disorder presents with generalized chorea predominantly affecting the faciolingual and brachial muscles, often accompanied by muscular hypotonia (165). The hypothesized pathophysiology involves neostriatal hyperviscosity due to erythrocytosis, leading to venous stasis, impaired cerebral perfusion, and disturbed dopaminergic regulation (164, 166). Dopaminergic hyperactivity has been suggested, possibly enhanced by platelet-derived dopamine accumulation in the striatum or estrogen deficiency (164, 166).

Evidence in PV is based in one case report. Huang et al. (165) reported a patient with PV with moderate asymmetrical bilateral reductions in striatal tracer uptake on ⁹⁹mTc-TRODAT-1 SPECT. Serial imaging showed a normalization of uptake and clinical improvement following therapeutic phlebotomies, suggesting a reversible presynaptic disturbance secondary to altered striatal perfusion or platelet-induced dopamine dysregulation rather than permanent neuronal loss. Conventional MRI is frequently unremarkable (165).

Diabetic chorea, also referred to as “diabetic striatopathy,” often presents as hemichorea-hemiballismus, more frequently in elderly women, with poorly controlled non-ketotic hyperglycemia (167). Pathologically, the disorder is characterized by selective striatal vulnerability to microvascular injury, including arteriolar wall thickening, capillary proliferation, erythrocyte extravasation, and patchy necrosis (168).

MRI consistently reveals T1-hyperintensity in the putamen, frequently unilateral and contralateral to the affected side, although bilateral cases have been described, that tend to resolve with glycemic control (167–170).

Presynaptic dopaminergic imaging in diabetic chorea is limited to two case reports. Sato et al. (169) demonstrated bilateral, right-predominant reductions in ¹²³I-FP-CIT binding in the caudate and putamen using DAT-SPECT, with an asymmetry index of 10.7%, correlating with the contralateral dominance of chorea. This finding, along with reduced FDG uptake and perfusion in the same regions on PET and ⁹⁹mTc-ECD SPECT, respectively, supports a model of focal nigrostriatal dysfunction in diabetic chorea. Notably, MIBG cardiac scintigraphy was normal, ruling out a generalized sympathetic denervation and underscoring the regional specificity of the damage (169). In another case, Belcastro et al. (170) reported strictly unilateral reductions in DAT binding in the putamen contralateral to symptoms, with a putamen/cortex ratio falling below the age-adjusted reference range. These results reinforce the presence of a localized presynaptic dopaminergic deficit, possibly resulting from energy failure in the metabolically vulnerable medium spiny neurons of the striatum (170).

Therapeutically, both conditions respond to the correction of the underlying systemic disturbance, phlebotomy in PV and glycemic normalization in diabetes (165, 170).

In conclusion, secondary chorea related to PV and diabetes mellitus represents a rare but informative window into the modulatory effects of systemic disorders on basal ganglia circuitry. While both disorders exhibit characteristic imaging abnormalities, the underlying mechanisms diverge, ranging from reversible perfusion-related dysfunction in PV to microvascular injury in diabetes. These insights underscore the importance of considering metabolic and hematologic etiologies in adult-onset chorea and the role of dopaminergic imaging in these disorders.