Description
Dopamine transporter imaging with single-photon emission computed tomography (DaT-SPECT), using radiopharmaceutical ioflupane injection, is a neuroimaging modality being evaluated to improve the differential diagnosis of parkinsonian syndromes from nonparkinsonian tremor, as well as dementia with Lewy bodies from Alzheimer disease.

Background
Parkinsonian Syndromes
Parkinsonian syndromes are a group of diseases that share similar cardinal signs, characterized by bradykinesia, rigidity, resting tremor, and gait disturbance. Parkinson Disease (PD) is the most common cause of parkinsonism.

Despite the well-known symptoms of PD, diagnosis is challenging even for experienced clinicians, particularly in the early stages of the disease. In addition, other etiologies such as essential tremor, corticobasal degeneration, multiple system atrophy, progressive supranuclear palsy, vascular parkinsonism, and drug-induced parkinsonism can lead to a similar set of symptoms. One recent approach to improve the accuracy of clinical diagnosis of PD and other parkinsonian syndromes is to evaluate the integrity of dopaminergic pathways in the brain using dopamine transporter imaging with single-photon emission computed tomography (DaT-SPECT) imaging.

Dementia with Lewy Bodies
Dementia with Lewy bodies is a type of dementia characterized by parkinsonism, visual hallucinations, cognitive fluctuation, sleep disorders, and severe neuroleptic sensitivity. Dementia with Lewy bodies is the second most common form of degenerative dementia; Alzheimer disease, which can have similar symptoms at onset, is the most common.

Diagnosis can be challenging, particularly when patients have multiple comorbidities including cerebrovascular disease and/or Alzheimer disease.¹ As with PD, dementia with Lewy bodies is characterized by the degeneration of nigrostriatal neurons; as such, DaT-SPECT is also proposed to differentiate dementia with Lewy bodies from Alzheimer disease.

DaT-SPECT
DaT-SPECT is based on the selective affinity of DaT ligands for dopamine-synthesizing neurons, which allows visualization of deficits in the nigrostriatal dopaminergic pathway.

DaT ligands include iodine 123I-2β-carbomethoxy-3β-(4-iodophenyl) tropane (123I-β-CIT), which is a cocaine analogue with an affinity for both dopamine and serotonin transporters. Intravenous 123I-β-CIT requires a delay between injection and scan of about 24 hours. Iodine-123 N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (123I-FP-CIT) is a fluoropropyl derivate of β-CIT that is selective for brain striatal DaT but can also bind to the serotonin transporter. Intravenous 123I-FP-CIT can be injected 3 to 6 hours before the scan (DaTscan). Other SPECT ligands with affinity for dopamine transporter include technetium 99m (2β((N,N¢-bis(2-mercaptoethyl) ethylene diamino)methyl) and 3β-(4-chlorophenyl) tropane (99mTc-TRODAT-1).^2,3

Binding of ligands with an affinity for DaT ligands in the striatum is, in general, reduced in PD, genetic parkinsonism, dementia with Lewy bodies, corticobasal degeneration, progressive supranuclear palsy, and multiple system atrophy. In contrast, striatal DaT ligand binding is expected to be within the normal range of Alzheimer disease, essential tremor, dystonic tremor, orthostatic tremor, drug-induced parkinsonism, and psychogenic parkinsonism.²

Visualization of striatal dopamine transporter binding, through DaT-SPECT, permits assessment of presynaptic dopaminergic deficit. It is proposed that an abnormal DaT-SPECT scan supports the diagnosis of PD, dementia with Lewy bodies, or other neurodegenerative parkinsonian syndromes, while a normal DaT-SPECT scan in a symptomatic patient supports the diagnosis of a disease not affecting the nigrostriatal dopaminergic pathway.

Analysis of DaT-SPECT images can be visual, semiquantitative, or quantitative. In patients with PD, physical symptoms start after 30% to 50% of dopaminergic neurons have degenerated.^4,5 Symptomatic patients with PD would be thus expected to have sufficient abnormality on DaT-SPECT for visual analysis to be adequate for interpretation. A variety of methods are being tested to improve the validity and reliability of ratings, including commercially available software to define the region of interest for analysis and the development of an atlas for visual interpretation. Several research centers are developing quantitative and semiquantitative classification methods for the evaluation of DaT-SPECT images.^6,7,8,9

Anatomic variation in the brain, including vascular lesions, may interfere with the distribution of the iodine-123 tracer and could result in an abnormal scan.¹⁰ Dopamine agonists and levodopa may also affect DaT expression, which could influence the ability of DaT-SPECT to monitor the progression of disease unless these agents are discontinued prior to imaging. Patients with clinically diagnosed PD or dementia with Lewy bodies, who present with a normal DaT-SPECT scan, are referred to in the literature as having "scans without evidence of dopaminergic deficit." While many of these patients are ultimately diagnosed with non-PD syndromes, a portion of patients with normal DaT-SPECT imaging are confirmed to have PD or dementia with Lewy bodies by the reference standard. In studies where clinical diagnosis is used as an endpoint, scans without evidence of dopaminergic deficit are present in 3% to 20% of PD patients.¹¹ In a study of patients clinically diagnosed with dementia with Lewy bodies, van der Zande et al. (2016) found that 10% of these patients had normal scans.¹² Further research may shed light on these cases.

Regulatory Status
In 2011, DaTscan™ (GE Healthcare) was approved by the U.S. Food Drug Administration (FDA) through a new drug application and is "indicated for striatal dopamine transporter visualization using single-photon emission computed tomography brain imaging to assist in the evaluation of adult patients with suspected parkinsonian syndromes. In these patients, DaTscan may be used to help differentiate ET [essential tremor] from tremor due to parkinsonian syndromes (idiopathic Parkinson's disease, multiple system atrophy, and progressive supranuclear palsy). DaTscan is an adjunct to other diagnostic evaluations."¹³

In July 2021, aducanumab (Aduhelm™; Biogen), an amyloid beta-targeted antibody, was approved for the treatment of mild cognitive impairment or mild dementia due to Alzheimer disease. The safety and efficacy of aducanumab in patients with dementia with Lewy bodies has not been established as patients with any medical or neurological condition other than Alzheimer disease that might be a contributing cause to the subject's cognitive impairment were excluded from trials. The use of DaT-SPECT for the diagnosis, management, or surveillance of Alzheimer disease is considered out of scope for this policy.

FDA product code: KPS..

Related Policies
60106 Miscellaneous (Noncardiac, Nononcologic) Applications of Positron Emission Tomography
70163 Deep Brain Stimulation

Policy
Dopamine transporter imaging with single-photon emission computed tomography may be considered MEDICALLY NECESSARY when used for individuals with:

• Clinically uncertain Parkinson disease. 
• Clinically uncertain dementia with Lewy bodies.

Use of dopamine transporter imaging with single-photon emission computed tomography is investigational and/or unproven and therefore considered NOT MEDICALLY NECESSARY for all other indications not included above.

Policy Guidelines
The SPECT exam would be reported using CPT code 78607 — Brain imaging, tomographic (SPECT).

There is a specific HCPCS code for DaTscan: A9584 — Iodine I-123 ioflupane, diagnostic, per study dose, up to 5 millicuries. 

Benefit Application
Blue Card/National Account Issues
State or federal mandates (e.g., FEP) may dictate that all FDA-approved devices, drugs, or biologics may not be considered investigational, and thus these devices may be assessed only on the basis of their medical necessity.

Rationale
Evidence reviews assess whether a medical test is clinically useful. A useful test provides information to make a clinical management decision that improves the net health outcome. That is, the balance of benefits and harms is better when the test is used to manage the condition than when another test or no test is used to manage the condition.

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Testing for Clinically Uncertain Parkinson Disease
Clinical Context and Test Purpose
The purpose of dopamine transporter imaging with single-photon emission computed tomography (DaT-SPECT) is to differentiate essential tremor (ET) from tremor due to parkinsonian syndromes in order to guide appropriate management decisions. Specifically, in patients for whom the diagnosis of ET versus Parkinson Disease (PD) is unclear after clinical evaluation who later develop signs of suggestive of PD, ruling out parkinsonian syndromes with DaT-SPECT may minimize unnecessary dopaminergic treatment.

Diagnosis of Essential Tremor
The diagnostic criteria for ET from the International Parkinson and Movement Disorder Society (IPMDS) task force requires isolated tremor consisting of bilateral upper limb action (kinetic and postural) tremor, without other motor abnormalities that is at least 3 years in duration and with or without tremor in other locations along with the absence of other neurologic signs.¹⁴

Diagnosis of Parkinson Disease
The clinical diagnosis criteria for PD from the Movement Disorder Society (MDS) consists of an essential criterion, supportive criteria, exclusion criteria and red flags.¹⁵ The essential criterion is parkinsonism, defined as bradykinesia, in combination with either rest tremor or rigidity. The supportive criteria are: clear and dramatic beneficial response to dopaminergic therapy; levodopa-induced dyskinesia; rest tremor of a limb; and either olfactory loss or cardiac sympathetic denervation. There are 9 absolute exclusion criteria, any one of which rule out PD, and 10 red flags criteria. A diagnosis of clinically established PD requires the essential criterion, absence of any absolute exclusion criteria, at least two supportive criteria, and no red flags. A diagnosis of clinically probable PD requires the essential criterion plus the absence of absolute exclusion criteria, and if there are red flags, these must be counterbalanced by supportive criteria.

The question addressed in this evidence review is: In individuals for whom the diagnosis of ET versus PD is unclear after clinical evaluations, does the use of DaT-SPECT improve the net health outcome?

The following PICO was used to select literature to inform this review.

Populations
The populations of interest include individuals for whom the diagnosis of ET versus PD is unclear after clinical evaluation, in particular, patients suspected of having ET who develop signs suggestive of PD.

Interventions
The relevant intervention of interest is DaT-SPECT, used as a diagnostic adjunct to the physical exam of patients and review of their medical history.

Comparators
The diagnostic criteria for diagnosis of ET are clinical criteria.

The criterion standard for the diagnosis of PD is postmortem neuropathologic examination. In the absence of a criterion standard, clinical evaluation by general neurologists or expert clinicians and observation over time may be used as an interim reference standard endpoint for the diagnosis of PD. The accuracy of PD diagnosis is affected by clinician expertise and the duration of symptoms. While patients may be initially referred to a general neurologist, there is a statistically significant difference in diagnostic specificity between a generalist and a movement disorder specialist.¹⁶ Even in specialized movement disorders centers, up to 25% of patients may be misclassified, and some patients (e.g., those with ET who have been diagnosed with PD) may be erroneously treated.¹⁷

A meta-analysis of physician diagnosis of PD, relative to histopathology, was published in Rizzo et al. (2016).¹⁶ Clinical diagnosis of PD by expert clinicians had a sensitivity of 81.3% and a specificity of 83%, as assessed by criterion standards (histopathology). Notably, clinical diagnosis by general neurologists had a sensitivity of 89.7% and a specificity of 49.2%, as assessed by criterion standards (histopathology) or reference standards (diagnosis by experts). The accuracy of clinical diagnosis was also relative to the duration of symptoms. The positive predictive value was listed as 26% in a study examining the disease duration of fewer than 3 years, and 53% for disease duration of fewer than 5 years.

Outcomes
Health outcomes are defined as disease-related morbidity, functional outcomes, and treatment-related mortality and morbidity. There is a range of assessments for PD-related morbidity, including the 39-item Parkinson Disease Questionnaire, Movement Disorder Society revision of the Unified Parkinson's Disease Rating Scale, and Hoehn & Yahr staging system, which may be used to quantify health outcomes.¹⁸ These assessments catalog motor symptoms (i.e., tremor, slowness of movements, rigidity, instability), nonmotor symptoms (e.g., mood, fatigue, daytime sleepiness), and quality of life (e.g., limitations in daily activities due to symptoms). Outcomes may also include treatment-related morbidity and mortality, particularly in regards to the use of dopaminergic medications.

With the criterion standard of diagnosis of PD (histopathology), diagnostic accuracy can only be confirmed after death. The reference standard of PD (clinical diagnosis over time) varies both by the degree of clinician expertise and the duration of symptoms prior to evaluation by DaT-SPECT. An estimated mean of 10 years (range, 3.6 to 13.8 years) is useful for improving clinical diagnostic accuracy.¹⁶

The diagnostic criteria for ET require tremors of at least 3 years in duration.

Study Selection Criteria
For the evaluation of clinical validity of striatal dopamine transporter binding imaging, methodologically credible studies were selected using the following principles:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)
• Included a suitable reference standard; preference is given to studies with a reference standard of postmortem neuropathologic examination or clinical diagnosis with at least 3 years of follow-up
• Patient/sample clinical characteristics were described
• Patient/sample selection criteria were described
• Included a validation cohort separate from development cohort
• Diagnostic studies should report sensitivity, specificity, and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (e.g., receiver operating characteristic [ROC], area under ROC [AUROC], c-statistic, likelihood ratios) may be included but are less informative.

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

The most informative evaluation of diagnostic performance requires prospective, independent, and blinded assessment of test results compared with a criterion standard in an appropriate population. There are no such studies assessing DaT-SPECT in patients with clinically uncertain PD (see Tables 1 through 4).

Studies of clinical validity for DaT-SPECT in diagnosing PD rely on the reference standard endpoint of diagnosis by a clinician, based on physical diagnosis and patient history; preference is given to studies with at least 3 years of follow-up.

Review of Evidence
Retrospective Studies
Marshall et al. (2009) reported on a prospective, investigator-initiated, 3-year European multicenter study of 99 diagnostically uncertain cases of PD or ET.¹⁹ Patients with other potential causes of parkinsonism or tremor and patients with major comorbid illness were excluded; 3 healthy volunteers were included. DaT-SPECT scans at baseline, 18 months, and 36 months were reported by masked nuclear physicians, using visual analysis with high interreader agreement (κ range, 0.94 to 0.97). The baseline clinical diagnosis and reference standard endpoint was video analysis of the patient, at the start of the study and after 36 months, by movement disorder specialists who were blinded to imaging data and patient history. Comparison of the baseline DaT-SPECT scans with the reference standard endpoint revealed a sensitivity of 78% and specificity of 97%. Comparison of the baseline clinical diagnosis with the reference standard endpoint showed a sensitivity of 93% and specificity of 46%. Of the 71 patients with clinical diagnosis of parkinsonian syndrome (including PD, multiple system atrophy, and progressive supranuclear palsy) at the end of this study, 1 patient had a DaT-SPECT scan that changed from normal to abnormal between the baseline and the scan at 36 months, and 1 patient had a DaT-SPECT scan that changed from abnormal to normal at the same time. Both patients were clinically diagnosed with PD. Of note, 15 (21%) patients with a clinical diagnosis of PD had unexpectedly normal DaT-SPECT imaging at baseline, 18 months, and 36 months. It is not known whether these cases of scans without evidence of dopaminergic deficit resulted from a false-negative DaT-SPECT scan or an incorrect reference standard endpoint of clinical diagnosis. Strengths and weaknesses of this study are detailed in Tables 1, 3, and 4.

Vlaar et al. (2008) retrospectively reviewed a population of patients with clinically uncertain PD but the reference standard endpoint did not use clinicians blinded to DaT-SPECT scans.2⁰ Publications by Kupsch et al. (2012, 2013),^21,22 Hauser et al. (2014),²³ and Bajaj et al. (2014),²⁴ derive from a common data set on clinically uncertain parkinsonian syndrome (including PD, multiple system atrophy, and progressive supranuclear palsy), which did not use clinicians blinded to DaT-SPECT scans. Further strengths and weaknesses in study designs and analyses for these studies are detailed in Tables 1, 3, and 4. Three of 5 studies in a meta-analysis by Brigo et al. (2014) did not use clinicians blinded to DaT-SPECT scans.²⁵ One of 4 studies in the meta-analysis by O'Brien et al. (2014) did not use clinicians blinded to DaT-SPECT scans.²⁶ When a reference standard is not independent of the diagnostic test, it can result in an apparent increase in the sensitivity and specificity of the test. Therefore, the diagnostic accuracy reported in these studies must be interpreted cautiously.

Table 1. Clinical Validity Study Characteristics

Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

The preferred RCT would evaluate health outcomes in patients with clinically uncertain PD who received the new diagnostic test compared with patients who received standard of care. For the purposes of this trial, health outcomes are defined as disease-related symptoms, functional outcomes, and treatment-related mortality and morbidity. Physician confidence, changes in diagnosis, and changes in management were not sufficient to consider independently as health outcomes.

Kupsch et al. (2012, 2013) reported on an open-label, multicenter randomized trial from 19 university hospital centers in Europe and the U.S.^22,21 This reporting drew from a common data set on clinically uncertain parkinsonian syndrome (including PD, multiple system atrophy, and progressive supranuclear palsy), which was discussed previously and reviewed in Tables 1 through 4.^21,22,23,24 Patients were randomized to DaT-SPECT (n = 109) or no imaging (n = 123), with DaT-SPECT scans classified as normal or abnormal by a physician blinded to clinical history; they were then followed for 1 year by neurologists with (n = 12) or without (n = 7) movement disorder specialization. Health outcomes at 3 months after a scan revealed no significant difference in the quality of life.²² Again, health outcomes in the same population at 1 year after the scan showed no significant differences in the quality of life or health resource utilization between those who received a DaT-SPECT scan and those who did not.²¹

Chain of Evidence
Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

A chain of evidence demonstrating that DaT-SPECT results improve health outcomes would require that improved diagnostic performance (negative predictive value [NPV], positive predictive value [PPV]) of the DaT-SPECT test, relative to the reference standard, resulting in specific management changes that have been shown to improve health outcomes. Changes in medications alone are not sufficient to demonstrate improved health outcomes unless these changes are demonstrated to be applied correctly and beneficially in the target population. While a meta-analysis of 13 studies utilizing DaTscan (N = 950) by Bega and coworkers (2021) reported a change in management in 54% of patients (95% confidence interval [CI], 47% to 61%; I2 = 85%; p < .01), corresponding impacts on health outcomes were not reported.²⁷

Case Series
Sadasivan and Friedman (2015) reported on a case series of patients with the clinically uncertain parkinsonian syndrome (N = 65), including PD, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration, who were referred for DaT-SPECT over a 17-month period.²⁸ Scans were abnormal in 22 patients given a final diagnosis of parkinsonian syndrome. Change in clinical management was seen in 41 (63%) patients, of whom 30 (73%) were either clinically stable or improved at follow-up. A subset of 10 patients was found to have drug-induced PD without any striatal neurodegeneration noted on the DaT-SPECT scan; these patients were then advised to discontinue the drugs or reduce the doses of their drug intake. No follow-up information comparing DaT-SPECT with the reference standard (clinical diagnosis over sufficient time), which would validate treatment decisions, was provided. Specific health outcomes resulting from a specific change in management were also not provided.

Oravivattanakul et al. (2015) reported on a case series of patients with baseline diagnoses of neurodegenerative parkinsonism (including PD, multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration; n = 70), non-neurodegenerative parkinsonism (n = 46), uncertain diagnosis (n = 45), and ET (n = 14).²⁹ All but 3 of the 78 patients with abnormal DaT-SPECT scans were started or continued on medications. Of the 95 patients with normal DaT-SPECT scans, 23 patients were started or continued on medications. Drug management for patients with indeterminate DaT-SPECT scans (n = 2) was not discussed. Study weaknesses included the small sample size with uncertain diagnosis and uncertain duration of clinical follow-up.

Bega et al. (2015) reported on a case series of 83 patients with clinically uncertain PD who received DaT-SPECT.³⁰ Patients were classified by diagnostic dilemma, including PD versus ET (n = 18), PD versus drug-induced parkinsonism (n = 18), or PD versus vascular parkinsonism (n = 12). While the series detailed initiation, discontinuation, or escalation of medications for PD in these subpopulations, these changes in management were not linked to specific diagnostic decisions or DaT-SPECT results.

Several studies were excluded from this review because they lacked appropriate health outcome metrics, as described above. Two of them reviewed a prospective multicenter trial on the diagnostic and clinical management impact of DaT-SPECT on 118 patients with clinically uncertain parkinsonism syndrome^31,32; while imaging changed diagnosis and management, neither study detailed these outcomes relative to specific diagnostic changes.

Section Summary: Clinically Uncertain Parkinson Disease
A meta-analysis of postmortem histopathology studies established an expert clinical diagnosis as a reference standard with high sensitivity and low-to-moderate specificity. Studies using this reference standard are limited by limitations in study designs, conduct, and relevance. Specific areas of concern include unclear study populations, missing data, insufficient follow-up, and inconsistent blinding. The diagnostic accuracy of DaT-SPECT cannot be determined from these studies.

Evidence on clinical utility includes an RCT and several case series that have evaluated the effect of DaT-SPECT on diagnosis and changes in treatment. The RCT revealed that patients evaluated using DaT-SPECT had no improvement in health outcomes, when compared with those not evaluated using DaT-SPECT, at the 3 month and 1 year follow-up period. Several case series studies have documented a change in diagnosis and management but did not comment on health outcomes. One case series evaluating neurodegenerative parkinsonian syndromes, including PD, indicated that changes based on imaging scans resulted in stable or improved health outcomes, but lacked an appropriate reference standard to evaluate whether changes were made in the direction of more accurate diagnosis and more appropriate management. Therefore, a chain of evidence linking DaT-SPECT to improved patient outcome cannot be constructed.

Testing for Clinically Uncertain Dementia With Lewy Bodies
Clinical Context and Test Purpose
The purpose of DaT-SPECT testing of individuals with uncertain Dementia with Lewy bodies is to establish the clinical diagnosis of dementia with Lewy bodies in order to guide appropriate management decisions.

Diagnosis of Dementia with Lewy Bodies
The Consortium on Dementia with Lewy Bodies has developed consensus criteria for the clinical diagnosis of dementia with Lewy bodies.³³ Clinical signs and symptoms of dementia with Lewy bodies are organized into a hierarchy, based on diagnostic specificity, of essential, core and supportive features. Biomarkers are categorized as supportive or indicative. The criteria are summarized briefly in Tables 5 and 6 below; see the McKeith (2017) for complete criteria.

Table 5. Hierarchy of Clinical Features and Biomarkers from The Consortium on Dementia with Lewy Bodies

Antipsychotic use is a risk factor for mortality among people with dementia, in general. However, there is potential for severe adverse reactions to antipsychotic (neuroleptic) medications, particularly first-generation antipsychotics, for patients with dementia with Lewy bodies, including exacerbation of parkinsonism, severe confusion, heavy sedation, and even death.

The question addressed in this evidence review is: In individuals with uncertain dementia with Lewy bodies, does the use of DaT-SPECT testing improve the net health outcome?

The following PICO was used to select literature to inform this review.

Populations
The populations of interest include individuals with an uncertain diagnosis of dementia with Lewy bodies after assessment by a specialist in dementia disorders. The population would also include patients with an ongoing diagnostic dilemma of dementia with Lewy bodies versus Alzheimer disease (AD).

Based on the diagnostic criteria shown previously in Tables 5 and 6 , the following describes populations that could be evaluated for dementia with Lewy bodies and the potential use of DaT-SPECT for each population (Table 7).

Table 7. Potential Dementia with Lewy Bodies Populations for Consideration

DAT-SPECT: dopamine transporter imaging with single-photon emission computed tomography.

Population 1 (patients having 2 or more core clinical features of dementia with Lewy bodies) meets criteria for probable dementia with Lewy bodies; these patients do not have an uncertain diagnosis and therefore are not part of the population of interest for this review. Population 2 (patients having only 1 core clinical feature) meets the criteria for possible or probable dementia with Lewy bodies, both of which are treated symptomatically and therefore distinguishing between possible and probable is unlikely to lead to changes in management decisions and would not be the population of interest for this review. Population 3 (patients having no core clinical features but 1 or more suggestive features) would be the primary population of interest.

Interventions
The relevant intervention of interest is DaT-SPECT, used as a diagnostic adjunct to a physical exam and medical history.

The U.S. regulatory approval does not include an indication describing how DaT-SPECT should be interpreted in dementia with Lewy bodies.

Comparators
The criterion standard for the diagnosis of dementia with Lewy bodies is postmortem neuropathologic examination.

In the absence of comparisons with the criterion standard, diagnosis by expert clinicians may be used as a reference standard for diagnosis of dementia with Lewy bodies. However, the use of clinical diagnosis as reference standard is a major limitation. The sensitivity of the clinical criteria compared to the postmortem neuropathological is too low for the criteria to be a satisfactory standard.

In addition, DaT-SPECT scans are intended to be used as an adjunct to clinical assessment so studies with clinical diagnosis as the reference standard cannot demonstrate improvement in accuracy above clinical diagnosis and therefore have limited usefulness.

Outcomes
Health outcomes are defined as disease-related morbidity, functional outcomes, and treatment-related mortality and morbidity. Assessment of dementia with Lewy bodies may include tests such as the Lewy Body Composite Risk Score,³⁴ which assesses motor symptoms (i.e., rigidity, postural instability) and non-motor symptoms (i.e., daytime sleepiness, hallucinations). Assessment of dementia with Lewy bodies may also include general tests for dementia including the Clinical Dementia Rating test.

With the criterion standard for diagnosis of dementia with Lewy bodies (histopathology), diagnostic accuracy can only be confirmed after death.

The correct dementia clinical diagnosis may become more evident over time for some types of dementia. As dementia with Lewy bodies progresses, however, the symptoms converge with other types of dementia. Therefore, clinical diagnosis may become less discriminating with time and delayed verification designs using clinical diagnosis at follow-up as the reference standard may not be appropriate.

Study Selection Criteria
For the evaluation of clinical validity of striatal dopamine transporter binding imaging, methodologically credible studies were selected using the following principles:

• Reported on the accuracy of the marketed version of the technology (including any algorithms used to calculate scores)
• Included a suitable reference standard; preference is given to studies with a reference standard of postmortem neuropathologic examination
• Patient/sample clinical characteristics were described
• Patient/sample selection criteria were described
• Included a validation cohort separate from development cohort
• Diagnostic studies should report sensitivity, specificity and predictive values. Studies that completely report true- and false-positive results are ideal. Studies reporting other measures (e.g., ROC, AUROC, c-statistic, likelihood ratios) may be included but are less informative.

Clinically Valid
A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

The most informative evaluation of diagnostic performance requires prospective, independent, and blinded assessment of test results compared with a criterion standard in an appropriate population.

Review of Evidence
Studies with Postmortem Neuropathologic Examination Reference Standard
McCleery et al. (2015) reported a Cochrane systematic review of DaT-SPECT for the diagnosis of dementia with Lewy bodies that included neuropathological diagnosis at autopsy as the reference standard.³⁵ The review included papers published through 2013. Only 1 study (Walker 2009) was identified and is described in more detail below.

Primary studies evaluating the diagnostic accuracy of DaT-SPECT with postmortem neuropathologic as the reference standard are shown in Tables 8 through 11 and briefly described in the following paragraphs. Walker et al. (2009) included 22 patients who were diagnosed clinically with dementia with Lewy bodies or AD.³⁶ The DaT-SPECT visual ratings were independently performed by 3 raters. The raters classified each scan as 0 (normal uptake), 1 (slightly reduced uptake), or 2 (significantly reduced uptake). Scores of 0 or 1 were defined as a normal scan and a score of 2 was defined as an abnormal scan.

An additional study with postmortem neuropathologic as the reference standard has been published since the Cochrane review. Thomas et al. (2017) included 55 patients with clinical diagnosis of dementia with Lewy bodies or AD.³⁷ The scans were visually rated by 3 to 5 independent raters who were blinded to clinical information. The raters came to a consensus classification of either abnormal or normal. The sensitivity of clinical diagnosis was 87% (95% CI, 96 to 70) for diagnosing dementia with Lewy bodies.

Table 8. Study Characteristics of Clinical Validity Studies of DaT-SPECT with Postmortem Neuropathologic Exam as the Reference Standard

As shown below, neither study included the target population, i.e., patients having no core clinical features but 1 or more suggestive features. Neither study described how patients were chosen for inclusion from those that were eligible patients.

Table 10. Study Relevance Limitations

The study limitations stated in this table are those notable in the current review; this is not a comprehensive gaps assessment.
a Selection key: 1. Selection not described; 2. Selection not random or consecutive (i.e., convenience).
b Blinding key: 1. Not blinded to results of reference or other comparator tests.
c Test Delivery key: 1. Ti1ming of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.
d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data.
f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison to other tests not reported.

Studies with Clinical Diagnosis Reference Standard
As previously stated, clinical diagnosis as a reference standard is a major study limitation. However, the largest study to evaluate DaT-SPECT for dementia with Lewy bodies is the prospective, investigator-initiated, multicenter study by McKeith et al. (2007).³³ It reviewed 326 patients with a clinical diagnosis of probable (n = 94) or possible (n = 57) dementia with Lewy bodies or non-dementia with Lewy bodies (n = 147). Baseline diagnoses were established by a consensus panel of 3 clinicians without access to DaT-SPECT results; a diagnosis could not be made in 28 patients. DaT-SPECT scans were assessed visually by 3 nuclear medicine physicians with expertise in DaT-SPECT who were unaware of the clinical diagnosis. DaT-SPECT had a mean sensitivity of 77.7% for detecting clinically probable dementia with Lewy bodies, a mean specificity of 90.4% for excluding non-dementia with Lewy bodies dementia, a PPV of 82.4%, and an NPV of 87.5%. This phase 3 study did not use long-term clinical follow-up as the standard.

Clinically Useful
A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence
Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

The preferred RCT would evaluate health outcomes in patients with clinically uncertain dementia with Lewy bodies who received the new diagnostic test compared with patients who received the standard of care. Physician confidence, changes in diagnosis, and changes in management alone would not be sufficient to consider independently as health outcomes. Changes in management decisions were accepted as the reference standard only if the authors linked changes in medications to specific diagnostic changes made as a result of DaT-SPECT.

Several studies were excluded from this review because they lacked appropriate health outcome metrics. An RCT by Walker et al. (2015) reviewed the diagnostic change and diagnostic confidence alone, which were not considered meaningful health outcomes for this evidence review.³⁸ Reanalysis of the same data set by Walker et al. (2016) focused on correlating symptoms with DaT-SPECT results and was discounted because it falls outside the scope of this review of DaT-SPECT as a diagnostic tool.³⁹ Both studies were limited by a small population (N = 114) and short follow-up (6 months). Finally, Kemp et al. (2011) retrospectively evaluated 80 consecutive patients with dementia with Lewy bodies; while imaging affected patient management, these outcomes were not detailed with respect to specific diagnostic changes.⁴⁰ Further, many (irrespective of the imaging results) were in the earliest phase of their disease process and did not require immediate treatment for symptoms.

Chain of Evidence
Indirect evidence on clinical utility may use a chain of evidence linking the use of the results to inform management decisions that improve the net health outcome of care. Published evidence does not demonstrate a chain of evidence.

Section Summary: Clinically Uncertain Dementia With Lewy Bodies
Two studies have been published with postmortem neuropathologic examination as the reference standard. Neither study included the target population, i.e., patients having no core clinical features but one or more suggestive features. Neither study described how patients were chosen for inclusion from those that were eligible patients. Therefore, the clinical validity of the test has not been established so a chain of evidence cannot be constructed. No direct evidence of benefit is available.

Summary of Evidence
For individuals who have clinically uncertain PD who receive DaT-SPECT, the published evidence includes RCTs, cohort studies, and case series studies. Relevant outcomes are symptoms, functional outcomes, and treatment-related mortality and morbidity. In populations with clinically apparent PD, studies of diagnostic accuracy have reported high sensitivity and specificity for PD. Studies of clinical validity in the target population of clinically uncertain PD are limited by gaps in study design, conduct, and relevance. Evidence on clinical utility in the target population includes an RCT showing no significant difference in outcomes over time between patients who received a DaT-SPECT scan and those who did not. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

For individuals who have clinically uncertain dementia with Lewy bodies who receive DaT-SPECT, the published evidence includes RCTs, cohort studies, and case series studies. Relevant outcomes are symptoms, functional outcomes, and treatment-related mortality and morbidity. No studies with the optimal reference standard to assess clinical validity have been performed in the target population of clinically uncertain dementia with Lewy bodies. No studies have directly evaluated the effect of DaT-SPECT on health outcomes in the target population. The evidence is insufficient to determine that the technology results in an improvement in the net health outcome.

The purpose of the following information is to provide reference material. Inclusion does not imply endorsement or alignment with the evidence review conclusions.

Clinical Input From Physician Specialty Societies and Academic Medical Centers
2018 Input
Clinical input was sought to help determine whether the use of dopamine transporter imaging with single-photon emission computed tomography (DaT-SPECT) in individuals with clinically uncertain Parkinson disease (PD) or clinically uncertain dementia with Lewy bodies would provide a clinically meaningful improvement in net health outcome and whether the use is consistent with generally accepted medical practice. In response to requests, clinical input was received from 3 respondents, including 1 specialty society-level response and two physician-level responses identified through specialty societies.

In individuals who have clinically uncertain PD who receive DaT-SPECT, clinical input supports that DaT-SPECT is clinically useful when a negative result on DaT-SPECT is used to inform treatment decisions by reducing or avoiding unnecessary dopaminergic therapy. Clinical input highlights that the published randomized controlled trial also reported changes in management following DaT-SPECT imaging that may translate to improvements in health outcomes over time, and the 1 year study follow-up may be too short to demonstrate significant improvement in quality of life in a slowly progressive disease such as PD. Clinical input further supports that DaT-SPECT offers clinically valid diagnostic information about the presence or absence of functional loss in the dopamine system (i.e., nigrostriatal degeneration) and is clinically useful for clinically uncertain Parkinsonian syndrome when a negative result on DaT-SPECT is used to inform treatment decisions by reducing or avoiding unnecessary dopaminergic therapy.

In individuals who have clinically uncertain dementia with Lewy bodies who receive DaT-SPECT, clinical input supports that DaT-SPECT is clinically useful when a positive result on DaT-SPECT is used to inform treatment decisions by avoiding potentially harmful use of neuroleptics which may be used in dementia patients. Clinical input noted that DaT-SPECT offers clinically valid diagnostic information about the presence or absence of functional loss in the dopamine system (i.e., nigrostriatal degeneration) and is clinically useful for clinically uncertain dementia with Lewy bodies using a chain of evidence where a positive result on DaT-SPECT is used to inform treatment decisions by avoiding potentially harmful use of neuroleptics typically used in dementia patients.

Further details from clinical input are included in the Appendix.

Practice Guidelines and Position Statements
Guidelines or position statements will be considered for inclusion in ‘Supplemental Information' if they were issued by, or jointly by, a U.S. professional society, an international society with U.S. representation, or National Institute for Health and Care Excellence (NICE). Priority will be given to guidelines that are informed by a systematic review, include strength of evidence ratings, and include a description of management of conflict of interest.

American College of Radiology
In 2019, the American College of Radiology updated the appropriateness criteria for movement disorders and neurodegenerative diseases.⁴¹ The College categorized Ioflupane SPECT/computed tomography (CT) as "may be appropriate" for initial imaging of Parkinsonian syndrome. A strength of evidence rating was not given for this statement.

The American College of Radiology (2019) updated the appropriateness criteria for dementia.⁴² The College categorized Ioflupane SPECT or SPECT/CT brain as "may be appropriate" for initial imaging for suspected dementia with Lewy bodies. A strength of evidence rating was not given for this statement.

American Academy of Neurology
The practice parameters from the American Academy of Neurology (2006; reaffirmed 2013; retired 2018) stated that β-CIT (2β-carbomethoxy-3β-(4-iodophenyl) tropane) and IBZM (iodobenzamide) SPECT are possibly useful in distinguishing PD from essential tremor (5 class III studies).⁴³ There was insufficient evidence to determine whether these modalities are useful in distinguishing PD from other forms of parkinsonism.

Society of Nuclear Medicine and Molecular Imaging et al.
In 2020, the Society of Nuclear Medicine and Imaging and the European Association of Nuclear Medicine published a joint practice guideline and procedure standard for dopaminergic imaging in Parkinsonian syndromes.⁴⁴ The guideline indicated presynaptic dopaminergic imaging for "detecting loss of nigrostriatal dopaminergic neuron terminals of patients with parkinsonian syndromes, especially:

• To support the differential diagnosis between essential tremor and neurodegenerative parkinsonian syndromes. Note that presynaptic dopaminergic imaging is unable to distinguish IPD [idiopathic Parkinson disease] and DLB [dementia with Lewy bodies] from PSP [progressive supranuclear palsy], CBD [corticobasal degeneration], or putaminal variant of MSA [multiple system atrophy].
• To help distinguish between dementia with Lewy bodies and other dementias (in particular, Alzheimer’s disease, AD).
• To support the differential diagnosis between parkinsonism due to presynaptic degenerative dopamine deficiency and other forms of parkinsonism, e.g., between IPD and drug-induced, psychogenic, or vascular parkinsonism.
• To detect early presynaptic parkinsonian syndromes."

In 2011, the Society of Nuclear Medicine, now called the Society of Nuclear Medicine and Molecular Imaging, provided practice guidelines for DaT-SPECT.⁴⁵ The guidelines stated that the main indication for DaT-SPECT is striatal DaT visualization in the evaluation of adults with suspected parkinsonian syndromes to help differentiate essential tremor from tremor due to presynaptic parkinsonian syndromes (PD, multisystem atrophy, progressive supranuclear palsy). Other indications are the early diagnosis of presynaptic parkinsonian syndromes, differentiation of presynaptic parkinsonian syndromes from parkinsonism without a presynaptic dopaminergic loss (e.g., drug-induced parkinsonism, psychogenic parkinsonism), and differentiation of dementia with Lewy bodies from Alzheimer disease. The guidance stated that visual interpretation of the scan is usually sufficient for clinical evaluation, where the striatal shape, extent, symmetry, and intensity differentiate normal from abnormal. For semiquantitative analysis, each site should establish its own reference range by scanning a population of healthy controls or by calibrating its procedure with another center that has a reference database.

Movement Disorders Society
In 2015, the Movement Disorders Society (MDS) diagnostic criteria for PD are intended for use in clinical research but can be used to guide clinical diagnosis.¹⁵ The MDS considers the clinical expert opinion to be the criterion standard to diagnose PD and that diagnoses are usually made clinically without ancillary diagnostic testing. Methods that may become available as knowledge advances are diagnostic biochemical markers, anatomic neuroimaging, and methods to detect alpha-synuclein deposition. Normal functional neuroimaging of the presynaptic dopaminergic system, if performed, is listed as an absolute exclusion criterion for PD. MDS noted that, although dopaminergic neuroimaging can help to distinguish parkinsonism from PD mimics like essential tremor, "it does not qualify as a criterion for the differentiation of PD from other parkinsonian conditions like atypical parkinsonian syndromes." Normal functional neuroimaging of the presynaptic dopaminergic system is also listed as criteria for exclusion from diagnosis of PD in patients with early/de novo PD.⁴⁶

National Institute for Health and Care Excellence
In 2006, the NICE published guidance on the diagnosis and management of PD,⁴⁷ which was updated in 2017.^48,49 The 2006 guidance stated that iodine 123 N-(3-fluoropropyl)-2β-carbomethoxy-3β-(4-iodophenyl) nortropane (123I-FP-CIT) SPECT should be considered for people with tremor where essential tremor cannot be clinically differentiated from parkinsonism (based on studies with a level of evidence 1a or 1b); this recommendation is continued in 2017 guidance. Also unchanged was the recommendation that 123I-FP-CIT SPECT should be available to specialists with expertise in its use and interpretation (based on the level of evidence IV, expert opinion).

The NICE updated its 2016 guidance on dementia in 2018.⁵⁰ It recommended that 123I-FP-CIT SPECT be used to help establish the diagnosis in those with suspected DLB if the diagnosis is uncertain.

Dementia of Lewy Bodies Consortium
In 2017, the Dementia of Lewy Bodies Consortium published clinical guidelines on diagnosis and management, based on American expert opinion.⁵¹ The guidelines stated that reduced DaT uptake in basal ganglia demonstrated by SPECT is an indicative biomarker. As such, dementia with abnormal DaT-SPECT imaging would be classified as possible dementia with Lewy bodies. The presence of another core clinical feature (fluctuating cognition, recurrent visual hallucinations, rapid-eye-movement sleep disorder, parkinsonism motor abnormalities) in addition to dementia and abnormal DaT-SPECT imaging would allow classification as probable dementia with Lewy bodies. It was noted that patients with autopsy-confirmed dementia with Lewy bodies may have normal DaT-SPECT imaging.

U.S. Preventive Services Task Force Recommendations
Not applicable.

Ongoing and Unpublished Clinical Trials
Some currently ongoing and unpublished trials that might influence this review are listed in Table 12.

Table 12. Summary of Key Trials

References 

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Coding Section 

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

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