Lewy Body Dementia is an umbrella term encompassing DLB and Parkinson’s Disease Dementia (PDD). Both conditions are pathologically characterized by the accumulation of Lewy bodies and neurites (30, 31). While sharing similar pathological underpinnings, DLB and PDD often differ in their initial clinical presentations, progression, and overall clinical course (32, 33).

DLB typically presents with cognitive-psychiatric symptoms from its onset (1). Patients with DLB often exhibit cognitive fluctuations characterized by periods of clarity and episodes of confusion or drowsiness (34). Although memory impairment may manifest early in DLB, deficits in executive function, attention, and visuospatial abilities tend to be more pronounced in the early stages of the disease compared to AD (14, 35). In addition, episodic memory deficits in DLB generally improve with cueing, while episodic memory deficits in AD do not (36, 37). Psychiatric changes in DLB are common and include recurrent and well-formed visual hallucinations, symptoms of depression, anxiety, and apathy, and may be preceded by rapid eye movement sleep behavior disorder (RBD) (38). Motor features, such as bradykinesia and rigidity, may accompany or follow the onset of cognitive-behavioral symptoms but may not be evident in all DLB patients. The consensus criteria for DLB apply a “one-year rule” for the differentiation from PDD (1), which asserts that if cognitive decline leading to dementia occurs before or concurrently within one year of the onset of parkinsonian motor symptoms, the diagnosis is more likely to be DLB. Conversely, if dementia occurs more than one year after the onset of Parkinsonian symptoms, the diagnosis is more likely to be PDD.

PDD typically first manifests with motor features characteristic of PD (e.g., bradykinesia, rigidity, rest tremor). These motor symptoms are usually present for several years before the onset of cognitive symptoms (33). Findings from a recent meta-analysis reported that 15–20% of patients with PD patients developed dementia after five years and 46% at ten years, with this significantly increasing a survival rate greater than ten years (39). The cognitive profile of PDD includes difficulties with attention, processing speed, executive functioning, and visuospatial skills (40). Psychiatric and mood changes, such as apathy, depression, and visual hallucinations, are also observed in individuals with PDD (41).

The diagnostic criteria for DLB have evolved, culminating with the fourth consensus criteria in 2017 (Table 1) (1). These criteria build upon the core and supportive features established from prior iterations (2, 42, 43). Notably, the 2017 criteria elevated RBD to a core feature, removed the suggestive feature category, and downgraded antipsychotic hypersensitivity to a supportive feature. While this paper focuses on the 2017 criteria, it is acknowledged that some readers may still need to be fully acquainted with these updates, particularly concerning the integration of indicative biomarkers. Therefore, we will provide a brief overview of the role of these biomarkers in establishing a “probable” or “possible” diagnosis of DLB.

Indicative biomarkers (Table 2) include reduced DAT uptake demonstrated by SPECT or PET imaging, reduced MIBG on myocardial scintigraphy, and polysomnography (PSG) confirmation of RBD, each reflecting unique pathology underlying core clinical features. Supportive biomarkers include relative preservation of medial temporal lobe structures evident on CT/MRI scans, generalized low uptake on SPECT/PET perfusion/metabolism scans frequently accompanied by reduced occipital activity, preservation of 18Fluorodeoxyglucose PET uptake in the posterior cingulate “cingulate island sign” (52), and the presence of prominent posterior slow-wave EEG activity displaying periodic fluctuations in the pre-alpha/theta range. While these supportive biomarkers can assist in diagnosis, they lack specificity for DLB.

A “probable” DLB diagnosis is determined by either two or more core clinical features of DLB or one core clinical feature coupled with one or more indicative biomarkers. Core clinical features typically include fluctuating cognition, visual hallucinations, RBD, and Parkinsonian motor symptoms. These indicative biomarkers significantly enhance the specificity of the diagnosis, particularly when clinical features alone might be insufficient for a definitive diagnosis. A “possible” DLB diagnosis, on the other hand, is considered when only one of these core clinical features is present without any indicative biomarker evidence or when indicative biomarkers are present but without the core clinical features. However, diagnosing DLB should not be based on biomarkers alone (1), and a definitive diagnosis of DLB relies on autopsy neuropathological confirmation.

While myocardial scintigraphy using MIBG is a valuable indicative biomarker for DLB, its usage in the US is less common, primarily due to availability and expertise constraints (53). Moreover, this has not been approved by FDA for use in this indication. Alternatively, PSGs are typically only performed following sleep complaints. Thus, of the indicative biomarkers available in the US, DAT SPECT imaging is most likely to have a key role in diagnosing DLB.

An accurate diagnosis ensures patients receive the most appropriate and effective treatments, minimizing potential side effects and maximizing efficacy (13). This aspect is essential considering the heightened sensitivity of patients with DLB to various antipsychotic medications and anti-dopaminergic agents (i.e., prochlorperazine), which can exacerbate symptoms or lead to severe adverse reactions (54, 55).

While disease-modifying therapies (DMTs) for DLB are not yet available, early diagnosis is essential to start interventions that may slow symptom progression, alleviate discomfort, and improve quality of life (5). For example, early initiation of cholinesterase (ChE) inhibitors, which inhibit the enzyme acetylcholinesterase to increase the availability of acetylcholine and enhance cholinergic transmission, has shown considerable efficacy in managing DLB, especially given the cholinergic deficits in this condition. These benefits extend beyond cognitive improvement to potentially ameliorating behavioral (sleep disturbances) and psychiatric symptoms (hallucinations). Potentially slowing symptom progression leading to enhanced overall patient and caregiver reported outcomes and quality of life (13, 56).

Moreover, an early and precise diagnosis provides essential clarity for patients and their families, enabling informed decision-making regarding care, facilitating access to support services, and managing expectations. It also ensures that patients are referred to occupational therapy (OT) and physical therapy (PT) early, which may be more crucial in DLB than in AD (57, 58). From a research perspective, accurate diagnosis is necessary for enrolling the target participant in clinical trials, to ensure the accurate evaluation of therapeutic agents (14).

Additionally, receiving a correct diagnosis avoids the frustration and feelings of being misguided that can arise when diagnoses are later revised from AD to DLB or other conditions. This not only impacts patient trust but also significantly influences their treatment path and family’s understanding of the disease.

Diagnosing DLB poses challenges, particularly in non-specialized settings. Recognizing DLB is more straightforward in specialized clinics—like those focusing on memory, cognitive disorders, or movement disorders—where there is greater expertise in differentiating DLB from other common neurodegenerative conditions, such as AD or PD, which often present with overlapping symptoms. In general practice, however, variability in DLB clinical presentation coupled with limitations in diagnostic tools can hinder accurate diagnosis.

Beyond AD and PD, DLB must also be differentiated from other conditions, such as frontotemporal degeneration with Parkinsonism, vascular cognitive impairment, and posterior cortical atrophy. The latter, characterized by prominent visuospatial and visuoperceptual abnormalities, can result from DLB but is also seen in AD, corticobasal syndrome, and Creutzfeldt-Jakob disease (59, 60). This wide array of potential clinical diagnoses can lead to misdiagnosis or delayed diagnosis.

In a study of DLB care partners (61), the diagnosis of DLB can be delayed as much as 18 months, with most patients seeing more than three physicians over multiple visits. Misdiagnosis was common, with 78% receiving a diagnosis other than DLB, often depending on the presenting symptoms and the first provider encountered (e.g., movement disorder or cognitive behavioral neurologist, general neurologist, sleep specialist, psychiatrist, geriatrician, gastroenterologist). Common misdiagnoses included other forms of dementia, such as AD (26%), or related movement disorders, such as PD (39%). In another study, findings revealed that when behavioral symptoms such as visual hallucinations, delusions, and mood disorders are predominant, then a psychiatric diagnosis was made in 24% of cases (17). Alarmingly, about 22% of patients did not receive a diagnosis when first presenting to their physician. This lack of diagnosis occurred most frequently when patients first presented these symptoms to primary care physicians, who may lack the specialized training to recognize the early signs of DLB (61). In the instances where a diagnosis of DLB was eventually made, 62% of these diagnoses were made by neurologists. Other specialists involved in diagnosing DLB included psychiatrists (9%), geriatricians (8%), psychologists (8%), and, to a lesser extent, primary care physicians, comprising family physicians (5%) and internal medicine.

Qualitative, or visual, assessment remains the standard practice for interpreting DAT SPECT imaging results. This approach is consistent with the current EANM practice guideline/SNMMI procedure standard for dopaminergic imaging in Parkinsonian syndromes (20). Though interpreting a DaTscan image is relatively straightforward, formal image reading and its reporting are typically generated by nuclear medicine radiologists.

An abnormal DAT tracer uptake is typically characterized by either:

Note: Almost absent activity at the striata is sometimes known as a “burst striatum” appearance.

Examples of normal and abnormal scans are shown in Figure 1.

While the primary clinical assessment involves a qualitative evaluation that categorizes the scan as positive or negative, specific protocols, as outlined in the Society of Nuclear Medicine (SNM) (63), incorporate a more nuanced, semi-quantitative analysis. This includes assessing the degree of uptake reduction and its distribution pattern, which can provide further insight into the severity and progression of dopaminergic deficits. Recently, most of the NM departments in the US have used semi-quantitative software named DaTQUANT^™ (GE Healthcare), which enables the sharing of DAT image intensity measurement figures. This is done as an adjunct to the visual read.

The qualitative interpretation of DAT SPECT imaging is valuable for its potential to substantiate the clinical presentations seen in patients, providing an imaging-based confirmation of symptomatic observations. However, this method is inherently subjective, relying on the expertise of trained observers. Consequently, subtle changes in DAT density, especially in cases with borderline visual interpretations, may be overlooked or with a more balanced reduction at the striata that can be more challenging to perceive. This limitation underscores the value of incorporating semi-quantitative methods in analyzing DAT SPECT images. Findings from a study by Booij et al. (64) demonstrated that combining semi-quantification into the interpretation of ¹²³I-ioflupane SPECT scans enabled readers with limited experience to achieve a diagnostic accuracy comparable to that of experienced readers.

It is further noted that imaging patients with dementia and parkinsonian motor features presents specific challenges, such as motion artifacts that can adversely affect image quality and interpretation accuracy (65). These artifacts can significantly impact image quality and interpretation accuracy. To mitigate this, NM guidelines recommend specialized scanning protocols to reduce movement and other potential artifacts, enhancing the reliability of the scan results (20, 63).

Integrating clinical and radiologic expertise is fundamental in neurology, particularly for interpreting DAT SPECT imaging in DLB diagnosis. Neurologists and related practitioners must skillfully combine DAT SPECT scan results with the patient’s clinical symptoms, requiring a detailed review of the scans and effective communication of findings to patients and caregivers. Highlighting this, recent studies by Bega et al. (25) and Isaacson et al. (71) have shown the significant impact of DAT SPECT on clinical decision-making. These studies reveal that DAT SPECT imaging not only influences treatment strategies in 54% of patients but also a modification in diagnosis in about 31% of patients, particularly in differentiating between nigrostriatal dopaminergic degeneration and non-nigrostriatal degeneration in patients exhibiting ambiguous parkinsonian signs, thereby improving diagnostic precision in complex clinical situations.

In clinical and radiologic integration, the interpretation of the DAT SPECT imaging is closely coordinated with the patient’s clinical symptoms. For instance, in early PD, an asymmetric reduction in tracer uptake, particularly in the left putamen compared to the caudate nucleus (especially the posterior putamen), is often observed (66). In contrast, a more symmetric putaminal loss assessed with DAT SPECT is frequently observed in DLB and other atypical parkinsonian syndromes such as Multiple System Atrophy (MSA) and Progressive Supranuclear Palsy (PSP) (64). Additionally, these syndromes typically manifest with early involvement of the caudate nuclei, leading to attenuation of the striatum’s “comma” shape. This is due to simultaneous changes in the caudate nucleus and the putamen, which compromise the distinctive anatomy of these regions on imaging.

In visual readings of DAT SPECT images, distinguishing between putaminal and caudate involvement is standard practice. It is generally observed that putaminal loss is suggestive of dopaminergic deficits, while early caudate involvement may indicate atypical Parkinsonian syndromes. However, these observations should be approached with caution in a clinical setting. Individual scan interpretations can vary, and the presence or absence of a caudate signal does not have a universally established diagnostic value. Therefore, DAT SPECT imaging is primarily used to determine the presence or absence of dopaminergic deficits rather than ascertaining differential diagnosis based on specific regional involvement.

Evidence suggests that DAT imaging can aid in early diagnosis and prognosis. For example, Pasquini et al. (72) study on PD found that early caudate dopaminergic denervation was predictive of an increased risk of cognitive impairment, depression, and gait problems, underscoring the potential predictive value of DAT scans in identifying patients at risk for rapid disease progression. These findings are broadly consistent with findings by Yamamoto et al. (73), which showed a correlation between longitudinal changes in DAT uptake and progression of parkinsonism and cognitive symptoms in DLB. However, their study noted an inverse correlation between the progression of parkinsonism severity and DAT uptake changes in the left posterior putamen, differing from the patterns observed in PD. This distinction suggests that DAT scans may not uniformly predict symptom progression across disorders, reflecting diverse underlying pathophysiological mechanisms between PD and DLB.

An important consideration, however, is the timing of DAT scans in later clinical stages as well as different clinical presentations (74–78). In the Van der Zande et al. (74) study, the authors reported that for some cases where the initial scans showed no apparent dopaminergic deficits, these later evolved into clearly visible dopaminergic deficits, suggesting that early negative results may not preclude the development of dopaminergic deficits as the disease progresses.

In a 4-year longitudinal study of PD patients (77), motor symptom progression was associated with reduced DAT binding across all regions in PD, particularly in the putamen. Furthermore, the findings showed a more significant reduction in ipsilateral putamen than in contralateral putamen, suggesting a pattern that could help assess disease asymmetry and progression. However, a “floor effect” by year 4 indicates the diminishing utility of DAT scans to evaluate disease progression in later stages. In another study on PD (78), the progression of non-motor symptoms (NMS) was only weakly correlated with DAT binding across, suggesting that NMS may predominantly arise from non-dopaminergic pathways. This highlights the limitations of DAT imaging in cases where NMS are most pronounced.

In sum, the variability in the timing of DAT scan changes relative to symptom onset in DLB complicates the diagnostic process, potentially leading to initial misdiagnosis or delayed diagnosis. Moreover, the lack of direct correlation between DAT imaging findings and NMS progression underscores the need for a multimodal diagnostic approach beyond dopaminergic neuron integrity assessment. Clinicians should consider the timing of DAT scans relative to disease onset, the presence of both motor and non-motor symptoms, and the potential for disease progression despite initial negative imaging results. This approach emphasizes the importance of longitudinal monitoring and a multimodal diagnostic strategy incorporating DAT imaging and comprehensive clinical assessments.

Before ordering a DAT imaging, it is essential for clinicians to review the patient’s concurrent medication usage carefully. Certain medications can significantly alter DAT tracer uptake, thus impacting the visual interpretation of the scan. Key classes of substances that can interfere include psychostimulants (such as cocaine and amphetamines), certain antidepressants, and specific antipsychotic medications. These can lead to false abnormal or, rarely, false normal interpretations, which are critical considerations for practitioners relying on visual assessments of ¹²³I-ioflupane SPECT scans (79). Misinterpretations run the risk of misdiagnoses and, consequently, inappropriate treatment approaches. Note that the use of cholinesterase inhibitors, a first line of treatment for DLB does not appear to affect ¹²³I-FP-CIT uptake on SPECT imaging (80).

The recent systematic review (79) builds upon foundational work in this area, such as the review by Booij and Kemp (81), further elucidating the effects of these medications and substances on the visual assessment of DAT SPECT imaging, This ongoing research is critical for guiding practitioners in everyday clinical practice. Additionally, contraindications for DAT SPECT, including hypersensitivity to any components and considerations during pregnancy, must be carefully evaluated. Clinicians are advised to consult the prescribing information for detailed guidelines.

While we focus on medications frequently prescribed to elderly patients due to their prevalence in this demographic, the interaction of these medications with DAT SPECT is also pertinent in younger patients being evaluated for DLB. Understanding these interactions is essential for accurate interpretation and practical clinical application of DAT imaging. Below, we list medications commonly prescribed in the context of DLB evaluation, highlighting those often used in older patients. For a more extensive review of medication interactions with DAT SPECT, we refer to the systematic review by Chahid et al. (79). Table 3 integrates key findings from the Chahid et al. review with additional details on the mechanism of action and clinical uses of various medications relevant to DLB, offering a comprehensive overview of pharmacological considerations and their implications for DAT SPECT imaging.

These medications are often prescribed for depression and anxiety symptoms in DLB. They might slightly enhance the signal-to-noise ratio of DAT SPECT, but according to the guidelines (20), it is not recommended to withdraw SSRIs before conducting DAT imaging in routine clinical practice. This recommendation is based on the understanding that while SSRIs may influence striatal ¹²³I-ioflupane binding ratios quantitatively, the extent of this effect is relatively small, approximately 10%, mainly due to ¹²³I-ioflupane binding to the serotonin transporter outside of the striatum. The review by Chahid et al. (79) provides further insights into SSRI interference studies, reinforcing the notion that these effects, although present, are minimal and should not significantly impact the interpretation of visual assessments in clinical routine application. However, in the context of research studies where precision and quantitative measures are more critical, the potential influence of SSRIs on DAT imaging results should be considered.

Here, an abnormal DAT SPECT can support a DLB diagnosis in alignment with DLB consortium guidelines.

A 72-year-old man presents with a 2-year history of cognitive decline and behavioral issues. Cognitive testing reveals difficulty with word recall, which improves with recognition/cueing, executive function tasks, visual construction (i.e., clock drawing), and fluctuating attention. Mild mood changes (e.g., depression, apathy) are also present. On physical exam, there is generalized psychomotor slowing but no specific Parkinsonian features. Given the non-amnestic cognitive presentation, fluctuations, and behavioral changes, a diagnosis of probable DLB is suspected clinically, and a DAT SPECT is ordered to assist with the diagnosis.

An 81-year-old woman presents with a 3-year history of progressive memory decline. Following a brief hospitalization, she experienced an episode of delirium and hallucinations, which resolved over three days. No parkinsonism was found on the exam. Mental status testing demonstrated a moderate episodic memory impairment without benefits from cueing, mild deficits in orientation to date and day of the week, mild executive dysfunction, and impaired clock drawing. The family is interested in treatment with monoclonal antibodies, but it is difficult to differentiate between DLB and AD clinically. A DAT SPECT is ordered to assist with the diagnosis and treatment decisions.

A 68-year-old woman presents with a one-year history of mild cognitive changes. She complains of frequent vivid dreams and episodes of acting out her dreams during sleep, often resulting in injury to herself or her bed partner. Her husband reports that she talks, yells, flails her arms, and occasionally falls out of bed during these episodes. These episodes have been increasing in frequency over the past year. Additionally, she experiences constipation and occasional orthostatic dizziness. On cognitive testing, she demonstrates mild memory deficits, particularly in episodic memory, and difficulties with word recall. There are no significant Parkinsonian features on examination.

The patient’s presentation is suggestive of Mild Cognitive Impairment (MCI) with possible underlying Lewy body pathology, which is characterized by cognitive symptoms along with REM Sleep Behavior Disorder (RBD) and autonomic disturbances. Due to the complexity of her symptoms and potential differential diagnoses, further evaluation is warranted. Given the patient’s history of vivid dreams, acting out dreams during sleep, and cognitive deficits, a DAT SPECT is ordered to assist in the diagnosis. This case highlights the importance of DAT SPECT in patients with MCI-like symptoms where the presence of Lewy body pathology can be challenging to confirm based on clinical criteria alone.

It is essential to understand that a positive DAT SPECT, indicating dopaminergic deficits, does not provide a specific diagnosis but instead supports one. Furthermore, a negative result does not exclude diagnoses like DLB. Conducting a comprehensive review of DAT SPECT images in collaboration with a board-certified nuclear medicine radiologist, considering both visual rating and quantitative analysis, is recommended. This collaborative review should consider both visual rating and quantitative analysis, recognizing that DAT SPECT is a supportive biomarker that should be used in clinical symptoms and history. Notably, while DAT SPECT can help differentiate parkinsonian syndromes from other conditions, it does not distinguish among specific parkinsonian syndromes (such as PD, PSP, MSA, CBD, or DLB), and a holistic diagnostic approach should be employed to differentiate between them based on clinical features and additional diagnostic tests.

Clinicians, including neurologists, psychiatrists, and other healthcare providers, must consider several factors that can affect DAT SPECT appearances. Key factors include the radius of detector rotation, image processing, timing of injection, and patient movement during the scan. Additionally, variations in the guidelines or standards to interpret imaging can affect diagnostic conclusions and subsequent treatment decisions (65). Any patient movement during the scan can affect the scan’s appearance. Patients with dementia particularly may struggle to remain still during scanning, as scans take in the order of 20–30 min to perform and detectors rotate near the patient’s face. This can be a particular issue when interpreting scans for DLB, as appearances secondary to movement and scanning with wider radiuses of rotation can mimic those of more balanced loss. Proper training for radiologists and nuclear medicine specialists is essential to provide a trusted and accurate visual rating. Neurologists should also be comfortable with visual reads to provide clinical correlation and interpretation.

Focal loss at the striata can be secondary to strategically occurring infarcts or lesions, making appropriate correlation with anatomical imaging imperative to reduce false positive results. Structural lesions, such as strokes, in the basal ganglia or along the course of nigrostriatal neurons can impact the interpretation of DAT SPECT results. These lesions may disrupt the basal ganglia’s typical anatomical structures and neural pathways, leading to changes in radiotracer uptake patterns. For example, a small midbrain lesion, a putaminal lesion or a large middle cerebral artery infarct can all give asymmetric striatal uptake patterns that can potentially mimic DAT SPECT findings seen in PD or DLB. Clinicians and nuclear medicine radiologists should be aware of the potential influence of such structural lesions on DAT SPECT images.

It is essential to acknowledge that DAT imaging, like other medical imaging procedures involving radioisotopes, involves exposure to ionizing radiation (99). Clinicians and patients should be aware of the associated risks, particularly in cases where repeated scans are considered. The decision to undergo DAT SPECT should always be weighed against its potential benefits in aiding diagnosis and management. The Effective Dose resulting from a DaTscan administration with an activity of 185 MBq (5 mCi) is 3.94 mSv in an adult. Appropriate precautions, such as adhering to recommended safety protocols and frequent voiding, should be taken to minimize radiation exposure. Before consenting to the procedure, patients should also be informed of the risks and benefits.

As a specialized imaging technique, DAT SPECT may not be readily available in all nuclear medicine imaging facilities in the US. Insurance coverage, cost considerations, and the availability of the scan in community settings can act as potential barriers and should be considered for discussions with patients/families.

It might be beneficial for practitioners to have identified resources or directories of local DAT SPECT imaging centers, along with experienced radiologists or nuclear medicine specialists, ensuring accurate visual reads and timely and efficient imaging for patients.