Dementia with Lewy bodies (DLB)

Improving Diagnostic Confidence in Clinically Overlapping Dementias

Although dementia with Lewy bodies (DLB) is the second most common form of dementia, it is one of the most underdiagnosed and misdiagnosed neurodegenerative dementias due to its overlapping features with both Alzheimer’s disease (AD) and Parkinson’s disease dementia (PDD). DLB and PDD—both forms of Lewy body dementia—are associated with α-synuclein aggregates that significantly impact prognosis and functional decline. Delayed or inaccurate diagnosis can lead to inappropriate treatment, particularly the use of antipsychotics, which pose serious risks in this population. This can also lead to missed opportunities for early intervention.

The SAAmplify-ɑSYN clinically validated seed amplification assay (SAA) enables in vivo detection of misfolded ɑ-synuclein aggregates in cerebrospinal fluid (CSF). This assay can improve diagnostic accuracy in early, ambiguous, or mixed clinical presentations and supports critical treatment decisions. For neurologists, psychiatrists, geriatricians, and other frontline providers, integrating SAAmplify-ɑSYN into the diagnostic workup of patients with cognitive decline and neuropsychiatric symptoms can provide greater confidence in identifying DLB.  Incorporating SAAmplify-ɑSYN into clinical practice can support:

• Diagnostic clarification in ambiguous or atypical cases
• Early evidence of ɑ-synuclein pathology at the mild cognitive impairment (MCI) or prodromal stage
• Distinguishing DLB from other dementias, which can present with similar symptoms
• Helping refine diagnosis in mixed pathologies, such as DLB with concomitant AD pathology
• Informed treatment planning, including safer pharmacologic decision-making

DLB Stages and Clinical Characteristics

Dementia with Lewy bodies is a progressive neurodegenerative disorder characterized by a heterogeneous and often fluctuating clinical presentation. The disease typically progresses through the following stages:

1. Prodromal Stage: May present with anxiety, depression, subtle cognitive impairments (particularly affecting attention, executive function, or visuospatial skills), and sleep disturbances, such as idiopathic REM sleep behavior disorder (iRBD).
2. Mild Stage: Symptoms of confusion, executive dysfunction, visual hallucinations, and motor symptoms slowly starting to manifest.
3. Moderate Stage: Cognitive deficits and motor symptoms (bradykinesia, rigidity) worsen. Fluctuating cognition, recurrent visual hallucinations, and motor features with minimal tremor and poor levodopa response. Patients may start to experience neuropsychiatric symptoms, such as delusions and Capgras syndrome.
4. Severe stage: Profound cognitive impairment and motor disability often lead to full dependency on caregivers. Patients may experience frequent falls, dysautonomia (e.g. orthostatic hypotension), neuroleptic sensitivity, and psychosis.

Dementia with Lewy Bodies Diagnostic Criteria and Tools

According to the 2017 DLB Consortium criteria¹, DLB diagnosis relies on:

Core clinical features:

1. Cognitive fluctuations with pronounced variations in attention and alertness
2. Recurrent well-formed visual hallucinations
3. Idiopathic REM sleep behavior disorder (iRBD)
4. Spontaneous parkinsonism (bradykinesia with rigidity or rest tremor)

Indicative DLB biomarkers include:

1. Reduced dopamine transporter (DaT) uptake in basal ganglia on SPECT/PET
2. Low uptake in occipital lobe on FDG-PET (posterior hypometabolism)
3. Polysomnography-confirmed iRBD without atonia
4. Abnormal myocardial MIBG scintigraphy (reduced uptake)

Probable DLB:

• Two or more core clinical features, with or without indicative biomarkers
• One core feature with at least one indicative biomarker

Possible DLB:

• One core clinical feature without biomarkers
• Indicative biomarkers in the absence of core clinical features

Supportive Features (non-diagnostic but relevant):

• Severe antipsychotic sensitivity
• Occipital hypometabolism or cingulate island on FDG-PET
• Autonomic dysfunction (e.g., orthostatic hypotension, constipation)
• Hallucinations in non-visual modalities
• Apathy, anxiety, or depression
• Hypersomnia
• Preserved medial temporal lobe structures on MRI

Exclusion Criteria:

• Parkinsonism onset > 1 year before cognitive decline (i.e., supports PDD diagnosis)
• Evidence of another disorder accounting for symptoms

Clinical Use Cases

• Cognitive Decline and Parkinsonism: SAAmplify-ɑSYN “Detected” result in patients with parkinsonian features and early cognitive deficits supports DLB diagnosis over PD or PSP.
• Atypical Dementia Presentation: In patients diagnosed with AD but exhibiting visual hallucinations, iRBD, or neuropsychiatric symptoms, SAAmplify-ɑSYN can reveal coexisting Lewy body pathology (AD/DLB).
• Prodromal Cognitive Syndromes: SAAmplify-ɑSYN enables biologic evidence of a synucleinopathy in MCI or iRBD patients prior to full clinical expression of DLB.
• Mixed Phenotypes: In mixed or ambiguous phenotypes, such as cognitive decline with parkinsonism, SAAmplify-ɑSYN can support diagnosis in cases with overlapping AD and synucleinopathy biomarkers to aid in clinical classification and trial stratification.
• Clinical Trial Enrollment: Provides ɑ-synuclein status to support enrollment in trials targeting neuronal synucleinopathies.

ɑ-Synuclein Pathology and Its Role in Dementia with Lewy Bodies

ɑ-synuclein is central to DLB pathophysiology and is defined by the widespread accumulation of misfolded ɑ-synuclein aggregates in cortical and subcortical neurons, particularly in the limbic system and brainstem. These aggregates form Lewy bodies and Lewy neurites, which disrupt synaptic function, neuronal communication, and mitochondrial activity. Co-pathology with amyloid-beta and tau is common, particularly in patients with longer onset or amnestic DLB phenotypes. This distinction matters as studies show patients with mixed pathology decline more rapidly, have different neuropsychiatric symptoms, and may respond differently to treatments. (REF)

Diagnostic Innovation

SAAmplify-ɑSYN is a novel technology that amplifies trace amounts of misfolded ɑ-synuclein in CSF. The test involves mixing a patient’s CSF with recombinant ɑ-syn and a fluorescent dye, followed by cyclic shaking and incubation. If seeds are present, they induce aggregation, resulting in fluorescent signal. This test provides a binary qualitative result: Detected or Not Detected. For DLB, a “Detected” result reveals evidence of ɑ-synuclein pathology. Each sample is analyzed in triplicate with rigorous quality control.

In Practice: Incorporating ɑ-Synuclein as a Biomarker for Dementia with Lewy Bodies

DLB is a complex disease marked by cognitive fluctuations, hallucinations, and motor symptoms that overlap with AD and PD features. With growing evidence and clinical integration, SAAmplify-ɑSYN (ɑSYN SAA) can shorten the diagnostic journey, guide safer treatment strategies, and support earlier, biologically grounded diagnoses in DLB and related synucleinopathies.

References

¹McKeith, I. G. et al. “Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium.” Neurology vol. 89,1 (2017): 88-100. doi:10.1212/WNL.0000000000004058

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