Which serum biomarkers are associated with Lewy body disease (including dementia with Lewy bodies and Parkinson’s disease dementia) and are any validated for routine clinical use?

Serum Biomarkers in Lewy Body Disease

No serum biomarkers are currently validated for routine clinical diagnosis of Lewy body disease (dementia with Lewy bodies or Parkinson's disease dementia), and serum-based testing should not be used for diagnostic purposes at this time. 1, 2, 3

Current State of Serum Biomarkers

Alpha-Synuclein in Blood

• Serum/plasma alpha-synuclein measurements have been investigated but lack convincing evidence of robust reliability and validity from multiple laboratories, making them unsuitable for clinical use 1
• While alpha-synuclein markers are intended to measure the pathology most central to Lewy body disorders, the technology for reliable blood-based detection is not yet clinically available 1
• Research has focused primarily on cerebrospinal fluid (CSF) rather than serum for alpha-synuclein species detection, as CSF more directly mirrors pathological changes in the brain 2, 3

Other Emerging Serum Markers

• The CSF/serum albumin ratio has shown promise, with increased ratios observed in both Parkinson's disease and dementia with Lewy bodies compared to controls, but this requires paired CSF and serum samples and is not a pure serum biomarker 3
• Serum glucocerebrosidase (GCase) activity has been studied, showing reduced activity in Lewy body disease patients versus controls, but validation for routine clinical use is lacking 3

Why Serum Biomarkers Are Not Ready for Clinical Use

The fundamental limitation is that no serum biomarker has demonstrated sufficient sensitivity, specificity, or standardization across laboratories to warrant clinical implementation. 1, 2

Key Barriers to Clinical Translation

• Limited standardization of biomarker measurements from one locale to another prevents reliable interpretation 4
• Access to validated biomarker testing is restricted, even in research settings 4
• The core clinical diagnostic criteria provide very good diagnostic accuracy in most patients without requiring biomarker confirmation 4

Current Diagnostic Approach Without Serum Biomarkers

Established Diagnostic Tools

• Neuropsychological testing and structural MRI remain the most widely used and accessible diagnostic tests by Lewy body dementia specialists 5
• The Montreal Cognitive Assessment (MoCA) is more valid than MMSE for Lewy body disease because it assesses attention and executive functions 6
• Clinical diagnosis relies on identifying core features: fluctuating cognition, recurrent visual hallucinations, parkinsonism, and REM sleep behavior disorder 6, 7

Validated Biomarkers (Non-Serum)

• Dopamine transporter SPECT imaging (I-123 Ioflupane) shows decreased uptake and is an "indicative" biomarker for diagnosis 7, 1, 5
• FDG-PET demonstrates occipital hypometabolism and the "cingulate island sign" in Lewy body disease 7
• Cardiac myocardial scintigraphy (noradrenergic system imaging) is an indicative biomarker but rarely used in practice 8, 5
• Polysomnography for REM sleep behavior disorder confirmation is available but underutilized 8, 5

CSF Biomarkers (Not Serum) With Research Support

While not serum-based, CSF biomarkers show more promise than blood tests but still lack validation for routine clinical use in Lewy body disease. 3

CSF Alpha-Synuclein Species

• Lower levels of total alpha-synuclein and higher concentrations of oligomeric and phosphorylated alpha-synuclein have been observed in Parkinson's disease 3
• Detection of "pro-aggregating" alpha-synuclein in CSF has enabled discrimination of synucleinopathies with high sensitivity and specificity in research settings 3

CSF Alzheimer's Disease Biomarkers in Lewy Body Disease

• Low CSF Aβ42 levels have shown robust prognostic value for development of cognitive impairment in Parkinson's disease and dementia with Lewy bodies 3
• CSF tau and phosphorylated tau can help differentiate Alzheimer's disease from dementia with Lewy bodies, as Lewy body disease typically shows lower tau levels 3
• The Aβ42/Aβ38 ratio has demonstrated potential in differential diagnosis between Alzheimer's disease and dementia with Lewy bodies 3

Clinical Implications

Diagnosis of Lewy body disease must rely on clinical criteria, neuropsychological testing, and structural imaging, with selective use of dopaminergic imaging when diagnostic uncertainty exists. 5

When to Consider Advanced Biomarker Testing

• Diagnostic testing beyond MRI and neuropsychological testing is most helpful in "possible" dementia with Lewy bodies cases where clinical features are incomplete 5
• Biomarker testing assists with differential diagnosis when distinguishing between Alzheimer's disease, dementia with Lewy bodies, and Parkinson's disease dementia 5
• In mild cognitive impairment with suspected Lewy body pathology, dopamine transporter imaging may clarify diagnosis 5

Common Pitfall to Avoid

• Do not order serum alpha-synuclein testing or other blood-based Lewy body biomarkers for diagnostic purposes, as these lack validation and will not change management 1, 2
• Recognize that Lewy body disease frequently coexists with Alzheimer's disease pathology, particularly in older individuals, which complicates biomarker interpretation 4, 9
• Understand that amyloid PET has very limited usefulness for diagnosis and cannot distinguish between dementia with Lewy bodies and Parkinson's disease dementia 7