A compelling finding from the α-synuclein seed amplification assay (αSyn-SAA) indicates that a positive test result is significantly correlated with the clinical characteristics of dementia with Lewy bodies (DLB), particularly highlighting the presence of hyposmia, or diminished olfactory perception. This correlation was established through a comprehensive multicenter investigation that scrutinized αSyn-SAA outcomes among individuals diagnosed with DLB compared to neurologically intact control participants. The groundbreaking results of this research have been documented in a recent issue of Neurology (2024;103[3]:e209656).
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“DLB poses substantial diagnostic challenges, largely relying on clinical evaluations for confirmation,” states Cleveland Clinic neurologist James Leverenz, MD, a senior author of the study. “Our findings offer crucial insights that could refine diagnostic criteria while also backing the use of a direct biomarker in a clinical context.”
Dr. Leverenz is at the helm of the Cleveland Clinic Lou Ruvo Center for Brain Health in Cleveland, a major coordinating site for the expansive multicenter DLB Consortium. This consortium operates under the umbrella of the National Institute of Neurological Disorders and Stroke (NINDS) Parkinson’s Disease Biomarkers Program, which is tasked with gathering clinical data to bolster the discovery of biomarkers that could enhance the diagnostic accuracy for DLB.
The need for more-specific diagnosis
A definitive diagnosis of DLB can only be made post-mortem via autopsy, while current diagnostic practices lean heavily on established clinical features. These core features encompass significant cognitive decline with episodic fluctuations, parkinsonian symptoms, visual hallucinations, and REM sleep behavior disorder, with hyposmia serving as an additional supportive indicator. Existing biomarkers that aid in establishing a DLB diagnosis, such as FP-CIT scans, MRI, cardiac MIBG imaging, and polysomnography, are indirect measures and do not provide conclusive evidence of the disease.
Due to the potential subtlety or absence of key symptoms, coupled with the symptomatic overlap with Parkinson’s disease, Alzheimer’s disease, and other dementias, DLB is frequently subject to both under-diagnosis and over-diagnosis.
The recently developed αSyn-SAA provides a reliable measure of aggregates formed by a misfolded protein unique to Lewy bodies and Lewy neurites within the brain, rendering it a significant biomarker candidate for the diagnosis of DLB. Prior studies suggest that αSyn assays demonstrate over 90% sensitivity and specificity in identifying autopsy-confirmed DLB and Parkinson’s disease, even amidst a clinical presentation that is multifaceted.
The focus of the newly published study was to evaluate whether αSyn-SAA could effectively differentiate individuals with clinically diagnosed DLB from healthy controls, as well as to investigate the relationship between αSyn-SAA positivity and the clinical signs typically utilized in the diagnosis of DLB.
Study design and findings
Researchers assembled three distinct cohorts from patients listed in the DLB Consortium registry and other studies affiliated with the Parkinson’s Disease Biomarker Program, spanning the period from 2017 to 2021. These cohorts included:
- Patients with clinically diagnosed DLB (n = 191; mean age, 69.9 ± 6.8 years; 85% male)
- Age- and sex-matched controls without neurological impairment (n = 50)
- Younger controls (mean age)
All participants had CSF samples collected within 12 months of their baseline assessments, and αSyn-SAA testing was conducted as part of this research. For 82 participants, multiple samples collected over time were also available, and remarkably, only one individual displayed inconsistent αSyn-SAA results.
The αSyn-SAA test yielded positive results for 72% of patients in the DLB cohort, contrasting sharply with only 4% positivity in each control group. Moreover, among DLB patients exhibiting at least two of the core clinical features of the disease (n = 156), 78% yielded a positive testing result.
A detailed analysis of various standardized clinical assessments revealed notable contrasts within the DLB cohort based on αSyn-SAA test outcomes:
- Lower (worse) mean Montreal Cognitive Assessment score (18.8 ± 5.7 vs. 21.2 ± 5.2; P = .01)
- Higher (worse) mean score on the Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part III (33.8 ± 15.1 vs. 25.6 ± 16.4; P = .001)
- Greater likelihood to report REM sleep behavior disorder (86% vs. 62% of patients; P
- Greater likelihood to have hyposmia, defined as scoring less than the 15th percentile on the University of Pennsylvania Smell Identification Test (UPSIT) (90% vs. 32% of patients; P
The strongest predictor for αSyn-SAA positivity was the UPSIT score, achieving the highest area under the curve (0.87; 95% CI, 0.81-0.94). Patients who scored at or below the hyposmia threshold were found to be 18.3 times more likely to exhibit positive αSyn-SAA outcomes (95% CI, 7.52-44.6) compared to their age- and sex-matched peers with a normal sense of smell.
Implications for improving DLB diagnosis
The findings from this study offer Class III evidence confirming that CSF αSyn-SAA can effectively distinguish patients diagnosed with DLB from neurologically healthy controls, the authors assert.
Dr. Leverenz highlights that a noticeable fraction of individuals diagnosed with DLB did not show any positive results on the αSyn-SAA test. Patients who did test positive exhibited a higher likelihood of having REM sleep disorder, along with more severe hyposmia, cognitive decline, and parkinsonian symptoms. However, there was no significant difference in core clinical features such as visual hallucinations and cognitive fluctuations between those who were positive and those who were negative for the test.
“Our findings suggest the current diagnostic criteria may be prone to over-diagnosing DLB,” states Dr. Leverenz. “Based on our results and additional published studies, we advocate for placing greater emphasis on hyposmia evaluation, preferably employing an objective test like the UPSIT.”
He further mentions that less invasive methods for αSyn-SAA testing, utilizing skin biopsies and blood samples, are currently under exploration.
Dr. Leverenz extends his gratitude to the other significant contributors from various sites, alongside the Cleveland Clinic, involved in the DLB Consortium, the NINDS Parkinson’s Disease Biomarkers Program, and the Lewy Body Dementia Association, including partner institutions like Barrow Neurological Institute, Columbia University, Rush University, Thomas Jefferson University, University of California San Diego, University of Miami, University of North Carolina, University of Pennsylvania, University of Pittsburgh, and VA Puget Sound Health Care System/University of Washington.
Te for the incorporation of the αSyn-SAA test into the diagnostic process for DLB. This could enhance diagnostic precision and help differentiate DLB from other types of dementia, ultimately improving patient outcomes through more tailored management strategies.”
The study emphasizes the need for further research to validate αSyn-SAA’s utility across diverse populations and clinical settings. This would enable healthcare professionals to better leverage the test in routine practices, ensuring that patients receive appropriate diagnoses and interventions in a timely manner.
the findings highlight the potential for αSyn-SAA to serve as a valuable biomarker in the diagnosis of DLB, addressing long-standing challenges associated with its identification. By refining diagnostic accuracy, clinicians can significantly improve patient care and potentially slow disease progression through early and effective treatment.
