By Harini Sarva, MD
Assistant Professor of Clinical Neurology, Weill Cornell Medical College
This paper demonstrated that cerebrospinal fluid (CSF) alpha-synuclein seeding assays can distinguish between clinically diagnosed dementia with Lewy bodies and controls, and that the presence of hyposmia with core clinical features had the highest predictive value of detecting CSF alpha-synuclein.
Coughlin DG, MacLeod KR, Middleton JS, et al. Association of CSF alpha-synuclein seeding amplification assay results with clinical features of possible and probable dementia with Lewy bodies. Neurology 2024;103:e209656.
Cross-sectional and longitudinal cerebrospinal (CSF) samples were obtained from subjects enrolled into longitudinal dementia with Lewy body (DLB) observational studies. Defined clinical diagnostic criteria, including the presence of parkinsonism, cognitive fluctuations, rapid eye movement (REM) sleep behavior disorder, and hallucinations, were used to diagnosis DLB. Age-matched controls and younger healthy patients with less likelihood of having DLB pathology also were studied and their CSF samples were analyzed.
Not all DLB patients had ancillary testing, such as polysomnography, meta-iodobenzylguanidine (MIBG) cardiac scans, or DaTscans. Validated scales, such as the Montreal Cognitive Assessment (MoCA), International Parkinson and Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS UPDRS) part III, sleep scales, and hallucination inventories, were used to assess degree of core features.
A total of 191 clinically diagnosed DLB patients, 50 age-matched controls, and 49 younger controls were studied. Of the 191 diagnosed DLB patients, more than 70% had positive CSF assays for alpha-synuclein seeding, while only about 4% of either control group had positive assays; thus, the analysis demonstrated a clear distinction between those with clinically diagnosed DLB and controls of both age groups.
Those with one or more core clinical features and hyposmia had greater rates of positive CSF assays compared to DLB features without hyposmia. Hyposmia compared to MDS UPDRS or MoCA scores had a higher predictive value of positive CSF seeding assay results.
The DLB patients with positive CSF analysis compared to those without had worse MDS UPDRS, MoCA, University of Pennsylvania Smell Identification Test
(UPSIT), and REM Sleep Behavior Disorder (RBD) scores. Longitudinal analysis demonstrated that those with a negative CSF assay at baseline had a negative assay a year later and that those with positive assays remained positive.
COMMENTARY
Several studies have demonstrated the efficacy of CSF seeding assays in distinguishing between Parkinson’s disease and controls with hyposmia having a high predictive value in these studies. This study also confirms these results in the DLB population. However, it is interesting to note that only 72% of the clinically diagnosed DLB patients had positive assays, suggesting that clinical criteria use alone may lead to overcalling this diagnosis.
There also is the concern that this assay may not be used enough, since patients may have subtle core features that may not be picked up through the validated rating scales commonly used. Thus, UPSIT, which is a reliable objective measure of hyposmia, should be used routinely in our clinical evaluation of DLB patients since the results correlated very well with CSF assays.
Another consideration is that not all of the subjects had similar ancillary testing, such as positron emission tomography or polysomnogram (PSG) evaluation. Relying on surveys is not enough in adequately diagnosing DLB as Parkinson’s disease. Atypical parkinsonisms have a high misdiagnosis rate, especially in the first five years of diagnosis. Combining clinical criteria with UPSIT and/or PSG and other ancillary tests can increase the predictive value of which patients should undergo CSF analysis, since many may not want to have invasive testing or may not be able to obtain it because of medical contraindications. This is especially important since the CSF seeding assay has been shown to be reliable in longitudinal analysis despite small sample size.
Accurate diagnosis of DLB in life, as opposed to relying on autopsy for definitive diagnosis, will enable development of therapeutic options and enrollment of appropriate patients into clinical trials.
