In a recent study published in the Nature Medicine Journal, researchers evaluated the impact of Lewy body (LB) positivity (+) on clinical outcomes such as cognition and smell among cognitively and neurologically unimpaired individuals.
The study also compared LB pathology effects to those of tau and Aβ protein pathologies.
Study: Cognitive effects of Lewy body pathology in clinically unimpaired individuals. Image Credit: KaterynaKon/Shutterstock.com
Advances in detecting misfolded α-synuclein (α-syn) within the cerebrospinal fluid of LB+ individuals have shown high specificity and sensitivity in detecting neuropathologically verified LB disease (LBD), particularly among individuals with cortical and limbic LBs and clinically diagnosed Parkinson's disease (PD).
However, limited studies have examined the impact of LB positivity on clinical outcomes among cognitively and neurologically unimpaired people as an independent pathology or existing simultaneously with Alzheimer's disease (AD) pathology.
Understanding the influence of LB pathology is crucial for designing preclinical Lewy body disease (LBD) trials, planning screening procedures, and selecting outcome measures with high sensitivity.
About the study
In the present study, researchers assessed the influence of Lewy body pathologies on cognition and clinical outcomes using a cerebrospinal fluid-based α-syn-seed amplification assay (SAA). The study occurred among 1,182 neurologically and cognitively unimpaired individuals who participated in the BioFINDER-1 (between 2007 and 2015, n=754) and 2 (between 2017 and 2021, n=428) studies.
The team evaluated cognitive outcomes longitudinally and cross-sectionally over ten years and performed survival analyses to investigate progression to PD or dementia with Lewy bodies (DLB) based on LD pathology presence at study initiation.
Alzheimer's disease pathology was described as tau- and Aβ-positive using positron emission tomography (PET) imaging or CSF using the National Institute of Aging-Alzheimer's Association (NIA-AA) criteria.
Lewy body pathology was described as α-synuclein SAA+ using real-time, quaking-induced conversion assays (RT-QuIC). Cognition and memory were assessed using the preclinical Alzheimer cognitive composite (PACC), and 10-word delayed recall tests, respectively.
Motor function was assessed using an informant-based cognitive impairment questionnaire (CIMP-QUEST) and the unified Parkinson's disease rating scale, Part III (UPDRS-III).
Linear mixed-effects (LME) modeling was performed to evaluate the effects of different AD/LB groups and the independent impacts of the LB, Aβ protein, and tau protein pathologies on longitudinal cognitive functions.
The team also performed a sensitivity analysis using altered cognition as a study outcome and adjusting for initial cognitive test scores.
The participants were aged 40 to 100 years, could speak Swedish, and scored ≥24.0 points on the mini-mental state examination (MMSE).
The study involved 94 participants (8.0%) with LB, tau, and Aβ pathologies. The majority (80%) did not have AD or LB pathology. In comparison, 74 (6.0%) had only Lewy body pathology, 147 (12%) had only Alzheimer's disease pathology, and 20 (two percent) had both Alzheimer's disease and Lewy body pathology.
LB pathology negatively impacted global memory and cognition, as well as longitudinal attention and executive functions. The tau protein had a similar cognitive impact, but the effects were less prominent for Aβ. LB positivity similarly influenced cross-sectional and longitudinal cognitive outcomes as AD pathology.
The impact of LB pathology on memory function was similar to that of tau pathology, both cross-sectionally and longitudinally.
Individuals with Lewy body and Alzheimer's disease (tau and Aβ) pathologies demonstrated swifter cognitive decay than individuals with either pathology. Lewy body, but not Alzheimer's disease pathology, was related to lowered smelling ability.
Only Lewy body-positive individuals developed clinical LBD in the ten years. All (LB, tau, and Aβ) pathologies were increasingly common with advancing age, and males had a >2.0-fold greater likelihood of demonstrating LB positivity than females.
AD+/LB- and AD-/LB+ individuals showed significantly worse baseline memory and cognition performances than AD-/LB- individuals. AD+/LB+ individuals showed worse cognitive scores than their AD–/ LB+ counterparts.
Tau protein and LB pathologies showed comparable and significant impacts on degrading memory and cognition. Only the Aβ protein pathology was independently linked with worse executive and attention functions but did not alone affect memory.
The cross-sectional effect sizes of LB pathology on cognitive, smell, and motor functions were similar regardless of Aβ and tau adjustment. There was a significant association between LB and Aβ status, with LB positivity more likely to occur in the presence of Aβ positivity.
During a follow-up of 4.5 years (mean), 70 individuals progressed to AD, 31 to vascular disease or dementia, 16 to DLB, and six to PD, irrespective of baseline biomarker status. Only LB+ participants progressed to dementia with Lewy bodies or Parkinson's disease.
The olfactory test estimated Lewy body positivity with an area under the curve (AUC) value of 0.8 (overall accuracy of 85.0%). According to the age-adjusted data, Lewy body pathology was more likely to be observed among Aβ-positive individuals (odds ratio for Lewy body, 1.7).
Non-significant associations were observed between Lewy body and tau protein status. Lewy body status did not show any association with the magnetic resonance (MR) measures for the integrity of grey matter in the preclinical population.
To conclude, based on the study findings, LB pathology, measured using α-syn SAA, is associated with early changes in cognitive performance and smell function in cognitively and neurologically unimpaired individuals and indicates an increased risk of near-term progression to PD or DLB.
The low prevalence of LB positivity (8%) in healthy middle-aged and elderly individuals indicates that large screenings are required to recruit adequately large populations, making CSF analyses a feasible but not optimal tool.
Cognitive measures sensitive to changes in preclinical AD are also sensitive to LB pathology and could be suitable for preclinical LBD trials.