Constructive Uses For Biomarker Testing In Dementia
Overview
The Investigating the Impact of Alzheimer’s Disease Diagnostics in British Columbia (IMPACT-AD BC) study aimed to evaluate the effects of Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarker testing on medical decision-making, personal decision-making, and health system economics. This observational, longitudinal cohort study enrolled 149 patients from February 2019 to July 2021. Patients referred to memory clinics were included if their dementia specialist ordered AD CSF biomarker testing as part of routine medical care and met appropriate use criteria for lumbar puncture and AD CSF biomarker testing.
Among patients with completed management questionnaires (n = 142), the median age was 64 years, 48% were female, and 60% had CSF biomarker profiles on the AD continuum. Clinical management changed in 89.4% of cases, with AD biomarker testing associated with decreased need for other diagnostic procedures such as brain imaging (–52.0%) and detailed neuropsychological assessments (–63.2%), increased referrals and counseling (57.0%), and guided AD-related drug prescriptions (+88.4% and –50.0% in biomarker-positive and -negative cases, respectively).
The discussion highlights the significant and positive changes in clinical management resulting from AD biomarker testing, including reduced healthcare resource utilization, therapy optimization, and increased patient and family member counseling. While some changes were directly linked to the AD biomarker profile, most changes were independent of baseline clinical presentation and cognitive impairment level, indicating broad utility for AD biomarker testing in eligible individuals.
Introduction
The effectiveness of amyloid-β (Aβ) peptides and tau proteoforms in cerebrospinal fluid (CSF) as diagnostic markers for Alzheimer’s disease (AD) pathology is well-established. Despite the modest performance of clinical diagnosis compared to neuropathological findings and amyloid positron emission tomography (PET), the implementation of AD biomarkers in clinical practice remains essential. In Canada, CSF testing is a pragmatic solution due to factors like cost effectiveness and resource availability. However, understanding how CSF biomarker testing influences clinical management is crucial for its broad and sustainable implementation.
While European studies have examined changes in diagnosis and physician confidence with AD CSF biomarker use, none have comprehensively assessed downstream changes in clinical management. To address these gaps, the Investigating the Impact of Alzheimer’s Disease Diagnostics in British Columbia (IMPACT-AD BC) study aimed to investigate the effects of CSF testing on patient management in memory clinics. This study focused on medical utility, personal utility, and health system economics.
The primary and secondary outcomes of the medical utility arm of the study revealed comprehensive assessments of changes in clinical management, diagnosis, and diagnostic confidence among physicians. This included analyses of overall changes, variations by clinical presentation, and differences across clinical disease stages. By providing insights into the impact of AD biomarker testing on patient care within the Canadian healthcare system, the study contributes to understanding the broader implications of implementing biomarker-based diagnostics for AD.
Method
The IMPACT-AD BC study, an observational longitudinal cohort investigation, aimed to evaluate the influence of Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarker testing on various aspects of clinical management, diagnosis, healthcare utilization, and patient outcomes. This study, preregistered with ClinicalTrials.gov (NCT05002699) and adhering to STROBE guidelines, enrolled patients for whom physicians deemed biomarker testing medically appropriate.
A total of 149 patients were enrolled between February 2019 and July 2021, selected from those referred to memory clinics, meeting specific criteria for lumbar puncture and AD CSF biomarker testing appropriateness. Dementia specialists, defined as physicians specializing in cognitive impairment or dementia care, completed detailed questionnaires before and after learning biomarker results.
The study’s procedures involved pre-biomarker management planning, CSF biomarker analysis, and post-biomarker management assessment. Dementia specialists completed questionnaires assessing diagnostic considerations, confidence levels, routine exams, and intended management plans before biomarker testing. CSF samples were analyzed for biomarkers, and the results were categorized into “on the AD continuum” or “not on the AD continuum.” Following biomarker disclosure to patients and care partners, specialists revisited the management questionnaire to evaluate changes in management strategies.
Outcome measures included assessing percentage changes in intended patient management between pre- and post-biomarker testing scenarios, categorized into various domains such as medication adjustments, diagnostic procedures, and referrals. Secondary outcome measures examined changes in clinical management by clinical presentation and disease stage, along with alterations in diagnosis and diagnostic confidence levels.
The study’s findings provide valuable insights into the impact of AD CSF biomarker testing on clinical decision-making, demonstrating significant positive changes in clinical management, reduced healthcare resource utilization, optimized pharmacotherapy, and increased counseling for patients and their families. These results have important implications for enhancing the positive impacts of biomarker testing and optimizing healthcare resource allocation in dementia management.
Statistical Analysis
In this study, the analysis focused on assessing the impact of biomarker profiles on clinical management in Alzheimer’s disease (AD). Binomial estimates were used to calculate the proportion of change in clinical management, along with Wilson 95% confidence intervals (CIs), for both the overall composite and individual components of the composite.
Additionally, two exploratory analyses were conducted. Firstly, the concordance between pre-biomarker diagnosis and AD biomarker profile was evaluated, with the rate of agreement reported along with 95% Wilson CI. Secondly, the association between the AD biomarker profile and changes in clinical management was explored using mixed-effects logistic regression.
Furthermore, post hoc analyses were performed to examine changes in the overall utilization of each management domain, stratified by baseline cognitive impairment level and AD biomarker profile. Similarly, changes in primary diagnosis and diagnostic confidence were assessed, stratified by biomarker profile.
These comprehensive analyses aimed to elucidate the relationship between AD biomarker profiles and subsequent changes in clinical management strategies, providing valuable insights into the potential impact of biomarker-based approaches on patient care and disease management in Alzheimer’s disease.
Result
The study enrolled 149 patient participants, of which 142 had complete pre- and post-biomarker management plan questionnaire pairs, forming the basis for the final analysis. These patients, with a median age of 64, were predominantly White (80%) and had varying levels of educational attainment, with 67% having partially or fully completed post-secondary education. The cohort primarily consisted of individuals with mild cognitive impairment (MCI), and a majority had undergone head CT or MRI scans. Biomarker profiling indicated that 60% of cases were on the Alzheimer’s disease (AD) continuum.
The primary outcome measure focused on changes in clinical management following AD biomarker testing. It revealed that AD biomarker testing led to changes in clinical management in 89.4% of patients, encompassing diagnostic procedures, referrals, counseling, and medication usage. Notably, physicians’ confidence in the primary diagnosis increased significantly with the use of biomarkers.
Secondary outcome measures explored changes in diagnostic confidence and clinical management based on different clinical presentations and levels of cognitive impairment. Biomarker testing reduced the number of cases with diagnostic uncertainty, particularly for patients initially in the gray zone for AD pathology. Moreover, changes in clinical management were observed across all clinical presentation groupings and levels of impairment, indicating the utility of biomarker testing irrespective of baseline cognitive status.
Exploratory analyses highlighted the concordance between pre-biomarker diagnosis and biomarker profile, with significant interactions observed in the change in the use of AD symptomatic medications. Post hoc analysis further elucidated changes in clinical management and diagnosis by AD biomarker profile, emphasizing the impact of biomarker testing on treatment decisions, diagnostic confidence, and referral practices.
In conclusion, the study underscores the significant role of AD biomarker testing in informing clinical management decisions and enhancing diagnostic accuracy and confidence. The findings emphasize the potential of biomarkers to guide personalized approaches to AD diagnosis and management, ultimately improving patient care and outcomes.
Conclusion
This longitudinal observational study investigated the impact of Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarker testing on clinical management. The findings revealed significant alterations in clinical management practices following biomarker testing, leading to increased certainty in diagnosing AD pathology and enhanced diagnostic confidence. Notably, biomarker testing reduced the need for additional costly diagnostic procedures, guided the prescription of AD symptomatic medications, and facilitated referrals to clinical trials.
One of the most significant changes observed was a decrease in the utilization of diagnostic procedures, particularly imaging studies, due to heightened diagnostic confidence provided by biomarker information. This reduction in unnecessary testing could have substantial cost-saving implications for healthcare systems, especially in countries facing resource constraints like Canada.
Additionally, the study highlighted a decrease in the need for detailed neuropsychological assessments, which are often burdensome for patients and resource-intensive for healthcare systems. This reduction in reliance on testing could alleviate patient stress and improve overall efficiency in diagnostic processes.
Referrals and counseling also saw notable changes post-biomarker testing, with increased counseling across all categories and more targeted referrals to clinical trials, particularly for individuals with an AD biomarker signature. The study emphasized the importance of timely diagnosis for accessing disease-modifying therapies (DMTs), especially in regions where DMT approval and reimbursement programs are limited.
Despite its strengths, including comprehensive data collection and a diverse patient cohort reflective of the Canadian population, the study had limitations, such as the time elapsed between pre- and post-biomarker management plans and potential selection biases. However, efforts were made to minimize biases through non-targeted enrollment and diverse physician recruitment.
In summary, the study underscored the transformative impact of AD biomarker testing on patient management and healthcare resource utilization. By optimizing diagnostic processes and facilitating timely access to interventions, biomarker testing has the potential to significantly enhance patient outcomes in AD care. These findings hold relevance amidst the expanding landscape of dementia diagnostics and emerging therapies for AD.
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