Challenges and opportunities for improving the landscape for Lewy body dementia clinical trials

Abstract

Lewy body dementia (LBD), including dementia with Lewy bodies and Parkinson’s disease dementia, affects over a million people in the USA and has a substantial impact on patients, caregivers, and society. Symptomatic treatments for LBD, which can include cognitive, neuropsychiatric, autonomic, sleep, and motor features, are limited with only two drugs (cholinesterase inhibitors) currently approved by regulatory agencies for dementia in LBD. Clinical trials represent a top research priority, but there are many challenges in the development and implementation of trials in LBD. To address these issues and advance the field of clinical trials in the LBDs, the Lewy Body Dementia Association formed an Industry Advisory Council (LBDA IAC), in addition to its Research Center of Excellence program. The LBDA IAC comprises a diverse and collaborative group of experts from academic medical centers, pharmaceutical industries, and the patient advocacy foundation. The inaugural LBDA IAC meeting, held in June 2019, aimed to bring together this group, along with representatives from regulatory agencies, to address the topic of optimizing the landscape of LBD clinical trials. This review highlights the formation of the LBDA IAC, current state of LBD clinical trials, and challenges and opportunities in the field regarding trial design, study populations, diagnostic criteria, and biomarker utilization. Current gaps include a lack of standardized clinical assessment tools and evidence-based management strategies for LBD as well as difficulty and controversy in diagnosing LBD. Challenges in LBD clinical trials include the heterogeneity of LBD pathology and symptomatology, limited understanding of the trajectory of LBD cognitive and core features, absence of LBD-specific outcome measures, and lack of established standardized biologic, imaging, or genetic biomarkers that may inform study design. Demands of study participation (e.g., travel, duration, and frequency of study visits) may also pose challenges and impact trial enrollment, retention, and outcomes. There are opportunities to improve the landscape of LBD clinical trials by harmonizing clinical assessments and biomarkers across cohorts and research studies, developing and validating outcome measures in LBD, engaging the patient community to assess research needs and priorities, and incorporating biomarker and genotype profiling in study design.

Treatment of Parkinson’s Disease with Cognitive Impairment: Current Approaches and Future Directions

“…It remains uncertain how best to identify populations for particular studies, such as whether to study PD without dementia (normal cognition and PD-MCI), PD with cognitive impairment (PD-MCI plus PDD), or the conditions separately. There are also debates regarding whether individuals with PDD should be combined with individuals with dementia with Lewy bodies for trials, as they both fall under the umbrella of Lewy body dementia [ 67 ]. Cognitive impairment in PD is a spectrum and how PD-MCI and PDD are operationalized for study design may affect results.…”

“…Cognitive impairment in PD is a spectrum and how PD-MCI and PDD are operationalized for study design may affect results. Other aspects of PD cognitive impairment need also to be considered in trial design, such as whether researchers need to account for the presence or absence of concomitant AD pathology [ 67 ]. Features of PDD, such as fluctuations, can also negatively affect accurate clinical trial measurements, and study participation requirements (e.g., travel, study visit frequency) can affect trial enrollment, retention, and outcomes [ 67 ].…”

“…Other aspects of PD cognitive impairment need also to be considered in trial design, such as whether researchers need to account for the presence or absence of concomitant AD pathology [ 67 ]. Features of PDD, such as fluctuations, can also negatively affect accurate clinical trial measurements, and study participation requirements (e.g., travel, study visit frequency) can affect trial enrollment, retention, and outcomes [ 67 ]. Finally, most measures used in studies of cognitive impairment in PD need further research to assess the validity, reliability, and clinically meaningful change of these measures when used in populations with PD and cognitive impairment [ 68 ].…”

Role of Mitochondrial Heat-shock Proteins and Immunophilins in Neuro Degenerative Diseases

“…All these observations highlight the critical role of CHIP and HSPs in Alzheimer's disease, Parkinson's disease, Lewy's Body Disease, prion or huntingtin pathologies. Table 2 summarizes the properties of all HSPs, immunophilins, and other molecular chaperones discussed here that are involved in the biology of aggregated proteins responsible for neurodegenerative diseases [107,135,195,[200][201][202]. [189,191,193,196] PTPA Protects against β-amyloid toxicity Nucleus, cytoplasm AD [131,132] (…”

Lewy Body Dementia Association’s Industry Advisory Council: proceedings of the second annual meeting

“…With the goal of stimulating clinical research in LBD treatments, in 2019, the Lewy Body Dementia Association (LBDA) formed an Industry Advisory Council (LBDA IAC) comprising a diverse group of academic and industry researchers as well as patient advocacy representatives. Proceedings of the inaugural meeting of the LBDA IAC were published along with detailed descriptions of the challenges being addressed (Goldman et al 2020). We now report the progress and current activities of the IAC as described at the second annual meeting held virtually on June 18, 2020.…”