Women Patients and Caregivers Report Greater Impact From Dementia With Lewy Bodies

Shannon Y. Chiu, MD, MSc

In a recent focused review published in Parkinsonism & Related Disorders, available evidence revealed that women with dementia with Lewy bodies (DLB) and caregivers for these patients are impacted more than men.¹ Findings from this study suggest gender may affect the clinical diagnosis of dementia and that having a better understanding of the differences will assist future developments of sex-specific strategies in DLB for clinical care.

The literature shows that women diagnosed with DLB tend to be older, have greater cognitive impairment at their initial visit, and meet DLB criteria later in comparison with men. In addition, women might be more likely experience visual hallucinations than men with DLB. Notably, though, the research demonstrates that parkinsonism can be milder in women with DLB than in men and that caregivers of those with DLB are more commonly women.

Lead author Shannon Y. Chiu, MD, MSc, assistant professor, department of neurology at the University of Florida College of Medicine, told NeurologyLive®, “Neurodegenerative diseases often present themselves differently based on sex. This is true in DLB, a disorder that causes memory and thinking problems along with other symptoms such as parkinsonism, hallucinations, cognitive fluctuations, and rapid eye movement sleep behavior disorder. Understanding the sex differences in DLB can help clinicians diagnose the disease earlier, treat symptoms better, and support caregivers.”

Criteria for inclusion in the review included peer-reviewed studies on DLB, which were identified through the databases of EMBASE and PubMed. Research published in English prior to July 2022 was included in the review analysis. Excluded studies were solely on research pertaining to Parkinson disease, Alzheimer disease, or other related dementias. The studies on DLB were used if the findings included sex- or gender-specific analyses, and although “sex” and “gender” can have different meanings, several studies have them used interchangeably. In this review, the focus was on identifying the differences between sex in DLB and the potential role of gender with future directions.

“In many of the studies we reviewed, clinical DLB samples typically had more men. However, there is some variability in prevalence and frequency of DLB by sex depending on the study population (eg, community vs. clinical or tertiary centers) or geographic location. For example, specialty clinics typically included more individuals with parkinsonism or RBD, which are more commonly diagnosed in men. Conversely, community samples typically had older individuals, where sex ratio may be more balanced or higher for women. The basis for potential sex differences by geographic location is unclear, but some studies in Japan, France and England showed more balanced sex ratio than studies in the US. At this time, it is also unknown whether race or ethnicity affects DLB sex differences,” Chiu said.

Additional findings included that visual hallucinations may be more common and occur earlier in women with DLB (38%-82%) than men (38%-76%), whereas REM sleep behavior disorder may be more common and occur earlier in men.2,3Multiple studies reported a higher frequency of parkinsonism in men with DLB, with frequency of fluctuations appeared similar between sexes. Women with DLB tend to present at an older age compared with men, showed greater cognitive impairment at initial visit, and had a later emergence of 2 or more core features needed for clinical diagnosis.^2-4

“Increasing awareness of sex differences in DLB clinical presentations and biomarker status is critical in ensuring more accurate and timely diagnosis, including at prodromal stages,” Chiu said. “Identification of endophenotypes of DLB, based on unique combinations of demographic and clinical features, along with pathological biomarkers, could inform future DLB diagnostic criteria revision, better understanding of disease progression, and prediction of treatment response.”

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Also, women were more likely to have Lewy body disease with coexisting AD-related pathology than so-called “pure” Lewy body disease, whereas men may present either alone.² Regarding the impact of sex on DLB progression, and assessment of six differences in biomarker and treatment, the research is mixed and limited. Notably, women provided majority of caregiving in DLB, and 1 study showed women caregivers reported higher relative stress than men caregivers.⁵

“Current research gaps include the need for more large-scale clinicopathological studies to evaluate both sex and gender differences in DLB; the lack of studies examining sex-based genetic risk factors and hormonal influences; the need for better understanding of biomarker differences by sex/gender; and more research on differential caregiver experiences by sex/gender,” Chiu noted.

Limitations of the review include that some studies targeting sex differences in DLB may have been missed because the examination was conducted in a secondary analysis. Additionally, the review centered on literature that explored sex in comparison to gender, since research was scarce on specifically evaluating gender. “Moving forward, we need to promote more equal sex representation in clinical trials. But more importantly, clinical trial results should include sex/gender-specific data to help identify better tests for diagnosing DLB, determine whether men and women react differently to DLB treatments, and allow for future meta-analyses,” Chiu added in conclusion.

Currently there are no FDA-approved therapies that reduce disease progression in DLB; however, one agent, CT1812 (Cognition Therapeutics), could potentially break that spell. In July 2022, the company announced that patient dosing commenced in the phase 2 SHIMMER trial (NCT0522514) of CT1812, an oral small molecule therapeutic in development for the treatment of DLB.⁶ The double-blind, placebo-controlled, randomized trial expected to enroll 120 adults aged 50 to 80 years old with DLB to be assigned to either placebo or 1 of 2 daily doses of CT1812 for 6 months.

In 2019, data from a phase 1, two-part single and multiple ascending dose study of CT1812 was published, with the therapeutic agent demonstrating a well-tolerated profile across all cohorts. Over a 14-day treatment period, those in part A received doses of the study drug ranging from 10 to 1120 mg, while those in part B were administered 280, 560, and 840 mg once daily. An elderly cohort, aged 65 to 75 years, were dosed at 560 mg once daily for 14 days, with cognitive testing performed at baseline and conclusion of the treatment period.⁷

REFERENCES
1. Chiu SY, Wyman-Chick KA, Ferman TJ, et al. Sex differences in dementia with Lewy bodies: Focused review of available evidence and future directions. Parkinsonism Relat Disord. 2023;107:105285. doi:10.1016/j.parkreldis.2023.105285
2. Choudhury P, Graff-Radford J, Aakre JA, et al. The temporal onset of the core features in dementia with Lewy bodies. Alzheimers Dement. 2022;18(4):591-601. doi:10.1002/alz.12411
3. van de Beek M, Babapour Mofrad R, van Steenoven I, et al. Sex-specific associations with cerebrospinal fluid biomarkers in dementia with Lewy bodies. Alzheimers Res Ther. 2020;12(1):44. Published 2020 Apr 17. doi:10.1186/s13195-020-00610-9
4. Bayram E, Coughlin DG, Banks SJ, Litvan I. Sex differences for phenotype in pathologically defined dementia with Lewy bodies. J Neurol Neurosurg Psychiatry. 2021;92(7):745-750. doi:10.1136/jnnp-2020-325668
5. Svendsboe E, Terum T, Testad I, et al. Caregiver burden in family carers of people with dementia with Lewy bodies and Alzheimer's disease [published correction appears in Int J Geriatr Psychiatry. 2017 Apr;32(4):470]. Int J Geriatr Psychiatry. 2016;31(9):1075-1083. doi:10.1002/gps.4433
6. Cognition Therapeutics doses first patient with dementia with Lewy bodies in phase 2 clinical study of CT1812. News release. Cognition Therapeutics. June 23, 2022. Accessed March 8, 2023. https://ir.cogrx.com/news-releases/news-release-details/cognition-therapeutics-doses-first-patient-dementia-lewy-bodies
7. Grundman M, Morgan R, Lickliter JD, et al. A phase 1 clinical trial of the sigma-2 receptor compelx allosteric antagonist CT1812, a novel therapeutic candidate for Alzheimer’s disease. Alzheimers Dement. 2019;23(5):20-26. doi:10.1016/j.trci.2018.11.001.