Also in this issue
Letter From the Editors
What's New? AI in primary care, CRISPR "cuts out" HIV, and more
Underwriting Updates GUM's new resource hub
Case ReView Underwriting chronic hepatitis B
Expert Q&A Genetics and Insurance
Longer Life Foundation
RGA's Global Medical Newsletter
Borderline Ovarian Tumor by Dr. Radhika Counsell Non-Alzheimer's Dementias Part II - Lewy Body Dementias by Dr. Karneen Tam Battling the Obesogenic Environment by Peter Hovard, Ph.D.
Featured Articles
Dr. Adela Osman
Vice President Head of Global Medical
adela.osman@rgare.com
Dr. Daniel D. Zimmerman, DBIM
Senior Vice President Chief Science Advisor
dzimmerman@rgare.com
This is the second edition on our all-digital platform. We hope you have been enjoying the new ReFlections experience, from our in-depth features to the new briefer articles on cutting-edge issues affecting our industry. Our features this month cover the latest medical and scientific advances for three important-to-understand conditions. Part II of Dr. Karneen Tam’s comprehensive article on non-Alzheimer’s dementias covers Lewy body dementias, Dr. Radhika Counsell provides a deep dive on borderline ovarian tumors, and Peter Hovard, Ph.D. discusses the latest research on how behavioral science techniques might aid those with obesity in their journey to weight loss. In Case ReView, Dr. Sheetal Salgaonkar discusses the evolving complexities of chronic hepatitis B and the challenges of underwriting these cases. Dr. Steve Woh, in Health View, tells readers about the latest developments in mental health-associated AI, and presents an update on how CRISPR may hold the key to curing HIV. And in our Expert Q&A interview, Dr. Daniel D. Zimmerman asks RGA’s genetics specialist, Dr. Sajel Lala Kana, for her perspectives on some of the most challenging genetics issues in reproductive and perinatal medicine. We think you will appreciate the discussion! We also would like to acknowledge ReFlections’ long-time copyeditor, Amy Friedman, Manager, Content Development, RGA, who is retiring next month. Amy, who came to RGA after a long and successful career in insurance journalism, was our secret sauce: For more than 10 years, she collaborated closely with both feature authors and us to ensure every article was engaging as well as on point. She also facilitated several improvements, from the 2015 redesign to the recent migration to our fresh new digital experience. As this is her final issue, we wanted to take this opportunity to thank her for her many contributions to ReFlections and to wish her all the best. She will be missed. Feedback is essential to our work, and you may have noticed you now have opportunities to give articles star ratings and to comment if you wish. The real-time feedback will help us understand the value our content offers and will help guide development of future issues. Please feel free to let us know what you think! As always, we look forward to continuing to serve our readers with the latest and most helpful information on clinical and insurance medicine topics. Please do not hesitate to tell us how we can continue to improve ReFlections for you. Thank you, Dan and Adela
Welcome to the June 2024 edition of ReFlections!
ReFlections
From the editors
In this issue
Borderline Ovarian Tumor: Implications for critical illness and terminal illness claims
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Non-Alzheimer’s Dementias: A closer look PART II: LEWY BODY DEMENTIAS
Battling the Obesogenic Environment: Risks, psychology, and treatments for today's obesity epidemic
Features
Borderline ovarian tumor (BOT) is an intermediate condition in the tumor spectrum. It can cause confusion for claims assessors examining critical illness insurance claims, due to the cells being potentially precancerous, as well as the possibility of microinvasion and of non-invasive peritoneal implants. Assessment of BOT-related terminal illness claims on life insurance policies can also be complicated, as some BOTs can transform into invasive low-grade serous carcinoma (LGSC). This article explores the implications of a BOT diagnosis for critical illness and terminal illness claims, using case study examples.
Abstract
References
https://doi.org/10.1002/ijc.23724 https://doi.org/10.1016/j.humpath.2004.03.003 https://link.springer.com/article/10.1007/s00428-016-2040-8 https://link.springer.com/article/10.1007/s00428-016-2040-8 https://doi.org/10.1016/S0893-3952(22)04457-X https://academic.oup.com/oncolo/article/17/12/1515/6403316# https://doi.org/10.1016/j.jogoh.2020.101965 https://doi.org/10.1097%2FPAP.0b013e3181b4fffa https://doi.org/10.1155/2023/4845887 https://pubmed.ncbi.nlm.nih.gov/35204549/ https://doi.org/10.1016/S1470-2045(11)70288-1 https://doi.org/10.1016/j.ygyno.2005.09.021 https://doi.org/10.1053/hp.2000.8048
About the author
Dr. Radhika (Radi) Counsell, MBBS, M.D., is a Consulting Medical Officer with RGA. A U.K.-based specialist in gynecological and breast cancers, she provides direct case consultation for annuities, critical illness, terminal illness, and medical insurance claims. She also provides review and input for RGA Global Underwriting Manual’s oncology guidelines and for new products under development. Dr. Counsell’s managerial role in the National Health Service (from which she recently retired) included the launching of the NHS Trust’s Acute Oncology Outreach Service, which provides opinions on cancer patients presenting with acute problems, leadership of the regional gynecological brachytherapy service, and Head of Chemotherapy. She has also taught and trained medical students, acute medicine doctors, oncology specialty trainees, and therapy radiographers. Dr. Counsell’s qualifications include former Membership of the Royal College of Physicians (MRCP) of the United Kingdom and Fellowship of the Royal College of Radiologists (FRCR). Her Bachelor of Medicine, Bachelor of Surgery (MBBS) degree, and her Medical Doctorate (M.D.) for research on magnetic resonance spectroscopy in breast cancer, are from University of London Medical School. She has lectured on oncology at medical and insurance events.
Dr. Radhika Counsell, MBBS, M.D.
Consulting Medical Officer, RGA U.K.
rcounsell@rgare.com
Borderline ovarian tumor (BOT) is an intermediate condition in the tumor spectrum.
Borderline ovarian tumor (BOT) comprises about 15% of all ovarian tumors.1 Clinically, these lesions are considered intermediate, between benign cystadenomas and invasive cancers, but they are not cancer. Their histological appearance is neither benign nor frankly malignant,2 and their growth rate is moderate and more controlled than ovarian cancer. At diagnosis, BOT is usually confined to the ovary, although non-invasive peritoneal implants can develop in about one-third of cases. Cellular proliferation with BOT is greater than with benign tumors, and the appearance of the cells is more abnormal. Unlike with malignant tumors, there is no destructive stromal invasion; however, microinvasion (i.e., the presence of BOT cells beyond the outer layer of the ovary) can occur. According to the latest World Health Organization (WHO) Classification 2014,3 the term “borderline ovarian tumor” is interchangeable with the term “atypical proliferative tumor.” Notably, use of the phrase “tumors of low malignant potential” to describe these neoplasms is no longer recommended.
Background
Peritoneal implants
FIGO is a staging system developed by the International Federation of Gynecology and Obstetrics (FIGO) specifically for female cancers, including cervical, ovarian, uterine, endometrial, and BOT. Each FIGO stage (see Figure 1) describes the anatomical extent of tumor presence within the body. However, it does not indicate whether the tumor is an invasive cancer.
FIGO staging of ovarian tumors
Classification and pathology
There are six subtypes of BOT.4 The majority, about 65% to 70%, are classified as serous (meaning it arose from the serous membrane). The less common subtypes are mucinous, endometrioid, clear cell, seromucinous, and borderline Brenner type. Expert opinion is that each subtype has its own distinct biology, pathology, and molecular profile, which means no single unifying concept exists for the range of BOT subtypes. The architecture of serous BOT is characterized by an overgrowth of cells, leading to multiple layers of stratification within the epithelial lining of the papillae and to tufting (i.e., cell detachment).5 Some tumors can exhibit a complex cribriform (also known as micropapillary) pattern. There is generally an absence of destructive stromal invasion. Serous BOT can also exhibit hierarchical branching of successively smaller papillae arising from larger, more centrally located papillae. Elongated micropapillae can arise directly from large central papillae as well. If this appearance is present in less than 10% of the whole tumor, the term “focal borderline change” is used as the descriptor, rather than BOT. If the cribriform or micropapillary architecture represents more than 10% of the tumor or 5 mm of a confluent area, some experts would label the tumor “micropapillary serous carcinoma.” Others prefer the term “serous borderline tumor with cribriform and/or micropapillary architecture,” as there is no destructive stromal invasion. In comparison with conventional serous BOT, micropapillary/cribriform serous BOTs are also more often bilateral, exophytic, at FIGO stage >1, and show invasive peritoneal implants.7 Although BOTs do not show destructive stromal invasion, microinvasion can be seen in 10% to 20% of these tumors. Microinvasion is defined as single cells, cell clusters, or haphazard nests of cells measuring less than 5 mm that invade the stromal core of the papillae or cyst wall. If the invasive component measures more than 5 mm, the tumor should be classified as an invasive cancer. Although BOT has a distinct histological appearance, some of its aspects can challenge the pathologist in making a correct diagnosis.6
BOT can be confined to the ovary or can be seen in the peritoneum and/or the lymph nodes. Implants in the peritoneum or omentum are not uncommon in serous BOT and may be evident in about a third of BOT patients at surgery.5 The presence of implants is often associated with an exophytic neoplasm (tumor on the surface of the ovary), as fragments of tumor on the surface of the ovary can easily break off and settle in other sites away from the ovary, such as in the pelvis and abdomen.9 Previously, BOT implants were classified as either non-invasive or invasive, depending on whether destructive stromal invasion was identified. According to the 2014 WHO classification, however, the presence of invasive implants represents cancer – specifically, low-grade serous carcinoma (LGSC).3 The classification also defines the two types of non-invasive implants as 1) epithelial, in that it develops in the ovary’s epithelial tissue, or 2) desmoplastic, as it is characterized by nests of epithelial cells within a reactive stroma. Molecular studies have found that borderline serous tumors and LGSCs carry similar mutations in the BRAF and KRAS oncogenes, implying the existence of a spectrum of change within LGSCs that develop from serous BOT.8
BOTs are neither benign tumors nor invasive cancers, although microinvasion of the stroma can be seen in some cases. The first case study highlights that BOTs can cause non-invasive implants within the peritoneum and that areas of BOT can develop in the lymph nodes. Although the extent of BOT warranted assignment of FIGO stage 3B, that does not indicate the tumor was an invasive malignancy. In this case, it was a BOT, and therefore did not meet the definition for an invasive cancer. The second case study highlights that recurrence can be due to transition of a BOT condition to LGSC. This is an invasive cancer which usually grows slowly. Even for advanced FIGO stage neoplasms or multiple recurrences, life expectancy for those with LGSC can be as much as seven to 10 years. Surgery is the mainstay of treatment for LGSC, as chemotherapy does not work very well. In this specific case, there were also signs of bowel obstruction due to compression from tumor masses that could not be removed. It was expected that she would have a few months of life left, so this was a valid terminal illness claim. BOT can impose challenges for the claims assessor when adjudicating applications for critical illness and terminal illness. Evaluating the histopathology report and clinical details will help the assessor make the most appropriate decision.
Conclusions
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Figure 1: The four FIGO stages
Source: Images courtesy Cancer Research UK (CRUK). This file is licensed under the Creative Commons Attribution – Share Alike 4.0 International license
FIGO 1 = confined to ovary
FIGO 2 = spread to pelvis
FIGO 3 = spread to abdomen
FIGO 4 = distant sites + parenchymal disease
Case Study 1: Critical illness claim
A 40-year-old woman presented with abdominal bloating. A CT scan revealed multiple tumor masses in her pelvis and abdomen, and a blood test for presence of the protein CA125, a marker for ovarian tumors, showed a level of 85 units/ml, substantially above the normal range of 0 to 35 units/ml. The woman underwent surgery to remove the tumors, and the surgeon also biopsied suspicious nearby lymph nodes that looked larger than normal. The histopathology report confirmed borderline serous tumor of both ovaries and the lymph nodes. In addition, non-invasive desmoplastic implants were evident in the peritoneum of the abdomen. The FIGO stage was given as 3B, in view of the spread beyond the pelvis of tumors of up to 2 cm in diameter and the peritoneal implants. To qualify for a benefit, critical illness policy definitions generally require a diagnosis of malignant tumor with histological confirmation, characterized by uncontrolled growth with invasion and destruction of normal tissue. Diagnoses such as premalignant, non-invasive, carcinoma in situ (Tis) or Ta, borderline malignancy, or low malignant potential, are generally not covered. In this specific case, there was histological confirmation of a borderline ovarian neoplasm. Also, although there were signs of tumor within the peritoneum with non-invasive implants and presence in the lymph nodes, there was no invasive cancer. Non-invasive implants are not uncommon and are thought to originate from cell fragments breaking off from the BOT.9 They can generally be seen on the surface of the opposite ovary or other organs within the pelvis and abdomen as well as in the peritoneum, omentum, diaphragm, and abdominal wall. About one-fourth of women with BOT can also have signs of BOT cells in lymph nodes near the ovaries, but this is not due to invasive cancer and does not appear to influence long-term survival.11 In this case, the claim was deemed to not meet the benefit definition as there was no invasive cancer.
The majority of women presenting with BOT are of childbearing age (premenopausal) and about one-third are under age 40. Most have FIGO stage 1 disease, with tumors in both ovaries in 25% to 50% of cases.12 The mainstay of treatment is surgery, as chemotherapy is generally not effective for BOT. As the majority of women who develop BOT want to preserve their fertility, the surgeon will usually remove only the lesion(s) and not the ovary itself. In the future, if the patient wishes, she might have a second prophylactic surgery to remove the opposite ovary and the uterus. The timing of such a surgery is usually after the woman has completed her family or after menopause. Life expectancy for these cases is excellent.13 A meta-analysis of 97 trials with more than 4,000 women after a mean follow-up duration of about seven years found that for women with FIGO stage 1 tumors, the overall disease-specific survival rate was 99.5%. For women with tumors at more advanced FIGO stages, survival rates were influenced by the types of peritoneal implants present: 95.3% for non-invasive peritoneal implants compared with 66% for invasive implants. Neither microinvasion in the primary ovarian tumor nor the presence of BOT cells in the lymph nodes had a significant adverse effect on life expectancy, with survival rates of 100% and 98%, respectively.
Clinical behavior of BOT
Factors associated with borderline tumor recurrence are: FIGO stage at first diagnosis, incomplete removal of tumor(s) at surgery, and histological subtype (e.g., serous with micropapillary pattern, mucinous tumor of the peritoneum, microinvasion). Recurrent BOT can usually be treated effectively with further surgery, and the 10-year survival rate for recurrent cases is greater than 95%. Recurrence for BOT can manifest as another BOT, or there can be malignant transformation to LGSC. These are generally slow-growing cancers, and five-year survival rates, even for tumors of advanced FIGO stages, are around 85%. Typically, non-serous BOTs are FIGO stage 1. Even if there is microinvasion, recurrence or metastases are uncommon. WHO 2014 argues there is little justification in calling these subtypes BOT and instead recommends calling them “atypical proliferative tumors.” (The terms “BOT” and “atypical proliferative tumor” are considered by WHO to be equivalent.)
Recurrence of borderline tumors
A 49-year-old woman had a first surgery for BOT four years ago. At the time, the surgeon removed both ovaries, as they were enlarged and contained tumor masses. The histopathology report noted serous BOT with micropapillae. She remained well until several months prior to filing her claim. She had developed bloating of the abdomen as well as intermittent vomiting and constipation. A CT scan suggested a recurrence of tumor masses at multiple sites in the abdominal peritoneum and omentum. A subsequent CT-guided biopsy confirmed recurrence of serous BOT. The risk factor for recurrence in her case was her subtype of BOT: serous with micropapillary pattern. The woman underwent surgery, and the surgeon found more tumor sites in the peritoneum than had been seen on the CT scan. In some areas, the bowel was being compressed by the tumors. Overall, it was difficult to remove all of the masses. The histopathology report showed additional areas of invasive peritoneal implants as well. By most policy definitions, an illness is considered terminal if the following conditions are satisfied: if there is no known cure, or if the illness being claimed for has progressed to a point where it cannot be cured and is expected to lead to death within 12 months. This means no treatments are available that may extend life expectancy, and the person has a 50% or greater chance of dying within the next 12 months. Many with advanced incurable cancer will continue to take medication to alleviate their symptoms. They may even have “best supportive care surgeries,” to relieve certain symptoms and improve quality of life, such as a bypass operation or stoma creation to ease the effects of a tumor blocking the bowel. (Best supportive care, whether it is medical or surgical, will not lengthen lifespan.) In this case, the woman had extensive invasive peritoneal implants from serous BOT and in some areas the cells had transformed to LGSC. She was experiencing bouts of pain, intestinal symptoms, and constipation from the tumors pressing the small bowel. She was prescribed analgesics, anti-emetics, and laxatives to help control her symptoms. Women can live with LGSC for some years, and the majority of those with advanced cases will live seven or more years. More than half with LGSC at advanced FIGO stages will live for 10 years.10 In this woman’s case, however, her surgeons had limited success removing her peritoneal tumor and were not able to bypass the areas with bowel impingement. Because of these factors, the woman had been advised by her doctors and surgeons that no further treatments could cure or stop her cancer progression. Chemotherapy is ineffective for BOT, and at that point, surgeons had done what was possible for her case. She therefore submitted a terminal illness claim on her life insurance policy. This claim was deemed to meet the policy’s terminal illness criteria: She had invasive cancer for which no effective treatments were available, and her life expectancy at time of claim was 12 months or less.
Case Study 2: Terminal illness claim
Non-Alzheimer’s Dementias: A closer look
Non-Alzheimer’s dementias present with a broad spectrum of clinical features. Many overlap with psychiatric conditions such as mood disorders and schizophrenia, and with neurological conditions such as autism spectrum disorder and motor neuron disease. This means diagnosis of these dementias may be delayed and arrived at only after long and complex clinical investigative processes. As lifespans continue to increase worldwide, insurers are formulating life and living benefit products to cover higher age limits. It is therefore likely that non-Alzheimer’s dementia claims will be seen more frequently. This article, the second of two about non-Alzheimer’s dementias, reviews and updates the current understanding of Lewy body dementia (LBD), a condition which encompasses two syndromes: dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). It covers their neuropathology, symptomatology, associated biomarkers, genetics, current treatments, and prognoses.
LBDs are alpha synucleinopathy disorders, a category of conditions characterized by the presence of misfolded aSyn proteins. These proteins form Lewy body aggregates inside the cells of the nervous system. Depending on where in the nervous system the abnormal buildups occur, neurotransmitter systems can be affected, which most likely accounts for the range of clinical presentations of LBD.2 Some non-dementia disorders are also classified as alpha synucleinopathy disorders, including multiple system atrophy (MSA), pure autonomic failures (PAF), and REM sleep behavior disorders (RBD). Although these are not LBDs,4 many cases of PAF and RBD will evolve to LBD, sometimes years after the initial diagnosis, suggesting the possibility of a neuropathological relationship rather than their being separate clinical entities.2 It must be emphasized that Lewy bodies are not the only proteinopathies found in LBD syndromes. Beta-amyloid and tau protein aggregations are also found in varying amounts and may worsen neurodegeneration as their buildups increase. Lewy bodies have been found in autopsies of individuals with clinical Alzheimer’s disease (AD) as well, implying that the neuropathological and clinical features of LBD may have significant convergence with AD. Cognitive impairment is the main defining feature of the two LBD syndromes. Both also share many overlapping clinical, neurochemical, and morphological characteristics.3 The two, however, are clinically differentiated by when Parkinson’s disease-type motor abnormalities emerge in relation to the development of the cognitive impairments. In DLB, the disease’s early stages present with cognitive deficits that are memory-sparing and with mild or absent motor abnormalities. Affected areas involve the cerebral and limbic cortex and manifest over time with cholinergic dysfunction (cognitive decline).1, 3 Variable autonomic and motor dysfunctions can also be evident, depending on the extent of the neuropathology. Language and memory functions are affected as well, as the disease progresses. PDD, on the other hand, typically develops in the context of well-established Parkinson’s disease (PD). Risk factors for PDD are long duration of PD and aging. About 10% of people with PD eventually develop dementia, but among those who have had PD for more than 10 years, the cumulative prevalence of PDD is around 75%. In these cases, the neuropathology is initially located mostly in the basal ganglia, and an impaired dopaminergic system is the primary disorder. As the neuropathology spreads more extensively, cognitive dysfunction develops.3
Understanding LBD
https://www.sciencedirect.com/science/article/pii/ S0011502922001250?via%3Dihub https://www.nature.com/articles/s41419-023-05672-9 https://pubmed.ncbi.nlm.nih.gov/29510692/ https://molecularneurodegeneration.biomedcentral.com/ articles/10.1186/s13024-019-0306-8 https://pubmed.ncbi.nlm.nih.gov/31694357/ https://cellandbioscience.biomedcentral.com/articles/ 10.1186/s13578-023-01152-x https://pubmed.ncbi.nlm.nih.gov/35173668/ https://cndlifesciences.com/syn-one-test/#:~:text=The%20Syn-One%20Test%20is%20a%20skin%20biopsy%20test,a%20synucleinopathy%20like%20Parkinson%E2%80%99s%20disease%20and%20related%20disorders https://www.alzforum.org/news/research-news/meet-two-new-biomarker-candidates-lewy-body-diseases https://link.springer.com/article/10.1007/s11910-018-0874-y https://www.ncbi.nlm.nih.gov/books/NBK482441/ https://pubmed.ncbi.nlm.nih.gov/29101136/ https://jamanetwork.com/journals/jama/fullarticle/2817521
Dr. Karneen Tam is Regional Medical Director, Asia Markets, for RGA Reinsurance Company’s Asia Pacific region. Based on South Africa, she supports the regional team in product creation, underwriting, claims, and pricing for multiple markets. She is a diabetologist with an MBBCh from the University of the Witwatersrand, South Africa and an M.Sc. in diabetes from University of South Wales, Cardiff, Wales (U.K.). She also has a strong interest in non-communicable disease management, particularly in how that might extend healthy lifespans, and how novel digital tools may change the landscape of healthcare delivery.
Dr. Karneen Tam, MBBCh, M.Sc.
Regional Medical Director RGA Asia
Karneen.Tam@rgare.com
There is to date no disease-modifying treatment for LBD syndromes.
Part II: Lewy Body Dementias
Click to view Case Study
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Lewy body dementia (LBD) is the second-most-frequently occurring of the three primary dementias (Alzheimer’s disease is first, then LBD, then frontotemporal dementia). Most symptomatic cases develop in people in their mid-60s, but the actual condition may begin as early as age 50. Worldwide incidence is about 3.5 per 100,000 and rises dramatically with age,1 but postmortem findings of LBD neuropathology may indicate a historic underestimation of LBD prevalence. Clinical presentations for LBD vary, as many of the symptoms associated with its two syndromes – dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD) – overlap with those of mood disorders, psychoses, neurological conditions, and metabolic disorders. To date, no single simple diagnostic test exists for LBD because of its variable clinical features. Delayed or erroneous diagnoses are therefore not uncommon. Prognoses for LBD patients are generally unfavorable. Morbidity and mortality are significant and higher than for other dementias, making people with LBDs likely life and living benefit claimants who will require correct assessments.
Introduction
Studies have looked at measuring levels of aSyn and synuclein subtypes in CSF and blood as potential LBD diagnostic markers. Accurate measurements can be made of aSyn in CSF, blood, saliva, and skin, but as yet, no aSyn levels have been determined that would differentiate an LBD from other dementias or from the normal population.6 (Invasive CSF tests are not suitable for routine clinical practice.6) Also, red blood cell hemolysis releases aSyn, which can cause erroneous lab measurements. A skin biopsy that tests for aSyn aggregates is in clinical use for Parkinson’s disease.8 A recent multicenter-based study found good correlation of positive aSyn skin biopsies to the presence of various aSyn-related disorders.13 Further research will be needed to evaluate biopsy processing feasibility beyond research conditions, as well as the detection accuracy in the general population. This has the potential to be a valuable diagnostic tool in the future. Other tissue biomarkers for LBD are still under investigation.7 In 2023, a new biomarker was found that showed promising potential for the detection and assessment of LBD. Several independent researchers detected high CSF and blood DOPA decarboxylase (DDC) levels in DLB candidates, including those in preclinical states, which differentiated them from controls and AD candidates. The cost, especially for the newer techniques, is high, but it is hoped that further research may result in a blood-based or skin biomarker that will help identify preclinical cases, diagnose at onset of symptoms, and assist in prognostication.9, 13
Novel LBD biomarkers
Preliminary understanding of LBD genetics
There is to date no disease-modifying treatment for LBD syndromes. The current approach to managing LBD is alleviating its symptoms by targeting the culprit neurotransmission impairments with as little pharmacological burden as possible to avoid drug interactions and possible adverse effects or reactions. Still, owing to the range and complexity of the symptoms, polypharmacy is the norm. Physical therapy, occupational therapy, and/or environmental adaptation may also be employed to reduce motor dysfunction and falls, and to help maintain general function and self-care abilities. From moderate disease stage onward, LBD requires intense supportive care.11 The cholinergic dysfunction in LBD appears to respond well to cholinesterase inhibitor agents. Donepezil and rivastigmine are two that are frequently used for cognitive impairment. Levodopa, which is used to treat PD and general Parkinson’s-related motor dysfunctions, can be helpful but may worsen LBD neuropsychiatric symptoms. Its efficacy in treating the Parkinson’s disease-like motor dysfunctions of LBD has also been shown to lessen over time. RBD sleep disturbances may be reduced by melatonin. Atypical antipsychotics are used cautiously for hallucinations and delusions. Autonomic dysfunctions are treated symptomatically.1 With current treatment and management strategies, the lifespan of an LBD patient after onset of cognitive symptoms may be variable but, on average, is only half as long as that for people with AD (about 3.3 years), according to one study.12
Treatment and prognosis
LBD symptomatology and biomarkers
No single defining or diagnostic biomarker is yet known for LBDs, making them challenging to diagnose. The current diagnostic approach is complex and symptomatology-based, as clinical presentations consist of manifestations of a wide range of deficits which can develop in multiple neurological transmission systems. The various neuropsychological and neurophysical symptoms include cognitive decline, sensory distortions such as hallucination, autonomic dysfunction, REM sleep abnormalities, motor dysfunction, mood disorders, and anxiety.5 Two key symptoms of early LBDs are the loss of sustained thinking ability and loss of awareness, which cause fluctuating levels of orientation and alertness. To mitigate misdiagnosis risk, clinicians may need to determine actual symptom presence and severity by asking specific types of questions, as certain symptoms may not be apparent at the time of examination. There is much ongoing research aimed at improving LBD diagnostic accuracy by creating more objective ways to evaluate for it. Various diagnostic criteria systems have already been developed, and the current criteria, last revised in 2017, incorporate clinical and imaging features.4 Certain symptoms are considered essential to qualify clinically as an LBD diagnosis, while others are more indicative and supplementary. Imaging findings such as reduced occipital metabolism, which can be detected on a positron emission tomography (PET) scan, for example, can support a diagnosis, but reduced dopamine uptake in the basal ganglia is specific and highly indicative. Of interest also are abnormal values of iodine-based myocardial scintigraphy, which indicates autonomic dysfunction of the heart, and loss of muscle atonia during REM sleep (detected by polysomnography). Coexistence of another alpha synucleinopathy disorder, RBD, also strengthens the LBD diagnosis.5 Within the LBD spectrum, PDD is differentiated from DLB by dementia symptoms beginning at least one year after onset of Parkinson’s disease. Some of LBD’s clinical features can also overlap with AD. Biomarkers may help to differentiate the two from one another. Understanding LBD’s variable clinical presentations and associated diagnostic processes can help claims assessors follow the claimant’s clinical experience and enable a valid assessment.
Since LBD’s recognition as a separate clinical entity in the mid-20th century, diagnoses for it are increasingly common, especially among individuals aged 60 and older. Affected individuals have marked disabilities, and their quality of life is compromised, which requires much medical and other support. Patients may benefit from previously obtained risk product cover, but once symptoms or a diagnosis emerge, they are not eligible for new risk cover. Claims processes would be more straightforward if insurers had sufficient knowledge and understanding of LBD’s heterogeneous presentations. Despite the increasing understanding of this group of syndromes, there are still significant knowledge gaps around these and other non-Alzheimer’s dementias. Much research is underway, and the recent discovery of potential blood biomarkers for LBD may have a significant impact in the future. As more is learned about the primary dementias, there may be significant pathophysiological overlap among them. Pathological protein aggregates are often not found in isolation in brains experiencing dementia, hinting at possible multiple neuropathogenic mechanisms that cause sufficient degeneration burden, leading to clinical manifestations. Further unraveling of causative genetic mutations may help locate the specific pathways involved, which might translate to finding effective treatments. Faced with such evolving developments, insurers are advised to stay well informed about relevant medical advances relating to non-Alzheimer’s dementias and other neurodegenerative disorders, to provide appropriate product development, support, and service to affected clients.
Conclusion
Figure 1: Clinical symptoms associated with LBD syndromes5
The NOVA food classification system, which is commonly used to describe population dietary patterns, defines UPFs as “industrial formulations of ingredients that undergo a series of physical, chemical, and biological processes.” First developed in Brazil in 2009, NOVA organizes foods into one of four groups, based on the level of processing involved.3
Categories of UPFs
Table 1: The NOVA Food Classification System3
Groups
Description
Examples
NOVA 1
NOVA 2
NOVA 3
NOVA 4
unprocessed or minimally processed foods
Unprocessed food items (e.g., seeds, fruits, leaves, stems, roots, eggs, milk, fungi) Food items minimally processed via drying, crushing, grinding, roasting, boiling, pasteurizing, chilling, freezing
Oils, butter, lard, sugar, salt; items derived from NOVA1 foods; and items that combine two such ingredients (e.g., salted butter) Items not intended to be consumed on their own but used to enhance the NOVA1 foods from which they are derived
Canned meat, fish, fruit, beans, vegetables; cured meats; fermented beverages; food items with added ingredients from NOVA1 or NOVA2 (e.g., bread) Items containing two or three ingredients that make modified versions of NOVA1 foods
Sweetened beverages (including soft drinks), sweets, cookies, potato/tortilla chips, re-formed meats (e.g., Spam), and ready-to-eat meals composed of substances derived from foods and additives Items containing additives such as preservatives, antioxidants, stabilizers, dyes, flavors, enhancers, sweeteners, and emulsifiers
processed culinary ingredients
processed foods
UPFs (industrial formulations)
Mandatory clinical symptoms for an LBD diagnosis: Dementia Specific impairments in attention, executive function, and visuospatial perception Recurrent and well-formed visual hallucinations readily described by patients, with details involving known people or strangers, animals, or objects One or more Parkinson’s-like motor dysfunctions, such as bradykinesia or involuntary slowing of movement; resting tremor; or muscle rigidity manifesting as stiffness
Core clinical symptoms specific to an early diagnosis of LBD may include: Significant fluctuations of alertness and attention Memory deficit Manifestation of RBD, which involves much motor action during REM sleep, including aggressive physical attacks o This may occur months or years before cognitive dysfunctions Certain characteristic cognitive abnormalities may be detected in mental state screening tests o The tests might not reveal these dysfunctions in early-stage disease due to cognition fluctuations
Non-core clinical symptoms supporting an LBD diagnosis may include: Excessive reactions to neuroleptics medications, which have been observed in many with LBD Severe autonomic dysfunctions leading to orthostatic blood pressure drop, which may exacerbate risk of syncope (fainting) and falls Constipation, incontinence, excessive daytime sleepiness (hypersomnia), and heightened sense of smell (hyperosmia) Auditory and olfactory hallucinations Anxiety and depression
Figure 2: Indicative and supportive biomarkers for LBD5
Supportive biomarkers: Intact medial temporal lobe structures on CT/MRI brain imaging; this differs from the loss of temporal lobe volume seen in AD Reduced occipital lobe metabolism or blood perfusion on molecular scans Presence of cingulate island sign on a fludeoxyglucose (FDG) PET scan EEG showing slow wave activity in posterior brain lobes with periodic fluctuations
Indicative biomarkers: Reduced dopamine transporter uptake in the basal ganglia, detected in a PET scan (PET is not routinely used in all suspected cases) Myocardial scintigraphy will show the cardiac sympathetic nerve damage caused by LB pathology; however, as this finding can also be a symptom of other autonomic neuropathies, it is not a specific LBD biomarker Polysomnographic finding of atonia loss during REM sleep (an LBD precursor), in conjunction with other clinical findings
This discovery also signals potential overlap of the genetic mechanisms of aSyn-spectrum PD and AD.6 As GBA and SNCA are both involved in aSyn protein synthesis or regulation, they are also associated with PD development. In addition, the presence of other gene mutations such as PARK7 and PARKN has demonstrated a high risk for Parkinson’s disease development, which is a precursor of some PDD cases. No highly penetrant pathogenic mutation has been identified for LBD to date, but family history remains a powerful risk prediction factor. Siblings of DLB patients, for example, have been found to have more than twice the risk of developing DLB.4 A more advanced understanding of the culprit genetic mechanisms and of related downstream molecular pathways may yield more effective treatments, diagnostics, and assessment tools in the future.
APOE codes for Apolipoprotein E glycoprotein, which is involved in cholesterol homeostasis. Gene mutations resulting in different APOE alleles can either promote or protect against AD. APOE allele 4, for instance, increases the risk of both AD and LBD. It is not clear, however, if the AD-protective APOE e2 allele has a similar beneficial effect specifically against DLB. BIN 1 is also associated with APOE4, but a more granular understanding of its potential pathogenic role is still to be established.6 GBA gene variants have been linked to PD risk and are associated with DLB pathogenesis. Mutated variants of this gene result in reduced glucocerebrosidase activity, leading to aSyn accumulation.6, 10 SNCA codes for aSyn and has a regulating effect on its expression. SNCA-AS1 is the mirror-image RNA messenger of the SNCA gene. Many mutations of SNCA have been observed, but pathogenic mutations are rare, with variable penetrance resulting in a wide range of phenotypes across multiple aSyn disorders, including PD, PDD, and DLB. Evidently, mutations located at different SNCA loci may be responsible for PD and DLB.6, 10 TMEM 175 is a potassium channel inside lysosomes that may play a role in balancing cellular pH. Deficiencies leading to altered pH and aSyn accumulation have been observed in neurodegenerative disorders, but a fuller understanding is still lacking.6
DLB typically occurs randomly in populations, but familial cases have been documented. A 2017 genome-wide association study (GWAS) identified five proteins of significant association with implications of their related genes in the disease process: APOE, GBA, SNCA-AS1, BIN1, and TMEM 175.6
Click here to read Part 1: Fontotemporal Dementia
The modern environment constantly encourages people to eat more calories than they expend. Most people worldwide not only have easy access to food; they are also subjected to the relentless and expert marketing of high-calorie foods designed to be tempting as well as easy to prepare and eat. These factors and more are contributing to today’s global obesity crisis. For insurers, it is important to understand the mortality and morbidity implications of this crisis, as it is predicted to escalate.1 By understanding how humans eat, insurers can also have a better grasp of how (or which) people in the current environment are able to cope more effectively (i.e., not gain weight)2 and consider how best to help arrest or prevent obesity in those who struggle.
Obesity is a major and growing concern, and risk, for the insurance industry. The causes are complex and have genetic, physiological, psychological, behavioral, socioeconomic, and industrial and commercial components.3
Trends in diet and obesity risks
As a Lead Behavioural Scientist for RGA, U.K.-based Peter Hovard and the behavioural science team develop research and practical methods for observing the actual ways people absorb, process, and react to information. The focus is on understanding how people truly think and behave, rather than on how it is assumed they do, and using this knowledge to help RGA’s clients design products, communications, and processes across the insurance journey. This may include applications that encourage honesty, simplify customer journeys, motivate lifestyle behavior change, and improve return-to work outcomes. Prior to joining RGA in 2020, Peter was Behavioural Science Lead for Royal & Sun Alliance (RSA) in the U.K., where he established the use of behavioral research and intervention design to improve outcomes for insurance customers. Peter received both a Bachelor of Science (B.Sc.) with honours in psychology with American studies, and a Ph.D. in the psychology of appetite and eating behavior, from the University of Sussex (U.K.). Peter’s research is featured in articles in academic journals and the behavioural science and insurance press.
Peter Hovard, Ph.D
Lead Behavioural Scientist, RGA
peter.hovard@rgare.com
Ultimately, to achieve meaningful change in dietary behaviors, the wider environment must change as well.
It is often said that the world today is obesogenic, i.e., an environment tending to cause obesity. Modern life is physically much easier than in past centuries – today, both work and transportation are much less physically demanding, and dwelling temperatures can be controlled easily. This means, compared to our ancestors, people don’t need to consume as many calories for their day-to-day needs, and their bodies don’t need to work as hard to regulate their temperature. Additionally, food is more energy-dense, easier to access, and marketed better than ever before. Expending less energy than is consumed is leading to people across the globe gaining weight to clinically concerning levels. The larger question, however, is this: If successfully regulating one’s energy intake is a fundamental physiological need, why are people so affected by these environmental conditions that it is causing poor health, in the form of obesity and obesity-related disease?
The crisis
Humans eat, not just for homeostasis but also for pleasure, which is experienced because the brain’s opioid systems are activated by eating palatable foods.12 Relationships are also learned between the sights, smells, and tastes of various foods and the positive biological outcomes (more energy) of eating them, via dopamine reward systems. This means people learn to experience foods such as doughnuts and hamburgers as tasty precisely because they are high in calories, thereby energy fuel.9 More concerning, however, is how learned cues that predict availability of energy from particular foods, such as sights, smells, and tastes, can also activate dopamine systems, which triggers “wanting” (i.e., desires for particular foods).13 People today are surrounded by advertising from a myriad of outlets, that stimulates a desire to eat calorie-dense foods, often resulting in eating whether needed or not.
Surrounded by temptation
What can insurers do to reduce dietary- and obesity-based risks? Among traditional treatments, the most effective for severe obesity with associated complications has long been bariatric surgery, a procedure which reduces stomach size, increases post-ingestion fullness, and improves morbidity and mortality outcomes.21 More recently, new and effective pharmacological interventions have emerged. Semaglutide, under the brand names Wegovy and Ozempic, and tirzepatide, under the brand names Mounjaro and Zepbound, mimic the effects of the gut hormone GLP-1 alone, or the hormones GLP-1 and GIP, to suppress appetite. Both have been demonstrated as effective in clinical trials and are approved by many government bodies for weight loss and diabetes management.22 Surgical and pharmacological interventions are generally reserved for severe obesity cases, which may be less prevalent in the insured population. These drugs are typically prescribed alongside behavior change interventions such as diets and exercise programs. Older pharmacological treatments aimed at appetite suppression were generally unsuccessful, as patients were able to override the reduced appetite effects and regain weight, and many were associated with serious side effects such as increased risk of cardiovascular diseases and mental health conditions.23 Several treatments are currently banned in many jurisdictions: sibutramine, for example, a selective serotonin reuptake inhibitor (SSRI), was withdrawn by the U.S. FDA due to increased risk of cardiovascular diseases, and rimonabant, a cannabinoid receptor antagonist, was withdrawn due to increased risk of psychiatric issues such as anxiety, depression, and suicide.
Treatments for severe obesity
Most people worldwide now live in countries where obesity-associated diseases are more likely causes of death than diseases due to underweight.5 Currently 43% of adults globally are classified as overweight,5 and by 2030 it is estimated that globally one in five women and one in seven men will be obese.1 Five million deaths were attributed to obesity in 2019, making it the fifth most significant risk factor that year. Other risks with dietary components, such as high blood pressure, blood sugar, and cholesterol, were also major factors in global deaths.6 Twenty percent (160 million years) of all years of life that people live with preventable disease were attributable to obesity in 2019.1 Obesity was associated with increased mortality during COVID-19.1 Obesity is associated with several serious comorbidities, including a three- to four-fold increase in mental health risk over time compared to non-obese individuals.7 Obesity is shown to have a significant impact on work absenteeism,8 making it a concern for disability income insurers.
However, obesity is also considered preventable, and what and how people eat is a major factor.5
It is a biological necessity for humans to regulate how much they eat: ensuring enough calories are eaten to function, but not so many that ultimately their mortality and morbidity risk increases. Clearly, it’s a struggle in today’s world. What makes it so difficult, thereby making obesity so much more likely? The main challenge faced now is that the physiological appetite controls that were useful for our ancestors ensured they were motivated to find and consume enough nutrition to survive in times of scarcity. Today, the challenge is very different, as high-calorie foods are abundant and easy for most to access.9 But the motivations to eat, endowed by evolution, have remained. Feedback received by the brain via nerves that are activated as the stomach fills (originally tested by inflating balloons in people’s stomachs10), or via hormones that respond to the nutrition in the body,9 communicates whether the body is nutritionally depleted or replete. This feedback is interpreted as either hunger or satiety. However, human physiology is highly protective of energy intake. Indeed, many who actively attempt to restrict their caloric intake in order to lose weight find they regain any weight lost because the restrictions generally trigger an increased motivation to eat.11
Why is today’s environment obesogenic?
It is well established that dietary habits are a major factor in several serious non-communicable chronic diseases, such as hypertension, heart disease, type 2 diabetes, cancer, and mental illness.1, 4 As obesity is often associated with these diseases, it is a growing concern.
Senses and thoughts about foods also play a role in appetite. If, for example, a food is expected to be filling because of previous learning, it will enhance feelings of fullness after eating it.14 One implication of this aspect of human psychobiology is that because typically beverages such as water contain few if any calories, drinking something does not signal to the body that it has consumed energy as strongly as does eating. People therefore do not experience as substantial a sense of fullness after downing a soft drink. Interestingly, soup is experienced as more filling if consumed with a spoon than as a beverage, because of the experiential signals eating with a spoon generate.15 Hence, high-calorie drinks are a particular concern, as the body does not experience them as having provided energy.
Mismatched expectations
Various other quirks of human psychology can lead people into overeating, such as:
Mindless eating
Distracted eating, where people fail to pay attention to fullness sensations when eating while watching television or playing video games, which often leads to overeating.16 Many food products, such as ready meals and snacks, are intended to be eaten while distracted. One of the most important predictors of how much is eaten at a meal or as a snack is the amount of food served as a portion.17 Large portion sizes, especially if predetermined by restaurants or with prepackaged meals, can easily lead to overeating. People differ in the extent to which they can or will consciously restrict their eating and so whether they are likely to experience disinhibition. This behavior occurs when a self-imposed dietary rule is broken, which paradoxically leads to subsequent overeating.18 Similarly, human self-control tends to be poor when faced with immediate rewards. Tasty, high-calorie foods, for example, are immediately rewarding from a psychobiological perspective, leading people to deprioritize longer-term health goals such as losing weight and keeping it off. Those who score high on impulsivity tests are particularly susceptible to succumbing to such temptations.2 Many, particularly those who restrict their eating, experience an interesting bias: They will estimate calories in a meal as lower if the food contains a “healthy” element. For example, a hamburger may be believed to have a lower calorie count than normal if it contains lettuce.19 This is an example of a health halo effect, where people overgeneralize the healthy qualities of foods, such as interpreting foods billed as “low fat” or “organic” as low-calorie or better for health.20
The factors described above are just some of the ways in which people struggle, physically and mentally, with the twin pressures of food abundance and modern marketing techniques. Ironically, many who consciously restrict their eating are also more susceptible to overeating.
Lifestyle change is still at the heart of intervention for obesity, for comorbidities such as diabetes, and for maintaining healthy diets and weights in the non-obese population. Surgical and pharmacological interventions are prescribed only if lifestyle changes have failed. Dietary interventions can be successful for weight loss24 and diabetes.25 Programs such as WeightWatchers, which provide incentives and nutrition coaching, have been commercially successful. There is some evidence for success in weight loss maintenance,26 and many elements of these programs are provided digitally. Part of the success of these programs is the focus on promoting dietary adherence. Most diets fail, and research has found that dietary adherence is more predictive of weight loss than the type of weight-loss food plan followed.11 This may be an area where insurers can influence behavior. With carefully considered incentives, communications, gamification, and – most importantly – scientifically validated behavior change techniques, insurers can help customers navigate the obesogenic environment. This could mean promoting food plan adherence or the maintaining of healthy food habits. It’s also likely that those with healthy behaviors are more disposed to self-select a wellness program which has a risk-selection benefit for insurers. To be successful, however, insurer-sponsored prevention and intervention programs must consider the science of dietary behavior. Given that those who restrict their energy intake often regain the weight lost (and sometimes more), successful interventions need to ensure that people’s nutritional requirements and preferences are met.11 Similarly, programs that encourage personalized goal-setting, self-monitoring techniques, and mutual support via social engagement may be more likely to be successful and engaging.27
Lifestyle changes and the insurer's role
The world is currently in an obesogenic age, with major morbidity and mortality risks that will worsen as the obesity crisis deepens. Insurers will benefit from understanding the behavioral dynamics at play in this environment. Insurers can help mitigate the environment by covering and supporting treatments for severely obese patients, and by promoting positive dietary behavior via wellness programs that create engagement to help and support people to maintain healthy habits. This may involve more than just providing dietary advice; it may also mean helping customers navigate environmental temptations, using behavioral science to develop successful and engaging approaches. Ultimately, to achieve meaningful change in dietary behaviors, the wider environment must change as well. Governments are already introducing interventions such as taxation of sugar in beverages to incentivize producers to reformulate products with lower calorie contents as well as public health campaigns that promote healthier diets. But with a vested interest in morbidity and mortality, the insurance industry can also consider how to contribute meaningfully to battling the obesogenic environment.
Fighting the battle against obesity
https://www.worldobesity.org/resources/resource-library/world-obesity-atlas-2022 https://psycnet.apa.org/record/2008-02994-035 https://www.gov.uk/government/collections/tackling-obesities-future-choices https://www.thelancet.com/article/S0140-6736(19)30041-8/fulltext https://www.who.int/news-room/fact-sheets/detail/obesity-and-overweight#:~:text=Most%20of%20the%20world’s%20population,Obesity%20is%20preventable https://ourworldindata.org/how-do-researchers-estimate-the-death-toll-caused-by-each-risk-factor-whether-its-smoking-obesity-or-air-pollution https://www.employment-studies.co.uk/resource/obesity-and-work https://www.instituteforgovernment.org.uk/article/explainer/sugar-tax#:~:text=18p%20per%20litre%20on%20soft,8g%20of%20sugar%20per%20100ml https://www.nature.com/articles/s41366-021-00894-3 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903294/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5618052/ https://onlinelibrary.wiley.com/doi/full/10.1111/j.1467-3010.2009.01753.x https://pubmed.ncbi.nlm.nih.gov/8622814/ https://onlinelibrary.wiley.com/doi/full/10.1111/nbu.12152 https://pubmed.ncbi.nlm.nih.gov/15639159/ https://pubmed.ncbi.nlm.nih.gov/26032197/#:~:text=Attention%20t o%20eating%20reduced%20later,from%20a%20third%20person%20perspective https://pubmed.ncbi.nlm.nih.gov/25447010/ https://pubmed.ncbi.nlm.nih.gov/7826055/ https://www.researchgate.net/publication/241107041_The_ Dieter's_Paradox https://pubmed.ncbi.nlm.nih.gov/28853950/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5964632/ https://pubmed.ncbi.nlm.nih.gov/34706925/ https://f1000research.com/articles/7-617 https://pubmed.ncbi.nlm.nih.gov/18368998/ https://pubmed.ncbi.nlm.nih.gov/31781857/ https://www.cambridge.org/core/services/aop-cambridge-core/content/view/CD34DEEA5686DA44B255BA5650A80A53/S0007114507862416a.pdf/weight-loss-maintenance-1-2-and-5-years-after-successful-completion-of-a-weight-loss-programme.pdf https://pubmed.ncbi.nlm.nih.gov/36782207/ https://pubmed.ncbi.nlm.nih.gov/11836454/
What’s New?
AI in Primary Care
Dr. Lauren Acton, MBChb, has joined RGA South Africa as Chief Medical Officer. Lauren completed her medical studies and obtained her Bachelor of Medicine, Bachelor of Surgery degree at the University of Pretoria in South Africa in 2006. After her internship and community service in Johannesburg, she pursued a Master’s degree in bioethics at the University of Stellenbosch, also in South Africa. Her experience encompasses both clinical and insurance medicine, having worked in a private practice as well as for a direct insurer and a reinsurer before coming to RGA.
After a quarter-century with RGA South Africa, Dr. Anthony (Tony) Crosley, the branch’s Chief Medical Officer, is retiring. Tony came to the South Africa office soon after its 1999 launch, and has played a major role in the success and market standing of the underwriting and medical teams. A physician and veteran of more than half-century in insurance medicine, Tony is a doyen of the field: his immense medical and insurance knowledge, work ethic, capabilities, and collegiality are well known, and will be missed. We wish him the very best in his life’s next journey.
Medical Team Updates
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Drug Watch: Additional Copy
Tomasik J, et al. JAMA Psychiatry. 2023 October 25; 81(1):101-6. https://jamanetwork.com/journals/jamapsychiatry/fullarticle/2811312
Metabolomic biomarker signatures for bipolar and unipolar depression
Editor's note: As climate change remains a significant factor in mortality and morbidity trends, these findings comprise part of a growing body of research showing the many impacts urban air pollution can have on health.
Association of PM2.5 exposure and Alzheimer disease pathology in brain bank donors—effect modification by APOE genotype
Hall M, et al. PLoS Medicine. 2024 Feb 24; 21(2): e1004343.
Health outcomes after myocardial infarction: A population study of 56 million people in England
Publications relevant to insurance medicine appearing recently in research literature.
Research Watch
Health View I
Medical Team Update
Drug Watch
RGA Thought Leadership
While Google Research’s current work with AMIE is research-only, implications for future primary care delivery needs to be considered carefully and responsibly. On one hand, this development could someday provide better, wider, and possibly cheaper, access to healthcare, therefore improving morbidity and ultimately mortality. On the other, AI’s possible impact on primary care practices, its credibility and reliability, and most importantly, its safety issues, alongside the need for data protection and privacy, should be given due consideration before widespread adoption for diagnostic use.
Read more about this topic on RGA’s Knowledge Center
Editor’s note: Understanding changes in social connection trends and their relationship with end-of-life outcomes is particularly important as the world’s population ages, especially when assessing risk and designing products for this cohort.
Social connection and end-of-life outcomes among older people in 19 countries: A population-based longitudinal study
Editor’s note: Risk of disease (both cardiac and non-cardiac) is significantly elevated post-MI, which will continue to impact risk stratification for living benefit products as the data develops. Patients may benefit from additional support and monitoring to help reduce their risk of developing further health conditions, and this will become vital to wellness programs.
Christensen GM, et al. Neurology. 2024 Mar 12; 102(5). https://doi.org/10.1212/WNL.0000000000209162
Pivodic L, et al. The Lancet Healthy Longevity. 2024 Apr; 5(4): e264-75. https://doi.org/10.1016/S2666-7568(24)00011-4
Myocardial infarction (MI) can result in a wide range of further health conditions which can have major long-term impacts on individuals. This nationwide cohort study analyzed hospital records for 34 million adults admitted to hospitals (constituting 145 million admission records) to investigate long-term health outcomes following a heart attack compared with individuals who did not have one. Of the 433,361 heart attack cases, up to a third developed heart failure or renal failure, 7% had further heart attacks, and 38% died within the nine-year study period. Heart failure, atrial fibrillation, stroke, peripheral arterial disease, severe bleeding, renal failure, diabetes, and depression were also found to have occurred more frequently for those who had had a heart attack. However, the risk of cancer was lower overall, and the risk of dementia did not differ.
Read more
Editor’s note: Metabolomic profiling has the potential to improve the differential diagnosis of mood disorders in clinically relevant scenarios which will impact risk assessment and claims adjudication in the future.
Exposure to fine particulate matter (PM2.5) has a well-documented association with Alzheimer’s disease (AD) and is also hypothesized to contribute to brain neuropathology via inflammation and oxidative stress. This study investigated the association between traffic-related PM2.5 and AD hallmark pathology, including effect modification by APOE genotype (a major genetic risk factor of AD) in an autopsy cohort. Traffic-related PM2.5 exposure was found to affect β-amyloid deposition in the brain. This association was particularly strong among donors without APOE ε4 alleles, i.e., no increased genetic risk of AD.
Social aspects of people’s lives, especially social connection, have a large and independent impact on health. This meta-analysis revealed that social connection has an independent effect on mortality risk comparable in magnitude to that of many well-known risk factors. The study examined changes in structure, function, and quality components of social connection in older people’s last years of life, and the extent to which social connection could predict end-of-life outcomes (i.e., symptoms, healthcare utilization, place of death). It found that loneliness is a potentially important predictor of certain symptoms at the end of life, such as pain, breathlessness, and anxiety or sadness.
Patients with depressive symptoms with misdiagnosed BD showed a distinct profile of metabolites compared with patients with depressive symptoms with MDD, and this metabolic signature enhanced the predictive value of diagnostic models based on self-reported patient information.
Bipolar disorder (BD) is frequently misdiagnosed as major depressive disorder (MDD) because of overlapping symptoms and the lack of objective diagnostic tools. This diagnostic study, which was approved by the University of Cambridge Human Biology Research Ethics Committee, used samples and data from the Delta study, conducted in the U.K. between April 27, 2018, and February 6, 2020, to identify BD in patients with a recent (within the past five years) diagnosis of MDD and current depressive symptoms. Digital questionnaire data were used along with dry blood samples, which were analyzed for 630 metabolites using a targeted mass spectrometry–based metabolomic platform.
Health View
Article
AI Chatbots Break Down Barriers to Much-Needed Mental Health Treatments
See More
Dr. Peter Farvolden, Mental Health Consultant, RGA Canada
Craig Armstrong, Director, Actuarial Analysis, Risk, and Behavioral Science, RGA
The Protein Science Revolution – Implications for Human Health and Mortality Assumptions
Raman Lalia, Senior Actuarial Associate
Multi-cancer Early Detection and Modeling the Potential Impact on Insurance
Georgiana Willwerth-Pascutiu, Vice President and Medical Director, RGA Global Medical
Clearing the Air – The Conundrum of Climate Change and the Impacts on Health
Linda Winterbottom, Claims Rehabilitation Consultant, RGA Australia
Artificial Intelligence – A New Frontier for Rehabilitation
Hilary Henly, Global Medical Researcher, Strategic Research, RGA
The Cost of Cancer: Price Versus Life
Dr. Adela Osman, Vice President, Head of Global Medical, RGA
Andrew Gaskell, Vice President, Global Actuarial Pricing and Research
For recent ReFlections articles, click here.
https://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1004343
Underwriting Update
Reference: https://blog.research.google/2024/01/amie-research-ai-system-for-diagnostic_12.html
Dr. Steve Woh
Medical Director and Health Claims
steve.woh@rgare.com
Dr. Lauren Acton, MBChb
Chief Medical Officer RGA South Africa
Lauren.Acton@rgare.com
Dr. Steve Woh, Medical Director and Health Claims, RGA
In January 2024, Google Research published a blog post about its Articulate Medical Intelligence Explorer (AMIE). AMIE, a research AI system, is built on a large language model (LLM) developed and optimized for medical diagnostic reasoning and conversations. According to the Google Research team that developed AMIE, it was trained in the many dimensions that would reflect quality in real-world clinical consultations from the perspective of both clinicians and patients. AMIE was tested with real examples of multi-turn dialogue (a single “turn” refers to one back-and-forth exchange) by simulating consultations with trained actors. The interactions were then compared with those generated by real clinicians, using 68 different performance axes, which included diagnostic accuracy, management plan, patient’s confidence in care, and empathy. Test results indicated that AMIE performed better than real clinicians in the majority of the axes. The research team also studied the efficacy of using AMIE to aid clinicians compiling lists of differential diagnoses based on redacted case reports and measured accuracy of the lists in four scenarios: standalone AMIE, clinicians assisted by AMIE, clinicians assisted by the internet, and unassisted clinicians. The lists were then reviewed and evaluated by a clinician who had access to the full case reports and had used them to generate a “gold standard” list of differential diagnoses after discussion with specialist experts. Standalone AMIE was found to achieve the highest level of accuracy and AMIE-assisted clinicians the second highest.
Health View II
Reference: https://www.cgtlive.com/view/excision-suppress-hiv-viral-replication-ebt-101-crispr-gene-therapy
While the implications of this exciting development are huge for mortality and morbidity improvement in affected patients with latent infections from these hard-to-cure viral diseases, their impact on treatment costs needs to be studied, especially from the perspective of health insurance. As with all gene therapies, hefty price tags, in the millions of dollars, are expected for these treatments, making it essential that they be properly studied, tested, and vetted.
A team of scientists with the U.S. biopharmaceutical firm Excision BioTherapeutics recently used the Nobel Prize-winning CRISPR/Cas9 system for gene editing to excise target genomes from HIV. By doing so, they believe they have eliminated the virus’s ability to reproduce, thereby curing an HIV infection. The scientists are currently engaged in phase I and phase II trials to study the technique’s safety and effects on viral load. Until very recently, a major factor preventing HIV infection from being cured has been its viral latency. This refers to the persistence of viral genetic material that is capable of replicating. While antiretroviral therapy (ART) is effective in suppressing viral replication and preventing disease progression to AIDS, it is unable to eliminate latent HIV, which can still replicate if the conditions are favorable to do so. CRISPR technology enables a more precisely targeted treatment that will remove the ability of HIV to replicate, thus directly addressing the issue of viral latency. If this novel technique proves successful, it could be a major milestone in the quest to cure HIV. Moreover, the technique, already in use with Casgevy to treat hemophilia and beta thalassemia, could also be used to address infections involving other latent viruses, such as hepatitis B and herpes simplex.
CRISPR “cuts out” HIV
Dr. Anthony Crosley
Dr. Anthony (Tony) Crosley
acrosley@rgare.com
Dr. Lauren Acton
Dr. Heather M. Lund, Regional Chief Medical Officer, RGA Asia
Accelerated Underwriting Analysis: Examining today’s accelerated underwriting and its bright future
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A Pinch of Accelerated Underwriting and a Dash of Simplified Issue: Could it be the perfect recipe for risk?
5 Obstacles to Implementing Automated Underwriting and How to Overcome Them
Please click the articles below to see some of RGA's recently published thought leadership on underwriting topics.
On April 3, 2024, RGA rolled out an all-new Coronary Artery Disease (CAD) Resource Hub for the Global Underwriting Manual.* This hub, housed on an all-digital platform, features a comprehensively revised and updated portfolio of all of RGA’s new underwriting CAD guidelines, related informational materials and tools. The new resource reflects more than a year of collaboration among RGA’s Global Manuals team, the Global Medical team, and a dedicated group of marketing and communications experts. The hub features:
Refreshed overview and guidelines Renamed risk categories Revamped risk classification tables Symptomatic CAD ratings based on angiography vs. no angiography Living benefits offered to screening asymptomatic CAD cohort A new standalone section covering myocardial bridging A new Coronary Artery Calcium (CAC) calculator
We invite underwriting, medical, and claims professionals to please click here to access and explore the new hub. And don’t hesitate to send us your questions or comments! We look forward to providing you with news and updates on GUM in future issues of ReFlections. *Global CAD guidelines and the CAC calculator are not applicable in North America. RGA clients in U.S. and Canada, please click here to access resources for these markets.
Case ReView
Dr. Sheetal Salgaonkar, MBBS, DBIM
Vice President and Director Global Medical, RGA India
ssalgaonkar@rgare.com
Expert Q&A
Q
Dr. Sajel Lala Kana
As in vitro fertilization technology continues to advance, what might be the ramifications for couples who carry certain adverse genetic variants, and how can preimplantation genetic testing (PGT) enhance family planning strategies?
Dr. Kana: In vitro fertilization (IVF) offers a valuable and powerful tool to couples who know they carry specific pathogenic genetic variants. Preimplantation genetic testing (PGT), which tests embryos intended for implantation, can increase the likelihood of healthy pregnancies by mitigating the risk of transmitting known pathogenic variants. This makes PGT a powerful strategy for improving the chances of having healthy, viable, and variant-free offspring. A study in the Journal of Medical Genetics confirmed that PGT can significantly improve pregnancy outcomes for couples at increased risk of transmitting one or more genetic disorders to offspring.1
Noninvasive prenatal genetic testing (NIPT) has ramped up in the last several years. Can you define it for us, and talk about its science, advantages, and disadvantages? Can you also tell us if it is commonly used in routine prenatal care, or whether it is more often reserved for certain cases depending on medical indications?
Dr. Kana: NIPT has emerged as a truly transformative technology in prenatal care. A simple maternal blood draw will contain circulating cell-free fetal DNA fragments (cffDNA), which can offer a valuable window into a fetus’s genetic makeup.2 Currently, NIPT is used primarily to screen for common chromosomal abnormalities such as Trisomy 21 (Down syndrome), Trisomy 18, Trisomy 13, and extra or missing copies of the X or Y chromosome. NIPT’s use in routine prenatal care is steadily increasing but may vary depending on individual circumstances such as maternal age and family history. While NIPT may boast high detection rates for these conditions and poses minimal risk to mother and fetus, it is crucial to acknowledge that this is fundamentally a screening tool, and its results are not a definitive diagnosis. The American College of Obstetricians and Gynecologists (ACOG), in fact, emphasizes that NIPT carries a small chance of false positives or negatives, and says further diagnostic procedures may be necessary, depending on the results.3
One of medicine’s most difficult diagnostic dilemmas is how best to assess newborns with complex medical disorders. Is genetic technology being applied to these situations, whether via whole genome sequencing or other types of genetic testing, and to what extent? Can application of these technologies make significant differences in care and outcomes for these newborns? And how does the genetic information about their child’s condition help parents understand and make informed decisions regarding their newborn’s health issues?
Dr. Kana: The field of neonatal care is experiencing a sizable paradigm shift due to the application of novel genetic-related technologies. For example, for newborns presenting with complex medical issues, whole genome sequencing (WGS), which can produce results for a clinical team in as little as 48 hours, offers a potentially powerful clinical tool, especially as results might reveal an underlying genetic cause of a child’s condition. An article in a recent issue of Nature Medicine highlighted how WGS might expedite and improve diagnostic accuracy for a wide range of genetic disorders in neonates.4 This could lead to a more precise understanding of a child’s condition, which could significantly impact case management, especially for a critically ill patient in an intensive care setting. Furthermore, by pinpointing a possible genetic cause, WGS can empower parents with valuable information regarding the condition, its prognosis, and its potential management options. This knowledge can equip them to make informed decisions about their child's care and connect with relevant support groups. Keep in mind that while genetic testing offers immense benefits, involvement of a clinical geneticist throughout the process is crucial. Their expertise is invaluable in interpreting results, providing genetic counseling, and guiding families through the complexities surrounding genetic testing and its implications.
The field of neonatal care is experiencing a sizable paradigm shift due to the application of novel genetic-related technologies.
Advancements in genetic science are significantly enhancing neonatal diagnostics, reproductive technologies, and the ability to manage a diverse array of conditions. These present a substantial opportunity for insurers to develop robust and inclusive risk models that can leverage these advancements, but significant challenges still remain. During a recent conversation with Dr. Daniel D. Zimmerman, Senior Vice President and Chief Science Advisor at RGA and co-editor of ReFlections, RGA Genetics Consultant Dr. Sajel Lala Kana offered detailed insights into some of the current issues in genetics that are most impacting clinical and insurance medicine.
References: 1. https://www.science.org/doi/10.1126/science.1058040 2. https://pubmed.ncbi.nlm.nih.gov/23168792/ 3. https://www.acog.org/clinical/clinical-guidance/practice-bulletin/articles/2020/10/screening-for-fetal-chromosomal-abnormalities 4. https://www.nature.com/articles/s41525-024-00404-0
Genetics Consultant, RGA
Dr. Sajel L. Kana is an experienced researcher and physician who serves as RGA’s Consultant Geneticist. In this role, she provides education, training, and advice to RGA professionals and partners about the life and health impact of various genetic variations. Her areas of expertise include genetic testing, genetic disorders, and the potential long-term genetics-related health risks within the insured population. She also assists RGA in developing insurance products that are scientifically and ethically sound, and beneficial to customers. Dr. Kana has served as a genetics consultant for healthcare startups and consultancy firms, focusing on genetic counseling, testing, and policy. A clinical geneticist within the Division of Clinical Genetics at Nicklaus Children’s Hospital in Miami, Florida, she earned her medical degree from St. George’s University School of Medicine in Grenada, and completed a residency in pediatrics at Louisiana State University Health Sciences Center in Shreveport. She also completed a fellowship in clinical genetics at Icahn School of Medicine at Mount Sinai, New York City. Dr. Kana is board-certified in general pediatrics. She is a member of the American Academy of Pediatrics, American College of Medical Genetics and Genomics, and the American Society of Human Genetics. Her work has been published in peer-reviewed journals and she has presented at medical conferences. She is also the co-author of “The Adventures of Red,” an illustrated children’s book about red blood cells.
About Dr. Kana
The Longer Life Foundation (LLF) is a collaboration of more than a quarter century between RGA and Washington University School of Medicine in St. Louis. We are pleased to bring you our May 2024 newsletter, which discusses the foundation’s many recent activities. To find out more about LLF and the research it has funded to date, please visit www.longerlife.org or reach out to Dr. Daniel D. Zimmerman at dzimmerman@rgare.com or Dr. Preeti Dalawari at preeti.dalawari@rgare.com.
Click here to read the newsletter
