Medical
  • Research and White Papers
  • July 2024

Non-Alzheimer’s Dementias: A closer look at Lewy body dementias

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In Brief

This article, the second of two articles about non-Alzheimer’s dementias, reviews and updates the current understanding of Lewy body dementia (LBD), including neuropathology, symptomatology, associated biomarkers, genetics, current treatments, and prognoses.

Abstract

  • 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.

Click here to read Part 1: Fontotemporal Dementia

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.

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Understanding LBD

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.

 


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. 

Novel LBD biomarkers 

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 

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Preliminary understanding of LBD genetics

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

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.

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

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.

Treatment and prognosis

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 

Conclusion

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. 

Meet the Authors & Experts

Karneen Tam
Author
Dr. Karneen Tam
Medical Consultant, RGA Asia Pacific

References