Lewy body dementia overview
Michael Inskip PhD, ESSAM AEP
Introduction
Lewy body dementia (LBD) is an aggressive and little-known type of dementia that is estimated to represent approximately 10-20% of all diagnosed dementia cases (Mueller et al., 2017). Like all other dementias, LBD involves a progressive decline in cognition leading to a functional impairment in daily activities. However, the defining features of LBD are the presence of a combination of core symptoms of Parkinsonism, fluctuating cognition, visual hallucinations, and sleep disturbance that affect the motor, psychiatric and autonomic system in addition to cognition (McKeith et al., 2017). There are not many known risk factors for the development of LBD, which develops sporadically, apart from older age, being male and some minor contributions from genes that increase the abnormal expression of proteins implicated in the disease process such as amyloid beta (amyloid plaques) and alpha-synuclein (Lewy bodies). However, the risk of adverse events and comorbidities in LBD when compared with Alzheimer’s dementia are higher, including the risk of falls, frailty (Ahmed et al., 2008; Borda et al., 2019), polypharmacy, infection, behavioural disturbances, and malnutrition (Aarsland et al., 2001; Hasegawa et al., 2013; Imamura et al., 2000; Peball et al., 2019; Roque et al., 2013; Soysal et al., 2019).
Research into effective treatments for LBD is relatively scarce and of low quality. For instance, medications approved for use in Alzheimer’s disease dementia and Parkinson’s disease are often less effective and carry a higher risk of adverse effects, while knowledge around the application of non-pharmacological treatments specific to LBD is lacking (Connors et al., 2018; M. Inskip et al., 2016). Additionally, many individuals with LBD are excluded from clinical trials in dementia and in Parkinson’s disease due to the presence of both cognitive and motor symptoms, despite similar clinical presentations (Inskip et al., 2016). However, in recent decades since the publication of the 1996 LBD consensus guidelines and updates in 2005 and 2017, there has been an increased focus on research into the aetiology, diagnosis and treatment of people living with LBD (McKeith et al., 2017).
Terminology
Lewy body dementia (LBD) is an umbrella term for the two presentations associated with this pathology; namely dementia with Lewy bodies (DLB) and Parkinson’s disease dementia (PDD). These two presentations of LBD are distinguished by a clinical cut off known as the ‘one year rule’; whereby dementia onset at the same time as Parkinsonism or within one year of symptoms is classified at DLB, and dementia onset greater than one year following a diagnosis of Parkinson’s disease is classified as PDD (McKeith et al., 2017).
Both dementias as well as Parkinson’s disease are caused by the same underlying disease; Lewy body disease, and all have similar symptoms. However the medical community remains divided on whether these two dementias are in fact two sides of the same coin or distinct entities that warrant different approaches (Postuma et al., 2016). In practice, the treatment strategy for someone who has had Parkinson’s disease for a decade and then develops dementia (PDD) can be substantially different to someone who develops dementia and Parkinsonism concurrently (DLB), even though they might converge in the later stages of the disease.
Etiology & Prognosis
Lewy body dementia typically develops in the seventh decade of life and like all dementia the person may undergo a prodromal stage (mild cognitive impairment [MCI]) where symptoms appear but are not severe enough to impact daily activities. However, given it is substantially more difficult and time-intensive to diagnose LBD in clinical practice than Alzheimer’s disease dementia, it is relatively rare for someone to receive a diagnosis of MCI of the LBD subtype. In the case of Parkinson’s disease dementia (PDD), Parkinson’s disease (PD) may be present for decades prior to a dementia diagnosis and increases the risk of developing dementia by 5-fold (Anang et al., 2014). Indeed, up to one-third of people with PD will converted to PDD over a 4-year period.
There has also been a focus in recent decades on the relationship between the presence of rapid eye movement sleep behaviour disorder (RBD), a sleep disorder involving the acting out of dreams during deep sleep, and the transition to dementia with Lewy bodies (DLB) later in life (McKeith et al., 2017). Both diseases are classified as synucleinopathies due to the involvement of abnormal clumps of alpha synuclein protein involved in the disease process. Those who develop RBD in mid to late life have an increased risk of being diagnosed with LBD. Longitudinal studies following people with RBD for more than a decade report that 90% will convert to a neurodegenerative disease, of which a quarter will be Lewy body dementia (Galbiati et al., 2019).
For people with either a DLB or PDD diagnosis, the average life expectancy from diagnosis is estimated to be 3–8 years (Mueller et al., 2017). Known factors which accelerate the disease course in LBD include comorbid Alzheimer’s disease pathology, the presence of hallucinations and fluctuating cognition, gait abnormalities, decreased brain volume, and orthostatic hypotension (significant lowering of blood when standing up) (Mueller et al., 2017). The risk of adverse events in LBD is much higher than Alzheimer’s disease dementia as previously outlined and in addition up to 25% of those with LBD are likely to experience at least one episode of delirium, an acute cognitive and psychiatric disturbance that can worsen dementia if left untreated (Mueller et al., 2017). Furthermore, those with LBD enter residential aged care 0.5 to 1.8 years earlier on average than their counterparts with Alzheimer’s disease dementia, and the cost of care is 2-fold higher (Mueller et al., 2017).
Diagnosis
Broadly, the classification of either PDD or DLB is defined by the ‘one-year rule’, however there are specific criteria which are used to diagnose each dementia. Testing for dementia will normally involve a thorough history given by the person or their caregiver/informant, cognitive testing, questionnaires relating to daily function, as well as additionally blood tests, imaging and other investigations to rule out potentially reversible causes or other conditions (de Lau et al., 2005).
The diagnosis of Parkinson’s disease dementia (PDD) is based upon the 2007 MDS criteria (Emre et al., 2007), and requires the presence of established Parkinson’s disease. Dementia is diagnosed when it is evident there are significant impairments in more than one cognitive domain that represent a decline from previous levels of cognition, and there exists an impairment in everyday activities as a result of this cognitive deficit (in contrast to the physical impairments of the PD).
The diagnosis of DLB is based upon the 2017 DLB Consortium criteria (McKeith et al., 2017). Consistent with all dementia, the essential criteria is that there must be a significant decline in cognition which leads to a functional impairment in everyday activities. Most often in both DLB and PDD, these cognitive deficits are observed in domains such as executive function (decision making), attention and concentration, and visual perception, with memory not necessarily impaired at diagnosis. In addition to this essential feature, diagnosis of DLB under most circumstances requires at least two core features to be present of the following: (1) Fluctuating cognition, especially in attention and alertness; (2) Recurrent and well-formed visual hallucinations; (3) REM Sleep Behaviour Disorder (RBD), and/or; (4) one or more features of Parkinsonism (i.e. rest tremor, bradykinesia or slowness of movement, or rigidity) (McKeith et al., 2017).
The diagnosis may be further reinforced by supportive features and biomarkers. Imaging can confirm low levels of dopamine in the basal ganglia region of the brain, or sleep studies can confirm the presence of RBD, to name a few. Additionally, a history of falling, anxiety, depression, delusions, orthostatic hypotension, and a sensitivity to antipsychotic medications are all supportive features of, but not crucial to the diagnosis.
Pathophysiology
Lewy body dementia belongs to a group of pathologies called synucleinopathies, which describes a range of diseases caused by cellular dysfunction due to the accumulation of abnormal levels of alpha synuclein protein. A particular type of alpha synuclein protein accumulation called a Lewy body that forms in the cell body causing cellular dysfunction and eventually neuronal death, defines the disease called Lewy body disease. Lewy body disease is the main pathological process that underlies Parkinson’s disease (PD), Parkinson’s disease dementia (PDD), and dementia with Lewy bodies (DLB).
Degeneration in key regions of the brain leads to a cluster of cognitive, psychiatric, motor and autonomic symptoms in LBD. Generally, for those who have PDD, Lewy bodies are first predominantly found in the brainstem and basal ganglia in the mid brain which control movement and autonomic processes, producing the symptoms consistent with Parkinson’s disease . The spread of Lewy bodies and death of neurons connecting to, or situated within, higher cortical regions involved in cognition is often a sign of disease progression and the onset of dementia. For DLB, Lewy bodies are often diffusely spread throughout the brain which in part explains the close onset of cognitive and motor symptoms, and predicts a more aggressive disease course (McKeith et al., 2017). The advancements in imaging and pathological staging over the last decade has enabled further classification and understanding of disease progression and proposed new biomarkers for tracking cellular damage and inflammation (McKeith et al., 2017; Mueller et al., 2017)
Treatments
Treatment for LBD is symptomatic, with no known disease-modifying or curative therapies currently available. The management of people with LBD is difficult due to the diverse and complex disease presentation, thus an individually tailored, multidisciplinary approach involving a combination of pharmacological and non-pharmacological treatment strategies is required.
Pharmacological treatments
Pharmacological treatments used in Alzheimer’s disease for cognition such as acetylcholinesterase inhibitors (AChIs) also show promise in LBD for improving global cognition and activities of daily living, while potentially slowing cognitive deterioration early in the disease course. The use of medications with anticholinergic properties (i.e. those that reduce acetylcholine, a neurotransmitter involved in normal cognitive processes) such as some antipsychotic, bladder incontinence or respiratory function medications may further impair cognition. Additionally, the use of antipsychotic medications to manage psychosis in LBD is generally not recommended unless there is clear benefit, as there is an increased risk of worsening of motor symptoms as well as a higher risk of having an adverse reaction and developing as potentially life-threatening syndrome known as neuroleptic malignancy syndrome (Taylor et al., 2020).
Conversely, dopaminergic medications (i.e. involved in improving dopamine signalling for movement symptoms) commonly used in Parkinson’s disease can exacerbate symptoms of psychosis such as hallucinations, agitation and delusions and may have to be titrated, substituted or discontinued by the treating physician depending on the severity of side effects. There is also a high prevalence of polypharmacy (>5 medications prescribed) and adverse effects in LBD with an average of eight medications prescribed five years after diagnosis (Borda et al., 2019). Often, additional medications needed for symptoms of constipation, urinary dysfunction, sleep disturbances, anxiety, and depression may add to overall pharmacological burden. The combination of medications used to treat the diverse spectrum of symptoms in LBD can often cause unwanted side effects and reduce the effectiveness of each, requiring a careful and considered approach by the physician to manage the most debilitating symptoms first and foremost (Taylor et al., 2020). See this fact sheet for more information.
Non-pharmacological treatments
There is little known about the effects of non-pharmacological treatments used specifically for LBD. Several reviews of the literature have concluded that more research needs to be done specifically within this cohort (Connors et al., 2018; Inskip et al., 2016). Currently, many of the treatments used within LBD have been effective in similar cohorts such as those with PD or other types of dementia and adapted to this condition.
Very limited evidence in a small number of case studies and pilot trials suggests electroconvulsive therapy (target application of electric pulses to areas of the brain) may improve symptoms of depression, anxiety and hallucinations. Similarly, a few case reports on deep brain stimulation (implanting a device to stimulate a specific region of the brain) document mild improvement in cognition and motor symptoms, however patients still declined with disease progression (Connors et al., 2018).
Exercise has promising effects for both PD and broadly in dementia, and yet is still widely under-evaluated in this cohort. Recently, the first pilot trial of exercise specifically in a Lewy body dementia cohort was conducted in Australia in a small group of nine individuals with varying disease severity (Inskip et al., 2019). Improvements were reported in strength, physical function, functional independence, frailty, mood, and cognition after a short eight week robust exercise intervention involving high intensity progressive resistance training, challenging balance exercises involving cognitive tasks, and training of functional tasks needed for daily living such as standing from a chair and transferring (Inskip, 2020). More details for exercise can be found here. Exercise of this type and intensity is likely the optimal for addressing the movement symptoms and high prevalence of frailty and falls risk noted in those with LBD. Research into exercise for LBD is in its infancy but moving in a promising direction. Larger and higher quality trials evaluating exercise for longer periods of time are needed to capture the effect of exercise against a backdrop of a rapidly progressing disease with frequent fluctuations in condition.
Conclusions
Lewy body dementia, consisting of PDD and LBD, is a little-known, fast progressing dementia that contributes to 10-20% of all dementia cases and has a higher prevalence of adverse events and conditions such as falls, frailty, depression and earlier entry into residential aged care. A relatively smaller prevalence compared to other dementias, shorter disease course, and a diverse spectrum of impairments affecting cognition, movement, mood and autonomic regulation makes the development and evaluation of treatments in LBD difficult. However, in recent decades LBD has increasingly been the focus of research into the etiology, pathophysiology, diagnosis and effective treatment which has led to comprehensive guidelines and a greater understanding of the condition, as well as a better quality of life for those living with LBD.
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