# Dementia with Lewy Bodies
## Dementia with Lewy Bodies

Dementia is a progressive degenerative neural disease that primarily affects those over the age of 65 years. It is currently the single greatest cause of disability in those aged over 65 in Australia (Alzheimers Australia, 2010). Dementia with Lewy Bodies (DLB) is a subgroup of dementia which has many of the characteristics of Parkinson's Disease. It is characterised by an aggregation of proteins found in the cell bodies of neurons in the brain (McKeith et al., 1996). This can cause early onset and rapid decline in cognitive faculties, coupled with memory loss, lack of co-ordination, hallucinations and sleep disorder. There is no clinical test (or cure) for the disease and therefore diagnosis is normally based upon the evaluation of symptoms. It can also be difficult to distinguish between DLB and Alzheimer's Disease (AD). Dementia with Lewy bodies is becoming increasingly recognised and is suspected to account for up to 10% of all dementia cases, making it the second most common form of dementia (DementiaGuide inc., 2011).

## Initial presentation, signs and symptoms

Recognising the initial signs of dementia can be difficult as they are often misattributed to being a ‘normal’ part of aging, or being due to other environmental stresses. Prominent memory impairment is not always observed in the early course of DLB, but tends to develop in most patients over the course of the disease (McKeith et al., 1996). Problems tend to present more in the retrieval of memories than the acquisition of new memories (McKeith et al., 1996). Fluctuating levels of attention and alertness are common in the early stages of the disease, however, this feature may be difficult to observe clinically and is often missed (McKeith et al., 1996). Fluctuations vary in length from rapid changes over minutes and hours, to slower changes over weeks and months (McKeith et al., 1996). Recurrent and vivid visual hallucinations are frequently reported early in DLB. Commonly, these hallucinations are what drive patients to seek treatment (McKeith et al., 1996). Up to 80% of LBD patients suffer neuropsychological symptoms, however, they greatly between cases with respect to the areas of the brain that are affected (Ballard et al., 1996). Types of problems include hallucinations, delusion, apathy, anxiety, depression and sleep disturbances (Ballard et al., 1996). Extrapyramidal symptoms, such as the motor symptoms of Parkinson’s disease, may either be present prior to the onset of dementia or sometime after. Rigidity and bradykinesia are the most common motor symptoms observed (McKeith et al., 1996). Reported rates of Parkinsonian motor symptoms presenting with DLB varies, it is estimated that half of DLB cases present without any motor symptoms initially, and a quarter never develop them (McKeith et al., 2002). Dementia with Lewy bodies is also associated with a high rate of depression (Lawlor, 2002).

## Pathophysiology

Dementia with Lewy bodies affects the brain by causing the destruction of cell bodies of neurons through the accumulation of protein aggregates, termed Lewy bodies (McKeith et al., 2002). This process primarily affects the cholinergenic and dopamine systems, destroying the neurons that create the neurotransmitters acetylcholine and dopamine (McKeith et al., 2002). The loss of dopamine producing neurons in the substantia nigra of the brainstem causes the Parkinsonian motor symptoms associated with Lewy body dementia (McKeith et al., 2002). The extent of dopamine dysfunction has been found to vary greatly between cases (Bohnen & Albin, 2011). The severity of motor symptoms appears proportional to the degree of dopamine dysfunction, explaining the variance in motor dysfunction between cases (Bohnen & Albin, 2011; McKeith et al., 2002). This may also give insight as to the reason DLB sufferers react adversely to neuroleptic medications, as these reduce the amount of striatal dopamine, acting to further worsen motor symptoms (McKeith et al., 2002). The loss of acetylcholine producing neurons, possibly in the basal nucleus of Meynert, manifests the cognitive deficit and neuropsychiatric features often associated with Alzheimer’s disease (McKeith et al., 2002; Lippa, Smith & Perry, 1999). The severity of dementia or cognitive deficit in DLB has been found to be correlated with a number of variables, including the density of lewy bodies, density of plaques and also the severity of cholinergenic deficit (McKeith et al., 2002).

## Clinical diagnosis

The clinical diagnosis of DLB is confirmed by the presence of a number of symptoms that contribute to an increasing probability of a diagnosis. The central feature that must be present for a positive diagnosis of DLB is progressively worsening cognitive impairment (McKeith et al., 1996). In addition to this, further features are grouped into “core” and “supportive” signs (McKeith et al., 1996). Core features include fluctuations in mood and cognitive state, visual hallucinations and motor parkinsonism (McKeith et al., 1996). Supportive features are transient loss of consciousness, repeated falls or syncope, neuroleptic sensitivity and systematised delusions or hallucinations (McKeith et al., 1996). A probable clinical diagnosis of DLB requires the presence of the central feature with at least one core feature and either an additional core feature or one supporting feature (McKeith et al., 1996).
Both the features and the management of DLB are similar to that of PD. The differential diagnosis lays in the timing of onset of symptoms (McKeith et al., 1996). A diagnosis of DLB is made when cognitive features of the dementing illness present prior to, or within a year of, onset of characteristic Parkinsonian signs (McKeith et al., 1996). Diagnosis of Parkinson’s disease with dementia (PDD) is made when the cognitive decline begins more than a year after the onset of motor symptoms. Despite DLB and PDD existing as two distinct clinical entities, there are very few differences between the two syndromes, these being; age of onset, temporal course of the disease and possibly responsitivity to levodopa (McKeith et al., 1996).

## Differential features

Dementia with Lewy bodies shares many features with both AD and PD, however, there are some key differences in the features of the diseases. For example, DLB patients perform disproportionately poorly when assessed on visuospatial tasks when compared with other forms of dementia such as AD (McKeith et al., 1996). Hallucinations feature in both DLB and AD, however, the characteristics of these differ. Hallucinations experienced in DLB are described as vivid and colourful, and patients are more likely to be aware that they are not real (McKeith et al., 2002). In AD, hallucinations are more persistent and my present with vocalisations (McKeith et al., 2002). While both DLB and PD sufferers generally exhibit extrapyramidal symptoms, the DLB population generally feature less tremor and myoclonus than the PD population (McKeith et al., 2002). The extrapyramidal symptoms in DLB tend to be more symmetrical, and appear to be less responsive to treatment with levodopa (McKeith et al., 2002).

## Management

There are currently no interventions available to slow or halt the progression of any type of dementia, therefore, the disease is essentially managed through attempts to reduce symptoms. The key component in the management of DLB is accurate diagnosis. Target symptoms are then identified and prioritised by the patient and carer in order of importance for management with regards to optimising quality of life and minimising carer burnout (Mosimann & McKeith, 2003). A baseline of symptoms should be obtained, and then non-pharmacological management, followed by pharmacological management as required should be commenced (Mosimann & McKeith, 2003). Non-pharmacological management should include ruling out other causes of impairment such as dehydration, metabolic imbalance or infections (Mosimann & McKeith, 2003). Management strategies include behavioural management, cognitive stimulation, environmental design and physical activity (Scottish Intercollegiate Guidelines Network, 2006). There is varying evidence to support each of these forms of management, however, the general consensus seems to be that therapies should be trialled and the outcomes monitored for the effectiveness on the specific patient.
Pharmacological management should include reviewing medications and attempting to reduce polypharmacy and any drug interactions. The pharmacological treatment of symptoms in DLB is complicated by the fact that treatment of one set of symptoms risks worsening others (Mosimann & McKeith, 2003). Currently, treatment with cholinesterase inhibitors is proving most efficient in the treatment of DLB symptoms with regards to the risk/benefit ratio and target the cognitive spectrum of symptoms (Mosimann & McKeith, 2003). Sufferers of DLB are often sensitive to neuroleptic medications and, as such, these are relatively contraindicated as they are associated with early mortality and increased morbidity (Mosimann & McKeith, 2003). Anti-parkinsonian drugs are often ineffective in the treatment of extrapyramidal symptoms in DLB and can act to exacerbate psychosis (Mosimann & McKeith, 2003). Experimenting with medication combinations may required to perfect the balance.

## History of management of dementia

In the past, the identification and diagnosis of dementing illness was a major limitation to the management of the disease, as can be inferred from available literature written more than thirty years ago (Roth, 1978). Often, the primary means of managing a patient with dementia was through sedation. The literature suggests difficulty in separating patients with a true dementing illness from those presenting with similar symptoms induced by a variety of other reasons, such as drug interactions or infections (Snyder & Harris, 1976). No further developments have been made with regards to curing or slowing the illness, therefore, the aims of treatment have remained constant; to optimise quality of life for the patient and minimise stress on the carer through management of presenting symptoms (Mosimann & McKeith, 2003). The pharmacological management of the disease has improved, especially with regards to recognising neuroleptic sensitivity and the side effects of medications (Mosimann & McKeith, 2003). Research continues with hope that it will uncover ways that the disease may be prevented, cured or slowed.

## Clinical management

There are numerous tools available for the clinical assessment of dementia. The Dementia Collaborative Research Centre (DCRC) is a government funded organisation that has created the Dementia Outcome Measure Suite which is a collection of clinical outcome assessment scales. The DCRC identifies two global rating scales as the highest rated tools for the assessment of dementia. The Dementia Severity Rating Scale is useful as a brief initial assessment tool, while the Clinical Dementia Rating is recommended for a further detailed assessment of and assesses cognitive and functional impairment (DCRC, n.d). The Mini-Mental State Examination is another widely used instrument that tests cognitive function (DCRC, n.d). There is an array of tools designed to measure specific aspects of impairment, including; cognitive, motor, psychiatric and general quality of life (DCRC, n.d). Assessment tools specific to the significant symptoms present in an individual will provide the most valuable information.

## Healthy aging

While there is no cure or prevention for DLB or any form of dementia, there is a theory that suggests that having a greater number of neural pathways available within the brain may slow the development of impairments due to a greater “cognitive reserve” (Stern, 2010). It has been suggested that attempting to increase or at least maintain neural pathways within the brain through continuing to challenge the mind will develop an increased number of alternative pathways and maximise the time it takes a dementing illness to cause severe dysfunction (Scarneas & Stern, 2003). In this way, the aging population is encouraged to engage in enjoyable stimulating activities (Scarneas & Stern, 2003).
There is a strong body of evidence supporting that exercise significantly improves quality of life for dementia sufferers. A randomised controlled trial by Miu, Szeto and Mak in 2008 found significant improvement in physical function of dementia sufferers who participated in an aerobic exercise and flexibility program when compared with a control group who received only routine medical intervention. Rolland et al. (2007) conducted a randomised controlled trial over a one year period and found that adherence to an exercise program predicts greater maintenance of function in activities of daily living. A review of literature of physiotherapy interventions in PD determined that the most effective interventions in maintaining function were; cueing to improve gait, application of cognitive movement strategies to improve transfers, specific exercises to improve balance, joint mobility and muscle power to improve physical capacity (Samyra, 2007). These findings of this final study have been extrapolated to apply to DLB patients as they often suffer the same motor symptoms. In view of this evidence, recommendations to the ageing population should include programs to improve cardiovascular fitness, lower and upper limb strength, balance and flexibility.

## Future direction of treatment

Research continues in the search for a way to prevent or slow the progression of dementia in any of its forms. One field of research is looking at the role of macroautophagy, in particular aggrephagy, which is a process that eliminates aggregations of proteins from cells (Yamamoto & Simonsen, 2011). Since these aggregated proteins play a role in neurodegeneration, there is hope that we can use this process in the fight against dementia. As it currently stands, however, the holistic approach of ensuring that both the patient and the carer’s priorities are emphasised in the treatment of this disease ensures the best outcomes possible with our current level of medical knowledge and technology.

## Research

1996
McKeith et al reported on the outcome of an international consortium which determined the clinical guidelines on DLB diagnosis
2005
McKeith et al produce the third report of the DLB consortium and revise and update the previous diagnostic criteria.
2010
Mollenhauer et al have evaluated the clinical criteria fo distinguishing between DLB and PDD.
Mukaetova-Ladinska et alhave suggested that a combination of Cerebrospinal Fluid measures may be able to differentiate DLB from other dementias, viz:- α-synuclein reduction in early DLB, a correlation between CSF α-synuclein and Aβ42 measures (characteristic for DLB only), and t-tau and p-tau181 profile (differentiating Alzheimer's Disease from DLB).