Dementia with Lewy Bodies: An Overview

INTRODUCTION

Dementia with Lewy bodies (DLB) is the second most prevalent form of degenerative dementia in the world. The Lewy body is the pathologic hallmark of Parkinson’s disease (PD). The presence of these changes in other brain areas (subcortical and cortical regions) is associated with a dementing process. This article will discuss the evolution of DLB, its relationship to other dementias, and unresolved diagnostic issues.

DEMENTIA IN PD: DEVELOPMENT OF THE CONCEPT

Dementia occurs in PD in approximately one-third of all cases.¹ In the late 1970s, the finding of Alzheimer-type changes in the brains of deceased patients with PD led to the assertion that the dementia in PD was actually Alzheimer’s disease (AD).² The development of better staining techniques to visualize Lewy bodies led to the discovery that these inclusion bodies can often be present in multiple brain areas, including the cortex.³ In subsequent years it became apparent that there is a diversity of diagnoses that may comprise the full population of cases of dementia in PD. Alzheimer’s disease, Parkinson’s disease with dementia (PDD), and DLB are now recognized as the three main disorders underlying cognitive deterioration in patients with PD. A number of unresolved questions remain with regard to dementing disorders in PD. The first question addressed in this article deals with the distinctions between the diagnostic entities PDD and DLB. The second question involves the validity of current diagnostic criteria for DLB. The third area explored is the complex relationship between AD and DLB.

PDD AND DLB
Although PDD and DLB are said to be separate entities, there is much to suggest that these disorders are the result of the same pathological and clinical process with slightly different presentations. There are numerous similarities that probably supercede any differences in presentation. PDD is generally defined as a disease that begins with movement disorder and manifests dementia after at least 2 years; DLB is defined as a disorder with a probable concomitant onset of dementia and parkinsonism (ie, within 1 year of each other). However, if one considers the similarities between PDD and DLB, a very considerable overlap is observed. In the realm of neuropathology, for example, the primary pathology in both disorders in that of cortical Lewy bodies with significant secondary pathology of AD changes in many cases. In fact, there is a high correlation between neuritic plaques and the presence of Lewy bodies in the brains of patients with PDD⁴ and DLB.⁵

The regions most commonly involved in the disorders are also the same, namely neocortex, limbic cortex, amygdala, nucleus basalis of Meynert, and substantia nigra.^4,6 Clinical similarities are striking between PDD and DLB. Visual hallucinations are said to occur 45% of the time in PDD⁷ and 40% of the time in DLB.⁸ Visual hallucinations occurred in 69% of patients with PD on dopaminergic medications,⁴ and in 64% of the patients with DLB being treated with the same medications.⁸ The presence of parkinsonism is part of the diagnosis of PDD in 100% of the cases, whereas it may be present in DLB cases 60% of the time.⁸ Both PDD and DLB manifest decreased sensitivity to dopaminergic agents^4,9 and increased sensitivity to neuroleptics.¹⁰ Both disorders show therapeutic responses to cholinesterase inhibitors.^11,12 Neurochemically, there is evidence of reduced cholinergic neurons in both PDD¹³ and DLB.¹⁴ A number of neuropsychological tests also show similar patterns of dysfunction in these two dementias. The same order of magnitude of impairment is found in PDD and DLB with regard to simple reaction time, choice reaction time, visual discrimination, and complex visual functions.¹⁵

DIAGNOSIS OF DLB

Because of the similarities and relationships among AD, PDD, and DLB, it is imperative that accurate approaches to diagnosis be implemented. Despite the similarities between PDD and DLB, traditionally these two disorders are still treated as separate entities. The course of cognitive decline in AD and DLB overlaps considerably. The attempt to more clearly define DLB has led to a process of refinement of diagnostic criteria, culminating in the consensus criteria for the clinical diagnosis of DLB, which were enunciated in 1996.¹⁶ These criteria now form the basis of diagnosis universally, although there is considerable lack of clarity in some of the criteria. For example, the concept of cognitive fluctuations is central to the diagnosis but is interpreted differently in varied circumstances. Some individuals have referred to fluctuations in certain cognitive functions,¹⁷ while others have referred to fluctuations in alertness and/or behavior.¹⁸

Likewise, the focus on visual hallucinations as a central criterion for the diagnosis of DLB is marred by the fact that most of these patients are taking dopaminergic drugs, which may be the true culprit in producing such sensory phenomena. A meta-analysis of reports of autopsy-confirmed cases of DLB determined that the presence of parkinsonism and the co-occurrence of parkinsonism within 12 months of dementia were valid criteria for the diagnosis of DLB, but that visual hallucinations occurred in a minority of patients and cognitive fluctuations may not be a valid marker at all.⁸ Visual hallucinations were found to occur in twice as many patients with DLB who were taking dopaminergic drugs as in those who were not. A second study looked at the prevalence of DLB in published autopsy samples of dementia cases. Universally, approximately 17% of all cases of dementia coming to autopsy have DLB. This was true in both Western cultures and Asian societies. In contrast, studies looking at the clinical diagnosis of DLB by utilizing the consensus criteria demonstrate an excess number of diagnoses of DLB in Western cultures (at least twice as common as autopsy results) and a paucity of diagnoses in Asian cultures.¹⁹ These results underscore the need to continue to question and study the validity of the consensus criteria.

INTERACTION: AD AND LB PATHOLOGY

There is obvious overlap between AD and LB pathological processes. For example, the frequent finding of AD changes in the brains of patients with PD and the development of parkinsonism in patients with advanced AD certainly demonstrate a relationship between these two disorders. The nature of the overlap has been unclear for many years but is starting to be unraveled. One study looked at three disorders, AD, DLB, and Lewy body variant of Alzheimer’s disease (LBV), a disease that has significant Alzheimer-type and Lewy body changes. Despite the similarities in various clinical measures between these three groups, patients with LBV had significantly more dementia than the other two groups, and had approximately seven times the number of Lewy bodies as patients with DLB.⁵ The question then is why Lewy bodies should be so prevalent in the presence of Alzheimer-type changes. One study in mice suggests an answer. Mice, which transgenically produce excessive amounts of both alpha-synuclein (the major component of Lewy bodies) and of amyloid-precursor protein (the precursor of amyloid in AD plaques), demonstrated significantly greater destruction of cholinergic neurons than mice that produced excessive amounts of only one of these two substances.²⁰ Furthermore, the mice receiving the double transgenic hit produced large numbers of inclusion bodies of alpha-synuclein, which were analogous to Lewy bodies. It is suggested that the activity of proteosomes, which are known to degrade alpha-synuclein,²¹ are decreased in AD, possibly by beta-amyloid activity.²² Through this process there may be subsequent accumulation of alpha-synuclein in the form of Lewy bodies. Hence, it would not be surprising that some patients with AD changes would have an excessive Lewy body proliferation in their brains.

SUMMARY

Lewy body pathology (synucleinopathy) accounts for a significant degree of cognitive dysfunction. The two dementing disorders most associated with Lewy bodies, Parkinson’s disease with dementia and dementia with Lewy bodies, may be arbitrarily divided into separate entities and may actually be considered a spectrum. The distinction between these two disorders is only one of a number of significant diagnostic issues in the arena of Parkinson’s disease and dementia. Efforts to refine diagnosis by development of a specific set of criteria for dementia with Lewy bodies have resulted in the reification of an approach that may have limited validity. The relative contribution of Alzheimer’s disease changes and of synucleinopathy to dementia in patients with Parkinson’s disease is also not totally clear. A possible interaction of these two processes suggests that rigid distinctions between them may be outmoded.