Dementia with Lewy Bodies: and Parkinson's Disease Dementia PDF

Preface

Although the history of dementia with Lewy bodies (DLB) is considerably shorter than that of Alzheimer's or Parkinson's disease, a comprehensive text about the disorder is already long overdue. The only other book published about DLB (Perry E, McKeith I, Perry R, Dementia with Lewy Bodies. Cam¬bridge University Press: New York, 1996) chronicled the debates that led up to the formulation of International Consensus Criteria for clinical and patho¬logical diagnosis of the disorder. This was a landmark publication, but it was very technical and therefore not easily accessible to the wide range of poten-tial readers interested in learning about DLB. In the following decade, a great deal of new information about DLB and experience of its diagnosis and management have been accumulated. This is what we have tried to capture in this volume.

Writing about DLB, shortly after the Consensus Criteria had been pub¬lished, one of us referred to it as 'an unwelcome newcomer'. There were several reasons for this. Most importantly, DLB appeared as a new 'type' of dementia at a time when clinicians and researchers had finally become com¬fortable with the idea that Alzheimer's disease (AD) and multi-infarct demen¬tia (MID), as it was then called, were the two common causes of dementia and that all other types were rare. It was bad enough to rock the boat by suggest¬ing that a third common cause of dementia existed, but even worse was the implication that this carried with it. The fact that relatively large numbers of people with DLB were apparently being (mis)diagnosed as having AD or MID, and that our classification systems were happy to accommodate that, sug¬gested that our understanding of those two disorders was also imperfect.

Secondly there were problems over nomenclature. A variety of terms were being used in the early 1990s to describe what were essentially the same group of patients. Diagnostic labels such as Lewy body dementia, Lewy body variant of AD (LBV), senile dementia of Lewy body type (SDLT), and diffuse Lewy body disease (DLBD) were all in use at the same time, and each had its proponents. The existence of this multiple terminology inevitably led many clinicians to reject the disorder as something too uncertain and imprecise for routine use.

Thirdly, there was the issue of the relationship between DLB and Parkinson's disease (PD). Lewy bodies are seen in the brain in both disorders, and, on the basis of neuropathological examination alone, it is impossible to say whether a person has had DLB or PD during life. Partly because of this, movement disorder specialists in particular considered that DLB was simply a variant, or an end-stage, of PD. It is certainly true that the dementia that com¬monly occurs late in the course of PD is often clinically similar to DLB.

An academic debate about the nosological status of LBV, SDLT, DLBD and PD with dementia might still be in progress were it not for two things. Firstly, the dementia field was beginning to move along very quickly in the early 1990s. New discoveries in molecular genetics were revolutionizing our under¬standing of AD, and the early cholinesterase inhibitor treatment trials were in progress. This was a climate in which new ideas were more likely to be accepted. Secondly, there was the suggestion that diagnosing DLB (whatever name it was given) might be justified on the grounds that many patients could than avoid suffering severe neuroleptic sensitivity reactions that carried increased morbidity and mortality.

Recognizing a need to act, the interested parties resolved their differences over nomenclature at a Consensus Meeting in Newcastle upon Tyne, UK in October 1995. The term DLB was picked for good reasons. It described exactly what had been observed up to that time - namely, a particular clin¬ical syndrome of dementia with fluctuating cognition, visual hallucinations and parkinsonism that seemed to occur almost exclusively in patients with Lewy bodies (LBs) at autopsy. So, dementia with LB it was. The term was deliberately chosen to be agnostic about the role of LBs in causing the dementia, because that was (and still is) an unknown. Opinion is currently in favor of LBs being 'good guys' that scavenge and sequester toxic a- synuclein protofibrils into less toxic aggregates within the cell body. The term DLB also had the advantage of being a new one, belonging to no par¬ticular individual researcher or group. Despite being a little unwieldy and containing the word 'dementia', which is disliked by many, it has been adopted globally and in its abbreviated format seems useable by clinicians, carers and patients alike. This action to coalesce the various terms under the DLB umbrella was probably the single most important step in progressing its acceptance as a clinical diagnosis. Now DLB is widely diagnosed across the globe and over the last decade we have witnessed a 30-fold expansion in the published literature. It has, for example, made it possible to use standard cri¬teria to recruit DLB patients into clinical and neuroimaging trials and other investigative studies. The problem over the boundary between DLB and PD dementia was resolved by an arbitary time cutoff, which stated that DLB should be diagnosed if the dementia features occur within 12 months or less of the onset of parkinsonism.

Each of these decisions and compromises that have been made remain open for discussion and deeper understanding in the light of new research, and all are addressed in this book. The role of Alzheimer-type pathology, for example, is now better understood. Whereas the debate was originally about whether DLB was simply a variant of AD (LBV) or a separate entity, it now seems clear that both Alzheimer and LB pathologies frequently coexist in the brains of elderly people with dementia. The clinical profile that emerges depends to some extent on the relative load and distribution of each pathol¬ogy - neocortical neurofibrillary tangles in particular altering the clinical pro¬file to look more like AD with prominent amnestic symptoms and reducing the probability of fluctuation, visual hallucinations and parkinsonism. The implication of this is that some DLB cases will lack these core features and be extremely difficult to recognize clinically. This explains at least in part why clinicians have so much trouble diagnosing DLB. It is not they who are lack¬ing in their powers of observation, nor are the clinical diagnostic criteria incorrect. It is simply that not all DLB cases present with the typical picture. To detect these patients, additional pieces of clinical evidence are required, for example a history of REM sleep behavior disorder (RBD) or of severe neuro¬leptic sensitivity. The other approach to improving diagnostic sensitivity for DLB is to use biological tests, the most promising of which so far are neuroimaging methods, particularly those labeling the dopamine transporter site in the basal ganglia.

Modifications to pathological and clinical criteria for DLB were discussed at the 3rd International DLB Workshop in September 2003 and are currently under review for publication. Most of the information and opinion that con¬tributed to that process is reflected in the chapters that follow, many of which were written by members of the consensus process.

For families dealing with DLB, the recognition that the clinical picture and burden of care is different for them compared with people affected with AD is a major step forward. But it carries with it many frustrations, not least that they often are more aware of DLB than their professional carers. The Alzheimer's and Parkinson's Associations and Societies, nationally and internationally, provide rapid access via the internet to a growing range of fact-sheets and other sources of information about DLB. More recently a carer-based organization specifically for DLB has been established offering on¬line communication with other families and providing more detailed and up- to-date information. The range of topics about which people who have DLB and their carers need to know is extensive. In addition to the fluctuating cog¬nitive impairments, which predominantly affect attention and visuopercep- tual abilities, there may also be psychiatric and behavioral abnormalities, motor deficits, autonomic dysfunction and sleep disorders. How to impart such a diverse range of facts without instilling pessimistic anticipation of the worst is truly a challenge. The reality is that many of these symptoms of DLB are amenable to treatment - often, but not always, pharmacological. As treat¬ment guidelines for DLB emerge, clinicians should become more confident about not only prescribing single therapies but also combining them to target all symptoms identified by patient and carer as troublesome enough to warrant intervention.

If so much progress has been made in the last decade, what can be hoped for in the next? The ideal would be a drug that significantly interrupted the pathological processing of a-synuclein and other proteins, arresting the neurodegenerative process. A useful clinical objective would be for our clini¬cal diagnostic methods to have improved to such a point that patients with DLB were reliably identifiable in the earliest stages of disease when applica¬tion of such a treatment would be of most benefit. If one makes analogy with the current status of amnestic mild cognitive impairment (MCI) as a predic¬tor for AD, it is clear that defining the MCI equivalent of LB disease is likely to be a difficult task. Research effort needs to be directed towards early detec¬tion of LB disease, likely using biological markers such as dopamine trans¬porter imaging in patients showing evidence of possible early symptoms. For those with established DLB, we need better symptomatic treatments. This may involve new drug discovery, but there is huge scope for improvement in the management of individual patients using tailored regimes of currently available medications. Specialist clinics for DLB patients may be one way to deliver these, and they could be embedded within existing provisions for people with dementia or movement disorders.

The chapters that follow trace the historical development of DLB, patho¬logical and clinical issues, pharmacological and nonpharmacological treat¬ments, pathophysiology and a personal perspective of this disorder, which has moved over a short space of time from unawareness, through reluctant acceptance, to now being the subject of intense activity. We hope that out of these pages will come further acceleration of the process of understanding DLB and its boundaries.