Summary

Though the history of Lewy body related diseases started in Germany, German neurology and psychiatry still ignore the existence of dementias with cortical Lewy bodies (LB). In order to estimate the proportion of senile dementia of the Lewy body type (SDLBT) in neuropathological postmortems in Germany, we screened all brains (n = 273) of adult patients, who died in 1991 and were examined by one neuropathologist at the University Medical Center in Mainz, Germany. A multi-stage approach to detecting LBs was used with final detection by ubiquitin immunohistochemistry.

Four cases were discovered (1.5% of all cases and 4.3% of demented or confused patients). Thirty cases from the series had a neuropathological diagnosis of Alzheimer's disease (AD). All four cases with cortical LBs showed additional neurofibrillary pathology. In other years, independent of this study, solitary cases attracted attention in which no additional neurofibrillary pathology was detected. The clinical spectrum and its nosological implications are discussed and a diagnostic separation between a condition with ‘pure’ cortical Lewy bodies and one representing a combination with Alzheimer pathology is suggested.

Introduction

In 1912 the history of Lewy body (LB)-related diseases started in Germany with Friederich H. Lewy's contribution to Lewandowsky's Handbuch der Neurologie (Lewy, 1912). In this chapter, concerning the pathology of paralysis agitans, Lewy gave the first description of ‘classical’ (‘brainstem-type’) and ‘serpiginous’ LBs in the neurons of the dorsal vagal nucleus. Lewy himself did not mention the substantia nigra in particular, even when he described the occurrence of LBs in other brainstem nuclei in his famous book Die Lehre vom Tonus und der Bewegung (Lewy, 1923).

Summary

Lewy bodies are an important histological feature of several neurodegenerative diseases typified by idiopathic Parkinson's disease. With the increasing recognition of dementia associated with Lewy bodies in cortical neurons it is desirable to have a better understanding of the biogenesis and function of these neuronal inclusions. There is considerable indirect evidence, based on immunohistochemical identification of constituent proteins, that the Lewy body is a structural manifestation of a cytoprotective cell response. When encountered in diagnostic practice a distinction is presently made between primary Lewy body disorders, where the Lewy body is felt to be closely related to the pathogenesis of disease, and coincidental Lewy body disorders where Lewy bodies are inconsistently associated with other pathological processes. This division is still arbitrary and based on relative ignorance about the functional biology of the Lewy body phenomenon.

Introduction

An important histological characteristic of idiopathic Parkinson's disease is the presence of intraneuronal inclusions termed Lewy bodies. Recent morphological and cell biological studies have also characterized Lewy bodies in a variety of disorders, particularly in the cerebral cortex in association with dementia. These observations have prompted important considerations as to the biological function of the Lewy body and whether the presence of Lewy bodies can be used to define specific types of neurodegenerative disease.

Functional biology of Lewy bodies

There are two distinctive morphological types of Lewy body, the classical (brainstem) type and the cortical type (Lowe, 1994). In addition, so-called pale bodies are felt to be a possible precursor of Lewy bodies (Dale et al., 1992; Hayashida et al., 1993).

Summary

In 1980 we proposed Lewy body disease (LBD) as a disease entity and classified it into three types: brainstem, transitional, and diffuse. The brainstem type is identical to Parkinson's disease, and the diffuse type is now called diffuse LBD (DLBD).

DLBD has become the subject of much attention since the publication of our studies on DLBD. It has recently been reported that DLBD is the second most common cause of dementia among the elderly. Our recent study of 79 consecutive autopsied dementia cases suggests that also in Japan DLBD is the second most common degenerative dementia, following Alzheimer-type dementia (ATD). In 1990, we divided DLBD into two forms: a pure form and a common form. Then, it was noted that in 30% of the common form DLBD cases no parkinsonism was detected, although Parkinson pathology was present. Very recently, we proposed cerebral type of LBD as yet another type of LBD, in which cortical dementia without parkinsonism is the predominant symptom and there are as many cortical Lewy bodies as in DLBD, but Parkinson pathology is absent. This feature suggests that the development of cortical Lewy bodies can precede Parkinson pathology. Therefore, this might explain why cortical dementia precedes Parkinson symptoms in many DLBD cases. Thus, LBD is now classified into four types, and DLBD is understood within the spectrum of LBD. The frequency of cortical Lewy bodies is important. More than five or ten cortical Lewy bodies per x 100 visual field in the predilection sites are necessary for the diagnosis of DLBD or cerebral type LBD in HE or ubiquitin-immunostained sections, respectively.

Summary

A clinical diagnosis of dementia of Lewy body type (DLT) was made in 10% of referrals to a clinical service providing psychogeriatric care to a locality based population of 18,000 people aged >65 years. Thirty per cent of referrals received a diagnosis of Alzheimer's disease and 22% of multi-infarct dementia. Inter-rater agreement for the three different diagnoses was equally good (kappa = 0.67) and the profile of differential diagnosis was stable in two consecutively sampled years. We suggest that a cluster of symptoms exists which we can reliably define in clinical practice as dementia of Lewy body type. It may be useful to view a person with any three of the following features, cognitive impairment, extrapyramidal symptoms, fluctuating confusion and visual hallucinations, as most likely having DLT, regardless of coexisting cerebrovascular disease or other physical illnesses, both to avoid potentially hazardous treatments such as conventional neuroleptics and to select patients for future beneficial interventions.

Introduction

Does Lewy body dementia* exist in clinical practice? Can it be recognized in the routine work of an old age psychiatry service? In whom do we recognize Lewy body dementia, and what character does it have? Our own interest in these questions began in the late 1980s when we were looking at cases of presumed Charles Bonnet syndrome. At the same time, colleagues in Newcastle were describing senile dementia of Lewy body type. We soon found the second diagnosis subsumed the first. In this chapter, we report on our subsequent experiences with the diagnosis of Lewy body dementia and attempt to answer our questions from the perspective of the sole service for elderly people with mental health problems within a geographically limited area.

Summary

Cortical Lewy bodies (LBs), neurofibrillary tangles (NFTs) and senile plaques (SPs) in the limbic and neocortical cortices of the temporal lobe were studied with anti-ubiquitin, anti-tau and anti-β-protein immunohistochemistry in senile dementia of Alzheimer type (SDAT), diffuse Lewy body disease (DLBD), Parkinson's disease (PD) with and without dementia, and normal controls. DLBD was characterized by numerous cortical LBs together with marked senile changes similar to those of SDAT though neocortical NFTs were significantly less than in SDAT. There were rare or no cortical LBs and neocortical NFTs in most PD cases with and without dementia while there were a few cortical LBs and moderate senile changes, in some cases with dementia. These findings suggest that either of the abundant cortical LBs and senile change, or both have produced dementia in DLBD, while the neuropathological background for dementia in PD cases may be heterogeneous and vary among individual cases.

Introduction

Diffuse Lewy body disease (DLBD) is a neuropathological entity in which abundant Lewy bodies (LBs) are found throughout the cerebral cortex as well as in the brainstem nuclei in the manner identical to Parkinson's disease (Kosaka et al., 1980, 1984). Marked senile changes including abundant senile plaques (SPs) and Alzheimer neurofibrillary tangles (NFTs) are also found in this condition. Immunohistochemical stains with tau and β-protein antibodies respectively demonstrate NFTs and SPs selectively and sensitively. Ubiquitin immunohistochemistry can immunostain LBs of both brainstem and cortical types sensitively (Kuzuhara et al., 1988; Lowe et al., 1988), and detect far more LBs than the conventional techniques (Lennox et al., 1989).

Summary

Lewy bodies remain an enigma. Their presence in the substantia nigra is often taken as a diagnostic criterion for idiopathic parkinsonism (IP, Parkinson's disease). Yet the first report of Lewy bodies in IP is an account of their appearance in the dorsal motor nucleus of the vagus, and the nucleus basalis of Meynert. More serious problems have arisen in recent years, partly as a result of improved techniques for detecting Lewy bodies. The more they have been looked for, the more they have been found. A further complicating factor is that they have different appearances in different regions of the brain. We know that Lewy bodies are made up from cytoskeletal products and they are associated with the death of neurons. They may contribute to the mechanism driving cell death. Alternatively, their formation may represent a compensatory adjustment in an attempt to ameliorate the demise of neurons. They have not helped us in an attempt to find the aetiology of IP, because they occur in such widely diverse settings as hereditary neurodegeneration (e.g. Hallervorden-Spatz disease) and viral infection (e.g. subacute sclerosing panencephalitis). Thus our knowledge, and our ignorance, concerning Lewy bodies leaves us in a tantalizing situation. Surely they are important clues to neurodegeneration, but as yet we have not been able to reveal the secrets that they should provide to help us unravel the pathogenesis of IP.

Introduction

James Parkinson described the clinical features of the disorder that bears his name in 1817 (Parkinson, 1817). In 1912, Lewy demonstrated the existence of neuronal inclusion bodies in the dorsal motor nucleus of the vagus and nucleus basalis of Meynert in Parkinson's disease.

Guidelines for brain sampling

Brain sampling

1. (i) Centres should continue current practice regarding which side of the cerebral hemisphere is sampled for histology (e.g. routinely from the right or left hemisphere, or alternatively right then left),

2. (ii) For cerebral hemisphere dissection the recommended coronal plane should be perpendicular to a line joining the inferior frontal and inferior occipital poles.

Neocortical regions

Coronal levels (CL) are indicated – see Fig. 1.

1. (i) Frontal BA8/9 The middle frontal gyrus in the superior frontal sulcus at the plane just rostral to the temporal tip CL8/9

2. (ii) Temporal BA21 The superior sulcal margin (superior temporal sulcus) of the middle temporal gyrus at the plane of the amygdaloid and mammillary body. CL14/15

3. (iii) Parietal BA40 The superior sulcal margin (intraparietal sulcus) of the parietal lobule at the plane lcm caudal to the posterior pole of the splenium. CL24/25

Limbic or paralimbic regions

1. (i) Anterior cingulate BA24 At a plane rostral to the anterior commissure approximately 1.5 cm caudal to the anterior pole of the genu. CLIO/11

2. (ii) Transentorhinal BA29 The sulcal margin (collateral sulcus) of the parahippocampal gyrus at the plane of the red nucleus. CL17/18.

Brain stem regions

The CERAD Neuropathological Assessment sampling protocols are recommended for the substantia nigra, locus coeruleus, and dorsal nucleus of vagus.

Guidelines for evaluation of Lewy body distribution and frequency Cortical Lewy body frequency

Assessment is on a semiquantitative scale. In each region the total number of Lewy bodies (LB) in the designated area are counted in either H&E or ubiquitin-stained sections (cases with concomitant Alzheimer's disease may need additional stains to discriminate Lewy bodies and globose neurofibrillary tangles).

Summary

A subpopulation of Alzheimer's disease (AD) patients with neocortical Lewy bodies (LB) and subtle extrapyramidal signs, a clinical-pathological phenotype that we have termed the Lewy body variant of AD (LBV), has an increased allele frequency of APO E e4 allele, similar to that observed in AD subjects without LB (pure AD), although individuals homozygous for the APO E e4 allele are overrepresented in pure AD as compared with age-matched controls, but not as markedly in subjects with LBV. Furthermore, we have found that the CYP2D6B mutant allele, a risk factor for Parkinson's disease (PD), is overrepresented in LBV, a finding that has been controversial. To further evaluate the involvement of the CYP2D6 locus in LBV, the Xbal restriction fragment length polymorphisms (RFLP) of CYP2D6, 44 kb, 15/9 kb, and 13 kb (D mutation), were examined for association with LBV. The 15/9-kb RFLP was found in pure AD or in non-AD individuals but was not found in LBV. On the other hand, the 44-kb Xbal RFLP in the presence of the concomitant CYP2D6B mutant allele was strongly associated with LBV. The tightest association with LBV was found in the combination of the 44-kb RFLP and CYP2D6B mutant allele in the absence of the 15/9-kb RFLP. A CYP2D6 deletion mutation D, detected as 13-kb RFLP, was not linked to LBV. Taken together, these findings suggest that the inactivation of CYP2D6 represented by the B or D mutation may not per se be the risk factor for LBV but that an independent mutation or allele linked to the CYP2D6B mutation and the 44-kb Xbal RFLP (such as NF-H or PDGfb genes) might be associated with LB formation in AD.

Summary

Clinical Alzheimer's disease (AD) is a heterogeneous disorder and it is possible to subgroup patients by a number of different criteria. One such subgrouping is those that have a positive response to cholinergic therapy and those who do not. This phenomenon has been clearly recognized in a number of therapeutic trials of cholinesterase inhibitors and is likely to be an issue in clinical practice. Tacrine, the first cholinesterase inhibitor to be licensed for the treatment of AD, has, at best, modest effects on 20–50% of patients and is associated with a high frequency of side effects which includes liver transaminitis. The potential of clinical tests or other investigations to identify those patients who are more likely to respond to cholinergic therapy would be a valuable aid in the clinical use of these therapies. In this paper we review the issue of heterogeneity in patient populations, in the design of trials and in the pharmacological compounds used in trials. We then summarize the findings of a number of small studies of potential response predictors which include the use of psychometric tests, orthostatic blood pressure, pupillary dilatation, the EEG, CSF neurochemistry and techniques involving functional imaging. Although some results are promising, generalizability is limited by the small numbers of patients studied, and the frequent open nature of the designs used. The main conclusion that can be drawn is that adequate doses are required to achieve therapeutic plasma levels before nonresponse is accepted.

Introduction

The evidence for the role of the cholinergic system in Alzheimer's disease (AD) has developed from work begun in the late 1970s demonstrating reductions in the levels of cholinergic marker in the brains of patients with AD (Rossor et al., 1982; Bird et al., 1983; Davies & Maloney, 1988).

Contributors to the chapters on treatment issues met together with other interested participants in the Workshop (Owen Collins, Alan Cross, Murat Emre, Ernst Jansen, Amos Korczyn, John O'Brien, Arjun Sahgal, and Peter Thompson) for a morning discussion of key areas relating to therapy. The group explored the biological basis for four symptom clusters in dementia with Lewy bodies (DLB): psychosis, cognitive deficits, affective and motor disorders. An important issue relating to therapy was considered to be the nature and extent of interactions between these different symptoms and the way in which they vary with time. Therapeutic strategies were discussed from several viewpoints: in terms of clinical experience with currently available Pharmaceuticals in treating these symptoms in other disorders; anecdotal experience with DLB patients; and theoretically based hypothesis-driven designs for future treatment. The group concentrated on neurotransmitter-orientated intervention since this was considered the most immediately relevant in relation to symptoms (neuroleptics or cholinergics for psychosis or dementia). It was appreciated that in the longer term, with increased understanding of aetiology and development of new preventative or neuroprotective approaches, therapeutic objectives would expand beyond the symptomatic range. Examples of such strategies include the potential of neurotrophins (Chapter 35) or antioxidants (Chapter 36).

The hypothesis that psychotic features such as hallucinations in DLB are associated with depleted neocortical cholinergic activities (Chapters 30 and 31) was considered in the light of present preliminary and conflicting evidence on the effects of anticholinesterases. Most of this evidence is based on trials of tacrine in clinically diagnosed cases of Alzheimer's disease (AD) which inevitably include some cases of DLB.

Summary

Dementia occurs in PD and lesser cognitive deficits, of ‘frontal-lobe’ type, are detectable in nondemented patients even at diagnosis. Cortical Lewy bodies, Alzheimer changes and vascular disease have been considered to underlie clinical dementia in PD but, in nondemented cases, attention has been more focused on the neurochemical changes. Dopamine deficiency causes disruption to frontostriatal circuits but noradrenergic, cholinergic and serotonergic deficts also occur and are involved in cognitive and affective disturbance in other conditions.

Modulation of these transmitter systems in PD using drugs with specific neurochemical effects suggests that dopamine deficiency causes selective impairment in ‘frontal lobe’ functions, such as working memory and planning, but many functions are unaffected. Noradrenergic modulation also affects frontal-lobe function although both facilitatory and inhibitory effects occur. Cholinergic deficits render patients sensitive to the effects of anticholinergic therapy, particularly on memory. Serotonergic deficits are related to depression.

Our longitudinal studies show that a subgroup of patients dement early. Risk factors for dementia include greater age at diagnosis and rapidly progressive motor disability. CT scans at diagnosis show a high incidence of abnormality, suggesting that structural rather than neurochemical pathology is responsible for the cognitive deficits. Predictive factors for dementia can be established from the neuropsychological profile at diagnosis.

The pathology of cognitive impairment in PD is multifaceted. Neurochemical deficits are more amenable to therapy through standard pharmacological means but another challenge is to identify early risk factors for the development of cortical pathology so that neuroprotection can be developed and targeted at appropriate patients.

Cognitive impairment in Parkinson's disease

Although motor deficits are the most consistent signs of Parkinson's disease (PD), cognitive dysfunction also occurs.

Lewy body dementia (LBD) burst on the scientific scene as a major concern for clinicians and pathologists little more than a decade ago. The Lewy body had previously been considered a common, if enigmatic, marker of idiopathic Parkinson's disease, but it suddenly became a focus of interest as ubiquitin stains revealed that up to 30 per cent of patients diagnosed clinically and pathologically with Alzheimer's disease have Lewy bodies in substantial numbers of cortical neurons. Is this a newly recognized dementing illness or a variant of Alzheimer's disease; what does the Lewy body tell us about deranged intracellular metabolism; do cortical Lewy bodies cause a dementia syndrome and if so how abundant must they be to produce cognitive impairment; is LBD clinically recognizable; what is the relationship between LBD and Parkinson's disease; does LBD have a different treatment response profile than Alzheimer's disease? These are the questions that the current volume strives to answer or at least to put into perspective and set the stage for future investigations.

Dementia with Lewy Bodies is organized into three sections: clinical aspects, pathology, and treatment. Prefaced by a fascinating biography of Lewy – who first described in 1913 the eosinophilic inclusions that came to bear his name – the clinical section addresses the current state of knowledge regarding the clinical syndrome associated with cortical Lewy bodies. Lewy body dementia and Alzheimer's disease are not differentiated by widely used clinical and research diagnostic criteria, and studies currently reported as describing the phenomenology and treatment of Alzheimer's disease almost certainly include a mixture of patients with Alzheimer's disease and patients with LBD.

Summary

Two characteristics of senile dementia of the Lewy body type (SDLT) compared with Alzheimer's disease (AD) are relevant to treatment management: relative hypocholinergic activities and behavioural disturbances such as psychotic manifestations with neuroleptic hypersensitivity. A better tacrine responsiveness of SDLT patients has been proposed. An open trial with tacrine (120mg/day) prescribed in 22 probable AD patients (meeting NINCDS–ADRDA criteria) resulted in no memory improvement in the four patients meeting SDLT criteria. The potential of GABAergic agents, particularly carbamazepine, in the management of delirium and psychotic symptoms in SDLT is discussed.

Introduction

In recent years there has been an increasing interest in behavioural disorders in dementia since psychiatric disturbance is considered to be one of the most troublesome aspects of the disease by many relatives of demented patients. They are an important risk factor for institutionalization. On the other hand, behavioural abnormalities are not usually considered in the diagnosis of degenerative dementia although psychotic symptoms and mood disorders may be the earliest signs of frontal lobe dementia or Lewy body disease. Episodic confusion, depressive and psychotic symptoms are frequently observed in senile dementia of Lewy body type (SDLT). Hallucinations are more often reported in SLDT than in dementia of Alzheimer type (AD) (Ballard et al., 1995). Dopamine hyperactivity is a putative neurochemical basis for psychosis and cholinergic/dopaminergic imbalance with relative dopamine excess linked to hallucinations in different neurological diseases such as Parkinson's disease. Moreover, physostigmine reduced delusions in two AD patients (Cummings et al., 1993). In SLDT, in which hallucinations are frequent, cholinergic hypometabolism (e.g. choline acetyltransferase decrease) has been reported (Perry et al., 1993).

Summary

Dementia is a constant manifestation of Parkinson's disease; it is the third most common cause of dementia after Alzheimer's disease and stroke. The clinical manifestations are similar to those seen in other degenerative disorders that cause dementia with some minimal differences; some specific disturbances such as depression and a decline in verbal fluency may identify individuals who are in the early stages of dementia. While patients advanced in age seem to be at higher risk of dementia with Parkinson's disease, the risk is uniform throughout the duration of disease. There are no known environmental risk factors specific for dementia, though many putative factors have been identified for Parkinson's disease. There is a strong evidence to suggest a genetic etiology, but more work is essential because of the unusual relationship between Alzheimer's disease, Lewy body dementia and the dementia of Parkinson's disease.

Introduction

Nearly all of the therapeutic success in Parkinson's disease during the last three decades have been dampened by the presence of dementia which occurs as a regular manifestation. There is general agreement that dementia is most common in older patients with Parkinson's disease and that it is the single most important factor limiting treatment. Most also agree that there is a considerable overlap in clinical manifestations with Alzheimer's disease and dementia of the Lewy body type. The frequency of dementia in Parkinson's disease is even higher than appreciated (Girotti et al., 1988; Mayeux et al., 1990) and it increases the mortality rate by at least twofold compared with nondemented persons of the same age with and without Parkinson's disease (Marder et al, 1991).

Summary

That cognitive decline is a feature of LBD is not disputed. The dispute arises about the type of cognitive decline, whether it has characteristic features that distinguish it from other forms of dementia, its severity and its course. Early case reports include descriptions of a variability of cognition, usually of arousal, in LBD confirmed by larger retrospective clinico-pathological series. Fluctuation in cognitive state either in the form of episodic confusional states resembling delirium or transient periods of reduced or loss of consciousness, superimposed on a background variability is described in 80% of patients in some series. This fluctuation of cognition may be less marked in those LBD cases who most resemble AD.

Some suggest that cognitive abnormality in LBD is milder at onset, and has characteristic features (especially deficits of attention). Others do not confirm these observations. The course of the cognitive decline is variable, a few cases have a rapid onset and decline, the mean durations of illness in most series are between five and seven years. EEG findings, which resemble those of experimental delirium, and neurochemistry in LBD suggest the most likely candidate for the variability in cognition in AD is the relative involvement of the cholinergic and dopaminergic systems. The contribution of cortical Lewy bodies themselves to the cognitive decline is as yet unknown.

Much of the controversy about Lewy body dementia (LBD) arises from the relatively small database and disparity of samples. The same consideration applies to a discussion of cognitive decline in LBD. From the first case reports (Okazaki et al., 1961) dementia has been described in the majority of cases.

Summary

There is considerable evidence to support a role for neurotrophins as a strategy for treating chronic neurodegenerative conditions causing dementia, especially Alzheimer's disease and probably others including senile dementia of Lewy body type. In particular, a wealth of animal and tissue culture research points to the potential of nerve growth factor (NGF) as a means of supporting subcortical cholinergic cells, thereby retarding the disease process. Very early pilot work in human subjects has already been undertaken and attempts are under way to try and improve the drug delivery systems needed to allow such peptides to enter the brain and reach their predominantly subcortical targets. If successful, this approach would have a wider application to a number of neurodegenerative disorders, not necessarily confined to cholinergic cell systems.

Introduction

The concept of neurotrophic support for developing neurons was first suggested in the 1950s when Levi-Montalcini described the effect of transplanted mouse sarcoma tissue on the developing sensory and sympathetic nervous system of chick embryos. (This is reviewed by Levi-Montalcini, 1987.) Work in this field has moved on rapidly, especially in the last five years, and now much is known about a whole family of neurotrophic molecules and also their receptor systems in both normal development and disease. It is clear that members of this family can act in a neuroprotective role in the central as well as the peripheral nervous system. NGF and its receptors are the neurotrophin system most explored, especially in relation to Alzheimer's disease (AD), as far as dementia is concerned.

The clinical workshop adopted a two-stage approach to the challenging task of agreeing clinical diagnostic criteria for dementia with Lewy bodies (DLB).

Session one – Where does DLB fit within the diagnostic framework?

The first step was to define the scope of the new criteria, in particular whether they ought to be part of a unifying diagnostic category covering the whole spectrum of clinical presentations of LB disorders, or whether they should restrict themselves to only one part of this. The subsequent task would then be to select and operationally define the specific items of diagnostic importance. Two existing sets of clinical diagnostic criteria (the Newcastle criteria for senile dementia of Lewy body type (SDLT) (McKeith et al., 1992) and the Nottingham criteria for dementia associated with cortical Lewy bodies (Byrne et al., 1991)) were tabled for consideration, as were supplementary data from other participants (all to be found in the preceding clinical chapters).

Preliminary discussion centred on the principle that diagnostic criteria should be framed in the way most relevant to established clinical procedures. It was agreed that a single set of clinical criteria encompassing the whole spectrum of LB disorders, ranging from motor Parkinson's disease (PD) to primary cognitive failure, would produce a diagnostic category containing enormous clinical heterogeneity. Such a system would be difficult to apply in clinical practice and would have low face validity.

Summary

We describe the clinical and single photon emission computerized tomography (SPECT) characteristics of nine patients with parkinsonian-dementia (PD) and contrast their clinical and SPECT characteristics with nine MMSE matched Alzheimer's disease (AD) patients. In six of the PD patients there was pathological confirmation of the diagnosis while in three others the diagnosis was based upon the clinical presentation. The PD patients significantly differed from the AD patients due to the high frequency of visual hallucinations, delusions, and atypical (SPECT) patterns. The clinical and SPECT patterns in PD differ from AD.

Introduction

There is an emerging literature on the neurologic (Perry et al., 1989; Crystal et al., 1990), neuropsychiatric (Perry et al., 1990a and 1990b), neuropsychological (Sakahian et al., 1988; Sahgal et al., 1992), neurochemical (Perry et al., 1990b,c; Dickson et al., 1991) and neuropathologic (Hansen et al., 1990; Dickson et al., 1991; Kosaka, 1993) features of patients who present with a mixture of parkinsonism and dementia (PD). There are three differing hypotheses regarding the classification of these PD patients. One theory emphasizes that senile plaques are commonly found with PD and suggests that PD patients are part of the spectrum of Alzheimer's disease (AD) (Hansen et al., 1990). In contrast, Perry et al. (1989) have hypothesized that the cortical Lewy bodies found at pathology in PD represent a unique disorder for which they coined the term senile dementia of the Lewy body type (SDLT).