Summary

Lewy bodies are neuronal cytoskeletal inclusions that contain ubiquitin and neurofilament proteins. Lewy bodies are found in a wide range of clinical settings, ranging from clinically normal people to those with various extrapyramidal movement disorders to those with a progressive dementia. There is a rough correlation between the number and distribution of Lewy bodies and the degree of cognitive impairment. People with numerous and widespread Lewy bodies are inevitably demented. The frequency of both Lewy bodies and senile changes of the Alzheimer type increase in frequency with age, and not surprisingly coexist in some patients. This has lead to controversy as to whether Lewy body disease (LBD) may actually be a variant of Alzheimer's disease (AD). It is our working hypothesis, on the other hand, that the two disorders are independent, and that when AD pathology is present in LBD, it represents an independent disease process. Qualitative differences in cytoskeletal pathology in LBD and AD associated with senile plaques and in certain regions of the limbic lobe support this hypothesis. Specific molecular markers for LBD do not currently exist, but recent studies suggest that frequency of apolipoprotein E e4 allele may be increased in Lewy body disorders with coexistent AD, but apparently not in LBD without AD type pathology.

Neuropathology of aging

Insights from prospective clinicopathological studies

Prior to the 1980s there was a paucity of hard scientific information about the pathological correlates of cognitive changes that accompany normal aging. Most of the pathological studies prior to that time were based on small case studies or retrospective analyses for which longitudinal quantitative neuropsychological data were usually not available.

Summary

Two alternative hypotheses – that there is either a unitary or a multiple neuropathological basis for dementia in diseases associated with Lewy bodies – are considered in relation to Parkinson's disease (PD) and Lewy body dementia (LBD including senile dementia of Lewy body type, SDLT). Densities of limbic (cingulate) cortical Lewy bodies, neocortical Lewy bodies, neocortical plaques, neocortical tangles, Braak staging, and Apo E frequency have been quantified in PD (demented and nondemented), SDLT, and Alzheimer's disease (AD with presenile and senile onset). Of these parameters the mean density of cingulate Lewy bodies is significantly greater in SDLT compared with all PD cases. There is no obvious correlation between Lewy body density and cognitive impairment assessed using a simple test of mental ability, and other measures of mental function in LBD may need to be considered. Since there is no absolute density of limbic Lewy bodies that clearly differentiates SDLT or demented PD cases from all nondemented PD cases, neuropathological criteria may need to incorporate severity of Alzheimer-type pathology as an additional optional factor. Mean neocortical plaque density is significantly lower in SDLT compared with AD cases but it is also significantly higher than in demented and nondemented PD cases, and higher than densities in normals. Even so, neocortical plaque density does not itself differentiate all SDLT cases from the normal. It is likely that the biological basis for dementia or psychoses in LBD, a cardinal feature of which is fluctuating symptomatology, is in part a functional or neurochemical abnormality.

Summary

Hallucinations are one of the defining features of the clinical syndrome associated with cortical Lewy body pathology. However, it is not clear whether the time course of hallucinations in Lewy body dementia is different from that in other dementias. We therefore studied the natural history of hallucinations in dementia. Since neuroleptics may be used to treat hallucinations and may have deleterious effects, we also examined the impact of neuroleptic use on cognitive decline. Ninety-eight patients with dementia were assessed every 4 months on a median of eight occasions. Fifty-one patients came to autopsy. Our longitudinal study shows that hallucinations beginning within the first three years of dementia are associated with cortical Lewy body pathology and reduced life expectancy. Patients with cortical Lewy body pathology were more likely to have persistent as opposed to fleeting hallucinations. This information could be incorporated into operational clinical criteria for Lewy body dementia. We did not find an increased mortality amongst those with cortical Lewy body pathology who took neuroleptics. However, men who took neuroleptics had a more rapid rate of cognitive decline than those who did not. This association was not apparent in women. We did not find evidence of increased fluctuation in cognitive ability in the Lewy body group.

Introduction

The appearance of hallucinations in the context of dementia has implications for diagnosis, prognosis and management. The possibility that hallucinations occur as part of a clinical syndrome is suggested by the findings that hallucinations co-occur more commonly than would be expected with fluctuating cognitive impairment (Ballard et al., 1993) and with extrapyramidal symptoms in patients having a clinical diagnosis of Alzheimer's disease (Mayeux et al., 1985).

Summary

The clinical features of diffuse Lewy body disease (DLBD) in the elderly were retrospectively reviewed in 12 cases which had been diagnosed on pathological grounds. Their ages at onset and at death were between 60 and 85 years and between 76 and 92 years respectively. All of them had dementia of mild to severe degree, and eight presented with persistent severe hallucination-delusion psychosis with or without delirium. A single case presented with symptoms typical of Parkinson's disease including resting tremor, cogwheel rigidity and akinesia, while four of them showed no parkinsonian features. In the other seven, dementia or psychosis was followed by rigidity and akinesia at a late stage in the disease. Four had a history of orthostatic hypotension with syncope reminiscent of Shy-Drager syndrome. One can suspect DLBD when an elderly patient presents with atypical dementia of varying degrees, in combination with any of persistent delusion-hallucination psychosis, mild parkinsonism, and orthostatic syncope or dizziness.

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 a manner identical to that seen in Parkinson's disease (Kosaka et al., 1980; Kosaka et al., 1984). Marked senile changes including abundant senile plaques and Alzheimer neurofibrillary tangles of diverse degree are also found in the elderly patients.

These criteria are proposed as being able to predict with high likelihood that dementia is associated with cortical Lewy bodies. They represent a refinement of earlier criteria proposed for Lewy body dementia. They are potentially applicable to patients with idiopathic Parkinson's disease who subsequently develop dementia. These criteria do not exclude the presence of concomitant Alzheimer pathology and many patients may simultaneously meet guidelines for the clinical diagnosis of Alzheimer's disease.

1. The central feature required for a diagnosis of DLB is progressive cognitive decline of sufficient magnitude to interfere with normal social or occupational function. Prominent or persistent memory impairment may not necessarily occur in the early stages, but is usually evident with progression. Deficits on tests of attention and of frontal-subcortical skills and visuospatial ability may be especially prominent.

2. […]

Summary

Lewy bodies (LB), the pathological hallmark of Parkinson's disease, occur in cortical as well as subcortical areas in the brains of about 10?–30% of patients with dementia clinically consistent with Alzheimer's disease (AD). Lewy body dementia (LBD) overlaps with AD both at autopsy, where most demented patients with cortical LB also have senile and neuritic plaques and to a lesser extent the neurofibrillary tangles typical of AD, and clinically, where patients with LBD generally meet clinical criteria for probable or possible AD. The nosology of LBD and proposed diagnostic criteria therefore need to take cognizance of AD.

A major pathological problem is how many plaques, tangles, or both are required to diagnose AD in the presence of LB. Similarly, since nondemented PD patients also show cortical LB, should LBD be defined pathologically by a threshold cortical LB count? A descriptive and quantitative approach to pathology in well-characterized patients with dementia (AD and LBD), and PD (with and without dementia) is needed.

Clinical criteria for LBD have been proposed and validated in studies that retrospectively reviewed entire case records. Key features are parkinsonian signs, cognitive fluctuations, hallucinations, and a ‘frontalsubcortical’ dementia profile. There are problems in reliably assessing and documenting each of these elements. We suggest a flexible approach that is compatible with published criteria and studies, and includes categories of probable and possible LBD, to help determine which combination of features optimally discriminates LBD from ‘pure’ AD and other dementias.

Summary

Among 290 demented subjects in a consecutive autopsy series of elderly individuals with or without parkinsonian signs, 41 cases or 14.1% showed abundant subcortical and cortical Lewy bodies satisfying the diagnosis of Lewy body dementia (LBD) they represented 35.7% of demented patients with parkinsonism (54% of those with idiopathic Parkinson's disease) (IPD) and 26.1% of confirmed cases of Alzheimer's disease (AD) with parkinsonism. Both elderly subjects without clinical parkinsonism (n = 83) and IPD patients (” = 39) showed significant negative correlations between Mini-Mental State and neuritic Alzheimer stages, while 10 of 18 LBD cases clinically presenting with IPD and dementia did not satisfy the CERAD criteria for AD but represented ‘plaque-only’ type of AD. The 41 cases of autopsy-proven LBD showed a female preponderance (31/10), mean age at death of 76 + 10.8 years and mean duration of 5.2 + 4.1 years. Among 31 clinically well documented LBD cases, all except 4 were severely demented, with initial cognitive impairment in 58%, parkinsonian symptoms in 26%, and later combination of both in 84%. Neuropathology revealed LBD without AD pathology in one, LBD with ‘plaque-predominant’ AD and CERAD-definite AD in 15 cases each. Morphometric analyses showed about 70% neuronal loss in the cholinergic nucleus basalis of Meynert in LBD, demented IPD, and AD cases. While these data suggest the importance of both cortical AD pathology and dysfunction of the ascending cholinergic system for mental decline in these disorders, both the significance of cortical Lewy bodies and the pathogenic relationships between IPD, LBD and LBD + AD await further elucidation.

Summary

Degeneration of the substantia nigra with Lewy bodies in remaining neurones is a key pathological marker of Parkinson's disease (PD). A number of observations suggest that processes of oxidative stress are taking place within substantia nigra in PD. Oxidative stress, and the associated finding of reduced activity of complex I of the mitochondrial respiratory chain, might be a primary cause of the pathology of PD. We have tested this hypothesis by examining indices of oxidative stress and mitochondrial enzyme activity in another brain region in which Lewy bodies are known to occur in PD, namely the substantia innominata. We have also examined similar indices in cingulate cortex of brains from patients with senile dementia of the Lewy body type. Tissues from Alzheimer's disease (SDAT) have also been included for comparison. These studies have shown that oxidative stress and altered mitochondrial activity do not necessarily occur in the other regions containing Lewy bodies, although there is evidence for oxidative stress in the same brain regions in SDAT. Oxidative stress and reduced mitochondrial complex I activity appear to be confined to the substantia nigra in PD, and may reflect the peculiar vulnerability of the substantia to such processes.

Introduction

The primary pathology of Parkinson's disease (PD) is the degeneration of the dopamine containing, pigmented neurones of the substantia nigra pars compacta, with Lewy bodies in remaining neurones. Neuronal loss with Lewy bodies is however more widespread involving a range of pigmented catecholamine-containing brain stem nuclei, such as the locus coerulus, as well as non-pigmented, non-catecholamine containing nuclei, such as the substantia innominata.

Summary

Using computerized neuropsychological tests of nonverbal visual recognition memory and attention/planning (which require intact temporal and fronto-striatal circuitry respectively), we have obtained evidence to support the view that senile dementias of Alzheimer's (SDAT) and Lewy body (SDLT) type can be distinguished from each other. The main conclusions reviewed here are that while both SDAT and SDLT patients suffer severe mnemonic deficiencies, which reflect degeneration of temporal lobe structures, SDLT patients have, in addition, attentional impairments which could arise from damage to dopaminergic frontostriatal mechanisms. In this latter respect, the cognitive aspects of the SDLT disorder resemble those seen in Parkinson's disease (PD) patients and others with frontal lobe dysfunctions.

Introduction

This review does not need to begin with a description of Lewy body dementia; the numerous reports in this book bear testimony to growing research interest in this disease. The aim is to provide a neuropsychological contribution to these efforts. But what can neuropsychology offer? By studying alterations in specific cognitive abilities under controlled conditions in a large group of subjects, we can obtain a precise idea of the nature of cognitive decline in the disorder and contrast it with related diseases such as senile dementia of the Alzheimer type. Moreover, experimental studies – usually on animal subjects – have, over many years, provided us with a great deal of evidence as to which neural pathways mediate what cognitive processes. Thus, neuropsychological studies can help pinpoint the neuroanatomical focus of a given cognitive dysfunction.

Summary

Noncognitive symptoms, particularly visual hallucinations and systematized delusions, are frequent symptoms in patients with Lewy body dementia (LBD) and may dominate the clinical picture. The neurobiological basis for these symptoms appears to be an imbalance in cortical monoaminergicxholinergic function.

Because these psychotic symptoms are distressing and may precipitate requests for institutionalization, clinicians frequently attempt pharmacological management, usually with neuroleptic medication. Abnormal sensitivity of LBD patients to neuroleptic medication has been established in two retrospective casenote studies in Newcastle. The increased mortality associated with neuroleptic medication is two- to threefold, 50% of neuroleptic treated patients being susceptible. Review of the case literature suggests that similar neuroleptic sensitivity responses have been noted in other centres but their clinical significance has not been appreciated. The mechanism underlying neuroleptic sensitivity in LBD appears to be nigrostriatal dopaminergic depletion, associated with a failure of adaptive upregulation of postsynaptic striatal D2 receptors.

These early reports of neuroleptic sensitivity in <B>LBD have already had an impact upon UK regulatory recommendations about the need for caution in neuroleptic prescribing in elderly patients with dementia. A systematic approach to the management of noncognitive symptoms in patients with LBD is described, and novel approaches including the use of atypical antipsychotics and cholinergic enhancers are discussed.

What are the ‘noncognitive’ symptoms of dementia?

It is the behavioural changes associated with dementia, rather than impairment of memory or other intellectual functions per se, which are the most frequent source of distress to sufferers and carers, and which act as major determinants of outcome, including the rate of cognitive decline, the probability of institutionalization and the survival time until death (Rabins, 1994).

The Workshop on Pathology addressed the following questions and objectives.

1. Lesions which need to be distinguished in the pathological assessment of Lewy body dementia and the methods which should be used in their pathological evaluation.

1. 2. Pathological diagnostic criteria and assessments which should:

1. (a) be applicable to general diagnostic work

2. (b) facilitate clinical correlative research studies

3. (c) anticipate developments in identification of genetic linkages with disease

4. (d) be nonjudgemental in relation to clinical syndromes

1. 3. Key areas for future pathological investigation.

2. 4. The relationship between the different terms which have been used to describe this condition (diffuse Lewy body disease, senile dementia of Lewy body type, Lewy body variant of Alzheimer's disease, cortical Lewy body disease, Lewy body dementia).

Terms of reference

It was agreed that the area of discussion comprised the neuropathology of patients who have cognitive decline associated with the presence of Lewy bodies (LB). For the purposes of the discussion the term ‘dementia with Lewy bodies’ (DLB) was considered most appropriate.

What lesions are significant?

The workshop identified the following pathological features as being relevant to DLB:

The nature of the Lewy body

It was agreed that Lewy bodies were, in general, easily identifiable intracytoplasmic eosinophilic inclusion bodies, being usually spherical but displaying other morphological forms. The terms brainstem, or classical Lewy bodies, were endorsed to describe the inclusions with a hyaline core and pale halo typically seen in nigral and locus coeruleus neurons. The term cortical Lewy body (CLB) was endorsed to describe the less well defined spherical inclusions seen in cortical neurons.

Summary

Dementia associated with Lewy bodies (here termed Lewy body dementia) is potentially recognizable in life. Clinical features such as fluctuations in cognitive performance, recurrent visual hallucinations and systematized delusions and spontaneous parkinsonism are all suggestive of the diagnosis and may occur before the dementia is established. Early gait disturbance, unexplained falls and sensitivity to neuroleptic treatment are also useful clinical pointers. The dementia itself is characterized by deficits in memory and language, together with a greater degree of impairment of attention, visuospatial skills and psychomotor processing than is seen in Alzheimer's disease. Two sets of clinical diagnostic criteria based upon some of these features have been proposed and validated by the Nottingham and Newcastle groups; both demonstrate good specificity but the Newcastle criteria appear to have superior sensitivity. A new set of consensus criteria, combining the most valuable features of both existing efforts, would represent an important advance in the clinical diagnosis of Lewy body dementia.

Introduction

There is an increasing consensus that the syndrome of dementia associated with Lewy bodies may be recognizable in life and distinguishable from other dementia syndromes such as Alzheimer's disease. This distinction would be valuable for research, especially for drug trials. But an accurate diagnosis of Lewy body dementia is even more important in routine clinical practice. Patients with Lewy body dementia may present with psychiatric rather than cognitive symptoms, including hallucinations, delusions or fluctuating confusional states; early recognition in these patients may allow a safer and more rational approach to investigation and treatment. In patients with established dementia, these same manifestations pose particular management pitfalls which are at least potentially avoidable.

Summary

Only a minority of Lewy body dementia brains lack concomitant Alzheimer disease pathology, but the percentages of combined Lewy body disease and Alzheimer disease versus pure Lewy body disease vary depending upon what neuropathological criteria are employed to make a diagnosis of Alzheimer disease. Using criteria from the Consortium to Establish a Registry for Alzheimer Disease, nearly 90% of all Lewy body dementia brains have definite or probable Alzheimer disease. Such Lewy body variants of Alzheimer disease also show medial temporal lobe neurofibrillary pathology intermediate in severity between that seen in pure Alzheimer disease and that encountered in elderly nondemented controls or pure Lewy body disease patients. Like Alzheimer disease, but unlike pure Lewy body disease, Lewy body variants of Alzheimer disease have an increased apolipoprotein ∈4 allelic frequency. If myriads of neocortical neurofibrillary tangles are deemed requisite for a diagnosis of Alzheimer disease, the percentage of mixed Alzheimer disease and Lewy body disease falls from 89% of all Lewy body dementia brains to 32%. Even in the absence of concomitant Alzheimer disease pathology, nosologic uncertainty persists in Lewy body disease since no established neuropathologic criteria can reliably distinguish pure Parkinson's disease from so-called diffuse Lewy body disease.

Introduction

‘When I use a word’, Humpty Dumpty said in a rather scornful tone ‘It means just what I choose it to mean – neither more nor less.’ ‘The question is,’ said Alice, ‘Whether you can make words mean so many different things.’ ‘The question,’ said Humpty Dumpty, ‘Is which is to be master – that's all.’

Summary

Cortical Lewy bodies are the defining pathological feature of Lewy body dementia. Ultrastructural, immunocytochemical and direct biochemical analysis confirm that Lewy bodies represent intraneuronal perikaryal accumulations of phosphorylated neurofilament proteins. Lewy bodies are thus a marker that the normal architecture of the neuronal cytoskeleton is disrupted.

Considerable evidence points to cytoskeletal disruption as a constituent part of the molecular pathogenesis of neurodegeneration. In terms of these cytoskeletal-related changes, Lewy body diseases appear to result from a disorder of neurofilament accumulation, in contrast to Alzheimer's disease in which the microtubule-associated protein, tau, accumulates. The two diseases appear to be distinct at a molecular level and evidence is amassing for a distinction at the genetic level. It seems that for both Alzheimer's disease and Lewy body dementia phosphorylation of cytoskeletal proteins is altered.

Experimental models have shown that changes in expression of neurofilaments lead to disruption of neurofilament assembly, neurofilament pathology and neuronal loss. Evidence is reviewed here that changes in neurofilament processing are intrinsic to the neurodegenerative process in Lewy body dementia.

Introduction

Alzheimer's disease (AD) is characterized by the pathological lesions of amyloid plaques and neurofibrillary tangles. In addition to plaques and tangles however, AD brains often contain cortical Lewy bodies which are also found in a subset of dementia patients with relatively few or even no discernible tangles. Neurofibrillary tangles are composed principally of abnormally phosphorylated tau assembled into paired helical filaments (PHF-tau), structures not confined to intracellular tangles but widely distributed in the brain as neuropil threads, extracellular tangles and in plaque associated neurites. How do these pathological lesions relate to each other – if at all?