Dementia with Lewy bodies

The objective was to summarize recent findings about the clinical features, diagnosis and investigation of dementia with Lewy (DLB) bodies, together with its neuropathology, neurochemistry and genetics. Dementia with Lewy bodies (DLB) is a primary, neurodegenerative dementia sharing clinical and pathological characteristics with both Parkinson's disease (PD) and Alzheimer's disease (AD). Antiubiquitin immunocytochemical staining, developed in the early 1990s, allowed the frequency and distribution of cortical LBs to be defined. More recently, alpha-synuclein antibodies have revealed extensive neuritic pathology in DLB demonstrating a neurobiological link with other "synucleinopathies" including PD and multiple system atrophy (MSA). The most significant correlates of cognitive failure in DLB appear to be with cortical LB and Lewy neurites (LNs) rather than Alzheimer type pathology. Clinical diagnostic criteria for DLB, published in 1996, have been subjected to several validation studies against autopsy findings. These conclude that although diagnostic specificity is high (range 79- 100%, mean 92%), sensitivity is lower (range 0- 83 %, mean, 49%). Improved methods of case detection are therefore required. Fluctuating impairments in attention, visual recognition and construction are more indicative of DLB than AD. Relative preservation of medial temporal lobe volume on structural MRI and the use of SPECT tracers for regional blood flow and the dopamine transporter are the most reliable current biomarkers for DLB. There are no genetic or CSF tests recommended for the diagnosis of DLB at present. Between 15 and 20% of all elderly demented cases reaching autopsy have DLB, making it the most common cause of degenerative dementia after AD. Exquisite, not infrequently fatal, sensitivity to neuroleptic drugs and encouraging reports of the effects of cholinesterase inhibitors on cognitive, psychiatric and neurological features, mean that an accurate diagnosis of DLB is more than merely of academic interest. Dementia developing late in the course of PD shares many of the same clinical and pathological characteristics.     

Alzheimer’s disease pathology in motor cortex in dementia with Lewy bodies clinically mimicking corticobasal degeneration

We report here a 70-year-old woman whose initial clinical presentation suggested corticobasal degeneration, but autopsy revealed dementia with Lewy bodies (DLB) with severe Alzheimer’s disease (AD)-type pathology accentuated in the motor cortex, in conjunction with a high burden of both cortical and brain stem LB. Review of the literature disclosed four patients with AD whose peri-Rolandic region was particularly involved by the disease and who exhibited similar clinical and neuropathological findings as in our patient except they lacked LB. It appears that DLB if associated with severe AD-type pathology can, like some unusual cases of AD, mimic corticobasal degeneration. Received: 20 October 1998 / Revised, accepted: 15 February 1999     

Dementia with Lewy bodies

The advent of new immunostains have improved the ability to detect limbic and cortical Lewy bodies, and it is evident that dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia, after Alzheimer's disease (AD). Distinguishing DLB from AD has important implications for treatment, in terms of substances that may worsen symptoms and those that may improve them. Neurocognitive patterns, psychiatric features, extrapyramidal signs, and sleep disturbance are helpful in differentiating DLB from AD early in the disease course. Differences in the severity of cholinergic depletion and type/distribution of neuropathology contribute to these clinical differences.     

Dementia with Lewy bodies and Parkinson's disease

Lewy bodies (LB) in the central nervous system are associated with several different clinical syndromes including Parkinson's disease (PD) and dementia with Lewy bodies (DLB). Long term follow up of PD patients finds up to 78% eventually develop dementia, most of these patients exhibiting fluctuating cognition and visual hallucinations similar to DLB and with extensive cortical LB at autopsy. alpha-Synuclein positive, neuritic pathology, in the putamen of DLB and Parkinson's disease dementia (PDD), may contribute to postural-instability gait difficulty, parkinsonism, diminished levodopa responsiveness and increased neuroleptic sensitivity. Cognitive and neuropsychiatric symptoms improve with cholinesterase inhibitor treatment in both patient groups. DLB and PDD should be seen as different points on a spectrum of LB disease. Distinguishing them as separate disorders may be useful in clinical practice, but may be of limited value in terms of investigating and treating the underlying neurobiology.     

The morphological basis of mental dysfunction in Parkinson's disease

Mental dysfunction including dementia in Parkinson's disease (PD), the incidence of which averages 20-40%, is suggested to have six-fold lifetime risk compared to age-matched controls. It is caused by a variety of functional and pathological lesions ranging from damage to subcortical-cortical networks to cortical and limbic Lewy body and neuritic Alzheimer pathologies, the relationship and impact of which are still under discussion. Based on two consecutive autopsy series of PD, with prevalence of cognitive impairment of 33% to 35.7%, its essential morphological changes and their impact on the natural history (survival) are discussed. Whereas cortical Lewy body stages 5 and 6 without additional pathologies only rarely were associated with dementia, around 20% of demented PD cases were classified as dementia with Lewy bodies (DLB) with variable degrees of Alzheimer (AD) pathology, and around one third showed severe neuritic AD lesions which occurred in PD patients with later disease onset and significantly shorter survival. Frequent close relations in the severity between alpha-synuclein and tau-pathologies suggest synergistic reaction and common underlying pathogenesis of both lesions. Clinico-pathological studies in PD showed a significantly negative relation between cognitive impairment and neuritic AD lesions somewhat different from that in AD, suggesting that neuritic AD pathology, either alone or in combination with cortical and limbic Lewy bodies, are major causes of mental and cognitive dysfunction in PD.     

Neuropathology of three clinical cases prospectively diagnosed as dementia with Lewy bodies

Concensus guidelines for the clinical and pathological diagnosis of dementia with Lewy bodies have recently been proposed based on retrospective studies (McKeith IG, Galasko D, Kosaka K et al. Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996; 47: 113–1124.) The present study tests these criteria prospectively in three cases which came to autopsy: a 57-year-old female followed for 5 years, an 86-year-old male followed for 3 years and a 66-year-old male followed for 11 years. All were considered to have dementia with Lewy bodies clinically, and at autopsy all had pathologically confirmed Lewy body disease. However, the Lewy bodies found in the 57-year-old were scanty and she also had marked Alzheimer-type pathology, making the contribution of Lewy bodies to the dementia uncertain. The 66-year-old had unusual cortical Lewy body pathology, previously only described in one other case (Masliah E, Galasho D, Wiley CA, Hansen LA. Lobar atrophy with dense-core (brain stem type) Lewy bodies in a patient with dementia. Acta Neuropathol 1990; 80: 453–458.) While this study prospectively validates the current criteria for dementia with Lewy bodies, there was considerable pathological variability in the cases.     

Neuroleptics are associated with more severe tangle pathology in dementia with Lewy bodies

BACKGROUND: Neuroleptics are only modestly effective in dementia and associated with a range of adverse effects including cognitive decline. Effects of the drugs on molecular pathology in brain tissue from people with dementia have not been investigated. OBJECTIVES: To compare the severity of Alzheimer type pathology in matched groups of people with dementia with Lewy bodies (DLB), treated and not treated with neuroleptics. METHODS: The relationship between neuroleptics and Alzheimer-type pathology was determined in 40 (17 neuroleptic treated, 23 neuroleptic free, matched for age, disease duration and psychosis) clinically prospectively studied, autopsy diagnosed DLB patients. RESULTS: In regression analyses, taking neuroleptics was significantly associated with increased neurofibrillary tangles but not amyloid plaques in cortical areas examined. The patient characteristics and the frequencies of key psychiatric symptoms were similar in the patients taking and not taking neuroleptics. CONCLUSION: Although patients were not randomized and the results which are observed need to be interpreted cautiously, if substantiated, this is an important finding with major implications for the pharmacological management of DLB patients and highlights the need to determine the impact of neuroleptics upon tangle pathology in AD.     

Comparison between Alzheimer's disease and vascular dementia: implications for treatment

Virtually 90% of the elderly with late-onset dementia exhibit neuropathological features consistent with Alzheimer's disease (AD), vascular dementia (VaD) or dementia with Lewy bodies (DLB), alone or in combination. Both AD and DLB reveal extensive senile plaques containing amyloid beta whereas neurofibrillary tangles evident as tau pathology are fewer in DLB, which also bears diffuse cortical Lewy bodies. Interestingly, however, there is considerable overlap between AD and VaD in terms of both risk factors and pathology. Cholinergic deficits are also encountered in VaD, which like AD may respond to cholinergic therapy. Cerebrovascular pathology, ischemic brain damage and autonomic dysregulation resulting in cerebral hypoperfusion appears fundamental in the pathogenesis of late-onset dementias.     

Fulminant Lewy body disease.

The clinical distinction between Parkinson's disease (PD) with dementia (PDD) and dementia with Lewy bodies (DLB) is challenged by most neuropathological studies showing nearly identical changes in both conditions. We report an unusual case of PD evolving into a rapidly progressive dementia leading to death within 3 months that showed nearly all clinical features of DLB. At autopsy, numerous Lewy bodies and Lewy neurites were found in several areas of the brainstem, the limbic system, and the neocortex, consistent with pure DLB. This case demonstrates that Lewy body disease may exhibit a dramatic course without any coexisting pathology and exemplifies that PD, PDD, and DLB may sometimes represent sequential, yet overlapping, phenotypes of a same clinicopathological entity.     

An atypical autopsy case of Lewy Body disease with clinically diagnosed major depression: A clinical,radiological and pathological study

We report an 84‐year‐old woman who was clinically diagnosed with late‐life major depression (LLMD) and having a diffuse type of dementia with Lewy bodies (DLB) neuropathologically. Clinically, this case showed depressive mood, anxiety, and irritation, but did not show cognitive dysfunction, visual hallucination, fluctuation of alertness and parkinsonism, which define the criteria for diagnosing DLB. Neuropathological examination demonstrated abundant Lewy‐related pathology including Lewy bodies and neurites in the hippocampal region and the cerebral cortex, and moderate levels in brain stem nuclei including the substantia nigra, locus ceruleus and dorsal raphe nucleus. These findings suggest the possibility that Lewy‐related pathology is associated with the depressive symptoms. Furthermore, it must be noted that some patients diagnosed with LLMD clinically may develop pathology of DLB without the typical or usual clinical symptoms.     

An autopsied case of Down syndrome with Alzheimer pathology and α-synuclein immunoreactivity

An autopsied case of a 49-year-old man with Down syndrome is described. The patient developed mental deterioration and parkinsonism at the age of 44 years. The brain revealed Alzheimer's disease (AD) pathology in addition to anomalies and lesions of premature senility. In the substantia nigra, many neurofibrillary tangles (NFT) and some Lewy bodies (LB) were found, suggesting that a limited degree of Parkinson's disease (PD) pathology may combine with AD pathology to develop parkinsonism. However, spongiform change and ubiquitin-positive spheroids in the central nucleus of the amygdala, which are peculiar to dementia with Lewy bodies (DLB), were observed, suggesting that the substantia nigra lesion is similar to that of DLB rather than that of PD. In addition, α-synuclein-positive neurons in the limbic areas, predominantly in the amygdala, were found. Their incidence and distribution did not fulfill the criteria of DLB. These neurons did not show the typical features of cortical type LB, and were mostly accompanied by tau-positive NFT. These findings suggest that the presence of α-synuclein-positive neurons does not always indicate the presence of LB, and that the present case should not be regarded as the complication of DLB in Down syndrome.     

Cortical Lewy body pathology in the diagnosis of dementia

Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) are distinguishable clinically but often not neuropathologically. This study aims to test whether the distribution of cortical Lewy bodies differs in these clinicopathological groups and to develop diagnostic protocols for their differentiation. Brains were obtained at autopsy from cases recruited from prospective clinical studies of dementia or movement disorders. All cases with significant pathologies other than Lewy bodies or plaques were excluded. Cases were categorised into either PD without dementia, DLB (dementia first or within 2 years of disease onset), or PD with a later onset of dementia (PDD). The distribution and density of Lewy bodies and Lewy neurites was determined using antibodies to ubiquitin and alpha-synuclein. Cortical Lewy body densities could not separate cases of DLB from those with PDD. However, semiquantitative thresholds in the parahippocampus could separate demented from non-demented cases with high sensitivity and specificity. Interactions between multiple pathologies were determined using factor analysis. Although many cases had CA2 Lewy neurites, this was not associated with severity or duration of either dementia or parkinsonism. Most DLB cases had significant plaque pathology, and severity and duration of dementia was related to both increasing parahippocampal Lewy body densities and neuritic plaque grade. Weighted kappa statistics revealed that the combination of these pathologies indicated a more severe dementia. These results suggest that dual pathologies cause DLB, and high densities of parahippocampal Lewy bodies indicate dementia regardless of additional pathologies.     

Lewy body pathology is a frequent co-pathology in familial Alzheimer's disease

Our institution is currently engaged in ongoing genetic studies of familial Alzheimer's disease (AD), which include clinical ascertainment and brain autopsy of both affected and non-affected family members. Here we describe the analysis of 22 AD families, each with at least one family member with a postmortem diagnosis of dementia with Lewy bodies (DLB). For this study, 47 brains were examined according to NINCDS-Reagan Institute criteria for the diagnosis of AD. Lewy body pathology was evaluated with alpha-synuclein immunohistochemistry. Four families, with either one or two autopsies showing Lewy body pathology, demonstrated linkage to 12p. Five families had two or more autopsies with Lewy body pathology, but their linkage status was unknown. The remaining 13 families had one autopsy demonstrating Lewy bodies. These findings suggest that at least one pathological form of DLB may be familial. In some families, the pathological phenotype is identical in all examined affected family members; but in others, there may be several pathologies that coexist. Careful neuropathological examination of affected family members may prove critical for future genetic analysis of AD and DLB.     

Cholinesterase inhibitors reduce cortical Abeta in dementia with Lewy bodies

Cholinesterase inhibitors (ChEIs) are effective symptomatic treatments in dementia with Lewy bodies (DLB), although effects on pathologic mechanisms are unknown. In the first human autopsy study examining the impact of ChEI treatment on brain pathology, we compared treated patients with DLB with matched untreated patients for cortical beta-amyloid (Abeta) and tau pathologies. Treated patients with DLB had significantly less parenchymal Abeta deposition, which is relevant to disease management and treatment of dementia patients using ChEI.     

The Alzheimer variant of lewy body disease: a pathologically confirmed case-control study

The objective of the study was to identify clinical features that distinguish patients with dementia with Lewy bodies (DLB), who were classified as Alzheimer's disease (AD) patients, from patients with AD. We examined a group of 27 patients from our memory clinic, originally diagnosed with AD, of whom 6 were postmortem found to have DLB. For the present study, we compared cognitive, noncognitive and neurological symptoms between the two groups. We found that there were no differences on ratings of dementia and scales for activities of daily living. Patients with DLB performed better on the MMSE and the memory subtest of the CAMCOG, but there was no difference in any other cognitive domain. Furthermore, genetic risk factors, including family history of dementia or allele frequency of the apolipoprotein epsilon4, did not discriminate between the two groups, and there were no differences on CCT scans. Taken together, our findings suggest that Lewy body pathology may be present in patients who do not show the typical clinical features which distinguish DLB from AD.     

Neuropathology of Parkinson's disease dementia and dementia with Lewy bodies with reference to striatal pathology

Dementia is relatively common in Parkinson's Disease (PD). When dementia occurs in the setting of PD, it is referred to as Parkinson's disease dementia (PDD), which is distinguished from the clinical syndrome in which dementia precedes extrapyramidal features, dementia with Lewy bodies (DLB). In this report, the neuropathology of PDD and DLB is reviewed and preliminary findings are reported on striatal pathology in 28 brains, including 7 PD, 7 PDD and 14 DLB. Sections of putamen immunostained for a-synuclein and investigated with image analysis show that striatal pathology is common and that both cortical and striatal a-synuclein pathology is greater in PDD and DLB than PD. Most cases of PDD and DLB have Alzheimer-type pathology, particularly amyloid plaques, which may act in an additive or synergistic manner with a-synuclein pathology. There are few pathologic differences between PDD and DLB, despite differences in their clinical course.     

Three years survival in patients with a clinical diagnosis of dementia with Lewy bodies

The majority of information available on the prognosis of dementia with Lewy bodies (DLB) is based on retrospective data from autopsy series, which are subject to selection bias due to the specific reasons patients are referred for post-mortem studies. The earlier studies comparing DLB patients with patients with Alzheimer's disease (AD) suggest that the mean duration of illness is shorter in DLB patients than in patients with AD. However, more recent studies have not observed significant differences between DLB and AD in age of onset, age at death or duration of illness. We report a 3 year follow-up of a cohort of 114 consecutive patients with dementia, referred to an old age psychiatric service and diagnosed using ICD 10 criteria and the McKeith and Byrne DLB criteria. The case notes of all patients were reviewed to determine the date of onset of symptoms and the date of first presentation to the psychiatric services. Information about outcome was gathered from case notes, hospital files and general practitioner (GP) records. Of the original sample of 114 patients, 106 could be traced. Sixty-four had died and 42 were still alive at the time of the follow-up. Thirty-two patients had originally been assigned the diagnosis of DLB, 43 the diagnosis of AD, 31 vascular dementia and other diagnoses. There were no differences between the AD and DLB group in age at onset, age at death or survival. We have not found any evidence that the prognosis of clinically diagnosed DLB patients is worse than that of patients with a clinical diagnosis of AD.     

Selective loss of dopamine D2 receptors in temporal cortex in dementia with Lewy bodies, association with cognitive decline

Dementia with Lewy bodies (DLB) is a progressive dementia frequently accompanied by psychotic symptoms. Similar symptoms can occur in Alzheimer's disease (AD) to a lesser extent. The use of neuroleptic medication to treat psychosis in both diseases is of modest efficacy and can induce severe adverse reactions in DLB. Dopamine D2 receptors in the cerebral cortex are the putative target for the antipsychotic action of these drugs, but the status of these receptors in DLB is unknown. Autoradiography was used to examine the density D2 receptors in postmortem temporal cortex tissue from prospectively assessed patients with neuropathologically confirmed DLB and AD. D2 receptors were substantially (over 40%) and significantly (P < 0.001) reduced in temporal cortex in DLB, and in DLB with concomitant Alzheimer pathology, but was not significantly changed in AD. This reduction correlated with greater cognitive decline (P < 0.01), but was not significantly related to visual or auditory hallucinations or delusions. D2 receptor density was inversely correlated with cortical Lewy body pathology in the neocortex (P < 0.001). The specific loss of D2 receptors associated with Lewy body pathology, in conjunction with our previous finding of low D2 receptors in striatum in DLB, provides a possible explanation for neuroleptic intolerance. That the reduction of D2 receptors correlated with cognitive decline suggests that neuroleptics, as dopamine D2 receptor antagonists, may have a deleterious effect on cognition in DLB.     

Progressive aphasia with Lewy bodies

Dementia with Lewy bodies (DLB) may include both Alzheimer and Lewy body pathology, but has never been reported to cause primary progressive aphasia. We report a 69-year-old woman who died 11 years after presenting with the syndrome of progressive aphasia. Six years after aphasia onset she developed visual hallucinations, and subsequently parkinsonism. Autopsy examination revealed Alzheimer's disease (AD), cortical Lewy bodies, and depigmentation and Lewy bodies in the substantia nigra and locus ceruleus. The aphasia most likely reflected the initial onset of AD, and the psychosis and parkinsonism most likely reflected the subsequent onset of Lewy body pathology. This first reported case of progressive aphasia occurring within the context of AD and Lewy body pathology uniquely illustrates the clinical and pathological nosological relationships between these two disease processes, and demonstrates a limitation of the general term, 'DLB'.     

Clinicopathologic correlates in temporal cortex in dementia with Lewy bodies

OBJECTIVE: To address the relationship between dementia and neuropathologic findings in dementia with Lewy bodies (DLB) in comparison with AD. METHODS: We evaluated the clinical presentation of autopsy-confirmed DLB in comparison with AD according to new Consortium on DLB criteria and compared the two conditions using quantitative neuropathologic techniques. This clinicopathologic series included 81 individuals with AD, 20 with DLB (7 "pure" DLB and 13 "DLB/AD"), and 33 controls. We counted number of LB, neurons, senile plaques (SP), and neurofibrillary tangles (NFT) in a high order association cortex, the superior temporal sulcus (STS), using stereologic counting techniques. RESULTS: The sensitivity and specificity of Consortium on DLB clinical criteria in this series for dementia, hallucinations, and parkinsonism are 53% and 83%, respectively, at the patient's initial visit and 90% and 68%, respectively, if data from all clinic visits are considered. In pathologically confirmed DLB brains, LB formation in an association cortical area does not significantly correlate with duration of illness, neuronal loss, or concomitant AD-type pathology. Unlike AD, there is no significant neuronal loss in the STS of DLB brains unless there is concomitant AD pathology (neuritic SP and NFT). CONCLUSIONS: The evaluation of new Consortium on DLB criteria in this series highlights their utility and applicability in clinicopathologic studies but suggests that sensitivity and specificity, especially at the time of the first clinical evaluation, are modest. The lack of a relationship of LB formation to the amount of Alzheimer-type changes in this series suggests that DLB is a distinct pathology rather than a variant of AD.