Clinicopathological multiplicity of dementia with Lewy bodies

‘Dementia with Lewy bodies (DLB)’ is a generic clinicopathological concept characterized by progressive dementia and Lewy bodies (LB). We examined 23 autopsied DLB cases clinicopathologically and immunohistochemically. These cases were classified into the neocortical type (10 cases), the limbic type (seven cases), the cerebral type (one case) and the brainstem type (none) according to our pathological criteria, which were based on the regional incidence of LB and the degree of neuronal loss in the substantia nigra. Each subtype of DLB was further divided into the common form and the pure form on the basis of the degree of Alzheimer pathology. The remaining five cases were not classified by our pathological criteria, and were designated ‘the senile dementia of Alzheimer type (SDAT) or Alzheimer's disease (AD) type of DLB with neocortical or limbic LB’. We examined how each subtype was correlated with various clinical features, such as the age of disease onset, the clinical duration, the degree of dementia, and the presence or absence of parkinsonism, fluctuating cognition and visual hallucination. The results of this study indicate that DLB can be clinicopathologically divided into a number of subtypes, that each subtype is preferentially correlated with some clinical feature, and that the neocortical type, common form, is the major type of DLB.     

Progression and staging of Lewy pathology in brains from patients with dementia with Lewy bodies

Using alpha-synuclein-immunohistochemistry, 27 brains of dementia with Lewy bodies (DLB) were investigated to identify the progression of Lewy pathology including Lewy bodies (LB) and LB-related neurites in the cerebrum. The numbers of alpha-synuclein-positive LB and LB-related neurites were semiquantitatively evaluated in the amygdala, hippocampus, entorhinal cortex, transentorhinal cortex, insular cortex, middle temporal cortex and superior frontal cortex. The results indicated that Lewy pathology within the neuron progresses first in the axonal terminal, subsequently in the cell body and finally in the dendrite, that Lewy pathology in the cerebral cortex progresses first in layers V-VI, subsequently in layer III and finally in layer II, and that Lewy pathology in the cerebrum progresses first in the amygdala, subsequently in the limbic cortex and finally in the neocortex. In addition, Lewy pathology was graded from stage I to stage IV based on the progression of Lewy pathology. The 27 brains examined were classified into 3 brains showing stage I, 11 showing stage II, 7 showing stage III and 6 showing stage IV. Comparing these stages with the pathological subtypes of DLB brains, brains of the subtype showing severe Alzheimer pathology corresponded to brains showing an advanced stage, suggesting that Alzheimer pathology exacerbates Lewy pathology.     

Dementia with Lewy bodies: Reclassification of pathological subtypes and boundary with Parkinson's disease or Alzheimer's disease

The present study is an attempt to reclassify the pathological subtypes of DLB based on both Lewy pathology and Alzheimer pathology, and to clarify the pathological boundary between DLB and Parkinson's disease (PD) or Alzheimer's disease (AD) in autopsied cases, using pathological and immunohistochemical methods. Dementia with Lewy bodies was classified into the limbic type and neocortical type according to the degree of Lewy pathology, including Lewy bodies (LB) and LB‐related neurites, by our staging and was classified into the pure form, common form and AD form according to the degree of Alzheimer pathology including NFT and amyloid deposits by Braak staging. These combined subtypes were lined up on a spectrum not only with Lewy pathology but also with other DLB‐related pathologies including Alzheimer pathology, neuronal loss in the substantia nigra, spongiform change in the transentorhinal cortex and LB‐related neurites in the CA2‐3 region. There were some similarities in both Lewy pathology and other DLB‐related pathologies between PD and DLB, although Lewy pathology of PD was below the lowest stage of Lewy pathology. In contrast, AD did not meet the stages of Lewy pathology, and there were also no similarities in other DLB‐related pathologies between AD and DLB. In addition, LB of AD showed the characteristics different from those of DLB on the coexistence of LB with NFT. These present findings suggest that DLB has pathological continuity with PD, but can be pathologically differentiated from AD. The present study clarified the pathological entity of DLB, compared with PD and AD.     

Frequency and distribution of TUNEL‐positive neurons in brains of dementia with Lewy bodies: Comparison with those in brains of Alzheimer's disease

The present study investigated the frequency and distribution of TUNEL‐positive neurons in brains of dementia with Lewy bodies (DLB) in comparison with those in brains of Alzheimer's disease (AD), Down syndrome (DS) and non‐demented elderly persons. In DLB brains, TUNEL‐positive neurons were increased in frequency compared with those in non‐demented elderly brains, and showed a distribution similar to those in AD and DS brains. DLB cases with TUNEL‐positive neurons showing severe Lewy pathology were all neocortical type, while DLB cases of the limbic type showing mild Lewy pathology did not demonstrate TUNEL‐positive neurons. In addition, we investigated the relationships between TUNEL‐positive neurons and pathological hallmarks of DLB or AD brains. TUNEL‐positive neurons had no Lewy bodies or neurofibrillary tangles, and were not located within amyloid deposits. These findings suggest that neuronal damage showing DNA fragmentations occurs in DLB brains as well as in AD and DS brains, and that it is accelerated by progression of Lewy pathology as well as Alzheimer pathology, although it is not directly related to their pathological hallmarks.     

Lewy body variant of Alzheimer’s disease or cerebral type Lewy body disease? Two autopsy cases of presenile onset with minimal involvement of the brainstem

Lewy bodies (LB) usually extend from the brainstem to the cerebrum in patients with Parkinson’s disease. However, whether the patterns of progression of LB and neuronal loss in Parkinson’s disease are identical to those in other Lewy body diseases (LBD) remains unclear. In addition, pathological data on the autonomic nervous system involvement in LBD are limited. We present here the clinicopathological characteristics of two autopsy cases with both Alzheimer’s disease and dementia with Lewy bodies (DLB), possibly diagnosed as having Lewy body variant of Alzheimer’s disease (LBV/AD). Our patients presented clinically with dementia without parkinsonism. Histopathologically, phosphorylated α‐synuclein‐positive LB and Lewy neurites were abundant in the limbic system, especially in the amygdala, and to a lesser degree, in the neocortex, including the primary motor cortex. The amygdala was also most severely affected by neuronal loss, and the other limbic areas and neocortex were affected to a lesser degree. Despite the existence of a small number of LB and many Lewy neurites, neurons in the brainstem nuclei were relatively well preserved. The Braak stages of concurrent neurofibrillary changes and senile plaques were stage V and C, respectively, in both cases. Tyrosine hydroxylase‐positive nerve fibers were relatively well spared in one case examined compared with Parkinson’s disease cases. Furthermore, many Lewy neurites immunopositive for phosphorylated α‐synuclein were found in the nerve fascicles of the epicardium in one case examined and in Parkinson’s disease cases to a lesser degree. These findings suggest that: (i) in at least some LBV/AD cases, the amygdala develops neuronal loss and Lewy‐related pathology prior to the brainstem nuclei; and (ii) the depletion of nerves in the heart tissue of LBV/AD is not necessarily complete despite the development of Lewy‐related pathology.     

Dementia with Lewy bodies showing advanced Lewy pathology but minimal Alzheimer pathology--Lewy pathology causes neuronal loss inducing progressive dementia

The present study concerns an autopsied case of dementia with Lewy bodies (DLB) showing advanced Lewy pathology but minimal Alzheimer pathology. The patient was a 50-year-old Japanese male without inheritance. His initial symptoms at the age of 43 suggested the diagnosis ofjuvenile idiopathic Parkinson's disease (PD), but were followed by memory disturbance 1 year later. He showed parkinsonism, dementia, personality change, fluctuating cognition and visual hallucinations 3 years later. Neuroradiological examination revealed moderate brain atrophy, predominantly in the frontal and temporal lobes. Neuropathological examination demonstrated a widespread occurrence of Lewy bodies (LB) with LB-related neurites not only in the brainstem but also in the cerebrum. The present case showed Lewy pathology which corresponded to stage IV by our staging and was parallel to neuronal loss. There was marked neuronal loss with many LB-related neurites in the CA2 of the hippocampus. Neurofibrillary tangles (NFT) were almost restricted to the entorhinal cortex, while senile plaques were absent. Consequently, the present case was pathologically diagnosed as having DLB of the neocortical type, pure form. In the present study, we suggest that Lewy pathology in the cerebral cortex could be responsible for progressive dementia.     

Autonomic dysfunctions in dementia with Lewy bodies

Twenty-nine cases of both clinically and neuropathologically diagnosed dementia with Lewy bodies (DLB) were retrospectively examined for autonomic symptoms. Twenty-eight cases showed some kind of autonomic dysfunction. Urinary incontinence (97 %) and constipation (83 %) were the two most common. Although urinary retention and episodic hypotension causing syncopal attacks were less common, the frequency was still high (28 % each). There were 18 cases (62 %) with severe autonomic failure. These 28 cases showed similar tendencies, with no significant differences between the subtypes of DLB (brainstem, limbic, and neocortical types or common and pure forms). We found that DLB of all pathological subtypes exhibits some kind and level of autonomic symptoms. Received: 20 August 2002, Received in revised form: 12 November 2002, Accepted: 18 November 2002 Correspondence to Y. Horimoto     

Cerebral type of Lewy body disease

A cerebral type of Lewy body disease (LBD) is proposed. Lewy body disease was split formerly into three types: brainstem type, transitional type and diffuse type. The diffuse type is now called diffuse Lewy body disease (DLBD). These three types are characterized pathologically by the presence of a large number of Lewy bodies in the CNS. In the brainstem type, Lewy bodies are numerous in the brainstem and diencephalon nuclei, and in DLBD, a vast number are present not only in these nuclei but also in the cerebral cortex and amygdala. In the cerebral type of LBD, as many Lewy bodies are found in the cerebral cortex and in the amygdala as there are in DLBD, but only rarely are they present in the brainstem and diencephalon nuclei. Thus, this type of LBD is different from other types in that it has no parkinson pathology. Therefore, parkinsonism fails to occur throughout the whole clinical course of this disease. The existence of a cerebral type of LBD suggests that Lewy bodies occur in the cerebral cortex earlier than in the brainstem nuclei and that cortical Lewy bodies appear even when the mesocortical dopaminergic system is intact. In addition, this might explain why dementia frequently precedes parkinsonism in DLBD.     

Pathological entity of dementia with Lewy bodies and its differentiation from Alzheimer’s disease

We reclassified the pathological subtypes of dementia with Lewy bodies (DLB), based on both Lewy pathology and Alzheimer pathology, to clarify the pathological entity of DLB and the boundary between DLB and Alzheimers disease (AD) in autopsied cases, using both pathological and immunohistochemical methods. DLB was classified as either limbic type or neocortical type according to the degree of Lewy pathology including Lewy bodies (LB) and LB-related neurites by our staging, and was classified as pure form, common form or AD form according to the degree of Alzheimer pathology including neurofibrillary tangles (NFT) and amyloid deposits by Braak staging. These combined subtypes were lined up on a spectrum, not only with Lewy pathology but also with other DLB-related pathologies including Alzheimer pathology, neuronal loss in the substantia nigra, spongiform change in the transentorhinal cortex and LB-related neurites in the CA2–3 region. In contrast, the Lewy pathology of AD did not meet the stages of Lewy pathology in DLB, and there were scarcely any similarities in other DLB-related pathologies between AD and DLB. In addition, the Lewy pathology of AD had characteristics different from that of DLB, including the coexistence rate of LB with NFT, and the immunohistochemical and immunoelectron microscopic findings of LB and LB-related neurites. These findings suggest that DLB is a distinctive pathological entity that can be differentiated from AD, although it shows some pathological subtypes.     

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.     

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.     

Diffuse Lewy body disease

Diffuse Lewy body disease (DLBD) has been studied from various viewpoints and, although clinical diagnostic criteria for DLBD have been proposed, diagnosis remains difficult. DLBD has been reported to be the second most common form of dementia in the aged, following Alzheimer‐type dementia. It has, however, been clinically under‐diagnosed. Therefore, the search for diagnostic markers for DLBD must continue. Very recently, ‘dementia with Lewy bodies’ (DLB) was proposed as a generic term for various forms of dementia with Lewy bodies, including DLBD and similar disorders. Cortical Lewy bodies are the most important pathologic marker for diagnosis of DLBD. At present, however, the mechanism responsible for cortical Lewy body formation has yet to be disclosed.     

The first autopsied case of diffuse Lewy body disease (DLBD): re‐examination by recent immunostaining methods

Materials from our first autopsied case of diffuse Lewy body disease (DLBD), that was originally reported in 1976, were re‐examined using recent immunohistochemical methods. Lewy pathology consisting of Lewy bodies and Lewy neurites appeared much more marked with alpha‐synuclein immunostaining than had been detected with classical stainings. This case and our other similar cases prompted us to propose the terms “Lewy body disease” in 1980 and “diffuse Lewy body disease” in 1984. We also reported in 1990 that DLBD was classified into two forms: a pure form and a common form. Based on these studies the term “dementia with Lewy bodies (DLB)” was proposed in 1996. Since 1980, we have insisted that DLB, Parkinson disease (PD), and PD with dementia (PDD) should be understood within the spectrum of Lewy body disease. This insistence has been recently accepted by the International Workshop and the International Working Group on DLB and PDD in 2005 and in 2006, respectively.     

Relationship between Parkinson disease with dementia and dementia with Lewy bodies

Parkinson disease (PD) and dementia with Lewy bodies (DLB) are considered Lewy body diseases (LBDs). To clarify the relation between PD with dementia (PDD) and DLB, 30 patients with LBD were divided into pathological subtypes according to the consensus guidelines for DLB. Patients with PDD showed neocortical and limbic type of LBD as well as patients with DLB. Dementia had not been noted in 2 patients with neocortical type. Our results indicate that PDD and DLB share a common pathological substrate and that the pathological subtypes of LBD show considerable overlap in clinical manifestations.     

Hypochondriasis as an early manifestation of dementia with Lewy bodies: an autopsied case report

Discrepancies between clinical and pathological diagnoses of dementia with Lewy bodies (DLB) may occur because the full disease progression remains unclear, especially during the early stage. Herein, we report the case of a 78‐year‐old Japanese man with hypochondriasis who had autopsy‐confirmed limbic‐type DLB pathology. He exhibited no core clinical features of DLB. We attempted to identify the clinicopathological correlations in the early stages of DLB. At the age of 77, he became hypochondriacal and exhibited progressive cognitive decline after the death of his wife. He was concerned about his poor physical condition, but hospital examinations did not identify any overtly abnormal findings. At 78 years of age, he consulted a neurologist with complaints of facial numbness and irritability. Neurological examination revealed no overt abnormality, and he scored 21 points on the Mini‐Mental State Examination. Magnetic resonance imaging of the brain showed mild bilateral ventricular enlargement. The patient was clinically diagnosed as having possible Alzheimer's disease. Approximately 1 month after his consult, he died of acute pneumonia in a psychiatric hospital to which he had been admitted for severe aggressive behaviour. He exhibited no core clinical features pointing towards a clinical diagnosis of DLB. Neuropathological investigation revealed limbic‐type Lewy body disease with concurrent minimum Alzheimer‐type pathology, which corresponds to high‐likelihood DLB pathology based on the Third Consortium DLB pathological criteria. The patient had minimum nigral degeneration, which is consistent with the absence of parkinsonism. This autopsied case suggests that some DLB patients exhibit hypochondriasis in the early stage of the disease, even if they lack the core clinical features of DLB.     

Clinical and neuropathological correlates of Lewy body disease

We investigated distribution of neuronal and glial inclusions in 30 brains obtained at autopsy from patients with Lewy bodies (LBs) disease, which was clinically diagnosed as Parkinson's disease (PD), dementia with Lewy bodies (DLB), or pure autonomic failure (PAF). The cases were classified, according to the guidelines for the pathological diagnosis of DLB, into three types: the neocortical type, the limbic type, and the brain stem-predominant type. All postmortem brains had coil-like glial inclusions as well as LBs, and the distribution pattern and density of glial inclusions and LBs varied. The distribution of glial inclusions was strikingly similar to that of LBs. In the cerebral cortex in particular, the number of glial inclusions was fairly well correlated with the number of LBs, irrespective of the three pathological types. In the brain stem, distribution was similar between glial inclusions and LBs, and there was no distinct pathological difference among the three types. Glial inclusions and LBs were immunohistopathologically similar with respect to ubiquitin, alpha-synuclein, and Gallyas-Braak staining. The clinical features of the three types of LB disease were also similar; i.e., parkinsonism, some dementia, and/or autonomic failure. The inclusions in neurons and glial cells occurred in parallel with respect to tissue distribution and immunohistochemical features, suggesting that accumulation of neuronal and glial inclusions in the LB diseases have a common pathological feature. Our findings suggest that DLB, PD with and without dementia, and PAF share one clinicopathological entity.     

Lewy body pathology in Alzheimer’s disease

Lewy bodies, the characteristic pathological lesion of substantia nigra neurons in Parkinson's disease (PD), are frequently observed to accompany the amyloid plaque and neurofibrillary tangle pathology of Alzheimer's disease (AD). However the typical anatomic distribution of Lewy bodies in AD is distinct from PD. The most common site of occurrence is the amygdala, where Lewy bodies are observed in approximately 60% of both sporadic and familial AD. Other common sites of occurrence include the periamygdaloid and entorhinal cortex, while neocortical and brainstem areas develop Lewy bodies in a lower percentage of cases. In contrast, dementia with Lewy bodies (DLB), defined by widespread neocortical and brainstem Lewy bodies but frequently accompanied by variable levels of AD-type pathology, represents the other end of a spectrum of pathology associated with dementia. The observation of Lewy bodies in familial AD cases suggests that like neurofibrillary tangles, the formation of Lewy bodies can be induced by the pathological state caused by Abeta-amyloid overproduction. The role of Lewy body formation in the dysfunction and degeneration of neurons remains unclear. The protein alpha-synuclein appears to be an important structural component of Lewy bodies, an observation spurred by the discovery of point mutations in the alpha-synuclein gene linked to rare cases of autosomal dominant PD. Further investigation of alpha-synuclein and its relationship to pathological conditions promoting Lewy body formation in AD, PD, and DLB may yield further insight into pathogenesis of these diseases.     

Clinical and quantitative pathologic correlates of dementia with Lewy bodies.

OBJECTIVES: To examine the distribution of cortical Lewy bodies (LB) and their contribution to the clinical syndrome in dementia with LB (DLB) and to address their relationship to the pathologic markers of AD and PD. METHODS: We studied 25 cases meeting neuropathologic criteria for DLB: 13 cases without AD (Braak stage I or II) and 12 cases with concomitant AD changes (Braak stages III to V). Age at onset, disease duration, and clinical symptoms were reviewed for each case. We quantified the regional distribution of LB in substantia nigra, paralimbic areas (cingulate gyrus, insula, entorhinal cortex, and hippocampus), and neocortex (frontal and occipital association areas) using anti-alpha-synuclein immunostaining. We compared the LB pathology between groups of patients with different symptoms at onset or with specific clinical phenotypes. RESULTS: There were no significant differences in clinical symptoms or LB density between cases with or without concomitant AD. LB density showed a consistent gradient as follows: substantia nigra > entorhinal cortex > cingulate gyrus > insula > frontal cortex > hippocampus > occipital cortex. LB density in substantia nigra and neocortex was not significantly different in cases that started with parkinsonism compared with those that started with dementia. There were no significant differences in LB density in any region among patients with or without cognitive fluctuations, visual hallucinations, delusions, recurrent falls, or parkinsonism. Duration of the disease correlated with a global LB burden for each case (p = 0.02) but did not correlate with LB density in any individual area. Paralimbic and neocortical LB density were highly correlated with each other (p<0.0001), but neither of these correlated well with the number of LB in substantia nigra. LB density did not correlate with Braak stage or frequency of neuritic plaques. CONCLUSIONS: There is a consistent pattern of vulnerability to LB formation across subcortical, paralimbic, and neocortical structures that is similar for DLB cases with or without concomitant AD. Paralimbic and neocortical LB do not correlate with LB in substantia nigra, suggesting that DLB should not be considered just a severe form of PD. LB density correlates weakly with clinical symptoms and disease duration.     

Dementia with Lewy bodies: neuropathology

The pathologic substrate of the clinical syndrome of dementia with Lewy bodies (DLB) remains to be determined. Only a few prospective clinicopathologic studies have been reported. In those reports, most cases of DLB had neocortical or limbic Lewy bodies and Alzheimer-type pathology below threshold for diagnosis of Alzheimer's disease. These results are in accord with recent retrospective clinicopathologic studies of dementia occurring in Parkinson's disease, in which cortical Lewy bodies, rather than concurrent Alzheimer's disease, are increasingly recognized as the pathologic substrate of dementia. Additional clinicopathologic studies are warranted to address the role of other Lewy-related pathology, most notably Lewy neurites, in the cognitive impairment of DLB.     

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.