Laminar distribution of beta-amyloid deposits in dementia with Lewy bodies and in Alzheimer's disease

This study tested whether the laminar distribution of the beta-amyloid (Abeta) deposits in dementia with Lewy bodies (DLB) cases with significant Alzheimer's disease (AD) pathology (DLB/AD) was similar to "pure" AD. In DLB/AD, the maximum density of the diffuse and primitive deposits occurred either in the upper laminae or a bimodal distribution was present with density peaks in the upper and lower laminae. A bimodal distribution of the classic Abeta deposits was also observed. Compared with AD, DLB/AD cases had fewer primitive deposits relative to the diffuse and classic deposits; the primitive deposits exhibited a bimodal distribution more frequently, and the diffuse deposits occurred more often in the upper laminae. These results suggest that Abeta pathology in DLB/AD may not simply represent the presence of associated AD.     

Lysosomes,autophagosomes and Alzheimer pathology in dementia with Lewy body disease

A failure of protein degradation may underpin Lewy body disease (LBD) where α‐synuclein is assimilated into the pathognomic Lewy bodies and Lewy neurites. We investigated histological alterations in lysosomes and autophagosomes in the substantia nigra (SN) and cingulate gyrus (CG) in 34 patients with LBD employing antibodies against phosphorylated α‐synuclein and lysosomal (lysosomal associated membrane proteins 1 and 2 (LAMP‐1 and LAMP‐2), cathepsin D (CTSD)) and autophagosomal (microtubule‐associated protein light chain 3α (LC3A)) proteins. Immunostained sections were qualitatively and semi‐quantitatively assessed for the appearance, distribution and intensity of staining. Four LBD patients had mutations in GBA1. There was significantly less LAMP‐1, LAMP‐2 and CTSD immunostaining in neurons of the SN in LBD cases compared to control cases and marginally less LAMP‐1 in patients with GBA1 mutations compared to those without. Loss of LAMP‐1 and CTSD immunoreactivity correlated with cell loss from the SN. There were no changes in LC3A immunoreactivity in the SN, nor any major changes in the CG, or glial cell activity in the SN and CG, for any of the markers. A proportion of amyloid plaques in both the LBD and control cases was immunoreactive for LAMP‐1 and LAMP‐2, but not CTSD or LC3A proteins. These immunohisochemical features were seen in glial cells, which were negative for amyloid‐β. Alterations in lysosomal structure or function, but not macroautophagy, may underpin the pathogenesis of LBD.     

Deposition of beta-amyloid subtypes 40 and 42 differentiates dementia with Lewy bodies from Alzheimer disease.

BACKGROUND: Alterations in the metabolism of the amyloid precursor protein and the formation of beta-amyloid (Abeta) plaques are associated with neuronal death in Alzheimer disease (AD). The plaque subtype Abeta(x-42) occurs as an early event, with Abeta(x-40) plaques forming at a later stage. In dementia with Lewy bodies (DLB), an increase in the amount of cortical Abeta occurs without severe cortical neuronal losses. OBJECTIVE: To advance our understanding of the natural history of Abeta in neurodegenerative diseases. DESIGN: We evaluated the expression of Abeta(x-40) and Abeta(x-42) in DLB using monoclonal antibodies and immunohistochemical techniques in 5 brain regions. The data were compared with those elicited with normal aging and from patients with AD. SETTING AND PATIENTS: A postmortem study involving 19 patients with DLB without concurrent neuritic degeneration, 10 patients with AD, and 17 aged persons without dementia for control subjects. RESULTS: The Abeta plaques were more numerous in patients with DLB than in controls in most brain regions, although the Abeta(x-42) plaque subtype was predominant in both conditions. Overall, Abeta(x-42) plaque density was similar in patients with DLB and those with AD, but Abeta(x-40) plaques were more numerous in persons with AD than in those with DLB. The ratio of Abeta(x-40) to Abeta(x-42) plaques was significantly reduced in persons with DLB compared with patients with AD. CONCLUSIONS: The Abeta plaques were more numerous in patients with DLB than persons with normal aging, but the plaque subtypes were similar. The relative proportion of the 2 Abeta plaque subtypes in DLB is distinguishable from that in AD.     

Contribution of Lewy body inclusions to dementia in patients with and without Alzheimer disease neuropathological conditions

CONTEXT: Lewy bodies (LBs) are intraneuronal inclusions in the brain that have been increasingly recognized as neuropathological lesions with relevance not only to Parkinson disease but also to Alzheimer disease. However, the degree to which the density of LBs in the brain contributes to the severity of dementia has not been clear. OBJECTIVE: To determine the degree to which LB "burden" contributes to dementia. DESIGN: Brain specimens were examined from 273 consecutive autopsies of elderly subjects residing in a nursing home. The numbers and densities of LBs were determined in multiple brain regions, and their correlation with a measure of cognition and functional status (Clinical Dementia Rating) during the 6 months preceding death was determined. SETTING AND PATIENTS: Postmortem study of nursing home residents. RESULTS: The severity of dementia correlated significantly and positively with the density of LBs. These correlations were independent of other neuropathological disorders commonly associated with dementia, including Alzheimer disease. The density of LBs correlated significantly with dementia severity whether or not the diagnostic criteria for Alzheimer disease were met and after the contribution of classical Alzheimer disease lesions, neuritic plaques, and neurofibrillary tangles had been accounted for by partial correlation analysis. CONCLUSION: Lewy body inclusions appear to contribute significantly to cognitive deficits in the elderly in a manner that is independent of other neuropathological disorders. Arch Neurol. 2000;57:1145-1150     

Lewy body dementia and Parkinson’s disease with dementia

Journal of Neurology - Parkinson’s disease (PD) is characterized by its motor impairment. However, non-motor symptoms such as psychiatric disorders, autonomic disturbances and sleep disorders...     

Cortical inflammation in Alzheimer disease but not dementia with Lewy bodies

BACKGROUND: There have been no previous studies on the role of inflammation in the brain for the second most common dementing disorder, dementia with Lewy bodies. OBJECTIVE: To investigate the degree of cortical inflammation in dementia with Lewy bodies (DLB) compared with Alzheimer disease (AD) and control brains. DESIGN AND MAIN OUTCOME MEASURES: Post-mortem tissue collection from a brain donor program using standardized diagnostic criteria. Brains collected from January 1, 1993, through December 31, 1996, were screened and selected only for the presence or absence of tau neuritic plaques. Results of immunohistochemistry for HLA-DR were quantified using area fraction counts. Counts were performed by investigators who were unaware of the diagnosis. Results were compared across groups using analysis of variance and posthoc testing. SETTING: A medical research institute in Sydney, Australia. PATIENTS: Eight brains with DLB and without the tau neuritic plaques typical of AD, 10 brains with AD and no Lewy bodies, and 11 nondemented controls without significant neuropathological features were selected from a consecutive sample. RESULTS: Compared with AD, DLB demonstrated significantly less inflammation in the form of HLA-DR-reactive microglia in all cortical regions (P<.001, posthoc). The level of inflammation in DLB was comparable to that seen in controls (P=.54, post hoc). CONCLUSIONS: Inflammation appears related to the tau neuritic plaques of AD. Despite similar clinical presentations, therapeutic anti-inflammatory strategies are not likely to be effective for pure DLB. Arch Neurol. 2000.     

Cortical Lewy body disease and Parkinson's disease dementia

PURPOSE OF REVIEW: The health and socioeconomic impacts of dementia with Lewy bodies and dementia associated with Parkinson's disease have become increasingly recognized. Whilst the nosological status of dementia with Lewy bodies has been better classified as 'Lewy body dementias', both conditions are now believed to represent a disease spectrum, characterized pathologically by synuclein protein and clinically by a variable admixture of cognitive, neuropsychiatric and extrapyramidal features. RECENT FINDINGS: Recent epidemiological studies are described and clinical and pathological similarities emphasized between dementia with Lewy bodies and Parkinson's disease. A number of investigational techniques are highlighted which have helped to better characterize dementia with Lewy bodies and discriminate it from Alzheimer's disease, whilst also shedding light upon the pathophysiology of both conditions. Finally, the therapeutic aspects of the Lewy body dementias will be considered, concentrating upon studies of the cholinesterase inhibitors. SUMMARY: The pathology underlying dementia with Lewy bodies and Parkinson's disease is heterogeneous, and is neither stereotyped in its topography nor its composition. Cholinesterase inhibitor drugs improve cognition and neuropsychiatric symptoms but the clinical response is unpredictable. Major future challenges are to better understand the pathophysiological basis underpinning the diseases, what determines clinical phenotypic expression and how disease-modifying therapies may best be developed and deployed.     

Diffuse Lewy body disease and progressive dementia

Thirty cases of diffuse Lewy body disease (DLBD) have been reported, primarily by neuropathologists, but an associated clinical syndrome has not been clearly defined. Four recent cases have led us to examine the clinicopathologic correlations. Patients are usually elderly, with symptoms lasting from 1 to 20 years. Progressive dementia or psychosis is typically the first and most prominent feature. Parkinsonian signs, initially mild or absent, become common eventually, and rigidity is usually severe. Involuntary movements, myoclonus, quadriparesis in flexion, orthostatic hypotension, and dysphagia have also been noted. Classic, concentric Lewy bodies are found profusely in the brainstem, basal forebrain, and hypothalamic nuclei, while less well defined "Lewy-like" bodies occur in limbic structures and in deep neocortical layers. In addition, focal spongiform changes in the mesial temporal lobe were found in two of our cases. We suggest that DLBD may be another specific cause of progressive dementia.     

Common inflammatory mechanisms in Lewy body disease and Alzheimer disease

Cortical Lewy body disease as a cause of dementia has been recognized for more than 40 years. Only in the past 15 to 20 years, however, has the true frequency of this entity come to be appreciated, primarily because of the advent of sensitive and specific immunohistochemical diagnostic techniques. We now know that there is frequent and extensive overlap, both clinically and pathologically, between Lewy body and Alzheimer diseases. Although some of this overlap may be attributable to common genetic and environmental risk factors, it is also now apparent that the 2 diseases share common neuroinflammatory mechanisms involving activation of microglia, overexpression of interleukin-1 and other inflammatory mediators, and inflammatory toxicity to neurons. Activated microglia are found in association with alpha-synuclein-containing neurons and glia in Parkinson disease, in dementia with Lewy bodies, and in multiple system atrophy, and these associations are reminiscent of microglial associations with neurofibrillary tangle-containing neurons in Alzheimer disease. In vitro and in vivo experimental work has shown reciprocal induction between alpha-synuclein and injured neurons on one hand and activated microglia and cytokine overexpression on the other. These neuroinflammatory processes may be a common link driving progression in both diseases and explaining the frequent overlap between the 2 diseases.     

Diffuse Lewy body disease with dementia and oculomotor dysfunction

The case is presented of an elderly patient who had dementia, axial rigidity, and bradykinesia with limitation of horizontal and vertical gaze. Pathological examination disclosed Lewy and Lewy-like bodies in the substantia nigra, locus ceruleus, and neocortex, leading to a final diagnosis of diffuse Lewy body disease. Similar inclusions were found in areas of the pons and midbrain believed to be associated with gaze control. Moderate numbers of neuritic plaques, but no neurofibrillary tangles, were present in limbic cortex and neocortex. Review of the literature has not shown previous association of diffuse Lewy body disease with both horizontal and vertical gaze anomalies.     

Nicotinic receptors in dementia of Alzheimer, Lewy body and vascular types

Objectives - Comparisons were made of nicotinic receptors in 3 major forms of dementia in old age. Although it is well established the involvement of nicotinic receptors in Alzheimer's disease (AD), their status in the other two main causes of dementia in old age – dementia with Lewy bodies (DLB) and vascular dementia (VaD) is not widely reported. Methods – Temporal cortex was examined for epibatidine and α-bungarotoxin binding, and immunoreactivity of α4 and α7 nAChR subunits. Results – There were selective abnormalities in nicotinic receptor subtypes in the disorders examined. In AD there is a loss of high affinity receptor binding, reflecting a selective loss of α4 subunit, but no change in α7 subunits. Similar abnormalities in ligand binding are also apparent in DLB. In the VaD series, there was no overall loss of epibatidine binding or immunoreactivity for α4 or α7 subunits. Conclusions – Loss of cortical receptor α4 subunit appears to be a characteristic feature of neurodegenerative dementia but not dementia of vascular origin. Since nicotinic receptors control cerebral vasodilation, the relative integrity of the receptors in VaD may auger well for nicotinic therapy in this disorder in which there is a cholinergic abnormality, to judge by the loss of the presynaptic enzyme.     

Alzheimer病和路易体痴呆患者血清及脑脊液金属元素含量的变化

目的 探讨Alzheimer病(AD)和路易体痴呆(DLB)患者血清及CSF中金属镁铜(Cu)、铁(Fe)、钙(Ca)、(Mg)、锌(Zn)、铅(pb)和锰(Mn)含量的变化.方法 使用电感耦合等离子体质谱法检测40例AD患者、20例DLB患者及18名正常对照者血清及CSF中Cu、Fe、Ca、Mg、Zn、Pb及Mn的含量.结果 (1) DLB组血清Zn含量明显低于AD组及正常对照组(均P＜0.05);(2)AD组及DLB组CSF Ca含量明显高于正常对照组(均P ＜0.05);(3)AD组CSF Fe含量明显高于DLB组及正常对照组(均P＜0.05).结论 AD及DLB患者体内或神经系统存在金属元素Zn、Fe、Ca稳态失衡,这些可能有助于评估AD和DLB患者神经系统的氧化应激损伤及对发病机制的研究.     

Association between progranulin and beta-amyloid in dementia with Lewy bodies

Recent studies demonstrated that progranulin plays an integral role in the pathogenesis of frontotemporal dementia. To begin to explore the role of progranulin in dementia with Lewy bodies, we investigate its association with pathologic proteins that characterize this disease. We assessed immunoreactivity for progranulin in medial temporal lobe structures of 12 cases of dementia with Lewy bodies. Similar data were collected for beta-amyloid burden, and alpha-synuclein pathology. Blinded investigators used a 0-3-point scale to quantify progranulin burden. Double labeling for progranulin and beta-amyloid was also performed. We were able to demonstrate progranulin immunoreactivity throughout the medial temporal lobe in all dementia with Lewy body cases. We identified a significant positive correlation (r = 0.606; P = .037) between beta-amyloid burden and progranulin. There was no significant correlation between alpha-synuclein pathology or Braak stage and progranulin. Progranulin and beta-amyloid colocalized in plaques in dementia with Lewy bodies, suggesting that there is likely a biological association between these 2 aggregated proteins.     

Spatial metabolic profiles to discriminate dementia with Lewy bodies from Alzheimer disease

Journal of Neurology - To differentiate dementia with Lewy bodies (DLB) from Alzheimer disease (AD) using a single imaging modality is challenging, because of their common hypometabolic findings....     

Risk of decline in functional activities in dementia with Lewy bodies and Alzheimer disease

We examined the risk of 1-year decline in 4 everyday activities in patients with dementia with Lewy bodies (DLB), relative to patients with Alzheimer disease (AD). Data were from the National Alzheimer's Coordinating Center, gathered from 32 Alzheimer's Disease Centers. Participants (n=1880) were: aged 60+ years, demented with a primary clinical diagnosis of probable AD or DLB, and had a global Clinical Dementia Rating of 0.5 to 2. The activities were measured with the Functional Activities Questionnaire. In modified Poisson regression models adjusted for demographics, baseline activity, years from symptom onset, cognitive impairment, and comorbidities; DLB participants aged 67 to 81 years had 1.5 to 2 times increased risk of decline in performing basic kitchen tasks, engaging in games/hobbies, and paying attention/understanding, relative to AD participants of the same age (P<0.05). There was no significant difference between AD and DLB participants beyond this age range. For decline in ability to go shopping alone, there was also no significant difference between AD and DLB participants. In summary, the functional course of DLB, relative to AD, may depend on the age of the patient. These findings may provide anticipatory guidance to families and healthcare providers, which may be useful in the planning of care strategies.