Neocortical Lewy Body Counts Correlate with Dementia in the Lewy Body Variant of Alzheimerʼs Disease

Samuel, William; Galasko, Douglas; Masliah, Eliezer; Hansen, Lawrence A.

doi:10.1097/00005072-199601000-00005

Cited by 126 publications

(61 citation statements)

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“…14 Thus, the amount of Lewy body formation does not relate to whether dementia occurs early (ie, DLB) or late (ie, PDD) in the disease course but correlates with the severity of dementia in PDD. Similar findings have been reported in other studies, 19,20 although in some studies, Alzheimer-type pathology was reported to be significantly associated with dementia in PD. …”

supporting

confidence: 91%

Are Parkinson’s Disease with dementia and Dementia with lewy Bodies the Same Entity?

Aarsland

Ballard

Halliday

2004

J Geriatr Psychiatry Neurol

184

102

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Dementias associated with cortical Lewy bodies are traditionally classified as dementia with Lewy bodies (DLB), characterized by parkinsonism, visual hallucinations and cognitive fluctuations, 1 or Parkinson's disease with dementia (PDD). Overall, DLB accounts for about 20% of late-onset dementia cases, 1 and dementia develops in the majority of cases with a diagnosis of PD. 2 As outlined below, there are clinical and neurobiological similarities between DLB and PDD patients. The distinction between the conditions as operationally defined within the standardized clinical criteria depends entirely on the duration of parkinsonism prior to dementia. The consensus criteria for a clinical diagnosis of DLB state that a diagnosis cannot be made if parkinsonian symptoms developed more than 1 year before the onset of dementia (although proposed recent changes to the criteria may alter this to making the diagnosis according to whether parkinsonism or cognitive impairment arises first). This raises several key conceptual questions; for example, are these conditions distinct or part of the same spectrum? If they are distinct conditions, is an arbitrary cutoff (either 1 year or which symptom presents first) a meaningful distinction between clinical entities with different clinical presentations? Addressing these issues is critical to taking forward our understanding of this spectrum of conditions, establishing biological markers, determining prognostic indicators, and, most important, designing appropriate intervention studies and developing treatment paradigms across the dementias associated with cortical Lewy bodies. In the current article, key issues pertaining to DLB and PDD are reviewed, and the similarities and differences in the clinical profile (cognitive deficits, neuropsychiatric symptoms, and parkinsonism), imaging, genetic predisposition, neurochemistry, and neuropathology are discussed to enable some conclusions about the relationship of the 2 conditions and to offer some suggestions for critical future research. Direct comparative studies of patients with PDD and DLB are necessary to explore the relationship between these 2 syndromes. We searched the MEDLINE using Parkinson* disease and dementia Are Parkinson's Disease With Dementia and Dementia With Lewy Bodies the Same Entity?Dag Aarsland, MD, PhD, C. G. Ballard, MD, MRCPsych, and Glenda Halliday, PhD ABSTRACTThe diagnosis of Parkinson's disease with dementia (PDD) or dementia with Lewy bodies (DLB) is based on an arbitary distinction between the time of onset of motor and cognitive symptoms. These syndromes share many neurobiological similarities, but there are also differences. Deposition of beta-amyloid protein is more marked and more closely related to cognitive impairment in DLB than PDD, possibly contributing to dementia at onset. The relatively more severe executive impairment in DLB than PDD may relate to the loss of frontohippocampal projections in DLB. Visual hallucinations and delusions associate with more abundant Lewy body pathology in temporal c...

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supporting

confidence: 91%

Are Parkinson’s Disease with dementia and Dementia with lewy Bodies the Same Entity?

Aarsland

Ballard

Halliday

2004

J Geriatr Psychiatry Neurol

184

102

View full text Add to dashboard Cite

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“…This notion is supported by studies showing that the density of ␣-syn pathological inclusions correlates with disease severity in demented PD and DLB patients (62)(63)(64)(65)(66). Moreover, transgenic mouse models suggest that ␣-syn inclusions impair cellular function by obstructing normal cellular trafficking and disrupting cell morphology (44,67).…”

Section: E46k Mutation In ␣-Synuclein Increases Amyloid Formationmentioning

confidence: 84%

The E46K Mutation in α-Synuclein Increases Amyloid Fibril Formation

Greenbaum

Graves

Mishizen-Eberz

et al. 2005

Journal of Biological Chemistry

344

312

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The identification of a novel mutation (E46K) in one of the KTKEGV-type repeats in the amino-terminal region of ␣-synuclein suggests that this region and, more specifically, Glu residues in the repeats may be important in regulating the ability of ␣-synuclein to polymerize into amyloid fibrils. It was demonstrated that the E46K mutation increased the propensity of ␣-synuclein to fibrillize, but this effect was less than that of the A53T mutation. The substitution of Glu 46 for an Ala also increased the assembly of ␣-synuclein, but the polymers formed can have different ultrastructures, further indicating that this amino acid position has a significant effect on the assembly process. The effect of residue Glu 83 in the sixth repeat of ␣-synuclein, which lies closest to the amino acid stretch critical for filament assembly, was also studied. Mutation of Glu 83 to a Lys or Ala increased polymerization but perturbed some of the properties of mature amyloid. These results demonstrated that some of the Glu residues within the repeats can have significant effects on modulating the assembly of ␣-synuclein to form amyloid fibrils. The greater effect of the A53T mutation, even when compared with what may be predicted to be a more dramatic mutation such as E46K, underscores the importance of protein microenvironment in affecting protein structure. Moreover, the relative effects of the A53T and E46K mutations are consistent with the age of onset of disease. These findings support the notion that aberrant ␣-synuclein polymerization resulting in the formation of pathological inclusions can lead to disease.

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“…Total plaque, neuritic plaque, and neurofibrillary tangle counts were then performed on midfrontal, rostral superior temporal, inferior parietal, entorhinal, and hippocampal regions. Brains were then staged for the degree of neurofibrillary pathology by a modification (Samuel et al, 1996) of the method of Braak and Braak (1991) by one neuropathologist (L.A.H.). Clinicopathological diagnosis of AD was made according to both National Institutes of Aging (NIA; Khachaturian, 1985) and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) criteria (Mirra et al, 1991).…”

Section: Neuropathologymentioning

confidence: 99%

Distinct cognitive profiles and rates of decline on the Mattis Dementia Rating Scale in autopsy-confirmed frontotemporal dementia and Alzheimer's disease

Rascovsky

Salmon

Hansen

et al. 2008

J Inter Neuropsych Soc

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Neuropsychological studies have shown that patients with Frontotemporal dementia (FTD) perform worse than patients with Alzheimer's disease (AD) on tests of conceptualization and verbal fluency, but better on tests of memory and visuospatial functions. However, it is not known if these distinct cognitive profiles are robust enough to be detected using a relatively brief dementia screening instrument such as the Mattis Dementia Rating Scale (MDRS). To address this issue, the MDRS subscale profiles of patients with autopsy-confirmed FTD (n 5 17) or AD (n 5 34) were compared. Results showed distinct cognitive profiles in which FTD patients performed worse than AD patients on the Initiation0Perseveration and Conceptualization subscales while performing better on the Memory and Construction subscales. The distinct subscale profiles correctly classified 85% of AD patients and 76% of FTD patients. Profiles were maintained in a subset of mildly-to-moderately demented patients (MDRS Ն 105) and correctly classified 89% of these patients. In addition, FTD patients (mean 5 30.0 points0year) declined faster than AD patients (mean 5 14.8 points0year) on MDRS total and specific subscale scores. These results suggest that the MDRS may be a useful adjunct to other clinical measures for distinguishing FTD from AD and tracking the progression of the disorder. (JINS, 2008, 14, 373-383.)

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Neocortical Lewy Body Counts Correlate with Dementia in the Lewy Body Variant of Alzheimerʼs Disease

Cited by 126 publications

References 0 publications

Are Parkinson’s Disease with dementia and Dementia with lewy Bodies the Same Entity?

Are Parkinson’s Disease with dementia and Dementia with lewy Bodies the Same Entity?

The E46K Mutation in α-Synuclein Increases Amyloid Fibril Formation

Distinct cognitive profiles and rates of decline on the Mattis Dementia Rating Scale in autopsy-confirmed frontotemporal dementia and Alzheimer's disease

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