Comparison of Lewy body variant of Alzheimer’s disease with pure Alzheimer’s disease

Heyman, Albert; Fillenbaum, Gerda G.; Gearing, M.; Mirra, Suzanne S.; Welsh-Bohmer, Kathleen A.; Peterson, Bercedis L.; Pieper, Carl F.

doi:10.1212/wnl.52.9.1839

Cited by 101 publications

(63 citation statements)

References 32 publications

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“…2 One possibility is that excess A␤ in AD overloads proteasome capacity, leading to incomplete ubiquitin-dependent degradation of ␣-syn, and accumulation of ␣-syn119, which then can give rise to conventional ␣-syn pathology in some cases. This hypothesis is also supported by the observations that A␤ pathology tends to be relatively more severe than phospho-tau pathology in LBV compared with pure AD 35 and that truncated forms of ␣-syn are proportionally more abundant in LBV compared with DLBD. 16 We have not definitively proven that ␣-syn119 is in an aggregated form in AD, but our findings suggest that this is the case.…”

Section: Discussionmentioning

confidence: 57%

“…This hypothesis is not inconsistent with the finding that combined conventional Lewy pathology and AD pathology in LBV is not associated with shortened patient survival compared with pure AD. 35 Evidence from cell culture studies suggests that aggregation intermediates (oligomers and protofibrils) of ␣-syn and other proteins implicated in neurodegenerative diseases are neurotoxic whereas ␣-syn monomers are not and mature, fully polymerized fibrils may even have neuroprotective qualities. 2,36 -39 Hence, it is possible that by the time conventional ␣-syn pathology becomes evident and AD turns to LBV, the bulk of damage has already been inflicted by ␣-syn119 oligomers and protofibrils.…”

Section: Discussionmentioning

confidence: 99%

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Abnormal Neurites Containing C-Terminally Truncated α-Synuclein Are Present in Alzheimer's Disease without Conventional Lewy Body Pathology

Lewis

Jou

et al. 2010

The American Journal of Pathology

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The pathological hallmark of Parkinson's disease and diffuse Lewy body disease (DLBD) is the aggregation of ␣-synuclein (␣-syn) in the form of Lewy bodies and Lewy neurites. Patients with both Alzheimer's disease (AD) and cortical Lewy pathology represent the Lewy body variant of AD (LBV) and constitute 25% of AD cases. C-terminally truncated forms of ␣-syn enhance the aggregation of ␣-syn in vitro. To investigate the presence of C-terminally truncated ␣-syn in DLBD, AD, and LBV, we generated and validated polyclonal antibodies to truncated ␣-syn ending at residues 110 (␣-syn110) and 119 (␣-syn119), two products of 20S proteosome-mediated endoproteolytic cleavage. Double immunofluorescence staining of the cingulate cortex showed that ␣-syn110 and ␣-syn140 (full-length) aggregates were not colocalized in LBV. All aggregates containing ␣-syn140 also contained ␣-syn119; however, some aggregates contained ␣-syn119 without ␣-syn140, suggesting that ␣-syn119 may stimulate aggregate formation. Immunohistochemistry and image analysis of tissue microarrays of the cingulate cortex from patients with DLBD (n ‫؍‬ 27) , LBV (n ‫؍‬ 27) , and AD (n ‫؍‬ 19) and age-matched controls (n ‫؍‬ 15) revealed that AD is also characterized by frequent abnormal neurites containing ␣-syn119. Notably, these neurites did not contain ␣-syn ending at residues 110 or 122-140. The presence of abnormal neurites containing ␣-syn119 in AD without conventional Lewy pathology suggests that AD and Lewy body disease may be more closely related than previously thought.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Abnormal Neurites Containing C-Terminally Truncated α-Synuclein Are Present in Alzheimer's Disease without Conventional Lewy Body Pathology

Lewis

Jou

et al. 2010

The American Journal of Pathology

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“…This is consistent with studies 8,22 that indicate that patients with Lewy bodies had higher frequencies of hallucinations, delusions, depression, and confusion. Although other studies 17,18,20 have reported no differences.The strengths of our study included the use of a large, well-characterized sample composed of data collected from AD centers across the United States. Nevertheless, our study had some limitations.…”

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confidence: 66%

“…5,6 In contrast to this stereotypical pattern, Lewy bodies in AD may also be found concentrated in the amygdala without significant involvement of the brainstem or neocortical regions, 2,3 a distribution that has been called AD with amygdala Lewy bodies. 3,7 These cases with both Lewy body and AD pathology are 8,1418 There is controversy as to whether there are differences in parkinsonian features, 8,14,16,19,20 cognitive deficits, 16,17,[19][20][21] cognitive decline, 8,14 and the presence of visual hallucinations 8,17,18,20,22 between AD with Lewy bodies and AD without Lewy bodies (eTable in the Supplement). These diverse findings may partly reflect the relatively small sample sizes used in some of these studies or the limitations with the clinical or neuropathological data.…”

Section: Main Outcomes and Measures-clinical And Neuropsychiatric Tesmentioning

confidence: 99%

P1‐206: Clinical features of Alzheimer disease with and without lewy bodies

Chung

Babulal

Monsell

et al. 2015

Alzheimer's & Dementia

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edu).Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, or interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.Supplemental content at jamaneurology.com Author Contributions: Dr Morris had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Conflict of Interest Disclosures:Dr Morris has participated or is currently participating in clinical trials of antidementia drugs sponsored by the following companies and studies: Janssen Immunotherapy, Pfizer, Eli Lilly/Avid Radiopharmaceuticals, the SNIFF (Study of Nasal Insulin to Fight Forgetfulness) study, and the A4 (Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease) trial. Dr Morris has served as a consultant for Lilly USA, ISIS Pharmaceuticals, and the Charles Dana Foundation. He receives research support from Eli Lilly/Avid Radiopharmaceuticals and is funded by National Institutes of Health grants P50AG005681, P01AG003991, P01AG026276, and U19AG032438.Additional Information: The NACC database is funded by NIA/National Institutes of Health grant U01 AG016976. The NACC data were obtained from the NIA-funded AD centers (grants P30 AG019610 [PI Eric Reiman, MD] EXPOSURES-Standardized neuropathologic assessment and then brain autopsy after death. HHS Public Access MAIN OUTCOMES AND MEASURES-Clinical and neuropsychiatric test scores.RESULTS-The mean (SD) age at death was statistically significantly younger for participants who had AD with Lewy bodies (77.9 [9.5] years) than for participants who had AD without Lewy bodies (80.2 [11.1] years) (P = .01). The mean (SD) age at onset of dementia symptoms was also younger for participants who had AD with Lewy bodies (70.0 [9.9] years) than for participants who had AD without Lewy bodies (72.2 [12.3] years) (P = .03). More men than women had AD with Lewy bodies (P = .01). The frequency of having at least 1 APOE ε4 allele was higher for participants who had AD with Lewy bodies than for participants who had AD without Lewy bodies (P = .03). CONCLUSIONS AND RELEVANCE-Participants with both AD and Lewy body pathology have a clinical phenotype that may be distinguished from AD alone. The frequency of Lewy bodies in AD and the association of Lewy bodies with the APOE ε4 allele suggest potential common mechanisms for AD and Lewy body pathologies.The 2 neuropathological hallmarks of Alzheimer disease (AD) are the extracellular Aβ plaques and the intracellular neurofibrillary tangles, of which the latter is composed of hyperphosphorylated tau protein. 1 Lewy bodies are intraneuronal cytoplasmic inclusions comprising aggregates of α-synuclein 2,3 and are readily detected by immunohistochemistry using anti-α-synuclein antibodies. In up to 50% of cases of sporadic late-onset AD, comorbid Lewy bodies are found. 2 Lewy bodies are frequent in the setting of moderate-tosevere levels of A...

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“…39,40 The underlying pathologic substrate of motor signs in AD is not clear. They may 41,42 or may not [43][44][45][46][47] be associated with Lewy bodies. As previously published, 4 in this study motor signs were not significantly related to Lewy bodies.…”

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confidence: 99%

Man-in-the-barrel syndrome caused by a pontine lesion

Paulin¹,

Seze²,

Wyremblewski³

et al. 2005

Neurology

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Abstract-Objective:To examine whether the presence of motor signs has predictive value for important outcomes in Alzheimer disease (AD). Methods: A total of 533 patients with AD at early stages (mean Folstein Mini-Mental State Examination [MMSE] 21/30 at entry) were recruited and followed semiannually for up to 13.1 years (mean 3) in five University-based AD centers in the United States and European Union. Four outcomes, assessed every 6 months, were used in Cox models: cognitive endpoint (Columbia Mini-Mental State Examination Յ 20/57 [‫ف‬MMSE Յ 10/30]), functional endpoint (Blessed Dementia Rating Scale Ն 10), institutionalization equivalent index, and death. Using a standardized portion of the Unified PD Rating Scale (administered every 6 months for a total of 3,149 visit-assessments, average 5.9 per patient), the presence of motor signs, as well as of individual motor sign domains, was examined as time-dependent predictor. The models controlled for cohort, recruitment center, sex, age, education, a comorbidity index, and baseline cognitive and functional performance. Results: A total of 39% of the patients reached the cognitive, 41% the functional, 54% the institutionalization, and 47% the mortality endpoint. Motor signs were noted for 14% of patients at baseline and for 45% at any evaluation. Their presence was associated with increased risk for cognitive decline (RR, 1.72; 95% CI, 1.24 to 2.38), functional decline (1.80 [1.33 to 2.45]), institutionalization (1.68 [1.26 to 2.25]), and death (1.38 [1.05 to 1.82]). Tremor was associated with increased risk for reaching the cognitive and bradykinesia for reaching the functional endpoints. Postural-gait abnormalities carried increased risk for institutionalization and mortality. Faster rates of motor sign accumulation were associated with increased risk for all outcomes. Conclusions: Motor signs predict cognitive and functional decline, institutionalization, and mortality in Alzheimer disease. Different motor sign domains predict different outcomes.

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Comparison of Lewy body variant of Alzheimer’s disease with pure Alzheimer’s disease

Cited by 101 publications

References 32 publications

Abnormal Neurites Containing C-Terminally Truncated α-Synuclein Are Present in Alzheimer's Disease without Conventional Lewy Body Pathology

Abnormal Neurites Containing C-Terminally Truncated α-Synuclein Are Present in Alzheimer's Disease without Conventional Lewy Body Pathology

P1‐206: Clinical features of Alzheimer disease with and without lewy bodies

Man-in-the-barrel syndrome caused by a pontine lesion

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