Distinct Patterns of Antiamyloid-β Antibodies in Typical and Atypical Alzheimer Disease

Dorothée, Guillaume; Bottlaender, Michel; Moukari, Edmond; Souza, Leonardo Cruz de; Maroy, Renaud; Corlier, Fabian; Colliot, Olivier; Chupin, Marie; Lamari, Foudil; Lehericy, Stéphane; Dubois, Bruno; Sarazin, Marie; Aucouturier, Pièrre

doi:10.1001/archneurol.2012.604

Cited by 24 publications

(24 citation statements)

References 15 publications

(23 reference statements)

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“…In addition, serum levels of anti-Aβ and anti-RAGE autoantibodies are several times higher in AD patients, showing positive correlation with cognitive dysfunction [82]. Consistent with these findings, anti-Aβ antibodies were documented in AD patients [83] and aged Aβ PP mice with AD-like neuropathology [84]. Moreover, serum from these mice potentiated the neurotoxicity of Aβ, prompting the authors to suggest that humoral immune responses may promote neuronal degeneration [84].…”

Section: Discussionmentioning

confidence: 71%

Autoimmune Manifestations in the 3xTg-AD Model of Alzheimer's Disease

Marchese

Cowan

Head

et al. 2014

JAD

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Background Immune system activation is frequently reported in patients with Alzheimer's disease (AD). However, it remains unknown whether this is a cause, a consequence, or an epiphenomenon of brain degeneration. Objective The present study examines whether immunological abnormalities occur in a well-established murine AD model and if so, how they relate temporally to behavioral deficits and neuropathology. Methods A broad battery of tests was employed to assess behavioral performance and autoimmune/inflammatory markers in 3xTg-AD (AD) mice and wild type controls from 1.5 to 12 months of age. Results Aged AD mice displayed severe manifestations of systemic autoimmune/inflammatory disease, as evidenced by splenomegaly, hepatomegaly, elevated serum levels of anti-nuclear/anti-dsDNA antibodies, low hematocrit, and increased number of double-negative T splenocytes. However, anxiety-related behavior and altered spleen function were evident as early as 2 months of age, thus preceding typical AD-like brain pathology. Moreover, AD mice showed altered olfaction and impaired “cognitive” flexibility in the first 6 months of life, suggesting mild cognitive impairment-like manifestations before general learning/memory impairments emerged at an older age. Interestingly, all of these features were present in 3xTg-AD mice prior to significant amyloid-β or tau pathology. Conclusion The results indicate that behavioral deficits in AD mice develop in parallel with systemic autoimmune/inflammatory disease. These changes antedate AD-like neuropathology, thus supporting a causal link between autoimmunity and aberrant behavior. Consequently, 3xTg-AD mice may be a useful model in elucidating the role of immune system in the etiology of AD.

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Section: Discussionmentioning

confidence: 71%

Autoimmune Manifestations in the 3xTg-AD Model of Alzheimer's Disease

Marchese

Cowan

Head

et al. 2014

JAD

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“…These oligomers, rather than the amyloid-β insoluble fibrils, may the the molecular pathogens that trigger synaptic dysfunction in EOAD and negatively affect the number of nicotinic acetylcholinesterase receptors (99). Moreover, levels of anti-amyloid-β IgG (IgG1 and IgG3), which may help control the development of amyloid plaques, are lower in PCA vs. typical AD (100). These serum anti-amyloid-β antibodies may differentially react to amyloid-β oligomers in nonamnestic EOAD.…”

Section: Type 2 Admentioning

confidence: 99%

Early-onset Alzheimer's Disease: Nonamnestic Subtypes and Type 2 AD

Mendez

2012

Archives of Medical Research

141

110

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Patients with Alzheimer’s disease (AD), the most prevalent neurodegenerative dementia, are usually elderly; however, ~4–5% develop early-onset AD (EOAD) with onset before age 65. Most EOAD is sporadic, but about 5% of patients with EOAD have an autosomal dominant mutation such as Presenilin 1, Presenilin 2, or alterations in the Amyloid Precursor Protein gene. Although most Alzheimer’s research has concentrated on older, late-onset AD (LOAD), there is much recent interest and research in EOAD. These recent studies indicate that EOAD is a heterogeneous disorder with significant differences from LOAD. From 22–64% of EOAD patients have a predominant nonamnestic syndrome presenting with deficits in language, visuospatial abilities, praxis, or other non-memory cognition. These nonamnestic patients may differ in several ways from the usual memory or amnestic patients. Patients with nonamnestic EOAD compared to typical amnestic AD have a more aggressive course, lack the apolipoprotein E ε4 (APOE ε4) susceptibility gene for AD, and have a focus and early involvement of non-hippocampal areas of brain, particularly parietal neocortex. These differences in the EOAD subtypes indicate differences in the underlying amyloid cascade, the prevailing pathophysiological theory for the development of AD. Together the results of recent studies suggest that nonamnestic subtypes of EOAD constitute a Type 2 AD distinct from the usual, typical disorder. In sum, the study of EOAD can reveal much about the clinical heterogeneity, predisposing factors, and neurobiology of this disease.

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“…Amyloid imaging promises to become a remarkable tool for the clinical evaluation of AD [7, 8, 17-19] and offers a new opportunity to identify asymptomatic, amyloid-positive subjects for testing anti-amyloid therapeutic agents. However, because neuritic amyloid plaques may be seen at autopsy in clinically normal individuals and concurrent with other dementing diseases, a positive amyloid scan should be interpreted with caution, since this does not exclude a concurrent cause of dementia.…”

Section: Discussionmentioning

confidence: 99%

Positive Florbetapir PET Amyloid Imaging in a Subject with Frequent Cortical Neuritic Plaques and Frontotemporal Lobar Degeneration with TDP43-Positive Inclusions

Serrano

Sabbagh

Sue

et al. 2014

JAD

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Abnormal neuronal accumulation and modification of TAR DNA binding protein 43 (TDP-43) have recently been discovered to be defining histopathological features of particular subtypes of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), and are also common in aging, particularly coexisting with hippocampal sclerosis and Alzheimer's disease (AD) pathology. This case report describes a 72 year old Hispanic male with no family history of neurological disease, who presented at age 59 with obsessive behavior, anxiety, agitation and dysphasia. Positron emission tomography (PET) imaging using the amyloid ligand 18F florbetapir (Amyvid) was positive. Postmortem examination revealed frequent diffuse and neuritic amyloid plaques throughout the cerebral cortex, thalamus and striatum, Braak stage II neurofibrillary degeneration and frequent frontal and temporal cortex TDP-43-positive neurites with rare nuclear inclusions. The case is unusual and instructive because of the co-existence of frequent cortical and diencephalic amyloid plaques with extensive TDP-43-positive histopathology in the setting of early-onset dementia and because it demonstrates that a positive cortical amyloid imaging signal in a subject with dementia does not necessarily establish that AD is the sole cause.

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Distinct Patterns of Antiamyloid-β Antibodies in Typical and Atypical Alzheimer Disease

Cited by 24 publications

References 15 publications

Autoimmune Manifestations in the 3xTg-AD Model of Alzheimer's Disease

Autoimmune Manifestations in the 3xTg-AD Model of Alzheimer's Disease

Early-onset Alzheimer's Disease: Nonamnestic Subtypes and Type 2 AD

Positive Florbetapir PET Amyloid Imaging in a Subject with Frequent Cortical Neuritic Plaques and Frontotemporal Lobar Degeneration with TDP43-Positive Inclusions

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