Parallel Compensatory and Pathological Events Associated with Tau Pathology in Middle Aged Individuals with Down Syndrome

Head, Elizabeth; Lott, Ira T.; Hof, Patrick R.; Bouras, Constantin; Su, Jianping; Kim, R.; Haier, Richard J.; Cotman, Carl W.

doi:10.1093/jnen/62.9.917

Cited by 40 publications

(35 citation statements)

References 36 publications

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“…RNA levels for the synaptic protein, SNAP-25, are also increased in DS brain [Greber-Platzer et al, 2003]. Markers of normal and abnormal s accumulations and Ab are related to the extent and localization of several neuronal growth markers [Head et al, 2003]. These findings are also consistent with a sprouting response seen in response to entorhinal cortex dysfunction in rodents and human AD brain [Geddes et al, 1985;Gage and Bjorklund, 1986].…”

Section: Neurobiology Of Ad: Clues From Neuroimagingmentioning

confidence: 85%

Alzheimer's disease in Down syndrome: Neurobiology and risk

Zigman¹,

Lott²

2007

Ment. Retard. Dev. Disabil. Res. Rev.

244

221

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Down syndrome (DS) is characterized by increased mortality rates, both during early and later stages of life, and age-specific mortality risk remains higher in adults with DS compared with the overall population of people with mental retardation and with typically developing populations. Causes of increased mortality rates early in life are primarily due to the increased incidence of congenital heart disease and leukemia, while causes of higher mortality rates later in life may be due to a number of factors, two of which are an increased risk for Alzheimer's disease (AD) and an apparent tendency toward premature aging. In this article, we describe the increase in lifespan for people with DS that has occurred over the past 100 years, as well as advances in the understanding of the occurrence of AD in adults with DS. Aspects of the neurobiology of AD, including the role of amyloid, oxidative stress, Cu/ZN dismutase (SOD-1), as well as advances in neuroimaging are presented. The function of risk factors in the observed heterogeneity in the expression of AD dementia in adults with DS, as well as the need for sensitive and specific biomarkers of the clinical and pathological progressing of AD in adults with DS is considered.

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Section: Neurobiology Of Ad: Clues From Neuroimagingmentioning

confidence: 85%

Alzheimer's disease in Down syndrome: Neurobiology and risk

Zigman¹,

Lott²

2007

Ment. Retard. Dev. Disabil. Res. Rev.

244

221

View full text Add to dashboard Cite

show abstract

“…In 34,64,65,73,74,[77][78][79][80][81][82][83][84][85][86][87][88] . Diffuse plaques are typically not associated with other forms of neuropathology, such as activated glial cells or synaptic loss, whereas densecore plaques are often associated with dystrophic neurites and activated astroglia and microglia 89 .…”

Section: Neuropathological Changes In Ad-dsmentioning

confidence: 99%

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

et al. 2015

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Down syndrome, which arises in individuals carrying an extra copy of chromosome 21, is associated with a greatly increased risk of early-onset Alzheimer disease. It is thought that this risk Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts is conferred by the presence of three copies of the gene encoding amyloid precursor protein (APP) -an Alzheimer disease risk factor -although the possession of extra copies of other chromosome 21 genes may also play a part. Further study of the mechanisms underlying the development of Alzheimer disease in people with Down syndrome could provide insights into the mechanisms that cause dementia in the general population.Down syndrome (DS) is a complex, highly variable disorder that arises from trisomy of chromosome 21. It was one of the first chromosomal disorders to be identified 1 and occurs with an incidence of approximately 1 in 800 births 2 . Its prevalence within a given population is influenced by infant mortality rates, access to health care, termination rates, average maternal age 3 and life expectancy. Indeed, despite the increased availability of prenatal diagnosis and access to the option of termination, the global prevalence of DS is rising because of improvements in life expectancy: the number of adults with DS aged over 40 years has doubled in northern Europe since 1990 and, in the United Kingdom, one-third of the estimated 40,000 people with DS are thought to be over 40 years of age 4 .DS is the most common form of intellectual disability. In addition to the features that are found in everyone with the disorder, such as the characteristic facial dysmorphology, there are many DS-associated phenotypes that have variable penetrance and severity. For example, approximately 40% of individuals with DS have heart malformations (usually atrioventricular septal defects) 5 . A key feature of DS is a striking propensity to develop early-onset Alzheimer disease (EOAD). Complete trisomy of chromosome 21 universally causes the development of amyloid plaques and neurofibrillary tangles (NFTs), which are typical characteristics of AD brain pathology, by the age of 40, and approximately twothirds of individuals with DS develop dementia by the age of 60 (REFS 6,7). However, rates of dementia do not reach 100%, even in older individuals, suggesting that some individuals with DS are protected from the onset of AD (FIG. 1).All of the features of DS arise because of aberrant dosages of coding and/or non-coding sequences present on chromosome 21. Among these sequences, the gene encoding amyloid precursor protein (APP) is thought to have a key role in the pathology of AD. The additional copy of APP may drive the development of AD in individuals with DS (AD-DS) by increasing the levels of amyloid-β (Aβ), a cleavage product of APP that misfolds and accumulates in the brain in people with AD. Consistent with this hypothesis, individuals with small internal chromosome 21 duplications that result in three copies of APP -a rare familial trait known as duplic...

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“…The entorhinal cortex is the gateway of the hippocampal formation, a circuit made up of the dentate gyrus, CA3 and CA1 subfields, and the subiculum. As documented histologicallly in the brains of patients with AD [103], of individuals with Down's syndrome who develop AD [104], and in animal models [105], primary dysfunction in the entorhinal cortex can lead to compensatory synaptic growth in downstream hippocampal subregions. Thus, it is possible that while metabolism in the entorhinal cortex is diminished by cell-sickness, metabolism in other hippocampal subregions might actually increase as association with these compensatory responses.…”

Section: Comparing and Contrasting Imaging Moda-litiesmentioning

confidence: 99%

Imaging the Earliest Stages of Alzheimers Disease

Small²

2006

CAR

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Historical progress in medicine can be charted along the lines of technical innovations that have visualized the invisible. One hundred years ago, Alois Alzheimer exploited newly developed histological stains to visualize his eponymonous disease in dead tissue under the microscope. Now, as we are entering the second century of Alzheimer's disease research, technical innovation has endowed us with a range of in vivo imaging techniques that promise to visualize Alzheimer' disease in living people. The earliest stage of Alzheimer's disease is characterized by cell-sickness, not cell-death, and can occur before the deposition of amyloid plaques or neurofibrillary tangles. In principle, 'functional' imaging techniques might be able to detect this early stage of the disease, a stage that was invisible to Alzheimer himself. Here, we will first define the neurobiological meaning of 'function' and then review the different approaches that measure brain dysfunction in Alzheimer' disease.

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Parallel Compensatory and Pathological Events Associated with Tau Pathology in Middle Aged Individuals with Down Syndrome

Cited by 40 publications

References 36 publications

Alzheimer's disease in Down syndrome: Neurobiology and risk

Alzheimer's disease in Down syndrome: Neurobiology and risk

A genetic cause of Alzheimer disease: mechanistic insights from Down syndrome

Imaging the Earliest Stages of Alzheimers Disease

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