Metabolic and Vascular Imaging Biomarkers in Down Syndrome Provide Unique Insights Into Brain Aging and Alzheimer Disease Pathogenesis

Head, Elizabeth; Powell, David K.; Schmitt, Frederick A.

doi:10.3389/fnagi.2018.00191

Cited by 17 publications

(23 citation statements)

References 75 publications

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“…In the neurotypical AD population, we have identified a pro‐inflammatory endophenotype that identifies a specific subset of AD patients who benefitted from a “failed” nonsteroidal anti‐inflammatory drug (NSAID) trial 28 . It appears that this pro‐inflammatory endophenotype is also present within DS adults with MCI and AD, which is consistent with the increased role of inflammation among individuals with DS 46,47 . Prior work has shown that neuroinflammation is upregulated in fetal development in DS, which may accelerate the development of AD pathology 46 .…”

Section: Discussionsupporting

confidence: 58%

Proteomic profiles of incident mild cognitive impairment and Alzheimer's disease among adults with Down syndrome

O’Bryant

Zhang

Silverman

et al. 2020

Alzheimer's & Dementia: Diagnosis, Assessment &

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Introduction We sought to determine if proteomic profiles could predict risk for incident mild cognitive impairment (MCI) and Alzheimer's disease (AD) among adults with Down syndrome (DS). Methods In a cohort of 398 adults with DS, a total of n = 186 participants were determined to be non‐demented and without MCI or AD at baseline and throughout follow‐up; n = 103 had incident MCI and n = 81 had incident AD. Proteomics were conducted on banked plasma samples from a previously generated algorithm. Results The proteomic profile was highly accurate in predicting incident MCI (area under the curve [AUC] = 0.92) and incident AD (AUC = 0.88). For MCI risk, the support vector machine (SVM)‐based high/low cut‐point yielded an adjusted hazard ratio (HR) = 6.46 (P < .001). For AD risk, the SVM‐based high/low cut‐point score yielded an adjusted HR = 8.4 (P < .001). Discussion The current results provide support for our blood‐based proteomic profile for predicting risk for MCI and AD among adults with DS.

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Section: Discussionsupporting

confidence: 58%

Proteomic profiles of incident mild cognitive impairment and Alzheimer's disease among adults with Down syndrome

O’Bryant

Zhang

Silverman

et al. 2020

Alzheimer's & Dementia: Diagnosis, Assessment &

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“…The peripheral alterations presented above in this review suggest that DS subjects might be potentially more susceptible to developing brain insulin resistance than other children. Indeed, growing evidence highlight the role of metabolic defects as a risk factor for cognitive impairments also in DS (Caracausi et al, 2018;Head et al, 2018;Vacca et al, 2019).…”

Section: Brain Insulin Resistance Is a Feature Of Down Syndromementioning

confidence: 99%

“…With regard to brain alterations, accumulation of toxic catabolites (Caracausi et al, 2018;Gross et al, 2019) or dysfunction of key metabolic pathways were identified as crucial determinants triggering neuronal dyshomeostasis and neurodegeneration in DS (Head et al, 2018;Lott and Head, 2019;Vacca et al, 2019).…”

Section: Brain Insulin Resistance Is a Feature Of Down Syndromementioning

confidence: 99%

Down Syndrome Is a Metabolic Disease: Altered Insulin Signaling Mediates Peripheral and Brain Dysfunctions

et al. 2020

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Down syndrome (DS) is the most frequent chromosomal abnormality that causes intellectual disability, resulting from the presence of an extra complete or segment of chromosome 21 (HSA21). In addition, trisomy of HSA21 contributes to altered energy metabolism that appears to be a strong determinant in the development of pathological phenotypes associated with DS. Alterations include, among others, mitochondrial defects, increased oxidative stress levels, impaired glucose, and lipid metabolism, finally resulting in reduced energy production and cellular dysfunctions. These molecular defects seem to account for a high incidence of metabolic disorders, i.e., diabetes and/or obesity, as well as a higher risk of developing Alzheimer's disease (AD) in DS. A dysregulation of the insulin signaling with reduced downstream pathways represents a common pathophysiological aspect in the development of both peripheral and central alterations leading to diabetes/obesity and AD. This is further strengthened by evidence showing that the molecular mechanisms responsible for such alterations appear to be similar between peripheral organs and brain. Considering that DS subjects are at high risk to develop either peripheral or brain metabolic defects, this review will discuss current knowledge about the link between trisomy of HSA21 and defects of insulin and insulin-related pathways in DS. Drawing the molecular signature underlying these processes in DS is a key challenge to identify novel drug targets and set up new prevention strategies aimed to reduce the impact of metabolic disorders and cognitive decline.

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“…Markers of AD‐specific neurodegeneration include regional hypometabolism on FDG PET9 86‐88 or hippocampal atrophy 89‐91 have been studied in DS and parallel findings from the sporadic and autosomal dominant forms of AD. More recently, plasma neurofilament light chain (NfL) levels (also a marker of neurodegeneration) have been shown to correlate with clinical status of AD in DS 92 as well as standard AD biomarkers such as amyloid PET and tau PET 93 .…”

Section: Biomarker Assessments Of Amyloid Tau and Neurodegenerationmentioning

confidence: 99%

The AT(N) framework for Alzheimer's disease in adults with Down syndrome

Rafii

Ances

Schupf

et al. 2020

Alzheimer's & Dementia: Diagnosis, Assessment &

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The National Institute on Aging in conjunction with the Alzheimer's Association (NIA‐AA) recently proposed a biological framework for defining the Alzheimer's disease (AD) continuum. This new framework is based upon the key AD biomarkers (amyloid, tau, neurodegeneration, AT[N]) instead of clinical symptoms and represents the latest understanding that the pathological processes underlying AD begin decades before the manifestation of symptoms. By using these same biomarkers, individuals with Down syndrome (DS), who are genetically predisposed to developing AD, can also be placed more precisely along the AD continuum. The A/T(N) framework is therefore thought to provide an objective manner by which to select and enrich samples for clinical trials. This new framework is highly flexible and allows the addition of newly confirmed AD biomarkers into the existing AT(N) groups. As biomarkers for other pathological processes are validated, they can also be added to the AT(N) classification scheme, which will allow for better characterization and staging of AD in DS. These biological classifications can then be merged with clinical staging for an examination of factors that impact the biological and clinical progression of the disease. Here, we leverage previously published guidelines for the AT(N) framework to generate such a plan for AD among adults with DS.

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Metabolic and Vascular Imaging Biomarkers in Down Syndrome Provide Unique Insights Into Brain Aging and Alzheimer Disease Pathogenesis

Cited by 17 publications

References 75 publications

Proteomic profiles of incident mild cognitive impairment and Alzheimer's disease among adults with Down syndrome

Proteomic profiles of incident mild cognitive impairment and Alzheimer's disease among adults with Down syndrome

Down Syndrome Is a Metabolic Disease: Altered Insulin Signaling Mediates Peripheral and Brain Dysfunctions

The AT(N) framework for Alzheimer's disease in adults with Down syndrome

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