Browsing by Author "Flores-Aguilar, Lisi"

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    Cerebrovascular disease drives Alzheimer plasma biomarker concentrations in adults with Down syndrome
    (medRxiv, 2023-11-30) Edwards, Natalie C.; Lao, Patrick J.; Alshikho, Mohamad J.; Ericsson, Olivia M.; Rizvi, Batool; Petersen, Melissa E.; O’Bryant, Sid; Flores-Aguilar, Lisi; Simoes, Sabrina; Mapstone, Mark; Tudorascu, Dana L.; Janelidze, Shorena; Hansson, Oskar; Handen, Benjamin L.; Christian, Bradley T.; Lee, Joseph H.; Lai, Florence; Rosas, H. Diana; Zaman, Shahid; Lott, Ira T.; Yassa, Michael A.; Gutierrez, José; Wilcock, Donna M.; Head, Elizabeth; Brickman, Adam M.; Neurology, School of Medicine
    Importance: By age 40 years over 90% of adults with Down syndrome (DS) have Alzheimer's disease (AD) pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with DS have elevated cerebrovascular disease (CVD) markers that track with the clinical progression of AD, suggesting a role for CVD that is hypothesized to be mediated by inflammatory factors. Objective: To examine the pathways through which small vessel CVD contributes to AD-related pathophysiology and neurodegeneration in adults with DS. Design: Cross sectional analysis of neuroimaging, plasma, and clinical data. Setting: Participants were enrolled in Alzheimer's Biomarker Consortium - Down Syndrome (ABC-DS), a multisite study of AD in adults with DS. Participants: One hundred eighty-five participants (mean [SD] age=45.2 [9.3] years) with available MRI and plasma biomarker data were included. White matter hyperintensity (WMH) volumes were derived from T2-weighted FLAIR MRI scans and plasma biomarker concentrations of amyloid beta (Aβ42/Aβ40), phosphorylated tau (p-tau217), astrocytosis (glial fibrillary acidic protein, GFAP), and neurodegeneration (neurofilament light chain, NfL) were measured with ultrasensitive immunoassays. Main outcomes and measures: We examined the bivariate relationships of WMH, Aβ42/Aβ40, p-tau217, and GFAP with age-residualized NfL across AD diagnostic groups. A series of mediation and path analyses examined causal pathways linking WMH and AD pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. Results: There was a direct and indirect bidirectional effect through GFAP of WMH on p-tau217 concentration, which was associated with NfL concentration in the entire sample. Among cognitively stable participants, WMH was directly and indirectly, through GFAP, associated with p-tau217 concentration, and in those with MCI, there was a direct effect of WMH on p-tau217 and NfL concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. Conclusions and relevance: The findings suggest that among individuals with DS, CVD promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of AD. This work joins an emerging literature that implicates CVD and its interface with neuroinflammation as a core pathological feature of AD in adults with DS.
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    Correction to: Specific Susceptibility to COVID-19 in Adults with Down Syndrome
    (Springer, 2021-05-04) Illouz, Tomer; Biragyn, Arya; Frenkel-Morgenstern, Milana; Weissberg, Orly; Gorohovski, Alessandro; Merzon, Eugene; Green, Ilan; Iulita, Florencia; Flores-Aguilar, Lisi; Dierssen, Mara; De Toma, Ilario; Lifshitz, Hefziba; Antonarakis, Stylianos E.; Yu, Eugene; Herault, Yann; Potier, Marie-Claude; Botté, Alexandra; Roper, Randall; Sredni, Benjamin; Sarid, Ronit; London, Jacqueline; Mobley, William; Strydom, Andre; Okun, Eitan; Biology, School of Science
    The current SARS-CoV-2 outbreak, which causes COVID-19, is particularly devastating for individuals with chronic medical conditions, in particular those with Down Syndrome (DS) who often exhibit a higher prevalence of respiratory tract infections, immune dysregulation and potential complications. The incidence of Alzheimer’s disease (AD) is much higher in DS than in the general population, possibly increasing further the risk of COVID-19 infection and its complications. Here we provide a biological overview with regard to specific susceptibility of individuals with DS to SARS-CoV-2 infection as well as data from a recent survey on the prevalence of COVID-19 among them. We see an urgent need to protect people with DS, especially those with AD, from COVID-19 and future pandemics and focus on developing protective measures, which also include interventions by health systems worldwide for reducing the negative social effects of long-term isolation and increased periods of hospitalization.
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    Immune Dysregulation and the Increased Risk of Complications and Mortality Following Respiratory Tract Infections in Adults With Down Syndrome
    (Sage, 2021-01) Illouz, Tomer; Biragyn, Arya; Iulita, Maria Florencia; Flores-Aguilar, Lisi; Dierssen, Mara; De Toma, Ilario; Antonarakis, Stylianos E.; Yu, Eugene; Herault, Yann; Potier, Marie-Claude; Botté, Alexandra; Roper, Randall; Sredni, Benjamin; London, Jacqueline; Mobley, William; Strydom, Andre; Okun, Eitan; Medicine, School of Medicine
    The risk of severe outcomes following respiratory tract infections is significantly increased in individuals over 60 years, especially in those with chronic medical conditions, i.e., hypertension, diabetes, cardiovascular disease, dementia, chronic respiratory disease, and cancer. Down Syndrome (DS), the most prevalent intellectual disability, is caused by trisomy-21 in ~1:750 live births worldwide. Over the past few decades, a substantial body of evidence has accumulated, pointing at the occurrence of alterations, impairments, and subsequently dysfunction of the various components of the immune system in individuals with DS. This associates with increased vulnerability to respiratory tract infections in this population, such as the influenza virus, respiratory syncytial virus, SARS-CoV-2 (COVID-19), and bacterial pneumonias. To emphasize this link, here we comprehensively review the immunobiology of DS and its contribution to higher susceptibility to severe illness and mortality from respiratory tract infections.
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    Increased fibrin deposition in the brains of individuals with Down syndrome and Alzheimer’s disease
    (Wiley, 2025-01-03) Du, Annie; Flores-Aguilar, Lisi; Edwards, Natalie C.; Lao, Patrick J.; Ryu, Jae Kyu; Akassoglou, Katerina; Wilcock, Donna M.; Kofler, Julia; Ikonomovic, Milos D.; Lai, Florence; Brickman, Adam M.; Head, Elizabeth; Neurology, School of Medicine
    Background: Individuals with Down syndrome (DS) have an increased genetic risk of developing Alzheimer’s disease (AD), with most adults developing AD neuropathology in their 40s. Despite having a low frequency of systemic vascular risk factors such as hypertension and atherosclerosis, adults with DS display cerebrovascular pathology, including microbleeds, microinfarcts, and cerebral amyloid angiopathy. This suggests that blood‐brain barrier (BBB) integrity may be compromised allowing the extravasation of blood proteins in the brain parenchyma. The blood coagulation factor fibrin promotes immune‐mediated neurodegeneration and is a marker of BBB disruption in a wide range of neurological diseases. This study investigated the severity of fibrin deposition as a measure of BBB integrity in the brains of adults with DS and AD pathology (DSAD). We hypothesized that fibrin deposition is increased in DSAD in comparison to neurotypical controls without DS or AD. Method: Fibrin immunoreactivity was assessed by free‐floating immunohistochemistry in 30µm tissue sections from the occipital cortex from neurotypical controls (n = 12; 41‐65 years old) and DSAD (n = 12; 46‐66 years old). Using whole slide imaging, brain sections were digitized, and the severity of fibrin deposition was scored using Aperio Imagescope. Result: Individuals with DSAD display significantly higher fibrin deposition in the white and grey matter of the occipital cortex in comparison to the age‐matched neurotypical controls (p<0.0001). Conclusion: Neurotypical controls display minimal fibrin deposition in the brain parenchyma and perivascular space. However, compared to neurotypical controls, adults with DS at advanced stages of AD neuropathology display significant fibrin deposition in the occipital cortex, suggesting that the BBB may be compromised in this population.
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    Longitudinal changes in neuroimaging markers of small vessel disease: Implications for clinical trials
    (Wiley, 2025-01-09) Lao, Patrick J.; Edwards, Natalie C.; Flores-Aguilar, Lisi; Rizvi, Batool; Smith, Anna C.; Tudorascu, Dana; Rosas, H. Diana; Yassa, Michael A.; Handen, Benjamin L.; Christian, Bradley T.; Gutierrez, Jose; Wilcock, Donna M.; Head, Elizabeth; Brickman, Adam M.; Neurology, School of Medicine
    Background: Adults with Down syndrome (DS) overproduce amyloid precursor protein, develop amyloid plaques at an early age, and are diagnosed with Alzheimer’s disease (AD) dementia at a high frequency. There is emerging evidence that cerebrovascular disease is elevated across the AD continuum in older adults with DS, independent of age and vascular risk, around the same time as amyloid and tau, but the regional rates of accumulation within individuals are unknown. Method: Adults with DS from the multisite Alzheimer’s Biomarker Consortium‐Down Syndrome study (ABC‐DS; n=78; age=50±6; 40% women) have two timepoints of T2 FLAIR MRI (1.2±0.6 years apart) quantified as white matter hyperintensity volume (WMH), which represents ischemic small vessel disease. Participants underwent consensus diagnosis at both timepoints (59% Cognitively‐Stable at both timepoints, 9% Cognitively‐Stable to MCI‐DS, 8% MCI‐DS at both timepoints, 14% MCI‐DS to AD, 10% AD at both timepoints). The annual rate of change in frontal, temporal, parietal, and occipital WMH volume was assessed, adjusting for baseline WMH volume. Result: The annual rate of change in frontal WMH was not significantly different by diagnosis. The annual rate of change in temporal (0.7 [0.4, 1.1], p<0.001) and in occipital WMH (1.6 [0.7, 2.5], p=0.0008) was faster in the group that remained AD at both timepoints compared to the group that remained Cognitively‐Stable at both timepoints. The annual rate of change in parietal WMH was greater in the group that progressed from MCI‐DS to AD (0.6 [0.1, 1.0], p=0.02) and in the group that remained AD at both timepoints (1.1 [0.6, 1.7], p=0.0002) compared to the group that remained Cognitively‐Stable at both timepoints. Conclusion: In adults with DS, parietal WMH accumulates fastest in those that progress to or have a diagnosis of AD, while temporal and occipital WMH accumulate fastest in those with a diagnosis of AD. Posteriorly distributed WMH may have specificity for AD progression in adults with DS with implications for anti‐amyloid therapeutics that have cerebrovascular side effects.
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    Specific Susceptibility to COVID-19 in Adults with Down Syndrome
    (Springer, 2021) Illouz, Tomer; Biragyn, Arya; Frenkel‑Morgenstern, Milana; Weissberg, Orly; Gorohovski, Alessandro; Merzon, Eugene; Green, Ilan; Iulita, Florencia; Flores-Aguilar, Lisi; del Mar Dierssen Sotos, Maria; De Toma, Ilario; Lifshitz, Herziba; Antonarakis, Stylianos E.; Yu, Eugene; Herault, Yann; Potier, Marie-Claude; Botté, Alexandra; Roper, Randall; Sredni, Benjamin; Sarid, Ronit; London, Jacqueline; Mobley, William; Strydom, Andre; Okun, Eitan; Biology, School of Science
    The current SARS-CoV-2 outbreak, which causes COVID-19, is particularly devastating for individuals with chronic medical conditions, in particular those with Down Syndrome (DS) who often exhibit a higher prevalence of respiratory tract infections, immune dysregulation and potential complications. The incidence of Alzheimer’s disease (AD) is much higher in DS than in the general population, possibly increasing further the risk of COVID-19 infection and its complications. Here we provide a biological overview with regard to specific susceptibility of individuals with DS to SARS-CoV-2 infection as well as data from a recent survey on the prevalence of COVID-19 among them. We see an urgent need to protect people with DS, especially those with AD, from COVID-19 and future pandemics and focus on developing protective measures, which also include interventions by health systems worldwide for reducing the negative social effects of long-term isolation and increased periods of hospitalization.