Browsing by Author "Yassa, Michael A."

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    A pathway linking pulse pressure to dementia in adults with Down syndrome
    (Oxford University Press, 2024-05-09) Rizvi, Batool; Lao, Patrick J.; Sathishkumar, Mithra; Taylor, Lisa; Queder, Nazek; McMillan, Liv; Edwards, Natalie C.; Keator, David B.; Doran, Eric; Hom, Christy; Nguyen, Dana; Rosas, H. Diana; Lai, Florence; Schupf, Nicole; Gutierrez, Jose; Silverman, Wayne; Lott, Ira T.; Mapstone, Mark; Wilcock, Donna M.; Head, Elizabeth; Yassa, Michael A.; Brickman, Adam M.; Neurology, School of Medicine
    Adults with Down syndrome are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease and is linked to a diagnosis of dementia in adults with Down syndrome via structural imaging markers of cerebrovascular disease and atrophy. The study included participants with Down syndrome from the Alzheimer’s Disease - Down Syndrome study (n = 195, age = 50.6 ± 7.2 years, 44% women, 18% diagnosed with dementia). Higher pulse pressure was associated with greater global, parietal and occipital white matter hyperintensity volume but not with enlarged perivascular spaces, microbleeds or infarcts. Using a structural equation model, we found that pulse pressure was associated with greater white matter hyperintensity volume, which in turn was related to increased neurodegeneration, and subsequent dementia diagnosis. Pulse pressure is an important determinant of brain health and clinical outcomes in individuals with Down syndrome despite the low likelihood of frank hypertension.
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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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    Cerebrovascular disease is associated with Alzheimer's plasma biomarker concentrations in adults with Down syndrome
    (Oxford University Press, 2024-09-25) 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.; Alzheimer’s Biomarkers Consortium–Down Syndrome (ABC-DS) Investigators; Gutierrez, José; Wilcock, Donna M.; Head, Elizabeth; Brickman, Adam M.; Neurology, School of Medicine
    By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome.
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    Joint-label fusion brain atlases for dementia research in Down syndrome
    (Wiley, 2022-05-25) Queder, Nazek; Phelan, Michael J.; Taylor, Lisa; Tustison, Nicholas; Doran, Eric; Hom, Christy; Nguyen, Dana; Lai, Florence; Pulsifer, Margaret; Price, Julie; Kreisl, William C.; Rosas, Herminia D.; Krinsky-McHale, Sharon; Brickman, Adam M.; Yassa, Michael A.; Schupf, Nicole; Silverman, Wayne; Lott, Ira T.; Head, Elizabeth; Mapstone, Mark; Keator, David B.; Alzheimer’s Biomarkers Consortium; Neurology, School of Medicine
    Research suggests a link between Alzheimer's Disease in Down Syndrome (DS) and the overproduction of amyloid plaques. Using Positron Emission Tomography (PET) we can assess the in-vivo regional amyloid load using several available ligands. To measure amyloid distributions in specific brain regions, a brain atlas is used. A popular method of creating a brain atlas is to segment a participant's structural Magnetic Resonance Imaging (MRI) scan. Acquiring an MRI is often challenging in intellectually-imparied populations because of contraindications or data exclusion due to significant motion artifacts or incomplete sequences related to general discomfort. When an MRI cannot be acquired, it is typically replaced with a standardized brain atlas derived from neurotypical populations (i.e. healthy individuals without DS) which may be inappropriate for use in DS. In this project, we create a series of disease and diagnosis-specific (cognitively stable (CS-DS), mild cognitive impairment (MCI-DS), and dementia (DEM-DS)) probabilistic group atlases of participants with DS and evaluate their accuracy of quantifying regional amyloid load compared to the individually-based MRI segmentations. Further, we compare the diagnostic-specific atlases with a probabilistic atlas constructed from similar-aged cognitively-stable neurotypical participants. We hypothesized that regional PET signals will best match the individually-based MRI segmentations by using DS group atlases that aligns with a participant's disorder and disease status (e.g. DS and MCI-DS). Our results vary by brain region but generally show that using a disorder-specific atlas in DS better matches the individually-based MRI segmentations than using an atlas constructed from cognitively-stable neurotypical participants. We found no additional benefit of using diagnose-specific atlases matching disease status. All atlases are made publicly available for the research community.
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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.