Browsing by Author "Rizvi, Batool"

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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 emerges with age and Alzheimer's disease in adults with Down syndrome
    (Springer Nature, 2024-05-29) Lao, Patrick; Edwards, Natalie; Flores‑Aguilar, Lisi; Alshikho, Mohamad; Rizvi, Batool; Tudorascu, Dana; Rosas, H. Diana; Yassa, Michael; Christian, Bradley T.; Mapstone, Mark; Handen, Benjamin; Zimmerman, Molly E.; Gutierrez, Jose; Wilcock, Donna; Head, Elizabeth; Brickman, Adam M.; Neurology, School of Medicine
    Adults with Down syndrome have a genetic form of Alzheimer's disease (AD) and evidence of cerebrovascular disease across the AD continuum, despite few systemic vascular risk factors. The onset and progression of AD in Down syndrome is highly age-dependent, but it is unknown at what age cerebrovascular disease emerges and what factors influence its severity. In the Alzheimer's Biomarker Consortium-Down Syndrome study (ABC-DS; n = 242; age = 25-72), we estimated the age inflection point at which MRI-based white matter hyperintensities (WMH), enlarged perivascular spaces (PVS), microbleeds, and infarcts emerge in relation to demographic data, risk factors, amyloid and tau, and AD diagnosis. Enlarged PVS and infarcts appear to develop in the early 30s, while microbleeds, WMH, amyloid, and tau emerge in the mid to late 30s. Age-residualized WMH were higher in women, in individuals with dementia, and with lower body mass index. Participants with hypertension and APOE-ε4 had higher age-residualized PVS and microbleeds, respectively. Lifespan trajectories demonstrate a dramatic cerebrovascular profile in adults with Down syndrome that appears to evolve developmentally in parallel with AD pathophysiology approximately two decades prior to dementia symptoms.
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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.