Browsing by Author "Handen, Benjamin L."

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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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    Comparison of amyloid accumulation between Down syndrome and autosomal-dominant Alzheimer disease
    (Wiley, 2022) Boerwinkle, Anna H.; Gordon, Brian A.; Wisch, Julie K.; Flores, Shaney; Henson, Rachel L.; Butt, Omar Hameed; Chen, Charles D.; Benzinger, Tammie L. S.; Fagan, Anne M.; Handen, Benjamin L.; Christian, Bradley T.; Head, Elizabeth; Mapstone, Mark; Klunk, William E.; Rafii, Michael S.; O’Bryant, Sid E.; Price, Julie C.; Schupf, Nicole; Laymon, Charles M.; Krinsky-McHale, Sharon J.; Lai, Florence; Rosas, H. Diana; Hartley, Sigan L.; Zaman, Shahid; Lott, Ira T.; Silverman, Wayne; Brickman, Adam M.; Lee, Joseph H.; Allegri, Ricardo Francisco; Berman, Sarah; Chhatwal, Jasmeer P.; Chui, Helena C.; Cruchaga, Carlos; Farlow, Martin R.; Fox, Nick C.; Goate, Alison; Day, Gregory S.; Graff-Radford, Neill R.; Jucker, Mathias; Lee, Jae-Hong; Levin, Johannes; Martins, Ralph N.; Mori, Hiroshi; Perrin, Richard J.; Salloway, Stephen P.; Sanchez-Valle, Raquel; Schofield, Peter R.; Xiong, Chengjie; Karch, Celeste M.; Hassenstab, Jason J.; McDade, Eric; Bateman, Randall J.; Ances, Beau M.; Neurology, School of Medicine
    Background: Given the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)-like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our understanding of early AD pathology development. Method: We assessed amyloid positron emission tomography (PET) imaging in 192 participants with DS and 33 sibling controls from the Alzheimer’s Biomarker Consortium-Down Syndrome (ABC-DS) and 265 mutation-carriers (MC) and 169 familial controls from the Dominantly Inherited Alzheimer Network (DIAN) (Table 1). We calculated regional standard uptake value ratios (SUVR) using a cerebellar cortex reference region and converted global amyloid burden SUVR to centiloids. We compared amyloid PET by cognitive status and estimated-years-to-symptom-onset (EYO). EYO was calculated for DIAN participants by subtracting their age from parental age of symptom onset and for ABC-DS participants by subtracting their age from 50.2 years, a published average age of symptom onset in a large sample of individuals with DS (Fortea et al., 2020). In a subset of participants, we assessed the relationship between amyloid PET and CSF Aβ42/40. Result: The relationship between CSF Aβ42/40 and amyloid PET was similar in DS and MC participants (Figure 1). We did not observe significant differences between MC and DS grouped by cognitive status (Figure 2). However, when assessed over EYO, global amyloid burden was significantly elevated in MC at EYO ≥ -23 but was not elevated in DS until EYO ≥ -15 (Figure 3). We observed early cortical and subcortical amyloid PET increases in both groups, but we also measured some regional differences in amyloid PET changes between MC and DS, specifically in the medial occipital region (Figure 4 and 5). Conclusion: These results demonstrate similarities in the relationship between amyloid biomarkers and the levels of amyloid accumulation in ADAD and DS. However, we also observed a 5-10 year delay and some regional differences in amyloid accumulation in DS. This is important for future clinical trials to consider when recruiting participants and determining treatment efficacy.
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    A Double-Blind, Placebo-Controlled Trial of Oral Human Immunoglobulin for Gastrointestinal Dysfunction in Children with Autistic Disorder
    (Springer, 2009-01-16) Handen, Benjamin L.; Melmed, Raun D.; Hansen, Robin L.; Aman, Michael G.; Burnham, David L.; Bruss, Jon B.; McDougle, Christopher J.; Psychiatry, School of Medicine
    Controversy exists regarding the extent and possible causal relationship between gastrointestinal symptoms and autism. A randomized, double-blind, placebo-controlled, parallel groups, dose-ranging study of oral, human immunoglobulin (IGOH 140, 420, or 840 mg/day) was utilized with 125 children (ages 2–17 years) with autism and persistent GI symptoms. Endpoint analysis revealed no significant differences across treatment groups on a modified global improvement scale (validated in irritable bowel syndrome studies), number of daily bowel movements, days of constipation, or severity of problem behaviors. IGOH was well-tolerated; there were no serious adverse events. This study demonstrates the importance of conducting rigorous trials in children with autism and casts doubt on one GI mechanism presumed to exert etiological and/or symptomatic effects in this population.
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    Independent and interactive contributions of cerebrovascular disease, neuroinflammation, and tau pathophysiology to Alzheimer’s disease‐related diagnostic conversion in adults with Down syndrome
    (Wiley, 2025-01-09) Edwards, Natalie C.; Lao, Patrick J.; Alshikho, Mohamad J.; Rizvi, Batool; Flores Aguilar, Lisi; Petersen, Melissa; O’Bryant, Sid E.; Tudorascu, Dana; Handen, Benjamin L.; Gutierrez, Jose; Wilcock, Donna M.; Head, Elizabeth; Brickman, Adam M.; Neurology, School of Medicine
    Background: By age 40 years, adults with Down syndrome (DS) develop Alzheimer’s disease (AD) pathology and progress to dementia in their 60s. Despite minimal systemic vascular risk factors, individuals with DS have MRI evidence of cerebrovascular injury that progresses with AD severity, suggesting an intrinsic vascular component to DS‐AD that may interact with neuroinflammatory processes to promote tau pathology and cognitive decline. In the current study we examined whether cerebrovascular disease (CVD) burden and inflammation/astrocytosis independently and interactively were associated with incident diagnosis among adults with DS. Method: This study included 149 participants from the Alzheimer Biomarkers Consortium – Down Syndrome (baseline mean age[SD]=44.6[9] years) with available baseline MRI, plasma biomarker data, and at least two time‐points of clinical consensus diagnosis data (i.e., cognitively stable, mild cognitive impairment [MCI], and clinical AD) who were classified as cognitively stable or MCI at baseline. Logistic regression models assessed if baseline small vessel CVD, operationalized as white matter hyperintensity (WMH) volume, and plasma glial fibrillary acidic protein (GFAP), Aβ42/Aβ40, p‐tau217, and neurofilament light (NfL) concentrations are associated with conversion from a milder diagnosis to a more severe clinical diagnosis. Mediation models examined relationships between biomarkers and diagnostic conversion. All models adjusted for study site, sex/gender, latency between visit dates, and age group (below or above/equal to the median age of the sample). Result: Diagnostic conversion occurred in 26% of the sample. Higher baseline WMH volume (OR 1.08 [1.01, 1.81]), GFAP (OR 1.006 [1.003, 1.01]), and p‐tau217 (OR 20.56 [5.01, 112.43]), but not NfL nor Aβ42/Aβ40 concentrations were associated with higher odds of conversion to more severe cognitive impairment. GFAP concentration mediated the relationship between WMH and diagnostic conversion (ACME 0.05 [0.01, 0.1], p=0.006). P‐tau217 concentration mediated the relationship between GFAP and diagnostic conversion (ACME 0.13 [0.05, 0.23], p=0.004). Conclusion: Our findings suggest that among individuals with DS, CVD promotes AD‐related clinical progression by increasing astrocytosis which, in turn, promotes tau pathophysiology and downstream MCI and AD incidence. The results implicate CVD and its interface with inflammation as a core feature of AD in DS.
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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.