Browsing by Author "Lockhart, Samuel N."

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    Adverse Social Exposome by Area Deprivation Index (ADI) and Alzheimer’s Disease and Related Dementias (ADRD) Neuropathology for a National Cohort of Brain Donors within the Neighborhoods Study
    (Wiley, 2025-01-09) Kind, Amy J. H.; Bendlin, Barbara B.; Keller, Sarah A.; Powell, W. Ryan; DeWitt, Amanda; Cheng, Yixuan; Chamberlain, Luke; Lyons Boone, Brittney; Miller, Megan J.; Vik, Stacie M.; Abner, Erin L.; Alosco, Michael L.; Apostolova, Liana G.; Bakulski, Kelly M.; Barnes, Lisa L.; Bateman, James R.; Beach, Thomas G.; Bennett, David A.; Brewer, James B.; Carrion, Carmen; Chodosh, Joshua; Craft, Suzanne; Croff, Raina; Fabio, Anthony; Tomaszewski Farias, Sarah; Goldstein, Felicia; Henderson, Victor W.; Karikari, Thomas; Kofler, Julia; Kucharska-Newton, Anna M.; Lamar, Melissa; Lanata, Serggio; Lepping, Rebecca J.; Lingler, Jennifer H.; Lockhart, Samuel N.; Mahnken, Jonathan D.; Marsh, Karyn; Meyer, Oanh L.; Miller, Bruce L.; Morris, Jill K.; Neugroschl, Judith A.; O'Connor, Maureen K.; Paulson, Henry L.; Perrin, Richard J.; Pierce, Aimee; Raji, Cyrus A.; Reiman, Eric M.; Risacher, Shannon L.; Rissman, Robert A.; Rodriguez Espinoza, Patricia; Sano, Mary; Saykin, Andrew J.; Serrano, Geidy E.; Sultzer, David L.; Whitmer, Rachel A.; Wisniewski, Thomas; Woltjer, Randall; Zhu, Carolyn W.; Neurology, School of Medicine
    Background: Adverse social exposome (indexed by high national Area Deprivation Index [ADI]) is linked to structural inequities and increased risk of clinical dementia diagnosis, yet linkage to ADRD neuropathology remains largely unknown. Early work from single site brain banks suggests a relationship, but assessment in large national cohorts is needed to increase generalizability and depth, particularly for rarer neuropathology findings. Objective: Determine the association between adverse social exposome by ADI and ADRD neuropathology for brain donors from 21 Alzheimer’s Disease Research Center (ADRC) brain banks as part of the on‐going Neighborhoods Study. Methods: All brain donors in participating sites with neuropathology data deposited at the National Alzheimer’s Coordinating Center (NACC) and identifiers for ADI linkage (N = 8,637; Figure 1) were included. Geocoded donor addresses were linked to time‐concordant national ADI percentiles for year of death, categorized into standard groupings of low (ADI 1‐19), medium (20‐49) and high (50‐100) ADI. Neuropathological findings were drawn from NACC and reflected standard assessment practices at time of donation. Logistic regression models, adjusted for sex and age at death, assessed relationships between high ADI and neuropathology findings. Results: Of the N = 8,637 brain donors (Table 1), 2,071 of 2,366 assessed (88%) had AD pathology by NIA‐AA criteria; 4,197 of 6,929 assessed (61%) had cerebral amyloid angiopathy; 2582 of 8092 assessed (32%) had Lewy body pathology; 391 of 2351 assessed (17%) had non‐AD tauopathy; and 586 of 1680 assessed (35%) had TDP‐43 pathology. 2,126(25%) were high ADI; 3,171(37%) medium ADI and 3,340(38%) low ADI with 51% female and average age at death of 81.9 years. As compared to low ADI donors, high ADI brain donors had adjusted odds = 1.35 (95% CI = 0.98‐1.86, p‐value = 0.06) for AD pathology; 1.10 (0.98–1.25, p = 0.11) for cerebral amyloid angiopathy; 1.37 (1.21–1.55, p<0.01) for Lewy body; 1.09 (0.83–1.44, p = 0.53) for non‐AD tauopathy; and 1.40 (1.08‐1.81, p = 0.01) for TDP‐43 pathology (Table 2). Conclusions: This first‐in‐field study provides evidence that the adverse social exposome (high ADI) is strongly associated with an increased risk of Lewy body, an increased risk of TDP‐43, and a trend towards increased AD pathology in a national cohort of brain donors.
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    Alzheimer’s Disease Plasma Biomarker Results from across 14 Alzheimer’s Disease Research Centers
    (Wiley, 2025-01-09) Russ, Kristen A.; Asthana, Sanjay; Johnson, Sterling C.; Wilson, Rachael E.; Craft, Suzanne; Register, Thomas C.; Lockhart, Samuel N.; Nairn, Angus C.; Strittmatter, Stephen M.; van Dyck, Christopher H.; Foroud, Tatiana M.; Dage, Jeffrey L.; Neurology, School of Medicine
    Background: The Alzheimer’s Disease Center Fluid Biomarker (ADCFB) Initiative samples are analyzed centrally at NCRAD for AD plasma biomarkers. When combining NACC accessible data from across centers, biofluid biomarker data must be evaluated carefully. This will become more critical with the implementation of disease modifying therapies. Methods: Beta amyloid 1‐42 (Aβ42) and beta amyloid 1‐40 (Aβ40) were analyzed utilizing the Neurology 4‐Plex E kits on a Quanterix Simoa HD‐X. All assays were performed according to manufacturer’s instructions. NACC data from participants 65 or older was combined with biomarker results into one data set. Samples with PET results from the same visit as the blood collection were utilized for this analysis (n=114). Results: Data for amyloid and tau PET was used along with Aβ42/40 ratios to assess the area under the curve (AUC) for this data set (Figure 1). Amyloid PET and Tau PET by Aβ42/40 ROC analysis including age and APOE4 carrier status showed lower than expected AUCs (both 0.72). A subset of data (n=90) was analyzed using participants that were not on any FDA‐approved drugs for AD. This had no effect on AUCs for amyloid or tau PET by Aβ42/40 ratios. Distribution of Aβ42/40 ratios across sites showed a single site had a subset of very high Aβ42/40 ratios (n=8) in comparison to other sites. After removal of the Aβ42/40 outliers from the specific site from the data set, diagnostic accuracies of Aβ42/40 for both Amyloid PET (AUC=0.77) and Tau PET (AUC=0.76) were increased. More investigation into the exact cause of the outliers is necessary, but Aβ42/40 elevations independent from other biomarkers have been seen in clinical trials of Solanezumab and some other Aβ targeting antibodies. Conclusion: To avoid errors in data analysis when using shared data, it is important to track clinical trial co‐enrollment and drug type within ADCs at NACC. As FDA‐approved treatments become available or co‐enrollment of AD drug trials at centers occurs, it is critical to carefully track participant variables and review biofluid biomarker data when it is being combined across centers or studies.
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    Associations among plasma, MRI, and amyloid PET biomarkers of Alzheimer's disease and related dementias and the impact of health‐related comorbidities in a community‐dwelling cohort
    (Wiley, 2024) Rudolph, Marc D.; Sutphen, Courtney L.; Register, Thomas C.; Whitlow, Christopher T.; Solingapuram Sai, Kiran K.; Hughes, Timothy M.; Bateman, James R.; Dage, Jeffrey L.; Russ, Kristen A.; Mielke, Michelle M.; Craft, Suzanne; Lockhart, Samuel N.; Neurology, School of Medicine
    Introduction: We evaluated associations between plasma and neuroimaging-derived biomarkers of Alzheimer's disease and related dementias and the impact of health-related comorbidities. Methods: We examined plasma biomarkers (neurofilament light chain, glial fibrillary acidic protein, amyloid beta [Aβ] 42/40, phosphorylated tau 181) and neuroimaging measures of amyloid deposition (Aβ-positron emission tomography [PET]), total brain volume, white matter hyperintensity volume, diffusion-weighted fractional anisotropy, and neurite orientation dispersion and density imaging free water. Participants were adjudicated as cognitively unimpaired (CU; N = 299), mild cognitive impairment (MCI; N = 192), or dementia (DEM; N = 65). Biomarkers were compared across groups stratified by diagnosis, sex, race, and APOE ε4 carrier status. General linear models examined plasma-imaging associations before and after adjusting for demographics (age, sex, race, education), APOE ε4 status, medications, diagnosis, and other factors (estimated glomerular filtration rate [eGFR], body mass index [BMI]). Results: Plasma biomarkers differed across diagnostic groups (DEM > MCI > CU), were altered in Aβ-PET-positive individuals, and were associated with poorer brain health and kidney function. Discussion: eGFR and BMI did not substantially impact associations between plasma and neuroimaging biomarkers. Highlights: Plasma biomarkers differ across diagnostic groups (DEM > MCI > CU) and are altered in Aβ-PET-positive individuals. Altered plasma biomarker levels are associated with poorer brain health and kidney function. Plasma and neuroimaging biomarker associations are largely independent of comorbidities.
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    Emerging role of vascular burden in AT(N) classification in individuals with Alzheimer's and concomitant cerebrovascular burdens
    (BMJ, 2023-12-14) Chun, Min Young; Jang, Hyemin; Kim, Soo-Jong; Park, Yu Hyun; Yun, Jihwan; Lockhart, Samuel N.; Weiner, Michael; De Carli, Charles; Moon, Seung Hwan; Choi, Jae Yong; Nam, Kyung Rok; Byun, Byung-Hyun; Lim, Sang-Moo; Kim, Jun Pyo; Choe, Yeong Sim; Kim, Young Ju; Na, Duk L.; Kim, Hee Jin; Seo, Sang Won; Radiology and Imaging Sciences, School of Medicine
    Objectives: Alzheimer's disease (AD) is characterised by amyloid-beta accumulation (A), tau aggregation (T) and neurodegeneration (N). Vascular (V) burden has been found concomitantly with AD pathology and has synergistic effects on cognitive decline with AD biomarkers. We determined whether cognitive trajectories of AT(N) categories differed according to vascular (V) burden. Methods: We prospectively recruited 205 participants and classified them into groups based on the AT(N) system using neuroimaging markers. Abnormal V markers were identified based on the presence of severe white matter hyperintensities. Results: In A+ category, compared with the frequency of Alzheimer's pathological change category (A+T-), the frequency of AD category (A+T+) was significantly lower in V+ group (31.8%) than in V- group (64.4%) (p=0.004). Each AT(N) biomarker was predictive of cognitive decline in the V+ group as well as in the V- group (p<0.001). Additionally, the V+ group showed more severe cognitive trajectories than the V- group in the non-Alzheimer's pathological changes (A-T+, A-N+; p=0.002) and Alzheimer's pathological changes (p<0.001) categories. Conclusion: The distribution and longitudinal outcomes of AT(N) system differed according to vascular burdens, suggesting the importance of incorporating a V biomarker into the AT(N) system.
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    Over‐Representation of Extremely Wealthy Neighborhood Social Exposomes for Brain Donors within Alzheimer’s Disease Research Center Brain Banks assessed by the Neighborhoods Study
    (Wiley, 2025-01-09) Kind, Amy J. H.; Bendlin, Barbara B.; Powell, W. Ryan; DeWitt, Amanda; Cheng, Yixuan; Chamberlain, Luke; Sharrow, Jessica; Lyons Boone, Brittney; Abner, Erin L.; Alosco, Michael L.; Apostolova, Liana G.; Bakulski, Kelly M.; Barnes, Lisa L.; Bateman, James R.; Beach, Thomas G.; Bennett, David A.; Brewer, James B.; Carrion, Carmen; Chodosh, Joshua; Craft, Suzanne; Croff, Raina; Fabio, Anthony; Tomaszewski Farias, Sarah; Goldstein, Felicia; Henderson, Victor W.; Karikari, Thomas K.; Kofler, Julia; Kucharska-Newton, Anna M.; Lamar, Melissa; Lanata, Serggio; Lepping, Rebecca J.; Lingler, Jennifer H.; Lockhart, Samuel N.; Mahnken, Jonathan D.; Marsh, Karyn; Meyer, Oanh L.; Miller, Bruce L.; Morris, Jill K.; Neugroschl, Judith A.; O'Connor, Maureen K.; Paulson, Henry L.; Perrin, Richard J.; Pettigrew, Corinne; Pierce, Aimee; Raji, Cyrus A.; Reiman, Eric M.; Risacher, Shannon L.; Rissman, Robert A.; Rodriguez Espinoza, Patricia; Sano, Mary; Saykin, Andrew J.; Serrano, Geidy E.; Soldan, Anja; Sultzer, David L.; Whitmer, Rachel A.; Wisniewski, Thomas; Woltjer, Randall; Zhu, Carolyn W.; Radiology and Imaging Sciences, School of Medicine
    Background: Adverse social exposome (indexed by national Area Deprivation Index [ADI] 80‐100 or ‘high ADI’) is linked to structural inequities and increased risk of Alzheimer’s disease neuropathology. Twenty percent of the US population resides within high ADI areas, predominantly in inner cities, tribal reservations and rural areas. The percentage of brain donors from high ADI areas within the Alzheimer’s Disease Research Center (ADRC) brain bank system is unknown. Objective: Determine ADI for brain donors from 21 ADRC sites as part of the on‐going Neighborhoods Study. Methods: All brain donors in participating ADRC sites with NACC neuropathology data and personal identifiers for ADI linkage (N = 8,637) were included (Figure 1). Geocoded donor addresses were linked to time‐concordant ADI percentiles for year of death. Results: Overall, only 5.6% of ADRC brain donors (N = 488) resided in a high ADI (disadvantaged) neighborhood at death. The remaining donors resided in more advantaged neighborhoods, with nearly 40% of donors living in the wealthiest quintile of neighborhoods, and over 300 brain donors originating from the wealthiest 1% of US neighborhoods (Figure 2). Donors from high ADI (disadvantaged) neighborhoods identified as 87% White (n = 424), 11% Black (55), 1% Multiracial (6) and <1% other/unknown race (3), with 1% Hispanic (5). None identified as American Indian/Alaska Native or Native Hawaiian/Pacific Islander/Asian. In comparison, donors from low ADI neighborhoods were 94% White (n = 7680), 3% Black (273), 1% Multiracial (75), <1% American Indian/Alaska Native (11), <1% Native Hawaiian/Pacific Islander/Asian (60), and <1% other/unknown race (50), with 3% Hispanic (230). Sex distribution was similar (54%, 51% female, respectively). Inclusion of high ADI donors varied dramatically across the 21 ADRC brain banks from a low of 0.6% to high of 20% of all a site’s donors (Figure 3). Conclusions: ADI was determined for over 8,600 brain donors in the ADRC system, demonstrating a marked over‐representation of donors from very low ADI (extremely wealthy) neighborhoods, in addition to site‐to‐site variability. This is the first time a comprehensive cross‐sectional social exposome assessment of this nature has been performed, opening windows for additional mechanistic study of the social exposome on brain pathology. Life course ADI assessments are on‐going.