Authors: Gordon, Brian A. | Blazey, Tyler | Benzinger, Tammie L. S. | Head, Denise
Article Type: Research Article
Abstract: The hippocampus is often treated as a uniform structure, but possesses differential projections to surrounding cortex along its longitudinal axis. This heterogeneity could create varied susceptibility to pathological influences, potentially leading to non-uniform volumetric associations with advancing age and Alzheimer's disease (AD). Previous examinations of aging and AD effects on hippocampal subdivisions have produced highly discrepant findings. To clarify these inconsistencies, we examined the hippocampal head, body, and tail in a large sample of 292 cognitively normal, 37 very mildly demented, and 18 mildly demented individuals, divided into two independent samples. As often done in the literature, we characterized qualitative …patterns across these regions, but extended these results by explicitly testing for quantitative differences. In each sample of cognitively normal individuals, the head and body demonstrated greater age effects than the tail. In each sample contrasting AD and cognitively normal individuals, all three regions showed significant volume reductions, with the greatest effect on the head. When examining increasing severity of dementia, the hippocampal head showed progressive volume loss, while the body and tail did not. The patterns of results examining both aging and AD were relatively consistent across the independent samples. These results indicate that there is an anterior-to-posterior gradient of loss within the hippocampus with both advancing age and AD. Show more
Keywords: Brain aging, dorsal hippocampus, long-axis, ventral hippocampus
DOI: 10.3233/JAD-130011
Citation: Journal of Alzheimer's Disease, vol. 37, no. 1, pp. 41-50, 2013
Authors: Hsu, Phillip J. | Shou, Haochang | Benzinger, Tammie | Marcus, Daniel | Durbin, Tony | Morris, John C. | Sheline, Yvette I.
Article Type: Research Article
Abstract: The earliest sites of brain atrophy in Alzheimer's disease are in the medial temporal lobe, following widespread cerebral cortical amyloid deposition. We assessed 74 cognitively normal participants with clinical measurements, amyloid-β-PET imaging, MRI, and a newly developed technique for MRI-based hippocampal subfield segmentation to determine the differential association of amyloid deposition and hippocampal subfield volume. Compared to amyloid-negative participants, amyloid-positive participants had significantly smaller hippocampal tail, presubiculum, subiculum, and total hippocampal gray matter volumes. We conclude that, prior to the development of cognitive impairment, atrophy in particular hippocampal subfields occurs preferentially with amyloid-β accumulation.
Keywords: Amyloid accumulation, cognitively normal elderly, hippocampal subfield volumes, presubiculum, subiculum
DOI: 10.3233/JAD-141743
Citation: Journal of Alzheimer's Disease, vol. 45, no. 1, pp. 27-33, 2015
Authors: Babulal, Ganesh M. | Roe, Catherine M. | Stout, Sarah H. | Rajasekar, Ganesh | Wisch, Julie K. | Benzinger, Tammie L.S. | Morris, John C. | Ances, Beau M.
Article Type: Research Article
Abstract: Background: Depression is also common with older age. Alzheimer’s disease (AD) studies suggest that both cerebrospinal fluid and positron emission tomography (PET) amyloid biomarkers are associated with more depressive symptoms in cognitively normal older adults. The recent availability of tau radiotracers offers the ability to examine in vivo tauopathy. It is unclear if the tau biomarker is associated with depression diagnosis. Objective: We examined if tau and amyloid imaging were associated with a depression diagnosis among cognitively normal adults (Clinical Dementia Rating = 0) and whether antidepressants modified this relationship. Methods: Among 301 participants, logistic regression models evaluated whether in vivo PET …tau was associated with depression, while another model tested the interaction between PET tau and antidepressant use. A second set of models substituted PET amyloid for PET tau. A diagnosis of depression (yes/no) was made during an annual clinical assessment by a clinician. Antidepressant use (yes/no) was determined by comparing medications the participants used to a list of 30 commonly used antidepressants. All models adjusted for age, sex, education, race, and apolipoprotein ɛ 4. Similar models explored the association between the biomarkers and depressive symptoms. Results: Participants with elevated tau were twice as likely to be depressed. Antidepressant use modified this relationship where participants with elevated tau who were taking antidepressants had greater odds of being depressed. Relatedly, elevated amyloid was not associated with depression. Conclusions: Our results demonstrate that tau, not amyloid, was associated with a depression diagnosis. Additionally, antidepressant use interacts with tau to increase the odds of depression among cognitively normal adults. Show more
Keywords: Alzheimer’s disease, antidepressants, biomarkers, depression, older adults
DOI: 10.3233/JAD-191078
Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1045-1055, 2020
Authors: Wisch, Julie K. | Roe, Catherine M. | Babulal, Ganesh M. | Schindler, Suzanne E. | Fagan, Anne M. | Benzinger, Tammie L. | Morris, John C. | Ances, Beau M.
Article Type: Research Article
Abstract: Background: Changes in resting state functional connectivity (rs-fc) occur in Alzheimer’s disease (AD), but few longitudinal rs-fc studies have been performed. Most studies focus on single networks and not a global measure of rs-fc. Although the amyloid tau neurodegeneration (AT(N)) framework is increasingly utilized by the AD community, few studies investigated when global rs-fc signature changes occur within this model. Objective: 1) Identify a global rs-fc signature that differentiates cognitively normal (CN) individuals from symptomatic AD. 2) Assess when longitudinal changes in rs-fc occur relative to conversion to symptomatic AD. 3) Compare rs-fc with amyloid, tau, and neurodegeneration biomarkers. Methods: …A global rs-fc signature composed of intra-network connections was longitudinally evaluated in a cohort of cognitively normal participants at baseline (n = 335). Biomarkers, including cerebrospinal fluid (Aβ42 and tau), structural magnetic resonance imaging, and positron emission tomography were obtained. Results: Global rs-fc signature distinguished CN individuals from individuals who developed symptomatic AD. Changes occurred nearly four years before conversion to symptomatic AD. The global rs-fc signature most strongly correlated with markers of neurodegeneration. Conclusion: The global rs-fc signature changes near symptomatic onset and is likely a neurodegenerative biomarker. Rs-fc changes could serve as a biomarker for evaluating potential therapies for symptomatic conversion to AD. Show more
Keywords: Alzheimer’s disease, biomarkers, neuroimaging, observational studies
DOI: 10.3233/JAD-191039
Citation: Journal of Alzheimer's Disease, vol. 74, no. 4, pp. 1085-1095, 2020
Authors: Thirunavu, Vineeth | McCullough, Austin | Su, Yi | Flores, Shaney | Dincer, Aylin | Morris, John C. | Cruchaga, Carlos | Benzinger, Tammie L.S. | Gordon, Brian A.
Article Type: Research Article
Abstract: Background: Both low and high body mass index (BMI) have been associated with an increased risk of dementia, including that caused by Alzheimer’s disease (AD). Specifically, high middle-age BMI or a low late-age BMI has been considered a predictor for the development of AD dementia. Less studied is the relationship between BMI and AD pathology. Objective: We explored the association between BMI and cortical amyloid-β (Aβ) burden in cognitively normal participants that were either in mid-life (45–60 years) or late-life (>60). Methods: We analyzed cross-sectional baseline data from the Knight Alzheimer Disease Research Center (ADRC) at Washington University. Aβ pathology …was measured in 373 individuals with Aβ PET imaging and was quantified using Centiloid units. We split the cohort into mid- and late-life groups for analyses (n = 96 and n = 277, respectively). We ran general linear regression models to predict Aβ levels from BMI while controlling for age, sex, years of education, and APOE4 status. Analyses were also conducted to test the interaction between BMI and APOE4 genotype and between BMI and sex. Results: Higher BMI was associated with lower cortical Aβ burden in late-life (β= –0.81, p = 0.0066), but no relationship was found in mid-life (β= 0.04, p > 0.5). The BMI×APOE4+ and BMI×male interaction terms were not significant in the mid-life (β= 0.28, p = 0.41; β= 0.64, p = 0.13) or the late-life (β= 0.17, p > 0.5; β= 0.50, p = 0.43) groups. Conclusion: Higher late-life BMI is associated with lower cortical Aβ burden in cognitively normal individuals. Show more
Keywords: Alzheimer disease, amyloid-β, apolipoproteins E, body mass index, obesity, positron emission tomography
DOI: 10.3233/JAD-190154
Citation: Journal of Alzheimer's Disease, vol. 69, no. 3, pp. 817-827, 2019
Authors: Ingber, Adam P. | Hassenstab, Jason | Fagan, Anne M. | Benzinger, Tammie L.S. | Grant, Elizabeth A. | Holtzman, David M. | Morris, John C. | Roe, Catherine M.
Article Type: Research Article
Abstract: Background: The influence of reserve variables and Alzheimer’s disease (AD) biomarkers on cognitive test performance has been fairly well-characterized. However, less is known about the influence of these factors on “non-cognitive” outcomes, including functional abilities and mood. Objective: We examined whether cognitive and brain reserve variables mediate how AD biomarker levels in cognitively normal persons predict future changes in function, mood, and neuropsychiatric behavior. Methods: Non-cognitive outcomes were examined in 328 individuals 50 years and older enrolled in ongoing studies of aging and dementia at the Knight Alzheimer Disease Research Center (ADRC). All participants were cognitively normal at baseline (Clinical …Dementia Rating [CDR] 0), completed cerebrospinal fluid (CSF) and structural neuroimaging studies within one year of baseline, and were followed for an average of 4.6 annual visits. Linear mixed effects models explored how cognitive reserve and brain reserve variables mediate the relationships between AD biomarker levels and changes in function, mood, and neuropsychiatric behavior in cognitively normal participants. Results: Education levels did not have a significant effect on predicting non-cognitive decline. However, participants with smaller brain volumes exhibited the worst outcomes on measures of mood, functional abilities, and behavioral disturbance. This effect was most pronounced in individuals who also had abnormal CSF biomarkers. Conclusions: The findings suggest that brain reserve plays a stronger, or earlier, role than cognitive reserve in protecting against non-cognitive impairment in AD. Show more
Keywords: Alzheimer’s disease, biomarkers, cognitive reserve, dementia
DOI: 10.3233/JAD-150478
Citation: Journal of Alzheimer's Disease, vol. 52, no. 3, pp. 1055-1064, 2016
Authors: Keleman, Audrey | Wisch, Julie K. | Bollinger, Rebecca M. | Grant, Elizabeth A. | Benzinger, Tammie L. | Morris, John C. | Ances, Beau M. | Stark, Susan L.
Article Type: Research Article
Abstract: Background: Behavioral markers for Alzheimer’s disease (AD) are not included within the widely used amyloid-tau-neurodegeneration framework. Objective: To determine when falls occur among cognitively normal (CN) individuals with and without preclinical AD. Methods: This cross-sectional study recorded falls among CN participants (n = 83) over a 1-year period. Tailored calendar journals recorded falls. Biomarkers including amyloid positron emission tomography (PET) and structural and functional magnetic resonance imaging were acquired within 2 years of fall evaluations. CN participants were dichotomized by amyloid PET (using standard cutoffs). Differences in amyloid accumulation, global resting state functional connectivity (rs-fc) intra-network signature, and hippocampal volume were …compared between individuals who did and did not fall using Wilcoxon rank sum tests. Among preclinical AD participants (amyloid-positive), the partial correlation between amyloid accumulation and global rs-fc intra-network signature was compared for those who did and did not fall. Results: Participants who fell had smaller hippocampal volumes (p = 0.04). Among preclinical AD participants, those who fell had a negative correlation between amyloid uptake and global rs-fc intra-network signature (R = –0.75, p = 0.012). A trend level positive correlation was observed between amyloid uptake and global rs-fc intra-network signature (R = 0.70, p = 0.081) for preclinical AD participants who did not fall. Conclusion: Falls in CN older adults correlate with neurodegeneration biomarkers. Participants without falls had lower amyloid deposition and preserved global rs-fc intra-network signature. Falls most strongly correlated with presence of amyloid and loss of brain connectivity and occurred in later stages of preclinical AD. Show more
Keywords: Alzheimer’s disease, biomarkers, falls, resting state functional connectivity, volumetrics
DOI: 10.3233/JAD-200192
Citation: Journal of Alzheimer's Disease, vol. 77, no. 2, pp. 745-752, 2020
Authors: Ting, Simon Kang Seng | Benzinger, Tammie | Kepe, Vladimir | Fagan, Anne | Coppola, Giovanni | Porter, Verna | Hecimovic, Silva | Chakraverty, Suma | Alvarez-Retuerto, Ana Isabel | Goate, Alison | Ringman, John M.
Article Type: Short Communication
Abstract: Mutations in PSEN1 are the most common cause of autosomal dominant familial Alzheimer's disease (FAD). We describe an African-American woman with a family history consistent with FAD who began to experience cognitive decline at age 50. Her clinical presentation, MRI, FDG-PET, and PIB-PET scan findings were consistent with AD and she was found to have a novel I238M substitution in PSEN1. As this mutation caused increased production of Aβ42 in an in vitro assay, was not present in two population databases, and is conserved across species, it is likely to be pathogenic for FAD.
Keywords: African, Alzheimer's disease, amyloid-β42, autosomal dominant, familial, gamma-secretase, in vitro, PIB-PET, presenilin-1, PSEN1
DOI: 10.3233/JAD-131844
Citation: Journal of Alzheimer's Disease, vol. 40, no. 2, pp. 271-275, 2014
Authors: Chen, Charles D. | Ponisio, Maria Rosana | Lang, Jordan A. | Flores, Shaney | Schindler, Suzanne E. | Fagan, Anne M. | Morris, John C. | Benzinger, Tammie L.S.
Article Type: Research Article
Abstract: Background: 18 F-flortaucipir PET received FDA approval to visualize aggregated neurofibrillary tangles (NFTs) in brains of adult patients with cognitive impairment being evaluated for Alzheimer’s disease (AD). However, manufacturer’s guidelines for visual interpretation of 18 F-flortaucipir PET differ from how 18 F-flortaucipir PET has been measured in research settings using standardized uptake value ratios (SUVRs). How visual interpretation relates to 18 F-flortaucipir PET SUVR, cerebrospinal fluid (CSF) biomarkers, or longitudinal clinical assessment is not well understood. Objective: We compare various diagnostic methods in participants enrolled in longitudinal observational studies of aging and memory (n = 189, 23 were cognitively impaired). Methods: …Participants had tau PET, Aβ PET, MRI, and clinical and cognitive evaluation within 18 months (n = 189); the majority (n = 144) also underwent lumbar puncture. Two radiologists followed manufacturer’s guidelines for 18 F-flortaucipir PET visual interpretation. Results: Visual interpretation had high agreement with SUVR (98.4%)and moderate agreement with CSF p-tau181 (86.1%). Two participants demonstrated 18 F-flortaucipir uptake from meningiomas. Visual interpretation could not predict follow-up clinical assessment in 9.52% of cases. Conclusion: Visual interpretation was highly consistent with SUVR (discordant participants had hemorrhagic infarcts or occipital-predominant AD NFT deposition) and moderately consistent with CSF p-tau181 (discordant participants had AD pathophysiology not detectable on tau PET). However, close association between AD NFT deposition and clinical onset in group-level studies does not necessarily hold at the individual level, with discrepancies arising from atypical AD, vascular dementia, or frontotemporal dementia. A better understanding of relationships across imaging, CSF biomarkers, and clinical assessment is needed to provide appropriate diagnoses for these individuals. Show more
Keywords: Alzheimer’s disease, cerebrospinal fluid, positron emission tomography, tauopathies
DOI: 10.3233/JAD-230032
Citation: Journal of Alzheimer's Disease, vol. 93, no. 2, pp. 765-777, 2023
Authors: Roe, Catherine M. | Stout, Sarah H. | Rajasekar, Ganesh | Ances, Beau M. | Jones, Jessica M. | Head, Denise | Benzinger, Tammie L.S. | Williams, Monique M. | Davis, Jennifer Duncan | Ott, Brian R. | Warren, David K. | Babulal, Ganesh M.
Article Type: Research Article
Abstract: Background: Emerging evidence shows that cognitively normal older adults with preclinical Alzheimer’s disease (AD) make more errors and are more likely to receive a marginal/fail rating on a standardized road test compared to older adults without preclinical AD, but the extent to which preclinical AD impacts everyday driving behavior is unknown. Objective: To examine self-reported and naturalistic longitudinal driving behavior among persons with and without preclinical AD. Method: We prospectively followed cognitively normal drivers (aged 65 + years) with (n = 10) and without preclinical AD (n = 10) for 2.5 years. Preclinical AD was assessed using amyloid positron emission tomography (PET) with Pittsburgh …Compound B. The Driving Habits Questionnaire assessed self-reported driving outcomes. Naturalistic driving was captured using a commercial GPS data logger plugged into the on-board diagnostics II port of each participant’s vehicle. Data were sampled every 30 seconds and all instances of speeding, hard braking, and sudden acceleration were recorded. Results: Preclinical AD participants went to fewer places/unique destinations, traveled fewer days, and took fewer trips than participants without preclinical AD. The preclinical AD group reported a smaller driving space, greater dependence on other drivers, and more difficulty driving due to vision difficulties. Persons with preclinical AD had fewer trips with any aggression and showed a greater decline across the 2.5-year follow-up period in the number of days driving per month and the number of trips between 1–5 miles. Conclusion: Changes in driving occur even during the preclinical stage of AD. Show more
Keywords: Alzheimer’s disease,, automobile driving,, biomarkers, motor vehicles
DOI: 10.3233/JAD-181242
Citation: Journal of Alzheimer's Disease, vol. 68, no. 4, pp. 1625-1633, 2019
