fMRI of Healthy Older Adults During Stroop Interference

The Stroop interference effect, caused by difficulty inhibiting overlearned word reading, is often more pronounced in older adults. This has been proposed to be due to declines in inhibitory control and frontal lobe functions with aging. Initial neuroimaging studies of inhibitory control show that older adults have enhanced activation in multiple frontal areas, particularly in inferior frontal gyrus, indicative of recruitment to aid with performance of the task. The current study compared 13 younger and 13 older adults, all healthy and well educated, who completed a Stroop test during functional magnetic resonance imaging. Younger adults were more accurate across conditions, and both groups were slower and less accurate during the interference condition. The groups exhibited comparable activation regions, but older adults exhibited greater activation in numerous frontal areas, including the left inferior frontal gyrus. The results support the recruitment construct and suggest, along with previous research, that the inferior frontal gyrus is important for successful inhibition

Comparability of Functional MRI Response in Young and Old During Inhibition

When using fMRI to study age-related cognitive changes, it is important to establish the integrity of the hemodynamic response because, potentially, it can be affected by age and disease. However, there have been few attempts to document such integrity and no attempts using higher cognitive rather than perceptual or motor tasks. We used fMRI with 28 healthy young and older adults on an inhibitory control task. Although older and young adults differed in task performance and activation patterns, they had comparable hemodynamic responses. We conclude that activation during cognitive inhibition, which was predominantly increased in elders, was not due to vascular confounds or specific changes in hemodynamic coupling

The Contribution of Blood Serum Biomarkers to the Prediction of Cognitive Decline by fMRI and Apolipoprotein-E in Healthy Older Adults

Biomarkers are a promising approach to the prediction and early intervention of Alzheimer\u27s disease. We demonstrated that cortical functional MRI (fMRI) activation during a semantic memory task and apolipoprotein-E ?4 allele inheritance (APOE?4) effectively predicted cognitive decline after 18-months in healthy, asymptomatic elders. Hippocampal volume added modest prediction, while AD family history and demographics were ineffective. Previous studies have linked plasma homocysteine (tHcy), vitamin B12 and creatinine values to cognitive funcitoning, cortical atrophy, hippocampal atrophy and neuropathology, and vascular integrity. Here we incorporated total plasma homocysteine (tHcy), B12 creatinine values into our previous predictive models. Of 78 healthy elders, 27 (34.6%) exhibited significant cognitive decline after 18-months. tHcy, but not B12 or creatinine, was marginally positively correlated with cortical semantic memory fMRI activation, particularly in stable participants. Logistic regression showed that tHcy, when added to APOE?4 and cortical fMRI, was a significant predictor of outcome and strengthed the already significant model (p = .007; C = .80 and R2 = .37). However, control for B12 and creatinine covariates diminished tHcy as a predictor (p = .084), though the model was still stronger than without this factor (C = .78 and R = 31). tHcy did not significantly interact with APOE?4, as has previously been reported. Neither B12 nor creatinine was similarly effective as a predictor. These results suggest that commonly investigated blood serum biomarkers are at best weakly associated with predicting age- and dementia-related cognitive decline in healthy, asymptomatic elders. fMRI and APOE?4 presently provided the best predictive model

The Contribution of Blood Serum Biomarkers to the Prediction of Cognitive Decline by fMRI and Apolipoprotein-E in Healthy Older Adults

Biomarkers are a promising approach to the prediction and early intervention of Alzheimer\u27s disease. We demonstrated that cortical functional MRI (fMRI) activation during a semantic memory task and apolipoprotein-E ?4 allele inheritance (APOE?4) effectively predicted cognitive decline after 18-months in healthy, asymptomatic elders. Hippocampal volume added modest prediction, while AD family history and demographics were ineffective. Previous studies have linked plasma homocysteine (tHcy), vitamin B12 and creatinine values to cognitive funcitoning, cortical atrophy, hippocampal atrophy and neuropathology, and vascular integrity. Here we incorporated total plasma homocysteine (tHcy), B12 creatinine values into our previous predictive models. Of 78 healthy elders, 27 (34.6%) exhibited significant cognitive decline after 18-months. tHcy, but not B12 or creatinine, was marginally positively correlated with cortical semantic memory fMRI activation, particularly in stable participants. Logistic regression showed that tHcy, when added to APOE?4 and cortical fMRI, was a significant predictor of outcome and strengthed the already significant model (p = .007; C = .80 and R2 = .37). However, control for B12 and creatinine covariates diminished tHcy as a predictor (p = .084), though the model was still stronger than without this factor (C = .78 and R = 31). tHcy did not significantly interact with APOE?4, as has previously been reported. Neither B12 nor creatinine was similarly effective as a predictor. These results suggest that commonly investigated blood serum biomarkers are at best weakly associated with predicting age- and dementia-related cognitive decline in healthy, asymptomatic elders. fMRI and APOE?4 presently provided the best predictive model

Key inflammatory pathway activations in the MCI stage of Alzheimer's disease

OBJECTIVE: To determine the key inflammatory pathways that are activated in the peripheral and CNS compartments at the mild cognitive impairment (MCI) stage of Alzheimer's disease (AD). METHODS: A cross-sectional study of patients with clinical and biomarker characteristics consistent with MCI-AD in a discovery cohort, with replication in the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Inflammatory analytes were measured in the CSF and plasma with the same validated multiplex analyte platform in both cohorts and correlated with AD biomarkers (CSF Aβ42, total tau (t-tau), phosphorylated tau (p-tau) to identify key inflammatory pathway activations. The pathways were additionally validated by evaluating genes related to all analytes in coexpression networks of brain tissue transcriptome from an autopsy confirmed AD cohort to interrogate if the same pathway activations were conserved in the brain tissue gene modules. RESULTS: Analytes of the tumor necrosis factor (TNF) signaling pathway (KEGG ID:4668) in the CSF and plasma best correlated with CSF t-tau and p-tau levels, and analytes of the complement and coagulation pathway (KEGG ID:4610) best correlated with CSF Aβ42 levels. The top inflammatory signaling pathways of significance were conserved in the peripheral and the CNS compartments. They were also confirmed to be enriched in AD brain transcriptome gene clusters. INTERPRETATION: A cell-protective rather than a proinflammatory analyte profile predominates in the CSF in relation to neurodegeneration markers among MCI-AD patients. Analytes from the TNF signaling and the complement and coagulation pathways are relevant in evaluating disease severity at the MCI stage of AD

Functional Magnetic Resonance Imaging of Semantic Memory as a Presymptomatic Biomarker of Alzheimer’s Disease Risk

Extensive research efforts have been directed toward strategies for predicting risk of developing Alzheimer\u27s disease (AD) prior to the appearance of observable symptoms. Existing approaches for early detection of AD vary in terms of their efficacy, invasiveness, and ease of implementation. Several non-invasive magnetic resonance imaging strategies have been developed for predicting decline in cognitively healthy older adults. This review will survey a number of studies, beginning with the development of a famous name discrimination task used to identify neural regions that participate in semantic memory retrieval and to test predictions of several key theories of the role of the hippocampus in memory. This task has revealed medial temporal and neocortical contributions to recent and remote memory retrieval, and it has been used to demonstrate compensatory neural recruitment in older adults, apolipoprotein E ε4 carriers, and amnestic mild cognitive impairment patients. Recently, we have also found that the famous name discrimination task provides predictive value for forecasting episodic memory decline among asymptomatic older adults. Other studies investigating the predictive value of semantic memory tasks will also be presented. We suggest several advantages associated with the use of semantic processing tasks, particularly those based on person identification, in comparison to episodic memory tasks to study AD risk. Future directions for research and potential clinical uses of semantic memory paradigms are also discussed. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease

Motor Timing Intraindividual Variability in Amnestic Mild Cognitive Impairment and Cognitively Intact Elders at Genetic Risk for Alzheimer’s Disease

Introduction: Intraindividual variability (IIV) in motor performance has been shown to predict future cognitive decline. The apolipoprotein E-epsilon 4 (APOE-ε4) allele is also a well-established risk factor for memory decline. Here, we present novel findings examining the influence of the APOE-ε4 allele on the performance of asymptomatic healthy elders in comparison to individuals with amnestic MCI (aMCI) on a fine motor synchronization, paced finger-tapping task (PFTT). Method: Two Alzheimer’s disease (AD) risk groups, individuals with aMCI (n = 24) and cognitively intact APOE-ε4 carriers (n = 41), and a control group consisting of cognitively intact APOE-ε4 noncarriers (n = 65) completed the Rey Auditory Verbal Learning Test and the PFTT, which requires index finger tapping in synchrony with a visual stimulus (interstimulus interval = 333 ms). Results: Motor timing IIV, as reflected by the standard deviation of the intertap interval (ITI), was greater in the aMCI group than in the two groups of cognitively intact elders; in contrast, all three groups had statistically equivalent mean ITI. No significant IIV differences were observed between the asymptomatic APOE-ε4 carriers and noncarriers. Poorer episodic memory performance was associated with greater IIV, particularly in the aMCI group. Conclusions: Results suggest that increased IIV on a fine motor synchronization task is apparent in aMCI. This IIV measure was not sensitive in discriminating older asymptomatic individuals at genetic risk for AD from those without such a genetic risk. In contrast, episodic memory performance, a well-established predictor of cognitive decline in preclinical AD, was able to distinguish between the two cognitively intact groups based on genetic risk

Computer-Aided Detection of Pathologically Enlarged Lymph Nodes On Non-Contrast CT In Cervical Cancer Patients For Low-Resource Settings

The mortality rate of cervical cancer is approximately 266,000 people each year, and 70% of the burden occurs in Low- and Middle- Income Countries (LMICs). Radiation therapy is the primary modality for treatment of locally advanced cervical cancer cases. In the absence of high quality diagnostic imaging needed to identify nodal metastasis, many LMIC sites treat standard pelvic fields, failing to include node metastasis outside of the field and/or to boost lymph nodes in the abdomen and pelvis. The first goal of this project was to create a program which automatically identifies positive cervical cancer lymph nodes on non-contrast daily CT images, which are widely available in LMICs(1). A region of interest which is likely to contain the nodal volumes relevant for cervical cancer was defined on a single patient CT(2). This region was deformed onto new patients using an in-house, demons-based deformation software. Edge detection and erosion filtering were used to distinguish potential positive nodes from normal structures. Regions on adjacent slices were then connected into a potential nodal 3D-structure. To differentiate these 3D structures from normal tissues, eighty-six features were generated based on the shape and mean pixel values of the structures, and four classification ensemble methods were tested to differentiate the positive nodes from normal tissues. A cohort of fifty-eight MD Anderson cervical cancer patients with pathologically enlarged lymph nodes were used as a training-test set. Similarly, twenty MD Anderson cervical cancer patients were obtained as a validation set. They contained 154 and 35 pathologically enlarged lymph nodes, respectively. Model comparison led to the selection of the Adaboost ensemble model, utilizing 17 features. In the validation set, 60% of the clinically significant positive cervical cancer nodes were identified along with a false/true positive ratio of ~4:1. The entire process takes approximately 10/number-of-cores-minutes. Our findings demonstrated that our computer-aided detection model can assist in the identification of metastatic nodal disease where high quality diagnostic imaging is not readily available. By identifying these nodes, radiation treatment fields can be modified to include pathologically enlarged lymph nodes, which is an essential element to providing potentially curative radiotherapy for cervical cancer

Genetic Risk for Alzheimer\u27s Disease Alters the Five-Year Trajectory of Semantic Memory Activation in Cognitively Intact Elders

Healthy aging is associated with cognitive declines typically accompanied by increased task-related brain activity in comparison to younger counterparts. The Scaffolding Theory of Aging and Cognition (STAC) (Park and Reuter-Lorenz, 2009; Reuter-Lorenz and Park, 2014) posits that compensatory brain processes are responsible for maintaining normal cognitive performance in older adults, despite accumulation of aging-related neural damage. Cross-sectional studies indicate that cognitively intact elders at genetic risk for Alzheimer\u27s disease (AD) demonstrate patterns of increased brain activity compared to low risk elders, suggesting that compensation represents an early response to AD-associated pathology. Whether this compensatory response persists or declines with the onset of cognitive impairment can only be addressed using a longitudinal design. The current prospective, 5-year longitudinal study examined brain activation in APOE ε4 carriers (N = 24) and non-carriers (N = 21). All participants, ages 65–85 and cognitively intact at study entry, underwent task-activated fMRI, structural MRI, and neuropsychological assessments at baseline, 18, and 57 months. fMRI activation was measured in response to a semantic memory task requiring participants to discriminate famous from non-famous names. Results indicated that the trajectory of change in brain activation while performing this semantic memory task differed between APOE ε4 carriers and non-carriers. The APOE ε4 group exhibited greater activation than the Low Risk group at baseline, but they subsequently showed a progressive decline in activation during the follow-up periods with corresponding emergence of episodic memory loss and hippocampal atrophy. In contrast, the non-carriers demonstrated a gradual increase in activation over the 5-year period. Our results are consistent with the STAC model by demonstrating that compensation varies with the severity of underlying neural damage and can be exhausted with the onset of cognitive symptoms and increased structural brain pathology. Our fMRI results could not be attributed to changes in task performance, group differences in cerebral perfusion, or regional cortical atrophy

Semantic Memory Activation in Individuals at Risk for Developing Alzheimer Disease

Objective: To determine whether whole-brain, event-related fMRI can distinguish healthy older adults with known Alzheimer disease (AD) risk factors (family history, APOE ε4) from controls using a semantic memory task involving discrimination of famous from unfamiliar names. Methods: Sixty-nine cognitively asymptomatic adults were divided into 3 groups (n = 23 each) based on AD risk: 1) no family history, no ε4 allele (control [CON]); 2) family history, no ε4 allele (FH); and 3) family history and ε4 allele (FH+ε4). Separate hemodynamic response functions were extracted for famous and unfamiliar names using deconvolution analysis (correct trials only). Results: Cognitively intact older adults with AD risk factors (FH and FH+ε4) exhibited greater activation in recognizing famous relative to unfamiliar names than a group without risk factors (CON), especially in the bilateral posterior cingulate/precuneus, bilateral temporoparietal junction, and bilateral prefrontal cortex. The increased activation was more apparent in the FH+ε4 than in the FH group. Unlike the 2 at-risk groups, the control group demonstrated greater activation for unfamiliar than familiar names, predominately in the supplementary motor area, bilateral precentral, left inferior frontal, right insula, precuneus, and angular gyrus. These results could not be attributed to differences in demographic variables, cerebral atrophy, episodic memory performance, global cognitive functioning, activities of daily living, or depression. Conclusions: Results demonstrate that a low-effort, high-accuracy semantic memory activation task is sensitive to Alzheimer disease risk factors in a dose-related manner. This increased activation in at-risk individuals may reflect a compensatory brain response to support task performance in otherwise asymptomatic older adults