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

Semantic Memory Functional MRI and Cognitive Function After Exercise Intervention in Mild Cognitive Impairment

Mild cognitive impairment (MCI) is associated with early memory loss, Alzheimer\u27s disease (AD) neuropathology, inefficient or ineffective neural processing, and increased risk for AD. Unfortunately, treatments aimed at improving clinical symptoms or markers of brain function generally have been of limited value. Physical exercise is often recommended for people diagnosed with MCI, primarily because of its widely reported cognitive benefits in healthy older adults. However, it is unknown if exercise actually benefits brain function during memory retrieval in MCI. Here, we examined the effects of exercise training on semantic memory activation during functional magnetic resonance imaging (fMRI). Seventeen MCI participants and 18 cognitively intact controls, similar in sex, age, education, genetic risk, and medication use, volunteered for a 12-week exercise intervention consisting of supervised treadmill walking at a moderate intensity. Both MCI and control participants significantly increased their cardiorespiratory fitness by approximately 10% on a treadmill exercise test. Before and after the exercise intervention, participants completed an fMRI famous name discrimination task and a neuropsychological battery, Performance on Trial 1 of a list-learning task significantly improved in the MCI participants. Eleven brain regions activated during the semantic memory task showed a significant decrease in activation intensity following the intervention that was similar between groups (p-values ranged 0.048 to 0.0001). These findings suggest exercise may improve neural efficiency during semantic memory retrieval in MCI and cognitively intact older adults, and may lead to improvement in cognitive function. Clinical trials are needed to determine if exercise is effective to delay conversion to AD

Neural Dedifferentiation in Relation to Risk for Alzheimer\u27s Disease

Functional magnetic resonance imaging (fMRI) research indicates that as an individual\u27s age increases, the task-related spatial extent of neural activation increases. This decrease in neural specificity, or dedifferentiation, is often demonstrated by older adults during challenging cognitive tasks. Cognitively intact individuals at-risk for Alzheimer\u27s disease (AD), as deemed by having an apolipoprotein-E ε4 allele or a family history of AD, demonstrate increased fMRI activation as compared to individuals at lower risk. Using a low effort, high accuracy event-related semantic memory task involving the presentation of famous and non-famous names, we examined spatial neural specificity through a measure of dedifferentiation using fMRI. In particular, the goal was to look at degree of dedifferentiation between older healthy subjects with or without risk factors for AD. Our results indicated that while there was not a significant difference between the two groups on the total amount of neural dedifferentiation, there was a significant interaction between stimulus type and risk group. Individuals at-risk for AD displayed greater dedifferentiation for non-famous names yet greater differentiation (i.e., less dedifferentiation) for famous names as compared to the low-risk group. These findings may reflect disturbances in memory formation for individuals at-risk for AD

Exercise Training and Functional Connectivity Changes in Mild Cognitive Empairment and Healthy Elders

Background: Effective interventions are needed to improve brain function in mild cognitive impairment (MCI), an early stage of Alzheimer’s disease (AD). The posterior cingulate cortex (PCC)/precuneus is a hub of the default mode network (DMN) and is preferentially vulnerable to disruption of functional connectivity in MCI and AD. Objective: We investigated whether 12 weeks of aerobic exercise could enhance functional connectivity of the PCC/precuneus in MCI and healthy elders. Methods: Sixteen MCI and 16 healthy elders (age range = 60–88) engaged in a supervised 12-week walking exercise intervention. Functional MRI was acquired at rest; the PCC/precuneus was used as a seed for correlated brain activity maps. Results: A linear mixed effects model revealed a significant interaction in the right parietal lobe: the MCI group showed increased connectivity while the healthy elders showed decreased connectivity. In addition, both groups showed increased connectivity with the left postcentral gyrus. Comparing pre to post intervention changes within each group, the MCI group showed increased connectivity in 10 regions spanning frontal, parietal, temporal and insular lobes, and the cerebellum. Healthy elders did not demonstrate any significant connectivity changes. Conclusion: The observed results show increased functional connectivity of the PCC/precuneus in individuals with MCI after 12 weeks of moderate intensity walking exercise training. The protective effects of exercise training on cognition may be realized through the enhancement of neural recruitment mechanisms, which may possibly increase cognitive reserve. Whether these effects of exercise training may delay further cognitive decline in patients diagnosed with MCI remains to be demonstrated

The Semantic Memory Imaging In Late Life Pilot Study

Introduction: Several functional magnetic resonance imaging (fMRI) studies have analyzed the famous name discrimination task (FNDT), an uncontrolled semantic memory probe requiring discrimination between famous and unfamiliar individuals. Completion of this simple task recruits a semantic memory network that has shown utility in determining risk for Alzheimer\u27s disease (AD). Specific semantic memory probes using biographical information associated with famous individuals may build on previous findings and yield superior information regarding risk for AD. Method: Sixteen cognitively intact elders completed the FNDT and two novel tasks during fMRI: Categories (matching famous individuals to occupational categories) and Attributes (matching famous individuals to specific bodies of work or life events). Five participants were carriers of the Apolipoprotein E (APOE) ε4 allele. Results: Relative to their respective control tasks, participants recruited brain regions for all three tasks consistent with previous research, including left temporal lobe, left angular gyrus, precuneus, posterior cingulate, and anterior cingulate. The FNDT generated significantly more activity than the other tasks in anterior cingulate and several posterior regions. Categories had significantly lesser activity than other tasks in inferior parietal lobe, precuneus, and posterior cingulate. Attributes, the most specific semantic probe, demonstrated the strongest left lateralization with significantly greater activity in left inferior frontal gyrus and anterior temporal lobe. APOE ε4 carriers had regions with greater activity across all three tasks, with the greatest number of regions for Attributes, including in left anterior temporal lobe. Discussion: This pilot study identified neural correlates of different levels of semantic processing. The FNDT, an unconstrained semantic knowledge probe, demonstrated greater activity across most regions. The Attributes task, a specific semantic probe, had focused left-lateralized activity, including anterior temporal lobe and inferior frontal gyrus. APOE ε4 carriers demonstrated significantly greater activity in left anterior temporal lobe during Attributes only, demonstrating this task\u27s potential utility for determination of AD risk

Predicting Cognitive Decline in Older Adults Through Multi-Voxel Pattern Analysis

Alzheimer\u27s disease (AD) is a progressive neurodegenerative disorder that is associated with cognitive and structural decline beyond what is seen in normal, healthy aging. Functional magnetic resonance imaging (fMRI) research indicates that prior to the onset of measureable cognitive impairment, individuals at-risk for AD demonstrate different patterns of neural activation than individuals at lower risk. Thus, differences in task-activated fMRI may be beneficial in predicting cognitive decline at a pre-symptomatic stage. The present study utilizes multi-voxel pattern analysis (MVPA) of baseline fMRI task-related activation to predict cognitive decline, with the hypothesis that famous and non-famous name task activation will discriminate older adults who go on to experience cognitive decline from those who do not. Ninety-nine cognitively intact older adults underwent neuropsychological testing and a semantic memory fMRI task (famous name discrimination). After follow-up neuropsychological testing 18-months later, participants were grouped as Stable (n = 65) or Declining (n = 34) based on \u3e 1.0 SD decline in performance on cognitive measures. MVPA classification accuracy was 90% for stimulus type (famous and non-famous names), thereby supporting the general approach. Mean MVPA classification accuracy for famous and non-famous names was 83% for both the Stable and Declining groups. Finally, MVPA produced greater than chance classification accuracy of participant groups for both famous name activation (56%) and non-famous name activation (55%) as determined via binomial distribution. The results of the current study suggest that MVPA possesses potential in predicting cognitive decline in older adults

Reduced hippocampal activation during episodic encoding in middle-aged individuals at genetic risk of Alzheimer's Disease: a cross-sectional study

BACKGROUND: The presence of the apolipoprotein E (APOE) ε4 allele is a major risk factor for the development of Alzheimer's disease (AD), and has been associated with metabolic brain changes several years before the onset of typical AD symptoms. Functional MRI (fMRI) is a brain imaging technique that has been used to demonstrate hippocampal activation during measurement of episodic encoding, but the effect of the ε4 allele on hippocampal activation has not been firmly established. METHODS: The present study examined the effects of APOE genotype on brain activation patterns in the medial temporal lobe (MTL) during an episodic encoding task using a well-characterized novel item versus familiar item contrast in cognitively normal, middle-aged (mean = 54 years) individuals who had at least one parent with AD. RESULTS: We found that ε3/4 heterozygotes displayed reduced activation in the hippocampus and MTL compared to ε3/3 homozygotes. There were no significant differences between the groups in age, education or neuropsychological functioning, suggesting that the altered brain activation seen in ε3/4 heterozygotes was not associated with impaired cognitive function. We also found that participants' ability to encode information on a neuropsychological measure of learning was associated with greater activation in the anterior MTL in the ε3/3 homozygotes, but not in the ε3/4 heterozygotes. CONCLUSION: Together with previous studies reporting reduced glucose metabolism and AD-related neuropathology, this study provides convergent validity for the idea that the MTL exhibits functional decline associated with the APOE ε4 allele. Importantly, these changes were detected in the absence of meaningful neuropsychological differences between the groups. A focus of ongoing work in this laboratory is to determine if these findings are predictive of subsequent cognitive decline

A Behavioral and Neural Investigation of the Impact of Age and Genetic Risk for Alzheimer’s Disease on Inhibitory Control

Significant advances have been made in understanding Alzheimer’s disease (AD), but our ability to accurately predict who will develop AD remains limited. Executive functioning has been neglected as a preclinical marker of AD, despite the vital role of these abilities (e.g., planning, set shifting, inhibition) in everyday functioning. Inhibitory deficits in particular have been found to predict impairment in activities of daily living, an important criterion in the diagnosis of AD. This study examined differences in behavioral task performance and underlying neural processing based on event related potentials (ERPs) during an inhibition task as a function of age and genetic risk for AD based on apolipoprotein-E (APOE) ε4 status. Participants included 49 healthy, cognitively intact older adults and 42 young adult college students. Genetic testing was conducted for older adults, 24 of whom were APOE ε4 carriers. Participants completed the Parametric Go/NoGo/Stop (PGNGS) task while EEG data was collected for later extraction of ERPs. Significant ERP differences by genetic risk emerged such that APOE ε4+ participants exhibited significantly more negative amplitudes than APOE ε4- participants at midline electrodes in response to Stop trials (Fz: p\u3c.001, FCz: p=.002, Cz: p=.012). These neural differences were seen in the absence of genetic risk differences in behavioral task performance, suggesting that psychophysiological measures may be more sensitive to early disease stage differences than neuropsychological testing alone. Expected age differences also emerged, with older adults exhibiting slower response times and longer ERP latencies in most task conditions and at most electrode sites. In conclusion, this study revealed significant ERP differences across genetic risk groups in cognitive intact older adults, revealing a new early marker of AD risk. Moreover, these findings underscore the importance of considering executive abilities, such as inhibition, as preclinical markers of risk for AD

Functional Interplay Between Neurocognitive Decline and Risk Factors in Older Adults: A Multivariate Latent Growth Curve Model of Risk

Alzheimer’s disease (AD) is a heterogeneous brain disease with multiple interacting risk factors, suggesting equifinality. Research indicates that the pathophysiological processes involved in AD are evident years prior to disease onset with significant variability in neurocognitive functioning being apparent during preclinical stages. Identification of individuals in preclinical stages is vital, as earlier interventions may prove more effective at ameliorating AD’s devastating effects. In this respect, clarifying relationships between risk factors and neurocognitive functioning in cognitively intact older adults can improve our understanding of mechanisms involved in preclinical AD, which may allow for earlier detection and intervention. The present study employed Latent Growth Curve modeling to longitudinally examine relevant risk factors relationship with neurocognitive functioning via neuropsychological assessment of executive attention, processing speed, episodic memory, language and working memory in 576 relatively healthy older adults over a three-year period. Results indicated on average Executive Attention/Processing Speed declined over time, while Memory and Language performance benefitted from practice effects over the three-year period. Substantial heterogeneity in initial levels of neurocognitive functioning and in linear changes in these processes were explained by individual differences in patterns of risk and resiliency variables. Specifically, differences in age, sex (men), and race (African Americans) respectively predicted worse neurocognitive functioning and Neurocardiovascular risk, while higher education and estimated intelligence predicted better neurocognitive functioning. Women were significantly higher in Depression/Endocrine risk. Neurocardiovascular and Depression/Endocrine risk factors emerged as unique predictors of worse neurocognitive functioning. Genetic risk for AD (apolipoprotein E genotype: APOE-e4) specifically associated with worse baseline Memory functioning, supporting episodic memory’s role as a neurocognitive endophenotype for AD. APOE-e4 also associated with lower estimated intelligence and Depression but not Neurocardiovascular history. In sum, the present study found distinct yet identifiable cognitive profiles of risk for neurocognitive decline. These results support conceptual models that suggest individual differences in sex, genetic risk, cognitive reserve, medical and mental health comorbidities in combination influence cognitive decline with age. These data have important treatment implications as they strongly indicate that there are modifiable risk factors that influence neurocognitive decline that can be targeted early on through behavioral and/or medical interventions

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