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Scholarly Works (108 results)

  • Thesis
  • Peer Reviewed
UC San Diego Electronic Theses and Dissertations (2019)

Rationale: Research in conventional mild cognitive impairment (MCI), a prodromal stage between normal aging and Alzheimer’s dementia (AD), has demonstrated neuropsychological heterogeneity using clustering techniques. The current dissertation aimed to 1) empirically establish baseline neuropsychological MCI subtypes; 2) explore longitudinal characterization of empirical subtypes using rigorous norms; and 3) examine the probability of transition between subtypes over time.

Design: Study 1 included 806 MCI participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Unique neuropsychological MCI subtypes and their associations with AD markers were investigated using latent profile analysis (LPA). Study 2 included 825 ADNI participants with baseline MCI that had follow-up at 12-months (n=751) and 24-months (n=639). Demographically-corrected T-scores were derived from the performance of 284 “robust” normal control participants assessed at baseline, 12-, and 24-months. Serial LPAs established neuropsychological subtypes for the MCI participants at each time point. Study 3 employed latent transition analysis to evaluate the likelihood of subtype change over time, as well as the influence of AD-risk factor covariates on transition probabilities.

Results: Study 1 produced 3-classes: mixed impairment, amnestic impairment, and cognitively normal neuropsychological subtypes. Amnestic and mixed classes had higher positivities on markers of AD than the cognitively normal class. In Study 2, 4-neuropsychological classes were separately established at baseline, 12-, and 24-months: multi-domain impairment ([MLT]), amnestic impairment (AMN), dysexecutive/below average cognition (DYS/BA), and average cognition (AVG) classes. The MLT and AMN subtypes declined over time on the majority of measures, while the AVG subtype had stable neurpsychological performance. The DYS/BA subtype demonstrated stable memory performance and improvement on language and attention/executive measures. Study 3 indicated a high probability (>86%) for participants of all subtypes to remain in their class over time. Covariates that modestly increased the likelihood of transition between classes included worse functional ability and AD-biomarker positivity.

Conclusions: This dissertation research used latent mixture models to establish analogous longitudinal neuropsychological profiles in conventionally diagnosed MCI. Results suggest that individuals are most likely to remain within their subtype across two years, including cognitively normal “false-positives.” Future studies should examine empirical MCI subtypes with the use of actuarial methods that may improve diagnostic accuracy.

    Cover page: Empirical Identification and Longitudinal Characterization of Mild Cognitive Impairment Subtypes using Latent Mixture Modeling
    • Article
    • Peer Reviewed
    UC San Diego Previously Published Works (2014)
    This virtual issue consists of studies previously published in the Journal of the International Neuropsychological Society and selected on the basis of their content related to one of the most highly researched concepts in behavioral neurology and neuropsychology over the past decade: mild cognitive impairment (MCI). The reliance on cognitive screening measures, staging-based rating scales, and limited neuropsychological testing in diagnosing MCI across most research studies may miss individuals with subtle cognitive declines or mis-diagnose MCI in those who are otherwise cognitively normal on a broader neuropsychological battery of tests. The assembled articles highlight the perils of relying on these conventional criteria for MCI diagnosis and reveal how the reliability of diagnosis is improved when sound neuropsychological approaches are adopted. When these requirements are met, we illustrate with a second series of articles that neuropsychological measures associate strongly with biomarkers and often reflect pathology beyond or instead of typical AD distributions. The final set of articles reveal that people with MCI demonstrate mild but identifiable functional difficulties, and a challenge for neuropsychology is how to incorporate this information to better define MCI and distinguish it from early dementia. Neuropsychology is uniquely positioned to improve upon the state of the science in MCI research and practice by providing critically important empirical information on the specific cognitive domains affected by the predominant neurodegenerative disorders of late life as well as on the diagnostic decision-making strategies used in studies. When such efforts to more comprehensively assess neuropsychological functions are undertaken, better characterizations of spared and impaired cognitive and functional abilities result and lead to more convincing associations with other biomarkers as well as to prediction of clinical outcomes.
      Cover page: Mild Cognitive Impairment: A Concept and Diagnostic Entity in Need of Input from Neuropsychology
      • Article
      • Peer Reviewed
      UC San Diego Previously Published Works (2017)
      Although dementia has been described in ancient texts over many centuries (e.g., "Be kind to your father, even if his mind fail him." - Old Testament: Sirach 3:12), our knowledge of its underlying causes is little more than a century old. Alzheimer published his now famous case study only 110 years ago, and our modern understanding of the disease that bears his name, and its neuropsychological consequences, really only began to accelerate in the 1980s. Since then we have witnessed an explosion of basic and translational research into the causes, characterizations, and possible treatments for Alzheimer's disease (AD) and other dementias. We review this lineage of work beginning with Alzheimer's own writings and drawings, then jump to the modern era beginning in the 1970s and early 1980s and provide a sampling of neuropsychological and other contextual work from each ensuing decade. During the 1980s our field began its foundational studies of profiling the neuropsychological deficits associated with AD and its differentiation from other dementias (e.g., cortical vs. subcortical dementias). The 1990s continued these efforts and began to identify the specific cognitive mechanisms affected by various neuropathologic substrates. The 2000s ushered in a focus on the study of prodromal stages of neurodegenerative disease before the full-blown dementia syndrome (i.e., mild cognitive impairment). The current decade has seen the rise of imaging and other biomarkers to characterize preclinical disease before the development of significant cognitive decline. Finally, we suggest future directions and predictions for dementia-related research and potential therapeutic interventions. (JINS, 2017, 23, 818-831).
        • Thesis
        • Peer Reviewed
        UC San Diego Electronic Theses and Dissertations (2023)

        Alzheimer’s disease is a debilitating, slowly progressive neurodegenerative disorder affecting over 50 million people globally, a figure expected to increase to 152 million by 2050. Not only is there a long prodromal period wherein individuals show early signs and risk factors for the disease, which are often mistaken as effects of normal aging, but insidious pathological processes are thought to begin taking place in the brain decades before individuals show severe cognitive impairments. Suitably, recent research efforts have focused on detecting signs of ad earlier in life to identify the disease preclinically and before irreversible damage occurs. However, knowing what to focus on in this preclinical period is proving to be a considerable challenge. The locus coeruleus (LC) is a small brainstem nucleus critical for healthy brain functioning that has been implicated in the pathogenesis of Alzheimer’s, and recent advances in neuroimaging allow for in-vivo examination. This dissertation aims to characterize the LC in-vivo using magnetic resonance imaging (MRI), neuropsychological testing, and biomarker assessment, with the goal of bettering our understanding of prodromal AD and AD risk. In Chapter 1 I detail our work optimizing a novel diffusion MRI analysis tool to establish a reliable method for reconstructing an LC projection pathway to the transentorhinal cortex, a region heavily affected by AD pathology. In Chapter 2, I explore how equilibrium probability within this pathway relates to cognition in the context of tau and amyloid biomarkers. Finally, in Chapter 3 I use an LC-sensitive anatomical MRI scan to measure relative LC signal, potentially a marker of nuclear integrity, and examine its associations with cognition in the context of tau and amyloid. Importantly, I show that the relationship between these MRI markers and cognition depends on tau and amyloid status, implicating a more complex relationship between macroscopic imaging measures and cognitive outcomes. This work has implications for preclinical AD research as well as clinical neuroimaging research aiming to uncover in-vivo disease markers in general.

          Cover page: The Locus Coeruleus: In-vivo Characterization with Magnetic Resonance Imaging and Associations with Alzheimer’s Disease-Related Markers
          • Article
          • Peer Reviewed
          UC San Diego Previously Published Works (2017)

          Objectives

          Cognitive dysfunction from high altitude exposure is a major cause of civilian and military air disasters. Pilot training improves recognition of the early symptoms of altitude exposure so that countermeasures may be taken before loss of consciousness. Little is known regarding the nature of cognitive impairments manifesting within this critical window when life-saving measures may still be taken. Prior studies evaluating cognition during high altitude simulation have predominantly focused on measures of reaction time and other basic attention or motor processes. Memory encoding, retention, and retrieval represent critical cognitive functions that may be vulnerable to acute hypoxic/ischemic events and could play a major role in survival of air emergencies, yet these processes have not been studied in the context of high altitude simulation training.

          Methods

          In a series of experiments, military aircrew underwent neuropsychological testing before, during, and after brief (15 min) exposure to high altitude simulation (20,000 ft) in a pressure-controlled chamber.

          Results

          Acute exposure to high altitude simulation caused rapid impairment in learning and memory with relative preservation of basic visual and auditory attention. Memory dysfunction was predominantly characterized by deficiencies in memory encoding, as memory for information learned during high altitude exposure did not improve after washout at sea level. Retrieval and retention of memories learned shortly before altitude exposure were also impaired, suggesting further impairment in memory retention.

          Conclusions

          Deficits in memory encoding and retention are rapidly induced upon exposure to high altitude, an effect that could impact life-saving situational awareness and response. (JINS, 2017, 23, 1-10).
            Cover page: Mechanisms of Memory Dysfunction during High Altitude Hypoxia Training in Military Aircrew
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2020)
            Abstract: Background: HIV‐associated neurocognitive disorders (HAND) occur in ∼45% of people with HIV (PWH). Older PWH are at‐risk for both HAND and age‐associated disorders including Alzheimer’s disease (AD) and its precursor, amnestic mild cognitive impairment (aMCI). Distinguishing aMCI from HAND among PWH is a diagnostic challenge given that both aMCI and HAND criteria include memory deficits. Differences between aMCI and HAND may include a more amnestic (recall and recognition deficits) and degenerative profile in aMCI versus milder (recall but not recognition deficits) and typically stable memory deficits in HAND. We exploited these differences to classify PWH based on aMCI+/‐ and HAND+/‐ status and compared trajectories of learning, recall and recognition performance among these classification groups. Method: Analyses included 685 PWH (ages 18‐79, 88% men) from the UCSD HIV Neurobehavioral Research Program. At baseline, aMCI status was determined based on a neuropsychological classification approach (Jak/Bondi) requiring impairment (<1.0 SD below normative mean) on two tests of recall and/or recognition (at‐least one recognition impairment required) from the Hopkins Verbal Learning Test‐Revised (HVLT‐R) and the Brief Visuospatial Memory Test‐R (BVMT‐R). HAND was diagnosed based on standard Frascati criteria. Using additive mixed model, trajectories of learning (averaged HVLT‐R and BVMT‐R learning scores), recall (averaged HVLT‐R and BVMT‐R recall scores) and HVLT‐R and BVMT‐R recognition z‐scores adjusted for age, sex, race and education were compared among classification groups. Result: Participants were classified into four groups: aMCI‐/HAND‐ (n=243), aMCI‐/HAND+ (n=199), aMCI+/HAND‐ (n=62) and aMCI+/HAND+ (n=181). There were significant diagnostic group X time interactions on learning and HVLT‐R and BVMT‐R recognition, but not recall (Figure 1). Learning showed significant change over time in the aMCI+/HAND+ and aMCI‐/HAND+ groups only. All groups showed significant, yet variable, patterns of change in HVLT‐R recognition. BVMT‐R recognition showed significant change over time in aMCI+/HAND‐ and aMCI+/HAND+ groups. Recall was poorest in the aMCI+/HAND+ versus other groups across time. Conclusion: Findings suggest that PWH with memory impairment combined with other cognitive deficits at baseline show the worst memory profiles over time. Research is needed into methods of differentiating other MCI subtypes from HAND and into potential compounding effects of AD‐ and HAND‐related pathologies.
              Cover page: Detecting amnestic MCI among persons with HIV with high rates of HIV‐associated neurocognitive disorder
              • Article
              • Peer Reviewed
              UC San Diego Previously Published Works (2014)
              Subjective cognitive complaints are a criterion for the diagnosis of mild cognitive impairment (MCI), despite their uncertain relationship to objective memory performance in MCI. We aimed to examine self-reported cognitive complaints in subgroups of the Alzheimer's Disease Neuroimaging Initiative (ADNI) MCI cohort to determine whether they are a valuable inclusion in the diagnosis of MCI or, alternatively, if they contribute to misdiagnosis. Subgroups of MCI were derived using cluster analysis of baseline neuropsychological test data from 448 ADNI MCI participants. Cognitive complaints were assessed via the Everyday Cognition (ECog) questionnaire, and discrepancy scores were calculated between self- and informant-report. Cluster analysis revealed Amnestic and Mixed cognitive phenotypes as well as a third Cluster-Derived Normal subgroup (41.3%), whose neuropsychological and cerebrospinal fluid (CSF) Alzheimer's disease (AD) biomarker profiles did not differ from a "robust" normal control group. This cognitively intact phenotype of MCI participants overestimated their cognitive problems relative to their informant, whereas Amnestic MCI participants with objective memory impairment underestimated their cognitive problems. Underestimation of cognitive problems was associated with positive CSF AD biomarkers and progression to dementia. Overall, there was no relationship between self-reported cognitive complaints and objective cognitive functioning, but significant correlations were observed with depressive symptoms. The inclusion of self-reported complaints in MCI diagnostic criteria may cloud rather than clarify diagnosis and result in high rates of misclassification of MCI. Discrepancies between self- and informant-report demonstrate that overestimation of cognitive problems is characteristic of normal aging while underestimation may reflect greater risk for cognitive decline.
                Cover page: Subjective Cognitive Complaints Contribute to Misdiagnosis of Mild Cognitive Impairment
                • Article
                • Peer Reviewed
                UC San Diego Previously Published Works (2017)

                Objectives

                Within the Alzheimer's Disease Neuroimaging Initiative (ADNI)'s mild cognitive impairment (MCI) cohort, we previously identified MCI subtypes as well as participants initially diagnosed with MCI but found to have normal neuropsychological, biomarker, and neuroimaging profiles. We investigated the functional change over time in these empirically derived MCI subgroups.

                Methods

                ADNI MCI participants (n=654) were classified using cluster analysis as Amnestic MCI (single-domain memory impairment), Dysnomic MCI (memory+language impairments), Dysexecutive/Mixed MCI (memory+language+attention/executive impairments), or Cluster-Derived Normal (CDN). Robust normal control participants (NCs; n=284) were also examined. The Functional Activities Questionnaire (FAQ) was administered at baseline through 48-month follow-up. Multilevel modeling examined FAQ trajectories by cognitive subgroup.

                Results

                The Dysexecutive/Mixed group demonstrated the fastest rate of decline across all groups. Amnestic and Dysnomic groups showed steeper rates of decline than CDNs. While CDNs had more functional difficulty than NCs across visits, both groups' mean FAQ scores remained below its suggested cutoff at all visits.

                Conclusions

                Results (a) show the importance of executive dysfunction in the context of other impaired cognitive domains when predicting functional decline in at-risk elders, and (b) support our previous work demonstrating that ADNI's MCI criteria may have resulted in false-positive MCI diagnoses, given the CDN's better FAQ trajectory than those of the cognitively impaired MCI groups. (JINS, 2017, 23, 521-527).
                  Cover page: Longitudinal Trajectories of Informant-Reported Daily Functioning in Empirically Defined Subtypes of Mild Cognitive Impairment
                  • Article
                  • Peer Reviewed
                  UC Irvine Previously Published Works (2018)
                  The apolipoprotein (APOE) ε4 allele has been proposed as an example of an antagonistic pleiotropy gene, conferring a beneficial effect on cognition in early life and a detrimental impact on cognition during later years. However, findings on the cognitive associations of the ε4 allele in younger persons are mixed. This PRISMA conforming study aimed to investigate APOE genotype (e4/non-e4) associations across seven cognitive domains (intelligence/achievement, attention/working memory, executive functioning, memory, language, processing speed and visuospatial abilities) in younger humans using a meta-analytic approach. Of 689 records reviewed, 29 studies (34 data-points) were selected for the quantitative synthesis. Participants' ages ranged from 2-40. Results showed that young ε4 carriers did not statistically differ from non-ε4 carriers across any cognitive domains. Overall, findings do not provide compelling support for an antagonistic pleiotropic effect of the ε4 allele across the lifespan.
                    Cover page: Meta-analysis of cognitive ability differences by apolipoprotein e genotype in young humans.
                    • Article
                    • Peer Reviewed
                    UC Irvine Previously Published Works (2020)
                    Hypertension is common among older adults and is believed to increase susceptibility to Alzheimer's disease, but mechanisms underlying this relationship are unclear. Hypertension also promotes circle of Willis atherosclerosis, which contributes to cerebral hypoperfusion and arterial wall stiffening, two potential mechanisms linking hypertension to Alzheimer's disease. To examine the role of circle of Willis atherosclerosis in the association between hypertension and Alzheimer's disease neuropathology, we analysed post-mortem neuropathological data on 2198 decedents from the National Alzheimer's Coordinating Center database [mean (standard deviation) age at last visit 80.51 (1.95) and 47.1% female] using joint simultaneous (i.e. mediation) modelling. Within the overall sample and among Alzheimer's dementia decedents, hypertension was indirectly associated with increased neuritic plaques and neurofibrillary tangles through its association with circle of Willis atherosclerosis. Similar indirect effects were observed for continuous measures of systolic and diastolic blood pressure. These results suggest that hypertension may promote Alzheimer's disease pathology indirectly through intracranial atherosclerosis by limiting cerebral blood flow and/or dampening perivascular clearance. Circle of Willis atherosclerosis may be an important point of convergence between vascular risk factors, cerebrovascular changes and Alzheimer's disease neuropathology.
                      Cover page: Hypertension and Alzheimer’s disease: indirect effects through circle of Willis atherosclerosis
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