Biomedical subjects

Andrew J Saykin

Publications and source records attributed to Andrew J Saykin.

At least 19 recordsLinked to original sources

PubMed2026

Interconnected influences of diet, gut microbiome, and metabolome on cognition across three metabolomics platforms.

Cognitive impairment is increasing with global aging, yet mechanisms linking diet, the gut microbiome, and metabolism to cognitive function remain unclear. To investigate a diet-microbiome-metabolome axis associated with cognition, we integrated fecal metagenomics, diet, and multi-platform plasma metabolomics in 505 older adults from four ADRCs. Several microbes broadly associated with circulating metabolites were also linked to multiple measures of cognitive performance. These taxa exhibited coordinated metabolic signatures, with cognition-positive microbes associated with antioxidant, lipid, and microbial-host co-metabolites, and microbes negatively associated with cognition were linked to inflammatory and aromatic amino acid-derived metabolites. Dietary patterns, particularly the Healthy Eating Index Greens and Beans component, were associated with microbial composition and metabolomic structure. Mediation analyses supported a diet-microbe-metabolite-cognition pathway, while metabolites remained associated with cognition after accounting for microbial features. These findings highlight the metabolome as a central integrator of diet, microbial activity, and cognitive function.

Journal Article↗

PubMed2026

Genetic modifiers of APOE-ε4-associated cognitive decline.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4-associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-ε4 carriers.

Humans↗

PubMed2024

Sex and APOE ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease.

INTRODUCTION: The effects of sex and apolipoprotein E (APOE)-Alzheimer's disease (AD) risk factors-on white matter microstructure are not well characterized. METHODS: Diffusion magnetic resonance imaging data from nine well-established longitudinal cohorts of aging were free water (FW)-corrected and harmonized. This dataset included 4741 participants (age = 73.06 ± 9.75) with 9671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex and APOE ε4 carrier status. RESULTS: Sex differences in FAFWcorr in projection tracts and APOE ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced. DISCUSSION: There are prominent differences in white matter microstructure by sex and APOE ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted. HIGHLIGHTS: Sex and apolipoprotein E (APOE) ε4 carrier status relate to white matter microstructural integrity. Females generally have lower free water-corrected fractional anisotropy compared to males. APOE ε4 carriers tended to have higher free water than non-carriers.

Humans↗

PubMed2007

Cognitive-behavioral management of chemotherapy-related cognitive change.

Adjuvant chemotherapy can produce mild cognitive decline among breast cancer survivors which adversely effects function and quality of life. However, no treatment to date has been proposed or developed for this problem despite large numbers of cancer patients who report post-treatment memory dysfunction. This paper presents data from a single arm pilot study of a brief cognitive-behavioral treatment aimed at helping breast cancer survivors manage cognitive dysfunction associated with adjuvant chemotherapy (Memory and Attention Adaptation Training; MAAT). Participants were twenty-nine women who were an average of 8 years post-chemotherapy for stage I and II breast cancer. All had reported complaints regarding memory and attention. Improvements in self-report of cognitive function, quality of life and standard neuropsychological test performance were observed at post-treatment, 2-month and 6-month follow-up. Participants also reported high treatment satisfaction and rated MAAT as helpful in improving ability to compensate for memory problems. Given these results, the treatment appears to be a feasible and practical cognitive-behavioral program that warrants continued evaluation among cancer survivors who experience persistent cognitive dysfunction.

Adult↗

PubMed2006

Self- and informant reports of executive function on the BRIEF-A in MCI and older adults with cognitive complaints.

Amnestic mild cognitive impairment (MCI) is characterized by impaired episodic memory, although subtle executive problems have been noted on neuropsychological tests. Recent research also has described a group of healthy, non-depressed older adults with significant cognitive complaints (CC) but normal performance on neuropsychological testing. These individuals show structural and functional brain changes intermediate between those seen in MCI and healthy older adults without such complaints (HC). We evaluated executive functions in MCI and CC using the Behavior Rating Inventory of Executive Function-Adult version (BRIEF-A), a newly developed self- and informant report questionnaire in 29 patients with amnestic MCI, 28 CCs, and 30 demographically matched HCs. MCI and CC participants reported significant difficulties with selective aspects of executive functioning relative to HCs despite clinically normal performance on neuropsychological tests of this cognitive domain. Scores were generally in the pattern of MCI>CC>HC, and findings were most pronounced for working memory. Additionally, MCI and CC participants were more likely than their informants to report clinically meaningful executive problems, though informants identified a similar pattern of difficulty overall. Results failed to reveal strong relations between the BRIEF-A and standardized neuropsychological tests of executive function. Overall findings indicate that the BRIEF-A is sensitive to subtle executive changes in MCI and CC and suggest the need for research to determine if executive complaints are predictive of clinical course.

Aged↗

PubMed2006

The fornix and mammillary bodies in older adults with Alzheimer's disease, mild cognitive impairment, and cognitive complaints: a volumetric MRI study.

The fornix and mammillary bodies are important limbic structures that have not been systematically investigated in the earliest stages of preclinical dementia. The present study examined volumetric changes in the fornix and mammillary bodies and improved previously established tracing guidelines to increase reliability and provide more comprehensive measurements. Volumetric measurements were made in euthymic older adults, including 16 patients with mild Alzheimer's disease (AD), 20 patients with amnestic mild cognitive impairment (MCI), 20 individuals with cognitive complaints (CC) but normal neuropsychological test performance, and 20 demographically matched healthy controls (HC). Structural magnetic resonance imaging included a T1-weighted 1.5-mm coronal volume, acquired on a GE 1.5T LX scanner. After adjustment for total intracranial volume (ICV), significant volume reductions were observed in the fornix and mammillary bodies in patients with AD as compared with HC, CC, and MCI participants. No volume differences were seen between the HC, CC, and MCI groups. Study findings are consistent with previous research showing volume decreases of the fornix and mammillary bodies in AD, and provide new data on the relative preservation of these structures in preclinical disease stages. Results suggest that atrophy of the fornix and mammillary bodies becomes apparent at the point of conversion from MCI to AD. Longitudinal assessments are needed to delineate the time course and extent of the observed volumetric changes.

Aged↗

PubMed2006

Functional magnetic resonance imaging of executive control in bipolar disorder.

Bipolar disorder has been associated with dysfunction of executive control processes. Using functional magnetic resonance imaging, we examined brain activation during a counting Stroop task in 11 healthy adults and 11 patients with bipolar I disorder. Results revealed greater activation for the healthy than bipolar disorder group in distributed brain regions that included the right inferior and medial frontal gyri. With the exception of one area within the left posterior cingulate gyrus that was correlated with mania severity, regional activations where group differences were observed were not associated with mood symptoms in the patient group. These findings add to the growing body of evidence implicating neural circuitry subserving executive control in bipolar disorder.

Adult↗

PubMed2006

Mechanisms of working memory dysfunction after mild and moderate TBI: evidence from functional MRI and neurogenetics.

Cognitive complaints are a frequent source of distress and disability after mild and moderate traumatic brain injury (TBI). While there are deficits in several cognitive domains, many aspects of these complaints and deficits suggest that problems in working memory (WM) play an important role. Functional imaging studies in healthy individuals have outlined the neural substrate of WM and have shown that regions important in WM circuitry overlap with regions commonly vulnerable to damage in TBI. Use of functional MRI (fMRI) in individuals with mild and moderate TBI suggests that they can have problems in the activation and allocation of WM, and several lines of evidence suggest that subtle alterations in central catecholaminergic sensitivity may underlie these problems. We review the evidence from fMRI and neurogenetic studies that support the role of catecholaminergic dysregulation in the etiology of WM complaints and deficits after mild and moderate TBI.

Brain Injuries↗

PubMed2006

Increased brain activation during working memory in cognitively intact adults with the APOE epsilon4 allele.

OBJECTIVE: Altered patterns of brain activity during cognitive tasks have been demonstrated using functional magnetic resonance imaging (fMRI) in mild cognitive impairment and Alzheimer's disease. However, there have been few studies of adults at genetic risk for Alzheimer's disease prior to the onset of symptoms. The purpose of this study was to determine whether brain activation patterns associated with working memory differ as a function of apolipoprotein E (APOE) genotype in cognitively intact adults. METHOD: Participants were cognitively intact, healthy adults who completed genotyping, comprehensive neuropsychological testing, and structural and functional neuroimaging. Twenty-two participants had the APOE epsilon3/epsilon3 genotype, and 13 participants had the APOE epsilon3/epsilon4 genotype. The study employed an auditory verbal N-back task to probe working memory-related brain activity. RESULTS: The epsilon3/epsilon3 and epsilon3/epsilon4 groups did not differ in demographic characteristics, cognitive ability, mood, or in-scanner task performance. The epsilon3/epsilon4 group showed greater activity during working memory in the medial frontal and parietal regions bilaterally and in the right dorsolateral prefrontal cortex. There were no regions in which the epsilon3/epsilon3 group showed greater activation than the epsilon3/epsilon4 group. CONCLUSIONS: These results indicate that differences in brain activity are evident in cognitively intact individuals who are at risk for late-onset Alzheimer's disease by virtue of their APOE allele status. As neuroprotective interventions become available, early detection will increase in importance. The combination of genetic and functional neuroimaging strategies may prove useful for monitoring individuals at risk for Alzheimer's disease before the onset of cognitive symptoms.

Adult↗

PubMed2006

Functional magnetic resonance imaging of the primary somatosensory cortex in piglets.

OBJECT: The piglet is an excellent model for the developing human brain, and has been used increasingly in various centers for studies of traumatic brain injury and other insults. Unlike rodent or primate models, however, there are few behavioral scales for the piglet, and the available ones are used to test general responsiveness rather than specific functional outcome. The differing behavioral repertoires of animals of different ages provide an additional challenge when age-dependent injury responses are compared. To overcome these experimental limitations of piglets in brain injury research, the authors developed a functional magnetic resonance (fMR) imaging paradigm that can be used to track recovery in the somatosensory cortex over time in anesthetized animals of different ages. METHODS: Fifteen fMR imaging studies in eight piglets were performed before and after scaled cortical impact injury to the primary somatosensory cortex subserving snout sensation. Specific anesthetic and imaging protocols enabled visualization of cortical activation, and comparison with somatosensory evoked potentials obtained before and after injury was obtained. A piglet brain template for group-level analysis of these data was constructed, similar to the fMR imaging techniques used in humans, to allow for group comparisons and longitudinal change analysis over time. CONCLUSIONS: Loss of function in a specifically traumatized cortical region and its subsequent recovery over time can now be demonstrated visually by fMR imaging in the piglet. Besides its value in understanding intrinsic recovery mechanisms and plasticity at different ages, this functional outcome measure will enable the use of the piglet model in treatment trials specifically designed for the immature brain.

Age Factors↗

PubMed2005

Regionally specific atrophy of the corpus callosum in AD, MCI and cognitive complaints.

The goal of the present study was to determine if there are global or regionally specific decreases in callosal area in early Alzheimer's disease (AD) and mild cognitive impairment (MCI). In addition, this study examined the corpus callosum of healthy older adults who have subjective cognitive complaints (CC) but perform within normal limits on neuropsychological tests. We used a semi-automated procedure to examine the total and regional areas of the corpus callosum in 22 patients with early AD, 28 patients with amnestic MCI, 28 healthy older adults with cognitive complaints, and 50 demographically matched healthy controls (HC). The AD, MCI, and CC groups all showed a significant reduction of the posterior region (isthmus and splenium) relative to healthy controls. The AD group also had a significantly smaller overall callosum than the controls. The demonstration of callosal atrophy in older adults with cognitive complaints suggests that callosal changes occur very early in the dementing process, and that these earliest changes may be too subtle for detection by neuropsychological assessments, including memory tests.

Aged↗

PubMed2005

Quality of life of long-term survivors of breast cancer and lymphoma treated with standard-dose chemotherapy or local therapy.

PURPOSE: This study compared the quality of life (QOL) of long-term survivors of breast cancer and lymphoma who had been treated with standard-dose systemic chemotherapy or local therapy only. PATIENTS AND METHODS: Long-term survivors (mean, 10.0 +/- 5.3 years after treatment) of breast cancer or lymphoma who had been treated with systemic chemotherapy (breast, n = 141, age = 57.0 +/- 10.1 years; lymphoma, n = 66, age = 55.8 +/- 13.5 years) or local therapy only (breast, n = 294, age = 65.8 +/- 9.1 years; lymphoma, n = 37, age = 50.4 +/- 12.8 years) were interviewed by phone using the Quality of Life-Cancer Survivors Tool. RESULTS: Multivariate analysis of covariance, controlling for sex, age, education, stage of disease, and time since last treatment, revealed that survivors who had been treated with systemic chemotherapy scored significantly lower on overall QOL compared with survivors treated with local therapy only (P = .04). Analysis of covariance on the subscale scores revealed that, compared with survivors who received local therapy, survivors treated with chemotherapy scored significantly lower on the Social subscale (P < .0001), but no differences emerged on the Psychological or Spiritual subscales. There was a statistically significant interaction between treatment and diagnosis (P = .01), as measured by the Physical subscale, indicating that lymphoma survivors treated with chemotherapy scored worse than all other groups. CONCLUSION: Important QOL differences emerged between the chemotherapy and local therapy groups, suggesting that long-term QOL may vary depending on the type of treatment and diagnosis.

Adaptation, Psychological↗

PubMed2005

FLAIR lesion volume in multiple sclerosis: relation to processing speed and verbal memory.

Information processing speed and episodic memory are two commonly affected cognitive abilities in MS. Insights into the mechanisms of and relationships between these abilities have recently come from structural neuroimaging techniques, but few studies have used fluid-attenuated inversion recovery (FLAIR), a neuroimaging sequence known to be sensitive to cortical and juxtacortical lesions in MS. We hypothesized that a volumetric index of FLAIR total lesion volume (TLV) would be associated with slowed processing speed and verbal memory dysfunction in MS. Twenty MS patients underwent FLAIR imaging and were administered measures of verbal memory and processing speed. Correlational and regression analyses indicated that TLV was directly and independently related to measures of processing speed and verbal memory, and TLV accounted for 56% of the variance in cognitive performance. These findings, considered in the context of prior work, suggest that FLAIR TLV is a useful predictor of commonly impaired cognitive functions in MS, and shows promise as a functionally relevant biomarker for disease status.

Adult↗

PubMed2005

Effect of the dopamine D2 receptor T allele on response latency after mild traumatic brain injury.

OBJECTIVE: The authors tested the hypothesis that the dopamine D2 receptor T allele (formerly described as the A1 allele) would be associated with poorer performance on memory and attention tasks following mild traumatic brain injury. METHOD: Thirty-nine patients with mild traumatic brain injury and 27 comparison subjects were genotyped. All subjects completed memory and attention tests, including the California Verbal Learning Test recognition task and the Continuous Performance Test. RESULTS: In both groups the T allele was associated with poorer performance on the California Verbal Learning Test recognition task. There was also a significant diagnosis-by-allele interaction on measures of response latency (Continuous Performance Test): the subjects with mild traumatic brain injury and the T allele had the worst performance. CONCLUSIONS: Genetic polymorphisms modulating central dopaminergic tone can affect cognitive outcome following mild traumatic brain injury.

Adult↗

PubMed2004

Cholinergic enhancement of frontal lobe activity in mild cognitive impairment.

Cholinesterase inhibitors positively affect cognition in Alzheimer's disease (AD) and other conditions, but no controlled functional MRI studies have examined where their effects occur in the brain. We examined the effects of donepezil hydrochloride (Aricept) on cognition and brain activity in patients with amnestic mild cognitive impairment (MCI), a diagnosis associated with a high risk of developing AD. Nine older adults with MCI were compared with nine healthy, demographically matched controls. At baseline, patients showed reduced activation of frontoparietal regions relative to controls during a working memory task. After stabilization on donepezil (5.7 +/- 1.7 weeks at 10 mg) patients showed increased frontal activity relative to unmedicated controls, which was positively correlated with improvement in task performance (r = 0.49, P = 0.05) as well as baseline hippocampal volume (r = 0.62, P < 0.05). The patients' overall cognitive function was stable or improved throughout the study. Short-term treatment with a cholinesterase inhibitor appears to enhance the activity of frontal circuitry in patients with MCI, and this increase appears to be related to improved cognition and to baseline integrity of the hippocampus. These relationships have implications for understanding the mechanisms by which cognition-enhancing medications exert their effects on brain function and for the use of functional MRI in early detection and treatment monitoring of AD and MCI.

Aged↗

PubMed2004

Cognitive effects of cytotoxic cancer chemotherapy: predisposing risk factors and potential treatments.

Increasing evidence suggests that systemic cancer chemotherapy can have significant long-term effects on cognition, particularly on verbal learning, memory, attention, and speed of information processing. These deficits can be a source of significant distress to survivors. There is much less known about the mechanisms, predisposing vulnerabilities, and treatment of these deficits. We will summarize current knowledge of chemotherapy-associated cognitive deficits. Emerging theories about the role of selected genetic polymorphisms in heightening the vulnerability to chemotherapy-induced cognitive decline will be described.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Neuropsychological impairment in borderline personality disorder.

In spite of accumulating evidence from neurological, neuroimaging, neuropsychological, and, more recently, developmental studies, borderline personality disorder (BPD) is not considered routinely a neurocognitive disorder. A review of the neuropsychological literature shows that the preponderance of BPD studies failed to examine a broad range of cognitive domains and, in particular, have not adequately evaluated attention. Nevertheless, most neuropsychological studies suggest that these patients' cognitive skills are compromised. The authors administered a neuropsychological battery designed to evaluate nine cognitive domains in twelve female inpatients diagnosed with BPD. Relative to a healthy normative group, inpatients with BPD were impaired in seven cognitive domains, with attention-vigilance and verbal learning and memory most pronounced. Neuropsychological performance was significantly related to degree of psychopathology. The authors recommend that clinicians routinely screen BPD patients for cognitive dysfunction and highlight the roles that this important knowledge can have in treatment.

Adolescent↗

PubMed2004

Executive dysfunction in attention-deficit/hyperactivity disorder: cognitive and neuroimaging findings.

Attention-deficit/hyperactivity disorder has been associated with a prominent disturbance of executive functions. There is no pathognomic neuropsychological profile for the disorder, however. Nonetheless, results of neuropsychological testing, in concert with other clinical information,provide a more comprehensive and detailed picture of the individual patient's cognitive and emotional strengths and weaknesses than a psychiatric diagnostic interview alone. This approach to the evaluation of ADHD therefore can provide a strong objective basis from which to make patient-specific recommendations for compensatory strategies and treatment. It should be noted, however, that although executive dysfunction in the form of impaired response inhibition remains the most prominent cognitive theory of ADHD, other theories have been put forth that also deserve further investigation. These include a disturbance in delay aversion (referring to intolerance for waiting) and impaired temporal processing, among others [79]. The neural substrates of executive dysfunction in ADHD have begun to be revealed by a growing body of structural and functional neuroimaging research. Although still in its infancy, neuroimaging of ADHD is pointing toward disruption of FSTC circuitry and the cerebellum as being central to the cognitive and motor abnormalities seen in the disorder. Further research using cognitive tasks assessing executive functions in combination with functional imaging techniques will provide further insight into the etiology of the disorder. It is expected that advances in structural and functional neuroimaging will yield valuable information that will facilitate the differential diagnosis of ADHD. Evidence cited suggests that psychostimulant medication can improve executive functions and their underlying FSTC circuitry. Furthermore, a recent study of adults with ADHD found significant improvements in organization skills and other symptoms of ADHD following cognitive remediation targeting several executive and emotional aspects of the disorder [80]. Additional studies investigating the effects of treatment on executive dysfunction and brain integrity in ADHD will be necessary to determine the degree to which the structural and functional brain abnormalities observed are mutable. Finally, because the myriad cognitive, behavioral and emotional symptoms in ADHD likely reflect the interplay of multiple cognitive and psychosocial factors, development of treatments for ADHD likely will require a multi-modal approach.

Attention Deficit Disorder with Hyperactivity↗