Publications
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| Title | Journal | Year | MeSH Terms* | Authors | Volume | Issue | Pages | Abstract | Link | PMC |
| Title | Journal | Year | MeSH Terms | Authors | Volume | Issue | Pages | Abstract | Link | PMC |
| Development of a subjective cognitive decline questionnaire using item response theory: a pilot study. | Alzheimer's and Dementia (Amsterdam) | 2015 | Katherine A Gifford, Dandan Liu, Raymond Romano 3rd, Richard N Jones, Angela L Jefferson. | 1 | 4 | 429-439 | BACKGROUND: Subjective cognitive decline (SCD) may indicate unhealthy cognitive changes, but no standardized SCD measurement exists. This pilot study aims to identify reliable SCD questions. METHODS: 112 cognitively normal (NC, 76±8 years, 63% female), 43 mild cognitive impairment (MCI; 77±7 years, 51% female), and 33 diagnostically ambiguous participants (79±9 years, 58% female) were recruited from a research registry and completed 57 self-report SCD questions. Psychometric methods were used for item-reduction. RESULTS: Factor analytic models assessed unidimensionality of the latent trait (SCD); 19 items were removed with extreme response distribution or trait-fit. Item response theory (IRT) provided information about question utility; 17 items with low information were dropped. Post-hoc simulation using computerized adaptive test (CAT) modeling selected the most commonly used items (n=9 of 21 items) that represented the latent trait well (r=0.94) and differentiated NC from MCI participants (F(1,146)=8.9, p=0.003). CONCLUSION: Item response theory and computerized adaptive test modeling identified nine reliable SCD items. This pilot study is a first step toward refining SCD assessment in older adults. Replication of these findings and validation with Alzheimer's disease biomarkers will be an important next step for the creation of a SCD screener. | PubMed Link | 4750048 | |
| The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview. | Journal of Alzheimer's Disease | 2016 | Angela L Jefferson, Katherine A Gifford, Lealani Mae Y Acosta, Susan P Bell, Manus J Donahue, L Taylor Davis, JoAnn Gottlieb, Deepak K Gupta, Timothy J Hohman, Elizabeth M Lane, David J Libon, Lisa A Mendes, Kevin Niswender, Kimberly R Pechman, Swati Rane, Frederick L Ruberg, Yan Ru Su, Henrik Zetterberg, Dandan Liu. | 52 | 2 | 539-59 | BACKGROUND: Vascular health factors frequently co-occur with Alzheimer's disease (AD). A better understanding of how systemic vascular and cerebrovascular health intersects with clinical and pathological AD may inform prevention and treatment opportunities. OBJECTIVE: To establish the Vanderbilt Memory & Aging Project, a case-control longitudinal study investigating vascular health and brain aging, and describe baseline methodology and participant characteristics. METHODS: From September 2012 to November 2014, 335 participants age 60- 92 were enrolled, including 168 individuals with mild cognitive impairment (MCI, 73±8 years, 41% female) and 167 age-, sex-, and race-matched cognitively normal controls (NC, 72±7 years, 41% female). At baseline, participants completed a physical and frailty examination, fasting blood draw, neuropsychological assessment, echocardiogram, cardiac MRI, and brain MRI. A subset underwent 24-hour ambulatory blood pressure monitoring and lumbar puncture for cerebrospinal fluid (CSF) collection. RESULTS: As designed, participant groups were comparable for age (p = 0.31), sex (p = 0.95), and race (p = 0.65). MCI participants had greater Framingham Stroke Risk Profile scores (p = 0.008), systolic blood pressure values (p = 0.008), and history of left ventricular hypertrophy (p = 0.04) than NC participants. As expected, MCI participants performed worse on all neuropsychological measures (p-values < 0.001), were more likely to be APOEɛ4 carriers (p = 0.02), and had enhanced CSF biomarkers, including lower Aβ42 (p = 0.02), higher total tau (p = 0.004), and higher p-tau (p = 0.02) compared to NC participants. CONCLUSION: Diverse sources of baseline and longitudinal data will provide rich opportunities to investigate pathways linking vascular and cerebrovascular health, clinical and pathological AD, and neurodegeneration contributing to novel strategies to delay or prevent cognitive decline. | PubMed Link | 4866875 | |
| Lower cardiac index levels relate to lower cerebral blood flow in older adults. | Neurology | 2017 | Angela L Jefferson, Dandan Liu, Deepak K Gupta, Kimberly R Pechman, Jennifer M Watchmaker, Elizabeth A Gordon, Swati Rane, Susan P Bell, Lisa A Mendes, L Taylor Davis, Katherine A Gifford, Timothy J Hohman, Thomas J Wang, Manus J Donahue | 89 | 23 | 2327-2334 | OBJECTIVE: To assess cross-sectionally whether lower cardiac index relates to lower resting cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) among older adults. METHODS: Vanderbilt Memory & Aging Project participants free of stroke, dementia, and heart failure were studied (n = 314, age 73 ± 7 years, 59% male, 39% with mild cognitive impairment). Cardiac index (liters per minute per meter squared) was quantified from echocardiography. Resting CBF (milliliters per 100 grams per minute) and hypercapnia-induced CVR were quantified from pseudo-continuous arterial spin-labeling MRI. Linear regressions with ordinary least-square estimates related cardiac index to regional CBF, with adjustment for age, education, race/ethnicity, Framingham Stroke Risk Profile score (systolic blood pressure, antihypertensive medication use, diabetes mellitus, current cigarette smoking, left ventricular hypertrophy, prevalent cardiovascular disease [CVD], atrial fibrillation), APOE ε4 status, cognitive diagnosis, and regional tissue volume. RESULTS: Lower cardiac index corresponded to lower resting CBF in the left (β = 2.4, p = 0.001) and right (β = 2.5, p = 0.001) temporal lobes. Results were similar when participants with prevalent CVD and atrial fibrillation were excluded (left temporal lobe β = 2.3, p = 0.003; right temporal lobe β = 2.5, p = 0.003). Cardiac index was unrelated to CBF in other regions assessed (p > 0.25) and CVR in all regions (p > 0.05). In secondary cardiac index × cognitive diagnosis interaction models, cardiac index and CBF associations were present only in cognitively normal participants and affected a majority of regions assessed with effects strongest in the left (p < 0.0001) and right (p < 0.0001) temporal lobes. CONCLUSIONS: Among older adults without stroke, dementia, or heart failure, systemic blood flow correlates with cerebral CBF in the temporal lobe, independently of prevalent CVD, but not CVR. | PubMed Link | 5719926 | |
| Hemodynamic mechanisms underlying elevated oxygen extraction fraction (OEF) in moyamoya and sickle cell anemia patients | J Cereb Blood Flow Metab | 2018 | Jennifer M Watchmaker, Meher R Juttukonda, L Taylor Davis, Allison O Scott, Carlos C Faraco, Melissa C Gindville, Lori C Jordan, Petrice M Cogswell, Angela L Jefferson, Howard S Kirshner, Manus J Donahue | 38 | 9 | 1618-1630 | Moyamoya is a bilateral, complex cerebrovascular condition characterized by progressive non-atherosclerotic intracranial stenosis and collateral vessel formation. Moyamoya treatment focuses on restoring cerebral blood flow (CBF) through surgical revascularization, however stratifying patients for revascularization requires abilities to quantify how well parenchyma is compensating for arterial steno-occlusion. Globally elevated oxygen extraction fraction (OEF) secondary to CBF reduction may serve as a biomarker for tissue health in moyamoya patients, as suggested in patients with sickle cell anemia (SCA) and reduced oxygen carrying capacity. Here, OEF was measured (TRUST-MRI) to test the hypothesis that OEF is globally elevated in patients with moyamoya (n = 18) and SCA (n = 18) relative to age-matched controls (n = 43). Mechanisms underlying the hypothesized OEF increases were evaluated by performing sequential CBF-weighted, cerebrovascular reactivity (CVR)-weighted, and structural MRI. Patients were stratified by treatment and non-parametric tests applied to compare study variables (significance: two-sided P < 0.05). OEF was significantly elevated in moyamoya participants (interquartile range = 0.38-0.45) compared to controls (interquartile range = 0.29-0.38), similar to participants with SCA (interquartile range = 0.37-0.45). CBF was inversely correlated with OEF in moyamoya participants. Elevated OEF was only weakly related to reductions in CVR, consistent with basal CBF level, rather than vascular reserve capacity, being most closely associated with OEF. | PubMed Link | 6125968 | |
| Cerebrospinal fluid β-amyloid(42) and neurofilament light relate to white matter hyperintensities. | Neurobiology of Aging | 2018 | Katie E Osborn, Dandan Liu, Lauren R Samuels, Elizabeth E Moore, Francis E Cambronero, Lealani Mae Y Acosta, Susan P Bell, Michelle A Babicz, Elizabeth A Gordon, Kimberly R Pechman, L Taylor Davis, Katherine A Gifford, Timothy J Hohman, Kaj Blennow, Henrik Zetterberg, Angela L Jefferson | 68 | 18-25 | White matter hyperintensities (WMHs) are associated with poorer brain health, but their pathophysiological substrates remain elusive. To better understand the mechanistic underpinnings of WMHs among older adults, this study examined in vivo cerebrospinal fluid biomarkers of β-amyloid42 deposition (Aβ42), hyperphosphorylated tau pathology, neurodegeneration (total tau), and axonal injury (neurofilament light [NFL]) in relation to log-transformed WMHs volume. Participants free of clinical stroke and dementia were drawn from the Vanderbilt Memory & Aging Project (n = 148, 72 ± 6 years). Linear regression models adjusted for age, sex, race/ethnicity, education, intracranial volume, modified Framingham Stroke Risk Profile (excluding points assigned for age), cognitive diagnosis, and APOE-ε4 carrier status. Aβ42 (β = -0.001, p = 0.007) and NFL (β = 0.0003, p = 0.01) concentrations related to WMHs but neither hyperphosphorylated tau nor total tau associations with WMHs reached statistical significance (p-values > 0.21). In a combined model, NFL accounted for 3.2% of unique variance in WMHs and Aβ42 accounted for an additional 4.3% beyond NFL, providing novel evidence of the co-occurrence of at least 2 distinct pathways for WMHs among older adults, including amyloid deposition and axonal injury. | PubMed Link | 6085839 | ||
| Neurofilament relates to white matter microstructure in older adults. | Neurobiology of Aging | 2018 | Elizabeth E Moore, Timothy J Hohman, Faizan S Badami, Kimberly R Pechman, Katie E Osborn, Lealani Mae Y Acosta, Susan P Bell, Michelle A Babicz, Katherine A Gifford, Adam W Anderson, Lee E Goldstein, Kaj Blennow, Henrik Zetterberg, Angela L Jefferson | 70 | 233-241 | Cerebrospinal fluid (CSF) neurofilament light (NFL) is a protein biomarker of axonal injury. To study whether NFL is associated with diffusion tensor imaging (DTI) measurements of white matter (WM) microstructure, Vanderbilt Memory & Aging Project participants with normal cognition (n = 77), early mild cognitive impairment (n = 15), and MCI (n = 55) underwent lumbar puncture to obtain CSF and 3T brain MRI. Voxel-wise analyses cross-sectionally related NFL to DTI metrics, adjusting for demographic and vascular risk factors. Increased NFL correlated with multiple DTI metrics (p-values < 0.05). An NFL × diagnosis interaction (excluding early mild cognitive impairment) on WM microstructure (p-values < 0.05) was detected, with associations strongest among MCI. Multiple NFL × CSF biomarker interactions were detected. Associations between NFL and worse WM metrics were strongest among amyloid-β42-negative, tau-positive, and suspected nonamyloid pathology participants. Findings suggest increased NFL, a biomarker of axonal injury, is correlated with compromised WM microstructure. Results highlight the role of elevated NFL in predicting WM damage in cognitively impaired older adults who are amyloid-negative, tau-positive, or meet suspected nonamyloid pathology criteria. | PubMed Link | 6119102 | ||
| Increased Left Ventricular Mass Index Is Associated With Compromised White Matter Microstructure Among Older Adults. | Journal of the American Heart Association | 2018 | Elizabeth E Moore, Dandan Liu, Kimberly R Pechman, James G Terry, Sangeeta Nair, Francis E Cambronero, Susan P Bell, Katherine A Gifford, Adam W Anderson, Timothy J Hohman, John Jeffrey Carr, Angela L Jefferson | 7 | 13 | BACKGROUND: Left ventricular (LV) hypertrophy is associated with cerebrovascular disease and cognitive decline. Increased LV mass index is a subclinical imaging marker that precedes overt LV hypertrophy. This study relates LV mass index to white matter microstructure and cognition among older adults with normal cognition and mild cognitive impairment. METHODS AND RESULTS: Vanderbilt Memory & Aging Project participants free of clinical stroke, dementia, and heart failure (n=318, 73±7 years, 58% male, 39% mild cognitive impairment) underwent brain magnetic resonance imaging, cardiac magnetic resonance, and neuropsychological assessment. Voxelwise analyses related LV mass index (g/m2) to diffusion tensor imaging metrics. Models adjusted for age, sex, education, race/ethnicity, Framingham Stroke Risk Profile, cognitive diagnosis, and apolipoprotein E-ε4 status. Secondary analyses included a LV mass index×diagnosis interaction term with follow-up models stratified by diagnosis. With identical covariates, linear regression models related LV mass index to neuropsychological performances. Increased LV mass index related to altered white matter microstructure (P<0.05). In models stratified by diagnosis, associations between LV mass index and diffusion tensor imaging were present among mild cognitive impairment participants only (P<0.05). LV mass index was related only to worse visuospatial memory performance (β=-0.003, P=0.036), an observation that would not withstand correction for multiple testing. CONCLUSIONS: In the absence of prevalent heart failure and clinical stroke, increased LV mass index corresponds to altered white matter microstructure, particularly among older adults with clinical symptoms of prodromal dementia. Findings highlight the potential link between subclinical LV remodeling and cerebral white matter microstructure vulnerability. | PubMed Link | 6064880 | ||
| Subclinical Compromise in Cardiac Strain Relates to Lower Cognitive Performances in Older Adults. | Journal of the American Heart Association | 2018 | Haily A Kresge, Omair A Khan, Madison A Wagener, Dandan Liu, James G Terry, Sangeeta Nair, Francis E Cambronero, Katherine A Gifford, Katie E Osborn, Timothy J Hohman, Kimberly R Pechman, Susan P Bell, Thomas J Wang, John Jeffrey Carr, Angela L Jefferson | 7 | 4 | BACKGROUND: Global longitudinal strain (GLS), reflecting total shortening of the myocardium during the cardiac cycle, has emerged as a more precise myocardial function measure than left ventricular ejection fraction (LVEF). Longitudinal strain may be selectively affected in subclinical heart disease, even in the presence of normal LVEF. This study examines subclinical cardiac dysfunction, assessed by GLS and LVEF, and cognition among older adults. METHODS AND RESULTS: Vanderbilt Memory and Aging Project participants who were free of clinical dementia, stroke, and heart failure (n=318, 73±7 years, 58% male) completed neuropsychological assessment and cardiac magnetic resonance to quantify GLS and LVEF. Linear regression models related GLS and LVEF to neuropsychological performances, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive diagnosis, and APOE*ε4 status. Models were repeated with a cardiac×cognitive diagnosis interaction term. Compromised GLS (reflected by higher values) related to worse naming (β=-0.07, P=0.04), visuospatial immediate recall (β=-0.83, P=0.03), visuospatial delayed recall (β=-0.22, P=0.03), and verbal delayed recall (β=-0.11, P=0.007). LVEF did not relate to worse performance on any measure (P>0.18). No diagnostic interactions were observed. CONCLUSIONS: Our study results are among the first to suggest that compromised GLS relates to worse episodic memory and language performance among older adults who are free of clinical dementia, stroke, and heart failure. Subclinical cardiac dysfunction may correlate with cognitive health in late life, even when LVEF remains normal. The results add to growing evidence that GLS may be a more sensitive and preferred method for quantifying subclinical changes in cardiac function. | PubMed Link | 5850190 | ||
| Higher Aortic Stiffness Is Related to Lower Cerebral Blood Flow and Preserved Cerebrovascular Reactivity in Older Adults | Circulation | 2018 | Angela L Jefferson, Francis E Cambronero, Dandan Liu, Elizabeth E Moore, Jacquelyn E Neal, James G Terry, Sangeeta Nair, Kimberly R Pechman, Swati Rane, L Taylor Davis, Katherine A Gifford, Timothy J Hohman, Susan P Bell, Thomas J Wang, Joshua A Beckman, John Jeffrey Carr | 138 | 18 | 1951-1962 | BACKGROUND: Mechanisms underlying the association between age-related arterial stiffening and poor brain health remain elusive. Cerebral blood flow (CBF) homeostasis may be implicated. This study evaluates how aortic stiffening relates to resting CBF and cerebrovascular reactivity (CVR) in older adults. METHODS: Vanderbilt Memory & Aging Project participants free of clinical dementia, stroke, and heart failure were studied, including older adults with normal cognition (n=155; age, 72±7 years; 59% male) or mild cognitive impairment (n=115; age, 73±7 years; 57% male). Aortic pulse wave velocity (PWV; meters per second) was quantified from cardiac magnetic resonance. Resting CBF (milliliters per 100 g per minute) and CVR (CBF response to hypercapnic normoxia stimulus) were quantified from pseudocontinuous arterial spin labeling magnetic resonance imaging. Linear regression models related aortic PWV to regional CBF, adjusting for age, race/ethnicity, education, Framingham Stroke Risk Profile (diabetes mellitus, smoking, left ventricular hypertrophy, prevalent cardiovascular disease, atrial fibrillation), hypertension, body mass index, apolipoprotein E4 ( APOE ε4) status, and regional tissue volume. Models were repeated testing PWV× APOE ε4 interactions. Sensitivity analyses excluded participants with prevalent cardiovascular disease and atrial fibrillation. RESULTS: Among participants with normal cognition, higher aortic PWV related to lower frontal lobe CBF (β=-0.43; P=0.04) and higher CVR in the whole brain (β=0.11; P=0.02), frontal lobes (β=0.12; P<0.05), temporal lobes (β=0.11; P=0.02), and occipital lobes (β=0.14; P=0.01). Among APOE ε4 carriers with normal cognition, findings were more pronounced with higher PWV relating to lower whole-brain CBF (β=-1.16; P=0.047), lower temporal lobe CBF (β=-1.81; P=0.004), and higher temporal lobe CVR (β=0.26; P=0.08), although the last result did not meet the a priori significance threshold. Results were similar in sensitivity models. Among participants with mild cognitive impairment, higher aortic PWV related to lower CBF in the occipital lobe (β=-0.70; P=0.02), but this finding was attenuated when participants with prevalent cardiovascular disease and atrial fibrillation were excluded. Among APOE ε4 carriers with mild cognitive impairment, findings were more pronounced with higher PWV relating to lower temporal lobe CBF (β=-1.20; P=0.02). CONCLUSIONS: Greater aortic stiffening relates to lower regional CBF and higher CVR in cognitively normal older adults, especially among individuals with increased genetic predisposition for Alzheimer's disease. Central arterial stiffening may contribute to reductions in regional CBF despite preserved cerebrovascular reserve capacity. | PubMed Link | 6394409 | |
| Sex-Specific Association of Apolipoprotein E With Cerebrospinal Fluid Levels of Tau. | JAMA Neurology | 2018 | Timothy J Hohman, Logan Dumitrescu, Lisa L Barnes, Madhav Thambisetty, Gary Beecham, Brian Kunkle, Katherine A Gifford, William S Bush, Lori B Chibnik, Shubhabrata Mukherjee, Philip L De Jager, Walter Kukull, Paul K Crane, Susan M Resnick, C Dirk Keene, Thomas J Montine, Gerard D Schellenberg, Jonathan L Haines, Henrik Zetterberg, Kaj Blennow, Eric B Larson, Sterling C Johnson, Marilyn Albert, David A Bennett, Julie A Schneider, Angela L Jefferson | 75 | 8 | 989-998 | IMPORTANCE: The strongest genetic risk factor for Alzheimer disease (AD), the apolipoprotein E (APOE) gene, has a stronger association among women compared with men. Yet limited work has evaluated the association between APOE alleles and markers of AD neuropathology in a sex-specific manner. OBJECTIVE: To evaluate sex differences in the association between APOE and markers of AD neuropathology measured in cerebrospinal fluid (CSF) during life or in brain tissue at autopsy. DESIGN, SETTING, AND PARTICIPANTS: This multicohort study selected data from 10 longitudinal cohort studies of normal aging and AD. Cohorts had variable recruitment criteria and follow-up intervals and included population-based and clinic-based samples. Inclusion in our analysis required APOE genotype data and either CSF data available for analysis. Analyses began on November 6, 2017, and were completed on December 20, 2017. MAIN OUTCOMES AND MEASURES: Biomarker analyses included levels of β-amyloid 42, total tau, and phosphorylated tau measured in CSF. Autopsy analyses included Consortium to Establish a Registry for Alzheimer's Disease staging for neuritic plaques and Braak staging for neurofibrillary tangles. RESULTS: Of the 1798 patients in the CSF biomarker cohort, 862 were women, 226 had AD, 1690 were white, and the mean (SD) age was 70 [9] years. Of the 5109 patients in the autopsy cohort, 2813 were women, 4953 were white, and the mean (SD) age was 84 years. After correcting for multiple comparisons using the Bonferroni procedure, we observed a statistically significant interaction between APOE-ε4 and sex on CSF total tau (β = 0.41; 95% CI, 0.27-0.55; P < .001) and phosphorylated tau (β = 0.24; 95% CI, 0.09-0.38; P = .001), whereby APOE showed a stronger association among women compared with men. Post hoc analyses suggested this sex difference was present in amyloid-positive individuals (β = 0.41; 95% CI, 0.20-0.62; P < .001) but not among amyloid-negative individuals (β = 0.06; 95% CI, -0.18 to 0.31; P = .62). We did not observe sex differences in the association between APOE and β-amyloid 42, neuritic plaque burden, or neurofibrillary tangle burden. CONCLUSIONS AND RELEVANCE: We provide robust evidence of a stronger association between APOE-ε4 and CSF tau levels among women compared with men across multiple independent data sets. Interestingly, APOE-ε4 is not differentially associated with autopsy measures of neurofibrillary tangles. Together, the sex difference in the association between APOE and CSF measures of tau and the lack of a sex difference in the association with neurofibrillary tangles at autopsy suggest that APOE may modulate risk for neurodegeneration in a sex-specific manner, particularly in the presence of amyloidosis. | PubMed Link | 6142927 | |
| The 12-Word Philadelphia Verbal Learning Test Performances in Older Adults: Brain MRI and Cerebrospinal Fluid Correlates and Regression-Based Normative Data. | Dementia and Geriatric Cognitive Disorders Extra | 2018 | Katherine A Gifford, Dandan Liu, Jacquelyn E Neal, Michelle A Babicz, Jennifer L Thompson, Lily E Walljasper, Margaret E Wiggins, Maxim Turchan, Kimberly R Pechman, Katie E Osborn, Lealani Mae Y Acosta, Susan P Bell, Timothy J Hohman, David J Libon, Kaj Blennow, Henrik Zetterberg, Angela L Jefferson. | 8 | 3 | 476-491 | BACKGROUND/AIMS: This study evaluated neuroimaging and biological correlates, psychometric properties, and regression-based normative data of the 12-word Philadelphia Verbal Learning Test (PVLT), a list-learning test. METHODS: Vanderbilt Memory and Aging Project participants free of clinical dementia and stroke (n = 230, aged 73 ± 7 years) completed a neuropsychological protocol and brain MRI. A subset (n = 111) underwent lumbar puncture for analysis of Alzheimer's disease (AD) and axonal integrity cerebrospinal fluid (CSF) biomarkers. Regression models related PVLT indices to MRI and CSF biomarkers adjusting for age, sex, race/ethnicity, education, APOE-ε4 carrier status, cognitive status, and intracranial volume (MRI models). Secondary analyses were restricted to participants with normal cognition (NC; n = 127), from which regression-based normative data were generated. RESULTS: Lower PVLT performances were associated with smaller medial temporal lobe volumes (p < 0.05) and higher CSF tau concentrations (p < 0.04). Among NC, PVLT indices were associated with white matter hyperintensities on MRI and an axonal injury biomarker (CSF neurofilament light; p < 0.03). CONCLUSION: The PVLT appears sensitive to markers of neurodegeneration, including temporal regions affected by AD. Conversely, in cognitively normal older adults, PVLT performance seems to relate to white matter disease and axonal injury, perhaps reflecting non-AD pathways to cognitive change. Enhanced normative data enrich the clinical utility of this tool. | PubMed Link | 6323369 | |
| APOE genotype modifies the association between central arterial stiffening and cognition in older adults. | Neurobiology of Aging | 2018 | Francis E Cambronero, Dandan Liu, Jacquelyn E Neal, Elizabeth E Moore, Katherine A Gifford, James G Terry, Sangeeta Nair, Kimberly R Pechman, Katie E Osborn, Timothy J Hohman, Susan P Bell, J David Sweatt, Thomas J Wang, Joshua A Beckman, John Jeffrey Carr, Angela L Jefferson | 67 | 120-127 | Arterial stiffening is associated with cognitive impairment and prodromal Alzheimer's disease. This study tested the interaction between arterial stiffening and an Alzheimer's disease genetic risk factor (apolipoprotein E [APOE] genotype) on cognition among older adults. Vanderbilt Memory & Aging Project participants with normal cognition (n = 162, 72 ± 7 years, 29% APOE-ε4 carrier) and mild cognitive impairment (n = 121, 73 ± 8 years, 42% APOE-ε4 carrier) completed neuropsychological assessment and cardiac MRI to assess aortic stiffening using pulse wave velocity (PWV, m/s). Linear regression models stratified by cognitive diagnosis related aortic PWV × APOE-ε4 status to neuropsychological performances, adjusting for demographic and vascular risk factors. PWV × APOE-ε4 related to poorer performance on measures of lexical retrieval (β = -0.29, p = 0.01), executive function (β = -0.44, p = 0.02), and episodic memory (β = -3.07, p = 0.02). Among participants with higher aortic PWV, APOE-ε4 modified the association between central arterial stiffening and cognition, such that carriers had worse performances than noncarriers. Findings add to a growing body of evidence for APOE-vascular interactions on cognition in older adults and warrant further research into less heart-healthy cohorts where the association between PWV and cognition among older adults might be stronger. | PubMed Link | 5985659 | ||
| Perivascular spaces contribute to cognition beyond other small vessel disease markers. | Neurology | 2019 | Brittany S Passiak, Dandan Liu, Haily A Kresge, Francis E Cambronero, Kimberly R Pechman, Katie E Osborn, Katherine A Gifford, Timothy J Hohman, Matthew S Schrag, L Taylor Davis, Angela L Jefferson | 92 | 12 | e1309-e1321 | OBJECTIVE: To cross-sectionally relate multiple small vessel disease (SVD) neuroimaging markers to cognition among older adults. METHODS: Vanderbilt Memory & Aging Project participants free of clinical dementia and stroke (n = 327, age 73 ± 7 years, 59% male, 40% with mild cognitive impairment) completed neuropsychological assessment and 3T MRI to measure white matter hyperintensities (WMH), perivascular spaces (PVS), cerebral microbleeds (CMBs), and lacunes. Linear regressions related each SVD marker to neuropsychological performances and adjusted for age, sex, race/ethnicity, education, cognitive diagnosis, APOE ε4 presence, Framingham Stroke Risk Profile, and intracranial volume. RESULTS: WMH related to the most neuropsychological measures, including the Boston Naming Test, Animal Naming, Coding, Number Sequencing, Executive Function Composite, and Hooper Visual Organization Test performances (p ≤ 0.01). PVS related to multiple information processing and executive function performances (p ≤ 0.02). Lacunes and CMBs related to fewer measures than expected. Combined models simultaneously testing multiple statistically significant SVD predictors suggested that WMH, PVS, and CMBs each independently related to information processing and executive function performances; however, compared to other SVD markers, PVS remained statistically significant in models related to information processing and executive functioning performances. CONCLUSIONS: As expected, increased WMH corresponded to poorer performances across multiple cognitive domains. PVS, previously considered a benign neuroimaging feature in older adults, may have important clinical implications because PVS was related to information processing and executive function performances even in combined models. On the basis of models with multiple SVD predictors, WMH, PVS, and CMBs may each reflect a separate pathway of small vessel injury. | PubMed Link | 6511092 | |
| Cerebrospinal fluid and plasma neurofilament light relate to abnormal cognition. | Alzheimer's and Dementia (Amsterdam) | 2019 | Katie E Osborn, Omair A Khan, Haily A Kresge, Corey W Bown, Dandan Liu, Elizabeth E Moore, Katherine A Gifford, Lealani Mae Y Acosta, Susan P Bell, Timothy J Hohman, Kaj Blennow, Henrik Zetterberg, Angela L Jefferson | 11 | 700-709 | INTRODUCTION: Neuroaxonal damage may contribute to cognitive changes preceding clinical dementia. Accessible biomarkers are critical for detecting such damage. METHODS: Plasma and cerebrospinal fluid (CSF) neurofilament light (NFL) were related to neuropsychological performance among Vanderbilt Memory & Aging Project participants (plasma n = 333, 73 ± 7 years; CSF n = 149, 72 ± 6 years) ranging from normal cognition (NC) to mild cognitive impairment (MCI). Models adjusted for age, sex, race/ethnicity, education, apolipoprotein E ε4 carriership, and Framingham Stroke Risk Profile. RESULTS: Plasma NFL was related to all domains (P values ≤ .008) except processing speed (P values ≥ .09). CSF NFL was related to memory and language (P values ≤ .04). Interactions with cognitive diagnosis revealed widespread plasma associations, particularly in MCI participants, which were further supported in head-to-head comparison models. DISCUSSION: Plasma and CSF NFL (reflecting neuroaxonal injury) relate to cognition among non-demented older adults albeit with small to medium effects. Plasma NFL shows particular promise as an accessible biomarker with relevance to cognition in MCI | PubMed Link | 6827361 | ||
| Frailty Is Related to Subjective Cognitive Decline in Older Women without Dementia. | Journal of the American Geriatrics Society | 2019 | Katherine A Gifford, Susan P Bell, Dandan Liu, Jacquelyn E Neal, Maxim Turchan, Avantika S Shah, Angela L Jefferson. | 67 | 9 | 1803-1811 | OBJECTIVES: Physical frailty (or loss of physiologic reserve) is associated with cognitive impairment and dementia. Subjective cognitive decline (SCD) may represent early pathologic changes of dementia. The association between these disease markers is unclear. DESIGN: Cross-sectional analysis. SETTING: Community-based participants from the Vanderbilt Memory & Aging Project. PARTICIPANTS: A total of 306 older adults with normal cognition (NC; n = 174) or mild cognitive impairment (MCI; n = 132). MEASUREMENTS: Frailty was measured using standard methods, and a composite frailty score was calculated. SCD was quantified using the Everyday Cognition Scale (ECog; total score and four domain scores). Objective cognition was assessed with the Montreal Cognitive Assessment (MoCA). Proportional odds models, stratified by sex, related the frailty composite to MoCA and total ECog score adjusting for age, education, body mass index, cognitive diagnosis, depressed mood, Framingham Stroke Risk Profile, apolipoprotein E (APOE ε4) carrier status, and height (for gait speed models). Secondary models related individual frailty components to SCD domains and explored associations in NC only. RESULTS: In women, frailty composite was related to MoCA (odds ratio [OR] = .56; P = .04), a finding attenuated in sensitivity analysis (OR = .59; P = .08). Frailty composite related to ECog total (OR = 2.27; P = .02), planning (OR = 2.63; P = .02), and organization scores (OR = 2.39; P = .03). Increasing gait speed related to lower ECog total (OR = .06; P = .003) and memory scores (OR = .03; P < .001). Grip strength related to lower ECog planning score (OR = .91; P = .04). In men, frailty was unrelated to objective and subjective cognition (P values >.07). Findings were consistent in the NC group. CONCLUSION: Frailty component and composite scores are related to SCD before the presence of overt dementia. Results suggest that this association is present before overt cognitive impairment. Results suggest a possible sex difference in the clinical manifestation of frailty, with primary associations noted in women. Further studies should investigate mechanisms linking early changes among frailty, SCD, and cognition. J Am Geriatr Soc, 1-9, 2019. J Am Geriatr Soc 67:1803-1811, 2019. | PubMed Link | 6781867 | |
| Apolipoprotein E Genotype Modifies the Association Between Cardiac Output and Cognition in Older Adults. | Journal of the American Heart Association. | 2019 | Corey W Bown, Dandan Liu, Katie E Osborn, Deepak K Gupta, Lisa A Mendes, Kimberly R Pechman, Timothy J Hohman, Thomas J Wang, Katherine A Gifford, Angela L Jefferson | 8 | 15 | Background Subtle reductions in cardiac output relate to lower cerebral blood flow, especially in regions where Alzheimer's disease pathology first develops. Apolipoprotein E (APOE)-ε4 is a genetic susceptibility risk factor for Alzheimer's disease that also moderates vascular damage. This study investigated whether APOE-ε4 carrier status modifies the cross-sectional association between cardiac output and cognition. Methods and Results Vanderbilt Memory & Aging Project participants free of clinical stroke and dementia (n=306, 73±7 years, 42% female) underwent echocardiography to determine cardiac output (L/min), comprehensive neuropsychological assessment, and venous blood draw to determine APOE genotype and ε4 carrier status. Linear regressions related cardiac output to neuropsychological test performance, adjusting for age, sex, education, race/ethnicity, body surface area, cognitive diagnosis, Framingham Stroke Risk Profile, and APOE-ε4 status. Main effect models were null (P>0.19). With identical covariates, models were repeated testing a cardiac output×APOE-ε4 status interaction and again stratified by ε4 carrier status. Cardiac output×APOE-ε4 status related to naming (β=0.91, P=0.0009), category fluency (β=1.2, P=0.01), information processing speed (β=-5.4, P=0.001), visuospatial skill (β=0.85, P=0.003), and executive function performances (β=0.22, P=0.002). Stratified models suggested that lower cardiac output was associated with worse neuropsychological performances among APOE-ε4 carriers. Conclusions APOE-ε4 carrier status appears to modify the cross-sectional association between cardiac output and neuropsychological performance such that lower cardiac output relates to poorer performances among carriers of the ε4 allele. These findings add to increasing evidence that APOE-ε4 carrier status has important implications for associations between vascular and brain health in aging adults. | PubMed Link | 6761646 | ||
| Lower cardiac output is associated with neurodegeneration among older adults with normal cognition but not mild cognitive impairment. | Brain Imaging and Behavior | 2020 | Elizabeth E Moore, Dandan Liu, Corey W Bown, Haily A Kresge, Deepak K Gupta, Kimberly R Pechman, Lisa A Mendes, L Taylor Davis, Katherine A Gifford, Adam W Anderson, Thomas J Wang, Bennett A Landman, Timothy J Hohman, Angela L Jefferson | Subclinical cardiac dysfunction is associated with smaller total brain volume on magnetic resonance imaging (MRI). To study whether cardiac output relates to regional measurements of grey and white matter structure, older adults (n = 326) underwent echocardiogram to quantify cardiac output (L/min) and brain MRI. Linear regressions related cardiac output to grey matter volumes measured on T1 and white matter hyperintensities assessed on T2-FLAIR. Voxelwise analyses related cardiac output to diffusion tensor imaging adjusting for demographic, genetic, and vascular risk factors. Follow-up models assessed a cardiac output x diagnosis interaction with stratification (normal cognition, mild cognitive impairment). Cardiac output interacted with diagnosis, such that lower cardiac output related to smaller total grey matter (p = 0.01), frontal lobe (p = 0.01), and occipital lobe volumes (p = 0.01) among participants with normal cognition. When excluding participants with cardiovascular disease and atrial fibrillation, associations emerged with smaller parietal lobe (p = 0.005) and hippocampal volume (p = 0.05). Subtle age-related cardiac changes may disrupt neuronal homeostasis and impact grey matter integrity prior to cognitive impairment. | PubMed Link | |||||
| Mild Cognitive Impairment Staging Yields Genetic Susceptibility, Biomarker, and Neuroimaging Differences. | Frontiers in Aging Neuroscience | 2020 | Elizabeth E Moore, Dandan Liu, Kimberly R Pechman, Lealani Mae Y Acosta, Susan P Bell, L Taylor Davis, Kaj Blennow, Henrik Zetterberg, Bennett A Landman, Matthew S Schrag, Timothy J Hohman, Katherine A Gifford, Angela L Jefferson | 12 | 139 | INTRODUCTION: While Alzheimer's disease (AD) is divided into severity stages, mild cognitive impairment (MCI) remains a solitary construct despite clinical and prognostic heterogeneity. This study aimed to characterize differences in genetic, cerebrospinal fluid (CSF), neuroimaging, and neuropsychological markers across clinician-derived MCI stages. METHODS: Vanderbilt Memory & Aging Project participants with MCI were categorized into 3 severity subtypes at screening based on neuropsychological assessment, functional assessment, and Clinical Dementia Rating interview, including mild (n = 18, 75 ± 8 years), moderate (n = 89 72 ± 7 years), and severe subtypes (n = 18, 78 ± 8 years). At enrollment, participants underwent neuropsychological testing, 3T brain magnetic resonance imaging (MRI), and optional fasting lumbar puncture to obtain CSF. Neuropsychological testing and MRI were repeated at 18-months, 3-years, and 5-years with a mean follow-up time of 3.3 years. Ordinary least square regressions examined cross-sectional associations between MCI severity and apolipoprotein E (APOE)-ε4 status, CSF biomarkers of amyloid beta (Aβ), phosphorylated tau, total tau, and synaptic dysfunction (neurogranin), baseline neuroimaging biomarkers, and baseline neuropsychological performance. Longitudinal associations between baseline MCI severity and neuroimaging and neuropsychological trajectory were assessed using linear mixed effects models with random intercepts and slopes and a follow-up time interaction. Analyses adjusted for baseline age, sex, race/ethnicity, education, and intracranial volume for MRI models. RESULTS: Stages differed at baseline on APOE-ε4 status (early < middle = late; p-values < 0.03) and CSF Aβ (early > middle = late), phosphorylated and total tau (early = middle < late; p-values < 0.05), and neurogranin concentrations (early = middle < late; p-values < 0.05). MCI stage related to greater longitudinal cognitive decline, hippocampal atrophy, and inferior lateral ventricle dilation (early < late; p-values < 0.03). DISCUSSION: Clinician staging of MCI severity yielded longitudinal cognitive trajectory and structural neuroimaging differences in regions susceptible to AD neuropathology and neurodegeneration. As expected, participants with more severe MCI symptoms at study entry had greater cognitive decline and gray matter atrophy over time. Differences are likely attributable to baseline differences in amyloidosis, tau, and synaptic dysfunction. MCI staging may provide insight into underlying pathology, prognosis, and therapeutic targets. | PubMed Link | 7289958 | ||
| Cerebrospinal fluid biomarkers of neurodegeneration, synaptic dysfunction, and axonal injury relate to atrophy in structural brain regions specific to Alzheimer's disease. | Alzheimer's and Dementia | 2020 | Elizabeth E Moore, Katherine A Gifford, Omair A Khan, Dandan Liu, Kimberly R Pechman, Lealani Mae Y Acosta, Susan P Bell, Maxim Turchan, Bennett A Landman, Kaj Blennow, Henrik Zetterberg, Timothy J Hohman, Angela L Jefferson | 16 | 6 | 883-895 | INTRODUCTION: Patterns of atrophy can distinguish normal cognition from Alzheimer's disease (AD), but neuropathological drivers of this pattern are unknown. This study examined associations between cerebrospinal fluid biomarkers of AD pathology, synaptic dysfunction, and neuroaxonal injury with two AD imaging signatures. METHODS: Signatures were calculated using published guidelines. Linear regressions related each biomarker to both signatures, adjusting for demographic factors. Bootstrapped analyses tested if associations were stronger with one signature versus the other. RESULTS: Increased phosphorylated tau (p-tau), total tau, and neurofilament light (P-values <.045) related to smaller signatures (indicating greater atrophy). Diagnosis and sex modified associations between p-tau and neurogranin (P-values<.05) and signatures, such that associations were stronger among participants with mild cognitive impairment and female participants. The strength of associations did not differ between signatures. DISCUSSION: Increased evidence of neurodegeneration, axonopathy, and tau phosphorylation relate to greater AD-related atrophy. Tau phosphorylation and synaptic dysfunction may be more prominent in AD-affected regions in females. | PubMed Link | 7781154 | |
| Lower Left Ventricular Ejection Fraction Relates to Cerebrospinal Fluid Biomarker Evidence of Neurodegeneration in Older Adults. | Journal of Alzheimer's Disease | 2020 | Haily A Kresge, Dandan Liu, Deepak K Gupta, Elizabeth E Moore, Katie E Osborn, Lealani Mae Y Acosta, Susan P Bell, Kimberly R Pechman, Katherine A Gifford, Lisa A Mendes, Thomas J Wang, Kaj Blennow, Henrik Zetterberg, Timothy J Hohman, Angela L Jefferson | 74 | 3 | 965-974 | BACKGROUND: Subclinical cardiac dysfunction is associated with decreased cerebral blood flow, placing the aging brain at risk for Alzheimer's disease (AD) pathology and neurodegeneration. OBJECTIVE: This study investigates the association between subclinical cardiac dysfunction, measured by left ventricular ejection fraction (LVEF), and cerebrospinal fluid (CSF) biomarkers of AD and neurodegeneration. METHODS: Vanderbilt Memory & Aging Project participants free of dementia, stroke, and heart failure (n = 152, 72±6 years, 68% male) underwent echocardiogram to quantify LVEF and lumbar puncture to measure CSF levels of amyloid-β42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau). Linear regressions related LVEF to CSF biomarkers, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive diagnosis, and apolipoprotein E ɛ4 status. Secondary models tested an LVEF x cognitive diagnosis interaction and then stratified by diagnosis (normal cognition (NC), mild cognitive impairment (MCI)). RESULTS: Higher LVEF related to decreased CSF Aβ42 levels (β= -6.50, p = 0.04) reflecting greater cerebral amyloid accumulation, but this counterintuitive result was attenuated after excluding participants with cardiovascular disease and atrial fibrillation (p = 0.07). We observed an interaction between LVEF and cognitive diagnosis on CSF t-tau (p = 0.004) and p-tau levels (p = 0.002), whereas lower LVEF was associated with increased CSF t-tau (β= -9.74, p = 0.01) and p-tau in the NC (β= -1.41, p = 0.003) but not MCI participants (p-values>0.13). CONCLUSIONS: Among cognitively normal older adults, subclinically lower LVEF relates to greater molecular evidence of tau phosphorylation and neurodegeneration. Modest age-related changes in cardiovascular function may have implications for pathophysiological changes in the brain later in life. | PubMed Link | 7278528 | |
| Midlife Consequences of Cumulative Blood Pressure Exposure: Importance of a Lifespan Approach. | Circulation | 2020 | Angela L Jefferson | 141 | 9 | 725-727 | PubMed Link | 7378845 | ||
| Validity and Normative Data for the Biber Figure Learning Test: A Visual Supraspan Memory Measure. | Assessment | 2020 | Katherine A Gifford, Dandan Liu, Jacquelyn E Neal, Lealani Mae Y Acosta, Susan P Bell, Margaret E Wiggins, Kristi M Wisniewski, Mary Godfrey, Laura A Logan, Timothy J Hohman, Kimberly R Pechman, David J Libon, Kaj Blennow, Henrik Zetterberg, Angela L Jefferson | 27 | 6 | 1320-1334 | The Biber Figure Learning Test (BFLT), a visuospatial serial figure learning test, was evaluated for biological correlates and psychometric properties, and normative data were generated. Nondemented individuals (n = 332, 73 ± 7, 41% female) from the Vanderbilt Memory & Aging Project completed a comprehensive neuropsychological protocol. Adjusted regression models related BFLT indices to structural brain magnetic resonance imaging and cerebrospinal fluid (CSF) markers of brain health. Regression-based normative data were generated. Lower BFLT performances (Total Learning, Delayed Recall, Recognition) related to smaller medial temporal lobe volumes and higher CSF tau concentrations but not CSF amyloid. BFLT indices were most strongly correlated with other measures of verbal and nonverbal memory and visuospatial skills. The BFLT provides a comprehensive assessment of all aspects of visuospatial learning and memory and is sensitive to biomarkers of unhealthy brain aging. Enhanced normative data enriches the clinical utility of this visual serial figure learning test for use with older adults. | PubMed Link | 6212325 | |
| Lower Cardiac Output Relates to Longitudinal Cognitive Decline in Aging Adults. | Frontiers in Psychology | 2020 | Corey W Bown, Rachel Do, Omair A Khan, Dandan Liu, Francis E Cambronero, Elizabeth E Moore, Katie E Osborn, Deepak K Gupta, Kimberly R Pechman, Lisa A Mendes, Timothy J Hohman, Katherine A Gifford, Angela L Jefferson | 11 | 569355 | BACKGROUND: Subclinical reductions in cardiac output correspond to lower cerebral blood flow (CBF), placing the brain at risk for functional changes. OBJECTIVES: This study aims to establish the consequences of reduced cardiac output on longitudinal cognitive outcomes in aging adults. METHODS: Vanderbilt Memory and Aging Project participants free of clinical dementia and heart failure (n = 306, 73 ± 7, 58% male) underwent baseline echocardiography to assess cardiac output (L/min) and longitudinal neuropsychological assessment at baseline, 18 months, 3 and 5 years. Linear mixed-effects regressions related cardiac output to trajectory for each longitudinal neuropsychological outcome, adjusting for age, sex, race/ethnicity, education, body surface area, Framingham Stroke Risk Profile score, apolipoprotein E (APOE) ε4 status and follow-up time. Models were repeated, testing interactions with cognitive diagnosis and APOE-ε4 status. RESULTS: Lower baseline cardiac output related to faster declines in language (β = 0.11, p = 0.01), information processing speed (β = 0.31, p = 0.006), visuospatial skills (β = 0.09, p = 0.03), and episodic memory (β = 0.02, p = 0.001). No cardiac output x cognitive diagnosis interactions were observed (p > 0.26). APOE-ε4 status modified the association between cardiac output and longitudinal episodic memory (β = 0.03, p = 0.047) and information processing speed outcomes (β = 0.55, p = 0.02) with associations stronger in APOE-ε4 carriers. CONCLUSION: The present study provides evidence that even subtle reductions in cardiac output may be associated with more adverse longitudinal cognitive health, including worse language, information processing speed, visuospatial skills, and episodic memory performances. Preservation of healthy cardiac functioning is important for maintaining optimal brain aging among older adults. | PubMed Link | 7680861 | ||
| Free-water metrics in medial temporal lobe white matter tract projections relate to longitudinal cognitive decline. | Neurobiology of Aging | 2020 | Derek B Archer, Elizabeth E Moore, Niranjana Shashikumar, Logan Dumitrescu, Kimberly R Pechman, Bennett A Landman, Katherine A Gifford, Angela L Jefferson, Timothy J Hohman | 94 | 15-23 | Although hippocampal volume has served as a long-standing predictor of cognitive decline, diffusion magnetic resonance imaging studies of white matter have shown similar relationships. Still, it remains unclear if gray matter and white matter interact to predict cognitive impairment and longitudinal decline. Here, we investigate whether free-water (FW) and FW-corrected fractional anisotropy (FAT) within medial temporal lobe white matter tracts provides meaningful contribution to cognition and cognitive decline beyond hippocampal volume. Using data from the Vanderbilt Memory & Aging Project (n = 319), we found that FW was associated with baseline memory and executive function beyond that of hippocampal volume and other comorbidities. Longitudinal analyses demonstrated significant interactions of hippocampal volume and inferior longitudinal fasciculus (p = 0.043) and cingulum bundle (p = 0.025) FAT on memory decline and with fornix FAT (p = 0.025) on decline in executive function. Results suggest that FW metrics of white matter have a unique role in cognitive decline and should be included in theoretical models of aging, cerebrovascular disease, and Alzheimer's disease. | PubMed Link | 7483422 | ||
| Impact of Cardiovascular Hemodynamics on Cognitive Aging | 2021 | PubMed Link |
*MeSH: MeSH (Medical Subject Headings) is the NLM controlled vocabulary thesaurus used for indexing articles for PubMed.
