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- Jefferson, A. L., et al.
(författare)
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The Vanderbilt Memory & Aging Project: Study Design and Baseline Cohort Overview
- 2016
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 52:2, s. 539-559
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Tidskriftsartikel (refereegranskat)abstract
- 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 APOE epsilon 4 carriers (p = 0.02), and had enhanced CSF biomarkers, including lower A beta(42) (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.
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2. |
- Osborn, K. E., et al.
(författare)
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Cerebrospinal fluid beta-amyloid(42) and neurofilament light relate to white matter hyperintensities
- 2018
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Ingår i: Neurobiology of Aging. - : Elsevier BV. - 0197-4580. ; 68, s. 18-25
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Tidskriftsartikel (refereegranskat)abstract
- 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 beta-amyloid(42) deposition (A beta(42)), 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-epsilon 4 carrier status. A beta(42) (beta = -0.001, p = 0.007) and NFL (beta = 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 A beta(42) 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. (C) 2018 Elsevier Inc. All rights reserved.
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3. |
- Osborn, K. E., et al.
(författare)
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Adverse Vascular Risk Relates to Cerebrospinal Fluid Biomarker Evidence of Axonal Injury in the Presence of Alzheimer's Disease Pathology
- 2019
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Ingår i: Journal of Alzheimers Disease. - : IOS Press. - 1387-2877 .- 1875-8908. ; 71:1, s. 281-290
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Tidskriftsartikel (refereegranskat)abstract
- Background: Vascular risk factors promote cerebral small vessel disease and neuropathological changes, particularly in white matter where large-caliber axons are located. How Alzheimer's disease pathology influences the brain's vulnerability in this regard is not well understood. Objective: Systemic vascular risk was assessed in relation to cerebrospinal fluid concentrations of neurofilament light, a biomarker of large-caliber axonal injury, evaluating for interactions by clinical and protein markers of Alzheimer's disease. Methods: Among Alzheimer's Disease Neuroimaging Initiative participants with normal cognition (n = 117), mild cognitive impairment (n = 190), and Alzheimer's disease (n = 95), linear regression related vascular risk (as measured by the modified Framingham Stroke Risk Profile) to neurofilament light, adjusting for age, sex, education, and cognitive diagnosis. Interactions were assessed by cognitive diagnosis, and by cerebrospinal fluid markers of A beta(42), hyperphosphorylated tau, and total tau. Results: Vascular risk and neurofilament light were not related in the main effect model (p = 0.08). However, interactions emerged for total tau (p = 0.01) and hyperphosphorylated tau (p = 0.002) reflecting vascular risk becoming more associated with cerebrospinal fluid neurofilament light in the context of greater concentrations of tau biomarkers. An interaction also emerged for the Alzheimer's disease biomarker profiles (p = 0.046) where in comparison to the referent 'normal' biomarker group, individuals with abnormal levels of both A beta(42) and total tau showed stronger associations between vascular risk and neurofilament light. Conclusion: Older adults may be more vulnerable to axonal injury in response to higher vascular risk burdens in the context of concomitant Alzheimer's disease pathology.
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4. |
- Archer, D. B., et al.
(författare)
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The relationship between white matter microstructure and self-perceived cognitive decline
- 2021
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Ingår i: Neuroimage-Clinical. - : Elsevier BV. - 2213-1582. ; 32
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Tidskriftsartikel (refereegranskat)abstract
- Subjective cognitive decline (SCD) is a perceived cognitive change prior to objective cognitive deficits, and although it is associated with Alzheimer's disease (AD) pathology, it likely results from multiple underlying pathologies. We investigated the association of white matter microstructure to SCD as a sensitive and early marker of cognitive decline and quantified the contribution of white matter microstructure separate from amyloidosis. Vanderbilt Memory & Aging Project participants with diffusion MRI data and a 45-item measure of SCD were included [n = 236, 137 cognitively unimpaired (CU), 99 with mild cognitive impairment (MCI), 73 +/- 7 years, 37% female]. A subset of participants (64 CU, 40 MCI) underwent a fasting lumbar puncture for quantification of cerebrospinal fluid (CSF) amyloid-beta(CSF A beta(42)), total tau (CSF t-tau), and phosphorylated tau (CSF p-tau). Diffusion MRI data was post-processed using the free-water (FW) elimination technique, which allowed quantification of extracellular (FW) and intracellular compartment (fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity) microstructure. Microstructural values were quantified within 11 cognitive-related white matter tracts, including medial temporal lobe, frontal transcallosal, and fronto-parietal tracts using a region of interest approach. General linear modeling related each tract to SCD scores adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile scores, APOE epsilon 4 carrier status, diagnosis, Geriatric Depression Scale scores, hippocampal volume, and total white matter volume. Competitive models were analyzed to determine if white matter microstructural values have a unique role in SCD scores separate from CSF A1342. FW-corrected radial diffusivity (RDT) was related to SCD scores in 8 tracts: cingulum bundle, inferior longitudinal fasciculus, as well as inferior frontal gyrus (IFG) pars opercularis, IFG orbitalis, IFG pars triangularis, tapetum, medial frontal gyrus, and middle frontal gyrus transcallosal tracts. While CSF A beta(42) was related to SCD scores in our cohort (R-adj(2) = 39.03%; beta =-0.231; p = 0.020), competitive models revealed that fornix and IFG pars triangularis transcallosal tract RDT contributed unique variance to SCD scores beyond CSF A beta(42) (R-adj(2) = 44.35% and R-adj(2) = 43.09%, respectively), with several other tract measures demonstrating nominal significance. All tracts which demonstrated nominal significance (in addition to covariates) were input into a backwards stepwise regression analysis. ILF RDT, fornix RDT, and UF FW were best associated with SCD scores (R-adj(2) = 46.69%; p = 6.37 x 10(-12)). Ultimately, we found that medial temporal lobe and frontal transcallosal tract microstructure is an important driver of SCD scores independent of early amyloid deposition. Our results highlight the potential importance of abnormal white matter diffusivity as an early contributor to cognitive decline. These results also highlight the value of incorporating multiple biomarkers to help disentangle the mechanistic heterogeneity of SCD as an early stage of cognitive decline.
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5. |
- Moore, E. E., et al.
(författare)
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Association of Aortic Stiffness With Biomarkers of Neuroinflammation, Synaptic Dysfunction, and Neurodegeneration
- 2021
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 0028-3878 .- 1526-632X. ; 97:4
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Tidskriftsartikel (refereegranskat)abstract
- Objectives To test the hypothesis that increased aortic stiffening is associated with greater CSF evidence of core Alzheimer disease pathology (beta-amyloid [A beta], phosphorylated tau [p-tau]), neurodegeneration (total tau [t-tau]), synaptic dysfunction (neurogranin), neuroaxonal injury (neurofilament light [NFL]), and neuroinflammation (YKL-40, soluble triggering receptor expressed on myeloid cells 2 [sTREM2]), we analyzed pulse wave velocity (PWV) data and CSF data among older adults. Methods Participants free of stroke and dementia from the Vanderbilt Memory and Aging Project, an observational community-based study, underwent cardiac magnetic resonance to assess aortic PWV (meters per second) and lumbar puncture to obtain CSF. Linear regressions related aortic PWV to CSF A beta, p-tau, t-tau, neurogranin, NFL, YKL-40, and sTREM2 concentrations after adjustment for age, race/ethnicity, education, apolipoprotein (APOE) epsilon 4 status, Framingham Stroke Risk Profile, and cognitive diagnosis. Models were repeated testing PWV interactions with age, diagnosis, APOE epsilon 4, and hypertension on each biomarker. Results One hundred forty-six participants were examined (age 72 +/- 6 years). Aortic PWV interacted with age on p-tau (beta = 0.31, p = 0.04), t-tau, (beta = 2.67, p = 0.05), neurogranin (beta = 0.94, p = 0.04), and sTREM2 (beta = 20.4, p = 0.05). Among participants >73 years of age, higher aortic PWV related to higher p-tau (beta = 2.4, p = 0.03), t-tau (beta = 19.3, p = 0.05), neurogranin (beta = 8.4, p = 0.01), and YKL-40 concentrations (beta = 7,880, p = 0.005). Aortic PWV had modest interactions with diagnosis on neurogranin (beta = -10.76, p = 0.03) and hypertension status on YKL-40 (beta = 18,020, p < 0.001). Conclusions Among our oldest participants, >= 74 years of age, greater aortic stiffening is associated with in vivo biomarker evidence of neuroinflammation, tau phosphorylation, synaptic dysfunction, and neurodegeneration, but not amyloidosis. Central arterial stiffening may lead to cumulative cerebral microcirculatory damage and reduced blood flow delivery to tissue, resulting in neuroinflammation and neurodegeneration in more advanced age.
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6. |
- Moore, E. E., et al.
(författare)
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Cerebrospinal fluid biomarkers of neurodegeneration, synaptic dysfunction, and axonal injury relate to atrophy in structural brain regions specific to Alzheimer's disease
- 2020
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Ingår i: Alzheimer's and Dementia. - : Wiley. - 1552-5260 .- 1552-5279. ; 16:6, s. 883-895
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Tidskriftsartikel (refereegranskat)abstract
- 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. © 2020 the Alzheimer's Association
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7. |
- Moore, E. E., et al.
(författare)
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Mild Cognitive Impairment Staging Yields Genetic Susceptibility, Biomarker, and Neuroimaging Differences
- 2020
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- 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)-epsilon 4 status, CSF biomarkers of amyloid beta (A beta), 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 onAPOE-epsilon 4 status (early < middle = late;p-values < 0.03) and CSF A beta (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.
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8. |
- Kresge, Hailey A, et al.
(författare)
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Lower Left Ventricular Ejection Fraction Relates to Cerebrospinal Fluid Biomarker Evidence of Neurodegeneration in Older Adults.
- 2020
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Ingår i: Journal of Alzheimer's disease : JAD. - 1875-8908. ; 74:3, s. 965-974
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Tidskriftsartikel (refereegranskat)abstract
- Subclinical cardiac dysfunction is associated with decreased cerebral blood flow, placing the aging brain at risk for Alzheimer's disease (AD) pathology and neurodegeneration.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.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 cognitive (NC), mild cognitive impairment (MCI)).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).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.
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