Blood pressure (BP) plays an important role in white matter integrity. We sought to determine the role of intra-individual BP changes on white matter and evaluate the impact on gait speed and ...imbalance by sex. We identified 990 eligible participants in the population-based Mayo Clinic Study of Aging and analyzed fractional anisotropy (FA) in white matter regions. Using structural equation models (SEM), we assessed the effect of BP slope on corticospinal tract (CST) FA and downstream effects on gait speed and imbalance after age and sex effects. Of 990 participants, 438 (44%) were female with mean age of 76 years. In linear models predicting CST FA, a greater change in BP slope (0.0004; p = 0.026) and female sex (0.017; p < 0.001) were significant predictors of lower CST FA. SEMs showed that older age, female sex, and higher BP slope predicted lower CST FA, and lower CST FA predicted worse downstream motor control. Therefore, intra-individual BP slope and variability impact corticospinal tract microstructural properties of white matter with females having increased susceptibility to damage.
PET imaging with β-amyloid ligands is emerging as a molecular imaging technique targeting white matter integrity and demyelination. β-amyloid PET ligands such as
C-Pittsburgh compound B (
C-PiB) have ...been considered for quantitative measurement of myelin content changes in multiple sclerosis, but
C-PiB is not commercially available given its short half-life. A
F PET ligand such as flutemetamol with a longer half-life may be an alternative, but its ability to differentiate white matter hyperintensities (WMH) from normal-appearing white matter (NAWM) and its relationship with age remains to be investigated.
Cognitively unimpaired (CU) older and younger adults (
= 61) were recruited from the community responding to a study advertisement for β-amyloid PET. Participants prospectively underwent MRI,
C-PiB, and
F-flutemetamol PET scans. MRI fluid-attenuated inversion recovery images were segmented into WMH and NAWM and registered to the T1-weighted MRI.
C-PiB and
F-flutemetamol PET images were also registered to the T1-weighted MRI.
C-PiB and
F-flutemetamol SUV ratios (SUVrs) from the WMH and NAWM were calculated using cerebellar crus uptake as a reference for both
C-PiB and
F-flutemetamol.
The median age was 38 y (range, 30-48 y) in younger adults and 67 y (range, 61-83 y) in older adults. WMH and NAWM SUVrs were higher with
F-flutemetamol than with
C-PiB in both older (
< 0.001) and younger (
< 0.001) CU adults.
C-PiB and
F-flutemetamol SUVrs were higher in older than in younger CU adults in both WMH (
< 0.001) and NAWM (
< 0.001).
C-PiB and
F-flutemetamol SUVrs were higher in NAWM than WMH in both older (
< 0.001) and younger (
< 0.001) CU adults. There was no apparent difference between
C-PiB and
F-flutemetamol SUVrs in differentiating WMH from NAWM in older and in younger adults.
C-PiB and
F-flutemetamol show a similar topographic pattern of uptake in white matter with a similar association with age in WMH and NAWM.
C-PiB and
F-flutemetamol can also effectively distinguish between WMH and NAWM. However, given its longer half-life, commercial availability, and higher binding potential,
F-flutemetamol can be an alternative to
C-PiB in molecular imaging studies specifically targeting multiple sclerosis to evaluate white matter integrity.
Brain reserve can be defined as the individual variation in the brain structural characteristics that later in life are likely to modulate cognitive performance. Late midlife represents a point in ...aging where some structural brain imaging changes have become manifest but the effects of cognitive aging are minimal, and thus may represent an ideal opportunity to determine the relationship between risk factors and brain imaging biomarkers of reserve.
We aimed to assess neuroimaging measures from multiple modalities to broaden our understanding of brain reserve, and the late midlife risk factors that may make the brain vulnerable to age related cognitive disorders.
We examined multimodal structural and diffusion Magnetic Resonance Imaging (MRI), FDG PET neuroimaging measures in 50-65 year olds to examine the associations between risk factors (Intellectual/Physical Activity: education-occupation composite, physical, and cognitive-based activity engagement; General Health Factors: presence of cardiovascular and metabolic conditions (CMC), body mass index, hemoglobin A1c, smoking status (ever/never), CAGE Alcohol Questionnaire (>2, yes/no), Beck Depression Inventory score), brain reserve measures Dynamic: genu corpus callosum fractional anisotropy (FA), posterior cingulate cortex FDG uptake, superior parietal cortex thickness, AD signature cortical thickness; Static: intracranial volume, and cognition (global, memory, attention, language, visuospatial) from a population-based sample. We quantified dynamic proxies of brain reserve (cortical thickness, glucose metabolism, microstructural integrity) and investigated various protective/risk factors.
Education-occupation was associated with cognition and total intracranial volume (static measure of brain reserve), but was not associated with any of the dynamic neuroimaging biomarkers. In contrast, many general health factors were associated with the dynamic neuroimaging proxies of brain reserve, while most were not associated with cognition in this late middle aged group.
Brain reserve, as exemplified by the four dynamic neuroimaging features studied here, is itself at least partly influenced by general health status in midlife, but may be largely independent of education and occupation.
β-Amyloid (Aβ) plaques can co-occur with Lewy-related pathology in patients with dementia with Lewy bodies (DLB), but Aβ load at prodromal stages of DLB still needs to be elucidated. We investigated ...Aβ load on PET throughout the DLB continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD) to a stage of mild cognitive impairment with Lewy bodies (MCI-LB), and finally DLB.
We performed a cross-sectional study in patients with a diagnosis of iRBD, MCI-LB, or DLB from the Mayo Clinic Alzheimer Disease Research Center. Aβ levels were measured by Pittsburgh compound B (PiB) PET, and global cortical standardized uptake value ratio (SUVR) was calculated. Global cortical PiB SUVR values from each clinical group were compared with each other and with those of cognitively unimpaired (CU) individuals (n = 100) balanced on age and sex using analysis of covariance. We used multiple linear regression testing for interaction to study the influences of sex and
ε4 status on PiB SUVR along the DLB continuum.
Of the 162 patients, 16 had iRBD, 64 had MCI-LB, and 82 had DLB. Compared with CU individuals, global cortical PiB SUVR was higher in those with DLB (
< 0.001) and MCI-LB (
= 0.012). The DLB group included the highest proportion of Aβ-positive patients (60%), followed by MCI-LB (41%), iRBD (25%), and finally CU (19%). Global cortical PiB SUVR was higher in
ε4 carriers compared with that in
ε4 noncarriers in MCI-LB (
< 0.001) and DLB groups (
= 0.049). Women had higher PiB SUVR with older age compared with men across the DLB continuum (β estimate = 0.014,
= 0.02).
In this cross-sectional study, levels of Aβ load was higher further along the DLB continuum. Whereas Aβ levels were comparable with those in CU individuals in iRBD, a significant elevation in Aβ levels was observed in the predementia stage of MCI-LB and in DLB. Specifically,
ε4 carriers had higher Aβ levels than
ε4 noncarriers, and women tended to have higher Aβ levels than men as they got older. These findings have important implications in targeting patients within the DLB continuum for clinical trials of disease-modifying therapies.
Hypertension is associated with development of white matter hyperintensities (WMH) in the brain, which are risk factors for mild cognitive impairment. Hormonal shifts at menopause alter vascular ...function putting women at risk for both hypertension and WMH. Elevations in aortic hemodynamics precede the appearance of clinically defined hypertension but the relationship of aortic hemodynamics to development of WMH in women is not known. Therefore, this study aimed to characterize aortic hemodynamics in relationship to WMH in postmenopausal women. Aortic systolic and diastolic blood pressure (BP), aortic augmentation index (Alx) and aortic round trip travel time (Aortic
T
R
) by tonometry were examined in 53 postmenopausal women (age 60 ± 2 years). WMH was calculated from fluid-attenuated inversion recovery MRI using a semi-automated segmentation algorithm. WMH as a fraction of total white matter volume positively associated with aortic systolic BP (regression coefficient = 0.018;
p
= 0.04) after adjusting for age. In addition, WMH fraction was positively associated with AIx (0.025;
p
= 0.04), and inversely associated with Aortic
T
R
(−0.015;
p
= 0.04) after adjusting for age. Our results suggest that assessing aortic hemodynamics may identify individuals at risk for accelerated development of WMH and guide early treatment to reduce WMH burden and cognitive impairment in the future.
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•AD and CVD often co-exists and are leading causes of age-related cognitive decline.•We used SEM modeling to study the effects of vascular and AD pathways on cognition.•Higher SES had ...a protective effect on cognition with some mediation through the vascular pathway.•There is a significant effect of vascular risk on tau deposition.•CVD and AD biomarkers capture the relative effects of these pathways on cognition.
AD and CVD, which frequently co-occur, are leading causes of age-related cognitive decline. We assessed how demographic factors, socioeconomic status (SES) as indicated by education and occupation, vascular risk factors, and a range of biomarkers associated with both CVD (including white matter hyperintensities WMH, diffusion MRI abnormalities, infarctions, and microbleeds) and AD (comprising amyloid-PET and tau-PET) collectively influence cognitive function.
In this cross-sectional population study, structural equation models were utilized to understand these associations in 449 participants (mean age (SD) = 74.5 (8.4) years; 56% male; 7.5% cognitively impaired).
(1) Higher SES had a protective effect on cognition with mediation through the vascular pathway. (2) The effect of amyloid directly on cognition and through tau was 11-fold larger than the indirect effect of amyloid on cognition through WMH. (3) There is a significant effect of vascular risk on tau deposition.
The utilized biomarkers captured the impact of CVD and AD on cognition. The overall effect of vascular risk and SES on these biomarkers are complex and need further investigation.
To determine the contribution of cerebral amyloid angiopathy (CAA) to Pittsburgh compound B (PiB)-PET tracer retention.
Participants from the Mayo Clinic Study of Aging and Mayo Clinic Alzheimer's ...Disease Research Center with antemortem PiB-PET imaging for β-amyloid (Aβ) who later underwent autopsy were included in this study. Pathologic regional leptomeningeal, parenchymal, capillary CAA, and Aβ plaque burden were calculated from one hemisphere. Regional lobar amyloid standardized uptake value ratio (SUVR) on PET was calculated from the same hemisphere sampled at autopsy. Single- and multiple-predictor linear regression models were used to evaluate the relative contributions of pathologically determined regional CAA and Aβ plaques to antemortem PiB-PET SUVR.
Forty-one participants (30 male, 11 female) with a mean (SD) age at death of 75.7 (10.6) years were included. Twenty-seven (66%) had high PiB signal with a mean (SD) of 2.3 (1.2) years from time of PET scan to death; 24 (59%) had a pathologic diagnosis of Alzheimer disease. On multivariate analysis, CAA was not associated with PiB-PET SUVR, while plaques remained associated with PiB-PET SUVR in all regions (all
< 0.05). In patients without frequent amyloid plaques, CAA was not associated with PiB-PET in any region.
We did not find evidence that pathologically confirmed regional CAA burden contributes significantly to proximal antemortem regional PiB-PET signal, suggesting that amyloid PET imaging for measurement of cortical amyloid burden is unconfounded by CAA on a lobar level. Whether CAA burden contributes to PiB-PET signal in patients with severe CAA phenotypes, such as lobar hemorrhage, requires further investigation.
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