Jack, Clifford R.

AbstractBackgroundIn animal models of Alzheimer’s disease (AD), aerobic exercise favorably modified the accumulation, degradation, and removal of Aβ and tau. However, human mechanistic randomized controlled trials (RCTs) are limited with mixed findings on hippocampal volume and biofluid Aβ and tau. Hence, an objective of the FIT‐AD Trial was to examine the effects of 6‐month aerobic exercise on magnetic resonance imaging (MRI) biomarkers in community‐dwelling older adults with AD dementia.MethodThe FIT‐AD Trial was a pilot RCT that first qualified participants for the main exercise study eligibility and then for MRI. Participants were randomized to moderate intensity cycling or low intensity stretching for 20‐50 minutes, 3 times a week for six months on a 2:1 ratio with three age strata (66‐75, 76‐85, and 85+ years of age) and followed up for another six months. MRI biomarkers included hippocampal volume, temporal meta‐regions of interest cortical thickness, white matter hyperintensity (WMH) volume, and network failure quotient (NFQ) measured at baseline, six months, and 12 months.ResultSixty participants met MRI eligibility, but one was excluded when this participant’s baseline MRI failed quality control. Among the 59 remaining participants, 38 were randomized to cycling and 21 to stretching. The sample characteristics (n=59) were 77.3±6.3 years old with 15.6±2.9 years of education and 53% men. Both groups experienced significant declines in hippocampal volume (2.64% in cycling vs. 2.89% in stretching) and cortical thickness (0.94% vs. 1.54%) over six months and over 12 months (hippocampal volume: 4.47% vs. 3.84%; cortical thickness: 2.27% vs. 1.79%). These declines didn’t differ between groups. WMH volume increased significantly, but the cycling group increased >50% less than stretching (10.9% vs. 24.5% over six months [f=4.47, p=.04]; 12.1% vs. 27.6% over 12 months [f=5.88, p=.02]). NFQ didn’t change significantly over time nor differed between group.ConclusionAerobic exercise may reduce hippocampal volume and cortical thickness declines during the intervention period; however, its effects are likely to be small and dose‐dependent and reverse after the intervention stops. Aerobic exercise is effective on reducing WMH progression but has no effect on NFQ.

AbstractBackgroundThe apolipoprotein ε4 (APOE4) allele is the most common and well established risk factor for typical late‐onset amnestic Alzheimer’s dementia. Less is known about the role of APOE in patients with atypical clinical presentations of AD, with studies often disagreeing on APOE4 frequencies in these cohorts. We aimed to assess relationships between APOE genotype and age, amyloid‐beta (Aβ) deposition and clinical phenotype in Alzheimer’s disease.Method138 atypical AD patients (57 posterior cortical atrophy and 81 logopenic aphasia) were recruited by the Neurodegenerative Research Group at Mayo Clinic, and underwent APOE testing and Pittsburgh Compound B PET. 318 typical AD patients with APOE genotype and known onset age were identified from ADNI (121 had Aβ‐PET). Aβ‐PET was quantified using the centiloid scale. Logistic regression was used to estimate the proportion of APOE4 carriers by onset age and clinical group. Linear regression was used to estimate mean Aβ centiloid by age, APOE4 status, and clinical group in patients who were Aβ‐positive (centiloid≥19).ResultThe overall frequency of APOE4 carriers was lower in atypical AD (52%) compared to typical AD (66%), particularly for ε4ε4 homozygotes (9% vs 20%). APOE4 frequency increased with age in atypical AD, but showed a bell‐shaped curve in typical AD where highest frequencies were observed between 65‐70 years (Figure). Typical AD showed higher APOE4 frequencies than atypical AD only between the ages of 57 and 69 years. Aβ centiloid was higher in atypical AD compared to typical AD by approximately 16 centiloid units, but did not differ according to APOE4 status (Figure). Aβ centiloid stayed relatively flat with increasing age for both carriers and non‐carriers in atypical AD, but declines with increasing age in typical AD. Relationships between APOE4 and age, as well as centiloid, did not differ between the two atypical AD phenotypes.ConclusionAPOE4 frequency differs between atypical and typical AD but is highly dependent upon age, with higher APOE4 frequency in typical AD only observed between 57 and 69 years. The findings highlight the importance of age and clinical phenotype in understanding the effects of APOE genotype in Alzheimer’s disease.

AbstractBackgroundProton MR Spectroscopy (1H MRS) provides non‐invasive measurements of alterations in brain biochemistry associated with neuronal and glial abnormalities in neurodegeneration. 1H MRS with along with automated voxel placement (AVP) improves the precision of 1H MRS metabolite measurements. Our objective was to investigate the association of 1H MRS metabolites obtained by the advanced sLASER single voxel 1H MRS protocol with early tau deposition as measured by AV‐1451 PET and Aβ deposition as measured by 11C‐Pittsburgh compound B (PiB) PET in cognitively unimpaired older adults.MethodCognitively unimpaired adults with median (range) age of 77 (66, 94) from the population‐based Mayo Clinic Study of Aging (MCSA) participated in the single‐voxel 1H MRS study (n=40). All participants had an MRI, 11C‐PiB and AV‐1451 PET examinations. The posterior cingulate cortex (PCC) and the left hippocampus (LHC) were chosen for the 1H MRS voxel locations because of their vulnerability to early AD pathology. Right hippocampus was not studied due to time constraints of the MR examination. 1H MRS was performed at 3T (Siemens) using an optimized sLASER protocol with AVP. Standardized uptake value ratios (SUVR) were calculated for global cortical and regional (PCC, LHC) PiB and AV‐1451. Associations between log transformed SUVRs and the concentration of MRS‐measured metabolites (µmol/g) were assessed using age‐adjusted Pearson correlations.ResultThe median (range) global PiB SUVR was 1.42 (1.20‐2.81) and AV‐1451 SUVR was 1.20 (0.94, 1.46). In the PCC, higher AV‐1451 SUVR was associated with lower N‐acetylaspartate (NAA) (r=‐0.375; p=0.019) and glutamate (r=‐0.354; p=0.027) concentrations. Higher global PIB SUVR was associated with higher myo‐inositol in the LHC (r=0.361; p=0.039).ConclusionLower levels of NAA, a marker of neuronal health, and the neurotransmitter glutamate are associated with local tau pathology in the PCC, suggesting early neuronal dysfunction in relation to tau accumulation. The association of hippocampal myo‐inositol, a putative glial marker, with the global cortical Aβ pathology suggests that myo‐inositol elevation may be an indicator of neuroinflammatory response to Aβ related pathology.

AbstractBackgroundIn longitudinal tau (flortaucipir) positron emission tomography (PET), a reliable method to detect a tau accumulation while minimizing a random variability is crucial. Variability can be a problem especially in the early stages of tau pathology in which only small regions and low levels of accumulation may exist relative to the range of random noise fluctuation.MethodWe recruited 76 participants who had serial scans for a total of 234 tau PET scans. In this cohort we tested a PET signal measurement method we developed called the “overlap index” (OI). The OI was calculated by identifying voxels that have elevated tau PET signal that overlap on two successive tau PET scans in the same participant (Figure 1). This analysis procedure tests the hypothesis that voxel‐wise, elevated‐uptake consistency might be more sensitive for early detection of tau tangles than standard ROI based measures. We compared OI to ROI based measures for early detection of increasing tau PET signal and detection clinical progression. A meta ROI used in this analysis included the amygdala, entorhinal cortex, fusiform, parahippocampal, and inferior temporal and middle temporal gyri.ResultOI showed regional progression of tau in the temporal lobe followed by increases throughout the brain at relatively low standardized uptake value ratio (SUVr) levels (Figure 2A and B). The topographical pattern of OI was in agreement in some respects with the sequential appearance of tau aggregation (Figure 2B and C). The high‐OI group (OI>0.5) had a significantly higher ΔSUVr compared to the low‐OI group (OI<0.5) (Figure 3A and B). OI identified subjects that did or didn’t have tau accumulation within meta SUVr subgroups even when below the meta ROI SUVr threshold. OI was associated with early clinical disease stage progression vs meta‐ROI SUVr measures (Figure 3C‐E).ConclusionIn this study, we found that OI tau PET measurement was able to quantify voxel‐wise consistency using a set of serial scans. OI may detect earlier tau tangle accumulation and earlier disease progression than standard SUVr measurements in tau PET.

AbstractBackgroundElevated systolic blood pressure (SBP) and diastolic blood pressure (DBP) are risk factors for white matter (WM) injury associated with cognitive decline and dementia. White matter hyperintensities (WMH) on MRI, markers of WM injury, increase with aging and are more common in women than in men after the age of 60. We examined SBP and DBP in relation to WMH volume and diffusion MRI measures of WM integrity in postmenopausal women.MethodWomen (n=144) with median age of 67 (range 58‐72) and of good cardiovascular health who were previously enrolled in the multi‐site randomized clinical trial, Kronos Early Estrogen Prevention Study (KEEPS), participated in the present observational KEEPS Continuation Study. SBP, DBP, and MRI data were collected approximately 9 years after the end of KEEPS menopausal hormones versus placebo 4‐year interventions. WM integrity was assessed with WMH volume measurements (log transformed) on structural MRI and with measures of WM microstructure on diffusion MRI. Multiple linear regression analyses, adjusted for age, were used to test for associations of SBP and DBP with MRI measures.ResultThe median SBP was 128 (range 86‐180) and DBP was 77 (range 47‐106). Higher SBP (r=0.332;p=0.015) and DBP (r=0.346;p=0.007) were associated with higher WMH volumes. Among the WM tracts, higher SBP was associated with lower fractional anisotropy (FA) in lateral orbitofrontal gyrus WM (r=0.198;p=0.039) and sagittal stratum (r=0.226;p=0.043), and higher DBP was associated with lower FA in the superior occipital gyrus WM (r=0.370;p=0.045). Higher SBP and DBP were associated with higher mean diffusivity (MD) in the external capsule [(r=0.311;p=0.007);(r=375;p<0.001)] and the fronto‐occipital fasciculus [(r=0.286;p=0.016); (r=0.303;p=0.008)]. Furthermore, higher DBP was associated with higher MD in the anterior corona radiata (r=0.233;p=0.039), internal capsule (r=0.303;p=0.042), and the middle (r=0.275; p=0.03) and superior frontal gyrus (r=0.269;p=0.03) WM.ConclusionElevated SBP and DBP measurements are associated with greater WM injury in postmenopausal women. In particular, the frontal lobe WM and its connecting tracts may be more vulnerable to elevation in SBP and DBP. Whether BP control reduces the risk for WM injury, a risk factor for dementia, in post‐menopausal women warrants study.

AbstractBackgroundWhite matter microstructure undergoes progressive changes during the life‐span but the neurobiological underpinnings related to aging and disease remains unclear. We used an advanced diffusion MRI, Neurite Orientation Dispersion and Density Imaging (NODDI), to investigate the microstructural alterations due to demographics, common age‐related pathological processes (amyloid, tau, and white matter hyperintensities (WMH)), and cognition. We also compared NODDI findings to the older Diffusion Tensor Imaging (DTI) model based findings.Method328 participants (264 cognitively unimpaired, 57 mild cognitive impairment (MCI), and 7 dementia with a mean age of 68.3 ±13.1 years) from the Mayo Clinic Study of Aging with multi‐shell diffusion imaging, FLAIR‐MRI as well as amyloid and tau PET scans were included in this study. White matter (WM) tract level diffusion measures (Figure 1) were calculated from DTI and NODDI. Pearson correlation and multiple linear regression analyses were performed with diffusion measures as the outcome and age, sex, education/occupation, WMH, amyloid, and tau as predictors. Analyses were also performed with each dMRI measure as a predictor of cognitive outcomes.ResultAge and WMH were the strongest predictors of all WM diffusion measures with low associations with amyloid and tau (Figure 1). However, neurite density decrease from NODDI was observed with amyloidosis specifically in the temporal lobes (Figure 2). WM integrity (mean diffusivity and free water) in the corpus callosum showed the greatest associations with cognitive measures (Table 1). All diffusion measures provided information about WM aging and WM disease processes and were associated with cognition.ConclusionNODDI and DTI are two different biophysical models that provide distinct information about variation in WM microstructural integrity. NODDI provides additional information about synaptic density, organization, and free water content which may aid in providing mechanistic insights into disease progression.

AbstractBackgroundAlzheimer’s disease biomarkers of tau pathology may be assessed by both CSF and PET. Cross‐sectional associations between CSF phosphorylated tau (p‐tau) and tau PET have been studied and regional tau PET SUVR has been shown to have similar diagnostic performance as CSF p‐tau. The association between CSF p‐tau and longitudinal tau PET has not been studied. CSF measures may be thought of as a result of the imbalance of influx vs efflux of soluble tau, whereas, tau PET reflects total tau accumulation into insoluble aggregates to date. We therefore hypothesize that baseline CSF p‐tau may be a leading indicator of future tau PET accumulation.MethodWe identified Mayo Clinic Study of Aging (MCSA) and Mayo Alzheimer’s Disease Research Center (ADRC) participants with diagnoses of cognitively unimpaired, mild cognitive impairment, and amnestic dementia who had CSF p‐tau (Elecsys p‐tau [181P]) and subsequent serial tau PET (flortaucipir) exams. The first tau PET scan was within 3 years of the CSF p‐tau collection. A longitudinal pipeline with two‐compartment partial volume correction was used to measure change in tau PET in a temporal‐lobe meta‐ROI (amygdala, fusiform, middle/inferior temporal, entorhinal, and parahippocampal regions) with a composite reference region (eroded supratentorial white matter, pons, and whole cerebellum). Spearman correlation was used to assess the association between CSF p‐tau and annual percent change in tau PET. A linear mixed effects model was fit to assess the association adjusting for age and sex.ResultThe study included 143 participants (76% cognitively unimpaired) (). CSF p‐tau was significantly associated with annual percent change in tau PET overall (Spearman R=0.19, p=0.023) () and after adjusting for age and sex (p<0.001) (). There was nonlinearity in the CSF p‐tau effect, with higher values (>20 pg/mL) having a greater association with annual change in tau PET than lower values.ConclusionIn a group of cognitively unimpaired and impaired participants, CSF p‐tau predicted subsequent tau PET accumulation rate. A threshold effect is suggested with subsequent tau PET accumulation primarily in participants with elevated CSF p‐tau levels near the Mayo threshold of 22 pg/mL.

AbstractBackgroundWhite matter (WM) 11C‐Pittsburgh compound‐B (PiB) and 18F‐Flutemetamol (FMT) uptake is increasingly being used as a reference region to calculate the standard uptake value ratios (SUVr) in longitudinal amyloid‐β PET studies. PiB uptake is lower in WM hyperintensities (WMH) in older adults. Furthermore, WM PiB uptake increases with aging. Our objective was to determine whether a similar variation in WM uptake exists with an 18F‐ligand FMT.MethodA cohort of cognitively unimpaired (CU) older adults with median (range) age of 67 (61, 83) years (N=31), and younger adults with median (range) age of 38 (30, 48) years (N=30) from the community responding to a study advertisement underwent MRI, PiB and FMT PET. MRI‐FLAIR images were segmented into WMH and normal appearing white matter (NAWM) and registered to the T1‐weighted image. PiB and FMT PET images were registered to the T1‐weighted image. PiB and FMT SUVrs from the WMH and NAWM compartments were calculated using cerebellar crus uptake as a reference.ResultWMH PiB SUVr and NAWM PiB SUVr were lower in the younger compared to the older adults (p<0.001). WMH FMT SUVr and NAWM FMT SUVr were lower in younger compared to older adults (p<0.001). PiB SUVr was lower than FMT SUVr both in younger and older adults in both WMH and NAWM compartments (p<0.001). In both age groups, PiB SUVr and FMT SUVr in WMH was lower than NAWM (p<0.001). AUROC analysis demonstrated no difference between PiB versus FMT SUVr in differentiating WMH from NAWM in younger and older adults.ConclusionWMH and NAWM SUVRs are higher with FMT than PiB, however both PiB and FMT show a similar topographic pattern of uptake in the WM with higher uptake in NAWM compared to WMH. Aging is associated with a decrease in myelin integrity and increase of WMH volume. Higher WMH and NAWM PiB and FMT uptake in the older compared to younger adults suggests that additional aging‐related mechanisms are influencing WM PET tracer uptake. Age and WMH volume should be considered when WM uptake is used as a reference region for the evaluation of cortical uptake of both PiB and FMT.

Abstract Dementia and mortality rates rise inexorably with age and consequently interact. However, because of the major logistical difficulties in accounting for both outcomes in a defined population, very little work has examined how risk factors and biomarkers for incident dementia are influenced by competing mortality. The objective of this study was to examine long-term associations between amyloid PET, APOE ɛ4, sex, education and cardiovascular/metabolic conditions, and hazard and absolute risk of dementia and mortality in individuals without dementia at enrolment. Participants were enrolled in the Mayo Clinic Study of Aging, a population-based study of cognitive ageing in Olmsted County, MN, USA. All were without dementia and were age 55–92 years at enrolment and were followed longitudinally. Predictor variables were amyloid PET, APOE ɛ4 status, sex, education, cardiovascular/metabolic conditions and age. The main outcomes were incident dementia and mortality. Multivariable, multi-state models were used to estimate mortality and incident dementia rates and absolute risk of dementia and mortality by predictor variable group. Of the 4984 participants in the study, 4336 (87%) were cognitively unimpaired and 648 (13%) had mild cognitive impairment at enrolment. The median age at enrolment was 75 years; 2463 (49%) were women. The median follow-up time was 9.4 years (7.5 years after PET). High versus normal amyloid (hazard ratio 2.11, 95% confidence interval 1.43–2.79), APOE ɛ4 (women: hazard ratio 2.24, 95% confidence interval 1.80–2.77; men: hazard ratio 1.37, 95% confidence interval 1.09–1.71), older age and two additional cardiovascular/metabolic conditions (hazard ratio 1.37, 95% confidence interval 1.22–1.53) were associated with the increased hazard of dementia (all P &lt; 0.001). Among APOE ɛ4 carriers with elevated amyloid, remaining lifetime risk of dementia at age 65 years was greater in women [74% (95% confidence interval 65–84%) high and 58% (95% confidence interval 52–65%) moderate amyloid], than men [62% (95% confidence interval 52–73%) high and 44% (95% confidence interval 35–53%) moderate amyloid]. Overall, the hazard and absolute risk of dementia varied considerably by predictor group. The absolute risk of dementia associated with predictors characteristic of Alzheimer’s disease was greater in women than men while at the same time the combination of APOE ɛ4 non-carrier with normal amyloid was more protective in women than men. This set of findings may be attributed in part to different biological effects and in part to lower mortality rates in women.