Jack, Clifford R

Background and Purpose— Superficial siderosis (SS) is characterized by hemosiderin deposition in the superficial layers of the central nervous system and can be seen during postmortem examination or with iron-sensitive magnetic resonance imaging techniques. The distribution of SS may predict the probable underlying cause. This study aimed to report the prevalence and natural history of SS in a population-based study. Methods— Brain magnetic resonance imaging scans from the MCSA (Mayo Clinic Study of Aging), a population-based study of residents 50 to 89 years of age in Olmsted County, Minnesota, were reviewed. Participants with imaging consistent with SS were identified from 2011 through 2016. An inverse probability weighting approach was used to convert our observed frequencies to population prevalence of SS. Additional data abstracted included amyloid positron emission tomography, Apolipoprotein E genotype, coexisting cerebral microbleeds, and extent of SS. Results— A total of 1412 participants had eligible magnetic resonance imaging scans. Two participants had infratentorial SS, restricted to the posterior fossa. Thirteen participants had cortical SS involving the cerebral convexities (7 focal and 6 disseminated). Only 3 of the participants with cortical SS (23%) also had cerebral microbleeds. The population prevalence of SS was 0.21% (95% confidence interval, 0–0.45) in those 50 to 69 years old and 1.43% (confidence interval, 0.53–2.34) in those over 69 years old. Apolipoprotein E ε2 allele was more common in those with SS (57.1% versus 15.0%; P <0.001). Compared with participants without SS, those with SS were also more likely to have a positive amyloid positron emission tomographic scan (76.9% versus 29.8%; P <0.001). Conclusions— SS may be encountered in the general elderly population. The association with increased amyloid burden and Apolipoprotein E ε2 genotype supports cerebral amyloid angiopathy as the most common mechanism. Longitudinal follow-up is needed to evaluate the risk of subsequent hemorrhage in cases of incidentally discovered SS.

Background and Purpose— Cerebral microbleed (CMB) location (deep versus strictly lobar) may elucidate underlying pathology with deep CMBs being more associated with hypertensive vascular disease and lobar CMBs being more associated with cerebral amyloid angiopathy. The objective of this study was to determine whether neuroimaging signs of vascular disease and Alzheimer pathology are associated with different types of CMBs. Methods— Among 1677 nondemented ARIC (Atherosclerosis Risk in Communities) participants (mean age=76±5 years; 40% men; 26% black) with 3-Tesla MRI scans at the fifth examination (2011–2013), we fit multinomial logistic regression models to quantify relationships of brain volumes (Alzheimer disease signature regions, total gray matter, frontal gray matter, and white matter hyperintensity volumes), infarct frequencies (lacunar, nonlacunar, and total), and apolipoprotein E (number of ε4 alleles) with CMB location (none, deep/mixed, or strictly lobar CMBs). Models were weighted for the sample selection scheme and adjusted for age, sex, education, hypertension, ever smoking status, diabetes mellitus, race site membership, and estimated intracranial volume (brain volume models only). Results— Deep/mixed and strictly lobar CMBs had prevalences of 8% and 16%, respectively. Larger white matter hyperintensity burden, greater total infarct frequency, smaller frontal volumes (in women only), and smaller total gray matter volume were associated with greater risk of both deep and lobar CMBs relative to no CMBs. Greater white matter hyperintensity volume was also associated with greater risk of deep relative to lobar CMBs. Higher lacunar and nonlacunar infarct frequencies were associated with higher risk of deep CMBs, whereas smaller Alzheimer disease signature region volume and apolipoprotein E ε4 homozygosity were associated with greater risk of lobar CMBs. Conclusions— CMBs are a common vascular pathology in the elderly. Markers of hypertensive small-vessel disease may contribute to deep CMBs while cerebral amyloid angiopathy may drive development of lobar CMBs.

Objective To investigate the associations between age, vascular health, and Alzheimer disease (AD) imaging biomarkers in an elderly sample. Methods We identified 430 individuals along the cognitive continuum aged >60 years with amyloid positron emission tomography (PET), tau PET, and magnetic resonance imaging (MRI) scans from the population‐based Mayo Clinic Study of Aging. A subset of 329 individuals had fluorodeoxyglucose (FDG) PET. We ascertained presently existing cardiovascular and metabolic conditions (CMC) from health care records and used the summation of presence/absence of hypertension, hyperlipidemia, cardiac arrhythmias, coronary artery disease, congestive heart failure, diabetes mellitus, and stroke as a surrogate for vascular health. We used global amyloid from Pittsburgh compound B PET, entorhinal cortex tau uptake (ERC‐tau) from tau‐PET, and neurodegeneration in AD signature regions from MRI and FDG‐PET as surrogates for AD pathophysiology. We dichotomized participants into CMC = 0 (CMC − ) versus CMC > 0 (CMC + ) and tested for age‐adjusted group differences in AD biomarkers. Using structural equation models (SEMs), we assessed the impact of vascular health on AD biomarker cascade (amyloid leads to tau leads to neurodegeneration) after considering the direct and indirect age, sex, and apolipoprotein E effects. Results CMC + participants had significantly greater neurodegeneration than CMC − participants but did not differ by amyloid or ERC‐tau. The SEMs showed that (1) vascular health had a significant direct and indirect impact on neurodegeneration but not on amyloid; and (2) vascular health, specifically the presence of hyperlipidemia, had a significant direct impact on ERC‐tau. Interpretation Vascular health had quantifiably greater impact on neurodegeneration in AD regions than on amyloid deposition. Longitudinal studies are warranted to clarify the relationship between tau deposition and vascular health. Ann Neurol 2017;82:706–718

OBJECTIVE To examine the associations of prediabetes, diabetes, and diabetes severity (as assessed by HbA1c and diabetes duration) with brain volumes and vascular pathology on brain MRI and to assess whether the associations of diabetes with brain volumes are mediated by brain vascular pathology. RESEARCH DESIGN AND METHODS Cross-sectional study of 1,713 participants in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NCS) (mean age 75 years, 60% female, 27% black, 30% prediabetes, and 35% diabetes) who underwent 3T brain MRI scans in 2011–2013. Participants were categorized by diabetes-HbA1c status as without diabetes (&lt;5.7% [reference]), with prediabetes (5.7 to &lt;6.5%), and with diabetes ([defined as prior diagnosis or HbA1c ≥6.5%] &lt;7.0% vs. ≥7.0%), with further stratification by diabetes duration (&lt;10 vs. ≥10 years). RESULTS In adjusted analyses, compared with participants without diabetes and HbA1c &lt;5.7%, participants with prediabetes and those with diabetes and HbA1c &lt;7.0% did not have significantly different brain volumes or vascular pathology (all P &gt; 0.05), but those with diabetes and HbA1c ≥7.0% had smaller total brain volume (β −0.20 SDs, 95% CI −0.31, −0.09), smaller regional brain volumes (including frontal, temporal, occipital, and parietal lobes; deep gray matter; Alzheimer disease signature region; and hippocampus [all P &lt; 0.05]), and increased burden of white matter hyperintensities (WMH) (P = 0.016). Among participants with diabetes, those with HbA1c ≥7.0% had smaller total and regional brain volumes and an increased burden of WMH (all P &lt; 0.05) compared with those with HbA1c &lt;7.0%. Similarly, participants with longer duration of diabetes (≥10 years) had smaller brain volumes and higher burden of lacunes (all P &lt; 0.05) than those with a diabetes duration &lt;10 years. We found no evidence for mediation by WMH in associations of diabetes with smaller brain volumes by structural equation models (all P &gt; 0.05). CONCLUSIONS More-severe diabetes (defined by higher HbA1c and longer disease duration) but not prediabetes or less-severe diabetes was associated with smaller brain volumes and an increased burden of brain vascular pathology. No evidence was found that associations of diabetes with smaller brain volumes are mediated by brain vascular pathology, suggesting that other mechanisms may be responsible for these associations.

Abstract Introduction Identifying at what point atrophy rates first change in Alzheimer's disease is important for informing design of presymptomatic trials. Methods Serial T1‐weighted magnetic resonance imaging scans of 94 participants (28 noncarriers, 66 carriers) from the Dominantly Inherited Alzheimer Network were used to measure brain, ventricular, and hippocampal atrophy rates. For each structure, nonlinear mixed‐effects models estimated the change‐points when atrophy rates deviate from normal and the rates of change before and after this point. Results Atrophy increased after the change‐point, which occurred 1–1.5 years (assuming a single step change in atrophy rate) or 3–8 years (assuming gradual acceleration of atrophy) before expected symptom onset. At expected symptom onset, estimated atrophy rates were at least 3.6 times than those before the change‐point. Discussion Atrophy rates are pathologically increased up to seven years before “expected onset”. During this period, atrophy rates may be useful for inclusion and tracking of disease progression.

ABSTRACTBACKGROUND AND PURPOSEGlutamate levels may be informative about the declining neuronal health in the central nervous system. We used an advanced proton MR spectroscopy (1H‐MRS) protocol composed of semi‐localization by adiabatic selective refocusing (sLASER) localization and FAST(EST)MAP shimming for detection of alterations in brain glutamate concentrations in patients with amnestic mild cognitive impairment.METHODSParticipants with amnestic mild cognitive impairment (n= 14; median age = 80) and age‐ and sex‐matched clinically normal controls (n= 32; median age = 79) from the population‐based Mayo Clinic Study of Aging were recruited prospectively to the 3T single‐voxel1H‐MRS study that examined metabolite changes in the posterior cingulate gyri. To be included, controls had to have low β‐amyloid load on [11C] Pittsburgh Compound B (PiB)‐PET (standard uptake value ratio; SUVr < 1.42) and patients with amnestic mild cognitive impairment had to have high β‐amyloid load (SUVr ≥ 1.42).RESULTSGlutamate concentration and the glutamate/myo‐inositol ratio were lower in patients with amnestic mild cognitive impairment than clinically normal controls (P< .05). Higher global cortical PiB‐PET SUVr correlated with lower glutamate/myo‐inositol (r= –.3,P= .04).CONCLUSIONSThe advanced sLASER with FAST(EST)MAP shimming is a promising protocol for identifying glutamate alterations. Advanced1H‐MRS protocols may add to the understanding of early Alzheimer's disease pathophysiology through detection of glutamate concentration in posterior cingulate gyri of individuals with amnestic mild cognitive impairment.