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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 (<5.7% [reference]), with prediabetes (5.7 to <6.5%), and with diabetes ([defined as prior diagnosis or HbA1c ≥6.5%] <7.0% vs. ≥7.0%), with further stratification by diabetes duration (<10 vs. ≥10 years). RESULTS In adjusted analyses, compared with participants without diabetes and HbA1c <5.7%, participants with prediabetes and those with diabetes and HbA1c <7.0% did not have significantly different brain volumes or vascular pathology (all P > 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 < 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 < 0.05) compared with those with HbA1c <7.0%. Similarly, participants with longer duration of diabetes (≥10 years) had smaller brain volumes and higher burden of lacunes (all P < 0.05) than those with a diabetes duration <10 years. We found no evidence for mediation by WMH in associations of diabetes with smaller brain volumes by structural equation models (all P > 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.

Altered cortical thickness has been observed in aging and various neurodegenerative disorders. Furthermore, reduced hippocampal volume has been reported in late-life depression. Even mild depressive symptoms are common in the elderly. However, little is known about the structural MRI measures of depressive symptoms in normal cognitive aging. Thus we sought to examine the association between depressive symptoms with cortical thickness and hippocampal volume as measured by brain MRI among community-dwelling participants. We conducted a cross-sectional study derived from the ongoing population-based Mayo Clinic Study of Aging, involving cognitively normal participants ( N = 1,507) aged≥70 years. We observed that depressive symptoms were associated with lower global cortical thickness and lower thickness in specific prefrontal and temporal cortical regions, labeled by FreeSurfer software, version 5.3. As expected, the strength of correlation was very small, given that participants were community-dwelling with only mild depressive symptoms. We did not observe associations between hippocampal volume and depressive symptoms. These findings may provide insight into the structural correlates of mild depressive symptoms in elderly participants.

Objective There is a need for inexpensive noninvasive tests to identify older healthy persons at risk for Alzheimer disease (AD) for enrollment in AD prevention trials. Our objective was to examine whether abnormalities in neuroimaging measures of amyloid and neurodegeneration are correlated with odor identification (OI) in the population‐based Mayo Clinic Study of Aging. Methods Cognitively normal (CN) participants had olfactory function assessed using the Brief Smell Identification Test (B‐SIT), underwent magnetic resonance imaging (n = 829) to assess a composite AD signature cortical thickness and hippocampal volume (HVa), and underwent 11 C‐Pittsburgh compound B (n = 306) and 18 fluorodeoxyglucose (n = 305) positron emission tomography scanning to assess amyloid accumulation and brain hypometabolism, respectively. The association of neuroimaging biomarkers with OI was examined using multinomial logistic regression and simple linear regression models adjusted for potential confounders. Results Among 829 CN participants (mean age = 79.2 years; 51.5% men), 248 (29.9%) were normosmic and 78 (9.4%) had anosmia (B‐SIT score < 6). Abnormal AD signature cortical thickness and reduced HVa were associated with decreased OI as a continuous measure (slope = −0.43, 95% confidence interval [CI] = −0.76 to −0.09, p = 0.01 and slope = −0.72, 95% CI = −1.15 to −0.28, p < 0.01, respectively). Reduced HVa, decreased AD signature cortical thickness, and increased amyloid accumulation were significantly associated with increased odds of anosmia. Interpretation Our findings suggest that OI may be a noninvasive, inexpensive marker for risk stratification, for identifying participants at the preclinical stage of AD who may be at risk for cognitive impairment and eligible for inclusion in AD prevention clinical trials. These cross‐sectional findings remain to be validated prospectively. Ann Neurol 2017;81:871–882

Background Diffusion tensor imaging measures of white matter ( WM ) microstructural integrity appear to provide earlier indication of WM injury than WM hyperintensities; however, risk factors for poor WM microstructural integrity have not been established. Our study quantifies the association between vascular risk factors in midlife and late life with measures of late‐life WM microstructural integrity. Methods and Results We used data from 1851 participants in ARIC (Atherosclerosis Risk in Communities Study) who completed 3‐T magnetic resonance imaging, including diffusion tensor imaging, as part of the ARIC Neurocognitive Study (ARIC‐NCS). We quantified the association among lipids, glucose, and blood pressure from the baseline ARIC visit (1987–1989, ages 44–65, midlife) and visit 5 of ARIC (2011–2013, ages 67–90, late life, concurrent with ARIC‐NCS) with regional and overall WM mean diffusivity and fractional anisotropy obtained at ARIC visit 5 for ARIC participants. We also considered whether these associations were independent of or modified by WM hyperintensity volumes. We found that elevated blood pressure in midlife and late life and elevated glucose in midlife, but not late life, were associated with worse late‐life WM microstructural integrity. These associations were independent of the degree of WM hyperintensity, and the association between glucose and WM microstructural integrity appeared stronger for those with the least WM hyperintensity. There was little support for an adverse association between lipids and WM microstructural integrity. Conclusions Hypertension in both midlife and late life and elevated glucose in midlife are related to worse WM microstructural integrity in late life.

Abstract Introduction Multiple intravenous doses of ponezumab, an anti‐amyloid antibody, were evaluated in subjects with mild‐to‐moderate Alzheimer's disease (AD). Methods In part A, 77 subjects were randomized to ponezumab 0.1, 0.5, or 1 mg/kg (75 treated) and 26 to placebo (24 treated). In part B, 63 subjects were randomized and treated with ponezumab 3 or 8.5 mg/kg and 32 with placebo. Subjects received 10 infusions over 18 months and were followed for 6 months thereafter. Results Ponezumab was generally safe and well tolerated. Most common adverse events were fall (16.7% ponezumab, 21.4% placebo), headache (13.8%, 21.4%), and cerebral microhemorrhage (13.8%, 19.6%). Plasma ponezumab increased dose‐dependently with limited accumulation. Cerebrospinal fluid penetration was low. Plasma Aβ 1–x and Aβ 1–40 showed robust increases, but cerebrospinal fluid biomarkers showed no dose response. Ponezumab had no effects on cognitive/functional outcomes or brain volume. Conclusions Multiple‐dose ponezumab was generally safe, but not efficacious, in mild‐to‐moderate AD.