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Middle aged individuals with Metabolic Syndrome are at high risk for cognitive decline. Dyssynchrony in the resting state Default Mode Network is one early indicator of brain vulnerability. We set out to explore the relationship between default mode resting state functional connectivity and cognitive performance in both memory and executive domains at midlife in the presence of Metabolic Syndrome components. Seed-based Correlation Analyses were performed between the seed voxel in the posterior cingulate cortex and the medial prefrontal cortex on 200 participants (ages 40–61). Executive domain scores were significantly predicted by the interaction between number of Metabolic Syndrome components and resting state connectivity in the Default Mode Network (p = .004) such that connectivity was negatively related to executive function at higher numbers of Metabolic Syndrome components. Results were not significant for memory. Our findings indicate that clusters of cardiovascular disease risk factors alter functional relationships in the brain and highlights the need to continue exploring how compensatory techniques might operate to support cognitive performance at midlife.

While it is generally appreciated that amyloid precedes symptomatic Alzheimer's disease (AD) by decades, a greater understanding of this timeline may increase prognostic accuracy, planning, and care of persons who are on the AD continuum.We examined trajectories of Clinical Dementia Rating-Sum of Boxes (CDR-SB) relative to estimated years of amyloid positivity (A+) inThe average amyloid chronicity at CDR-SB of 2.5 was 20.1 years. The average trajectory of CDR-SB accelerated after 10 years of elevated amyloid and varied greatly between 10 and 30 years. Exploratory analyses suggested that older age and higher volume of white matter hyperintensities shortened the interval between amyloid onset and cognitive impairment.The recontextualization of amyloid burden into the time domain will facilitate studies of disease progression, the influence of co-pathology, and factors that hasten or slow cognitive impairment.

Sex differences in cerebral white matter (WM) aging have been debated extensively over the past two decades without unequivocal resolution. We aimed to determine if the effects of age and arterial stiffness on white matter (WM) microstructure differ between sexes. Artery elasticity via carotid artery compliance (CAC) and WM diffusion metrics via diffusion tensor image derived fractional anisotropy (FA) and mean diffusivity (MD) were measured in 155 (87 females) middle-aged (40–62 years) adults. Males demonstrated poorer water diffusion metrics in WM than women in the corpus callosum body, cingulum, and cingulum (hippocampal). Age and CAC had greater effects on WM water diffusion in males than females in midlife independent of education and cardiovascular risk factors. Sex moderated age (cingulum FA, cingulum (hippocampal) MD, and uncinate MD, all p

Intact memory and problem solving are key to functional independence and quality of life in older age. Considering the unprecedented demographic shift toward a greater number of older adults than children in the United States in the next few decades, it is critically important for older adults to maintain work productivity and functional independence for as long as possible. Implementing early interventions focused on modifiable risk factors for cognitive decline at midlife is a strategy with the highest chance of success at present, bearing in mind the current lack of dementia cures. We present a selective, narrative review of evidence linking nutrition, body composition, vascular health, and brain function in midlife to highlight the phenotypic heterogeneity of obesity-related brain vulnerability and to endorse the development of individually tailored lifestyle modification plans for primary prevention of cognitive decline.

Summary Objective Growing prevalence of neuropathology and cognitive impairment are emerging consequences of the obesity epidemic. Adiposity indices used in examining the relationships between obesity, neuropathology, and cognition vary substantially in the literature leading to incongruent findings. Our aim was to determine the anthropometric measures most strongly associated with early white matter disease and cognitive function at midlife. Method Multiple adiposity indices were measured in 126 adults aged 40–62 who also completed a magnetic resonance imaging (MRI) scan to quantify white matter disease and a cognitive test battery. Anthropometric indices of obesity were compared to image-based estimates of visceral adipose tissue with dual-energy X-ray absorptiometry (DEXA) as predictors of current white matter disease and cognitive function. We also explored sex as a potential moderator of these relationships. Results Waist circumference (WC) was most strongly correlated with DEXA estimates of visceral adipose tissue ( r =0.871, p β =0.231, p =0.034), percent body fat ( β =0.230, p =0.045), and VAT ( β =0.247, p =0.027) significantly predicted subclinical white matter hyperintensities in the absence of cognitive impairment after accounting for age, sex, years of education, and cardiovascular risk factors. Sex was not a significant moderator of any of the observed relationships. Conclusions Of the anthropometric indices used in this study, WC, BF, and VAT successfully predicted subclinical white matter disease in cognitively normal adults at midlife. Increasing VAT may independently insidiously affect cerebral white matter prior to detectable cognitive changes, necessitating early intervention.

BACKGROUND: Metabolic syndrome (MetS) adversely affects the vasculature and cerebral white matter (CWM) integrity. Arterial stiffening has been associated with diminished CWM integrity. Physical activity (PA) can ameliorate components of MetS and subsequently affect arterial stiffening and CWM integrity. Our aim was to determine the role of PA on mitigating the adverse influence of MetS on arterial stiffness and CWM integrity. METHODS: In a cross-sectional study design, sixty-six middle-aged adults (40–62 years) composed of 18 sedentary MetS (Sed MetS), 21 physically active MetS (Active MetS), and 27 healthy individuals absent of MetS risk factors were studied. Carotid artery stiffness was assessed via simultaneous ultrasound and tonometry. CWM integrity was measured using diffusion tensor imaging (DTI) through metrics of fractional anisotropy (FA) and mean diffusivity (MD). RESULTS: Carotid β-stiffness index in Active MetS was lower than Sed MetS but was not different from Healthy controls (6.6±1.5, 7.7±2.1, and 5.6±1.6 au, p=0.001). CWM integrity was significantly greater in Active MetS subjects compared to Sed MetS subjects but statistically equal to Healthy controls in the anterior limb of the internal capsule, and splenium of the corpus callosum, uncinate fasciculus, and superior corona radiata (all p

The Brain and Body Donation Program (BBDP) at Banner Sun Health Research Institute (http://www.brainandbodydonationprogram.org) started in 1987 with brain-only donations and currently has banked more than 1600 brains. More than 430 whole-body donations have been received since this service was commenced in 2005. The collective academic output of the BBDP is now described as the Arizona Study of Aging and Neurodegenerative Disorders (AZSAND). Most BBDP subjects are enrolled as cognitively normal volunteers residing in the retirement communities of metropolitan Phoenix, Arizona. Specific recruitment efforts are also directed at subjects with Alzheimer's disease, Parkinson's disease and cancer. The median age at death is 82. Subjects receive standardized general medical, neurological, neuropsychological and movement disorders assessments during life and more than 90% receive full pathological examinations by medically licensed pathologists after death. The Program has been funded through a combination of internal, federal and state of Arizona grants as well as user fees and pharmaceutical industry collaborations. Subsets of the Program are utilized by the US National Institute on Aging Arizona Alzheimer's Disease Core Center and the US National Institute of Neurological Disorders and Stroke National Brain and Tissue Resource for Parkinson's Disease and Related Disorders. Substantial funding has also been received from the Michael J. Fox Foundation for Parkinson's Research. The Program has made rapid autopsy a priority, with a 3.0-hour median post-mortem interval for the entire collection. The median RNA Integrity Number (RIN) for frozen brain and body tissue is 8.9 and 7.4, respectively. More than 2500 tissue requests have been served and currently about 200 are served annually. These requests have been made by more than 400 investigators located in 32 US states and 15 countries. Tissue from the BBDP has contributed to more than 350 publications and more than 200 grant-funded projects.

BACKGROUND Individuals with metabolic syndrome (MetS) exhibit reduced cerebral blood flow. The mechanisms of this reduction remain unknown but arterial stiffening has been implicated as a contributor. We determined if MetS was associated with reduced cerebral blood flow at midlife, and if so, whether arterial stiffness was responsible for mediating their relation. METHODS Middle-aged (40–60 years) community dwelling adults (n = 83) were studied. MetS score was calculated for each subject. Middle cerebral artery hemodynamics was measured using transcranial Doppler ultrasound. Indices of aortic, systemic, and carotid artery stiffness were derived. RESULTS Subjects had subclinical MetS pathology (MetS score = 19.8 ± 10.4) that was inversely associated with cerebrovascular conductance (CVC: r = −0.261, P = 0.02). Carotid-femoral pulse wave velocity (cfPWV) (r = −0.188, P = 0.09), brachial-ankle pulse wave velocity (baPWV) (r = −0.161, P = 0.15), and carotid artery distensibility (r = −0.10, P = 0.37) abrogated the direct association of MetS score and CVC, demonstrating full mediation. Nonparametric bootstrapping further indicated significant indirect effects of cfPWV, baPWV, and carotid artery distensibility, fully mediating reductions of CVC exerted from sublcinical MetS. Carotid artery distensibility demonstrated the greatest effect on CVC (B = −0.0019, SE = 0.0012, −0.0050 to −0.0002 95% confidence interval). CONCLUSIONS Arterial stiffness, particularly the stiffness of the carotid artery, mediated reductions in CVC related to MetS.

Background: Mobility changes are concerning for elderly patients with cognitive decline. Given frail older individuals' vulnerability to injury, it is critical to identify contributors to limited mobility. Objective: To examine whether structural brain abnormalities, including reduced gray matter volume and white matter hyperintensities, would be associated with limited mobility among individuals with cognitive impairment, and to determine whether cognitive impairment would mediate this relationship. Methods: Thirty-four elderly individuals with mild cognitive impairment (MCI) and Alzheimer's disease underwent neuropsychological evaluation, mobility assessment, and structural brain neuroimaging. Linear regression was conducted with predictors including gray matter volume in six regions of interest (ROI) and white matter hyperintensity (WMH) burden, with mobility measures as outcomes. Results: Lower gray matter volume in caudate nucleus was associated with slower speed on a functional mobility task. Higher cerebellar volume was also associated with slower functional mobility. White matter hyperintensity burden was not significantly associated with mobility. Conclusion: Our findings provide evidence for associations between subcortical gray matter volume and speed on a functional mobility task among cognitively impaired individuals.

The aging U.S. population and the recent rise in the prevalence of obesity are two phenomena of great importance to public health. In addition, research suggests that midlife body mass index (BMI) is a risk factor for dementia, a particularly costly disease, in later life. BMI could influence brain health by adversely impacting cerebral white matter. Recently, greater BMI has been associated with lower white matter fractional anisotropy (FA), an index of tissue microstructure, as measured by diffusion-tensor imaging in midlife. The aim of this study was to investigate the role of abdominal obesity, the most metabolically active adipose tissue compartment, and white matter microstructure in midlife. Community dwelling participants (N = 168) between the ages of 40-62 underwent MRI scanning at 3T and a general health assessment. Inferences were made on whole brain white matter tracts using full-tensor, high-dimension normalization, and tract-based spatial statistics. Higher waist circumference was associated with higher FA, indicating more directional diffusion in several white matter tracts controlling for age, sex, triglycerides, systolic blood pressure, fasting glucose, and HDL-cholesterol. Post hoc analysis revealed that greater waist circumference was associated with lower axial diffusivity, indicating lower parallel diffusion; lower radial diffusivity, indicating lower perpendicular diffusion; and lower mean diffusivity, indicating restricted diffusion. This is the first study to report a positive relationship between obesity and FA, indicating a more complicated view of this relationship in the aging brain. Hum Brain Mapp 38:3337-3344, 2017. © 2017 Wiley Periodicals, Inc.

Some cognitively healthy individuals develop brain amyloid accumulation, suggestive of incipient Alzheimer's disease (AD), but the effect of amyloid on other potentially informative imaging modalities, such as Diffusion Tensor Imaging (DTI), in characterizing brain changes in preclinical AD requires further exploration. In this study, a sample (N = 139, mean age 60.6, range 46 to 71) from the Wisconsin Registry for Alzheimer's Prevention (WRAP), a cohort enriched for AD risk factors, was recruited for a multimodal imaging investigation that included DTI and [C-11]Pittsburgh Compound B (PiB) positron emission tomography (PET). Participants were grouped as amyloid positive (Aβ+), amyloid indeterminate (Aβi), or amyloid negative (Aβ−) based on the amount and pattern of amyloid deposition. Regional voxel-wise analyses of four DTI metrics, fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (Da), and radial diffusivity (Dr), were performed based on amyloid grouping. Three regions of interest (ROIs), the cingulum adjacent to the corpus callosum, hippocampal cingulum, and lateral fornix, were selected based on their involvement in the early stages of AD. Voxel-wise analysis revealed higher FA among Aβ+ compared to Aβ− in all three ROIs and in Aβi compared to Aβ− in the cingulum adjacent to the corpus callosum. Follow-up exploratory whole-brain analyses were consistent with the ROI findings, revealing multiple regions where higher FA was associated with greater amyloid. Lower fronto-lateral gray matter MD was associated with higher amyloid burden. Further investigation showed a negative correlation between MD and PiB signal, suggesting that Aβ accumulation impairs diffusion. Interestingly, these findings in a largely presymptomatic sample are in contradistinction to relationships reported in the literature in symptomatic disease stages of Mild Cognitive Impairment and AD, which usually show higher MD and lower FA. Together with analyses showing that cognitive function in these participants is not associated with any of the four DTI metrics, the present results suggest an early relationship between PiB and DTI, which may be a meaningful indicator of the initiating or compensatory mechanisms of AD prior to cognitive decline., Graphical abstract, Highlights • Study cohort of preclinical subjects (N = 139) at risk for Alzheimer's disease • Examination of four DTI metrics in three groups based on global amyloid load • Greater amyloid load was associated with higher fractional anisotropy. • Diffusivity was negatively associated with amyloid in fronto-lateral gray matter. • DTI metrics were not correlated with cognition at this early disease stage.

Background Metabolic syndrome (MetS)—a cluster of cardiovascular risk factors—is linked with cognitive decline and dementia. However, the brain changes underlying this link are presently unknown. In this study, we tested the relationship between MetS, cerebral blood flow (CBF), white matter hyperintensity burden, and gray matter (GM) volume in cognitively healthy late middle-aged adults. Additionally, the extent to which MetS was associated with cognitive performance was assessed. Design and Methods Late middle-aged adults from the Wisconsin Registry for Alzheimer's Prevention (N = 69, mean age = 60.4 years) underwent a fasting blood draw, arterial spin labeling perfusion MRI, T1-weighted MRI, T2FLAIR MRI, and neuropsychological testing. MetS was defined as abnormalities on three or more factors, including abdominal obesity, triglycerides, HDL-cholesterol, blood pressure, and fasting glucose. Results Mean GM CBF was 15% lower in MetS compared to controls. Voxel-wise image analysis indicated that the MetS group had lower CBF across a large portion of the cortical surface, with the exception of medial and inferior parts of the occipital and temporal lobes. The MetS group also had lower immediate memory function; a mediation analysis indicated this relationship was partially mediated by CBF. Among the MetS factors, abdominal obesity and elevated triglycerides were most strongly associated with lower CBF. Conclusions The results underscore the importance of reducing the number of cardiovascular risk factors for maintaining CBF and cognition in an aging population.

Higher systemic levels of the proinflammatory cytokine interleukin-6 (IL-6) were found to be associated with lower gray matter volume and tissue density in old rhesus macaques. This association between IL-6, and these brain indices were attenuated by long-term 30 % calorie restriction (CR). To extend these findings, the current analysis determined if a CR diet in 27 aged rhesus monkeys compared to 17 normally fed controls reduced circulating levels of another proinflammatory cytokine, interleukin-8 (IL-8), and raised levels of anti-inflammatory interleukin-10 (IL-10). Further, these cytokines were regressed onto imaged brain volume and microstructure using voxel-wise regression analyses. CR significantly lowered IL-8 and raised IL-10 levels. Across the two dietary conditions, higher IL-8 predicted smaller gray matter volumes in bilateral hippocampus. Higher IL-10 was associated with more white matter volume in visual areas and tracts. Consuming a CR diet reduced the association between systemic IL-8 and hippocampal volumes. Conversely, CR strengthened associations between IL-10 and microstructural tissue density in the prefrontal cortex and other areas, particularly in a region of dorsal prefrontal cortex, which concurred with our prior findings for IL-6. Consumption of a CR diet lowered proinflammatory and increased anti-inflammatory cytokine concentrations, which lessened the statistical association between systemic inflammation and the age-related alterations in important brain regions, including the hippocampus.

OBJECTIVE Insulin resistance dysregulates glucose uptake and other functions in brain areas affected by Alzheimer disease. Insulin resistance may play a role in Alzheimer disease etiopathogenesis. This longitudinal study examined whether insulin resistance among late middle–aged, cognitively healthy individuals was associated with 1) less gray matter in Alzheimer disease–sensitive brain regions and 2) worse cognitive performance. RESEARCH DESIGN AND METHODS Homeostasis model assessment of insulin resistance, gray matter volume, and the Rey Auditory Verbal Learning Test (RAVLT) were acquired in 372 participants at baseline and a consecutive subset of 121 individuals ~4 years later. Voxel-based morphometry and tensor-based morphometry were used, respectively, to test the association of insulin resistance with baseline brain volume and progressive gray matter atrophy. RESULTS Higher insulin resistance predicted less gray matter at baseline and 4 years later in medial temporal lobe, prefrontal cortices, precuneus, and other parietal gyri. A region-of-interest analysis, independent of the voxel-wise analyses, confirmed that higher insulin resistance was related to medial temporal lobe atrophy. Atrophy itself corresponded to cognitive deficits in the RAVLT. Temporal lobe atrophy that was predicted by higher insulin resistance significantly mediated worse RAVLT encoding performance. CONCLUSIONS These results suggest that insulin resistance in an asymptomatic, late middle–aged cohort is associated with progressive atrophy in regions affected by early Alzheimer disease. Insulin resistance may also affect the ability to encode episodic information by negatively influencing gray matter volume in medial temporal lobe.

BACKGROUND: Excessive adipose tissue, particularly with a central distribution, consists of visceral fat, which is metabolically active and could impinge upon central nervous system functioning. The aim of the current study was to examine levels of visceral adiposity in relation to key cerebral metabolite ratios localized in the occipitoparietal grey matter. METHODS: Seventy-three adults, aged between 40–60 years, underwent structural magnetic resonance imaging and single voxel (1)H Magnetic Resonance Spectroscopy ((1)H MRS). Visceral fat was assessed using Dual Energy X Ray Absorptiometry (DXA). RESULTS: Individuals with higher visceral fat mass and volume had significantly lower ratios of N-acetyl-aspartate to total creatine (phosphocreatine+creatine, PCr+Cr) (NAA/PCr+Cr) (β = −0.29, p=0.03, β = −0.28, p=0.04). They also had significantly higher ratios of myo-inositol to total creatine (mI/PCr+Cr ) (β = 0.36, p=0.01, β = 0.36, p=0.01). Visceral fat mass and volume were not significantly related to ratios of glutamate to total creatine (Glu/PCr+Cr). CONCLUSIONS: Visceral fat was associated with lower NAA/PCr+Cr ratio and higher mI/PCr+Cr ratios. While future studies are necessary, these results indicate central adiposity is associated with metabolic changes that could impinge upon the central nervous system in middle age.

Background Insulin resistance (IR) increases Alzheimer's disease (AD) risk. IR is related to greater amyloid burden post-mortem and increased deposition within areas affected by early AD. No studies have examined if IR is associated with an in vivo index of amyloid in the human brain in late middle-aged participants at risk for AD. Methods Asymptomatic, late middle-aged adults (N = 186) from the Wisconsin Registry for Alzheimer's Prevention underwent [C-11]Pittsburgh compound B (PiB) positron emission tomography. The cross-sectional design tested the interaction between insulin resistance and glycemic status on PiB distribution volume ratio in three regions of interest (frontal, parietal, and temporal). Results In participants with normoglycemia but not hyperglycemia, higher insulin resistance corresponded to higher PiB uptake in frontal and temporal areas, reflecting increased amyloid deposition. Conclusions This is the first human study to demonstrate that insulin resistance may contribute to amyloid deposition in brain regions affected by AD.

White matter hyperintensities (WMH) of presumed vascular origin, as seen on T2-weighted fluid attenuated inversion recovery magnetic resonance imaging, are known to increase with age and are elevated in Alzheimer's disease (AD). The cognitive implications of these common markers are not well understood. Previous research has primarily focused on global measures of WMH burden and broad localizations that contain multiple white matter tracts. The aims of this study were to determine the pattern of WMH accumulation with age, risk for AD, and the relationship with cognitive function utilizing a voxel-wise analysis capable of identifying specific white matter regions. A total of 349 participants underwent T1-weighted and high-resolution T2-weighted fluid attenuated inversion recovery magnetic resonance imaging and neuropsychological testing. Increasing age and lower cognitive speed and flexibility (a component of executive function), were both significantly associated with regional WMH throughout the brain. When age was controlled, lower cognitive speed and flexibility was independently associated with WMH in the superior corona radiata. Apolipoprotein E e4 and parental family history of AD were not associated with higher burden of WMH. The results contribute to a larger body of literature suggesting that white matter measures are linked with processing speed, and illustrate the utility of voxel-wise analysis in understanding the effect of lesion location on cognitive function.

Cerebral blood flow (CBF) provides an indication of the metabolic status of the cortex and may have utility in elucidating preclinical brain changes in persons at risk for Alzheimer's disease (AD) and related diseases. In this study, we investigated CBF in 327 well-characterized adults including patients with AD (n = 28), patients with amnestic mild cognitive impairment (aMCI, n = 23), older cognitively normal (OCN, n = 24) adults, and asymptomatic middle-aged adults (n = 252) with and without a family history (FH) of AD. Compared with the asymptomatic cohort, AD patients displayed significant hypoperfusion in the precuneus, posterior cingulate, lateral parietal cortex, and the hippocampal region. Patients with aMCI exhibited a similar but less marked pattern of hypoperfusion. Perfusion deficits within the OCN adults were primarily localized to the inferior parietal lobules. Asymptomatic participants with a maternal FH of AD showed hypoperfusion in hippocampal and parietofrontal regions compared with those without a FH of AD or those with only a paternal FH of AD. These observations persisted when gray matter volume was included as a voxel-wise covariate. Our findings suggest that having a mother with AD might confer a particular risk for AD-related cerebral hypoperfusion in midlife. In addition, they provide further support for the potential utility of arterial spin labeling for the measurement of AD-related neurometabolic dysfunction, particularly in situations where [18F]fluorodeoxyglucose imaging is infeasible or clinically contraindicated.

Little is known about the effect of obesity on brain structures and cognition in healthy older adults. This study examined the association between body mass index (BMI), regional volume differences in gray and white matter measured by magnetic resonance imaging (MRI), and cognitive functioning in older females. Participants included 95 community‐dwelling older females (ages 52–92 years) who underwent extensive neuropsychological testing and high‐resolution MRI scanning. Optimized voxel‐based morphometry techniques were employed to determine the correlation between BMI and regional gray and white matter volumes. Volumes of significant regions were then correlated with cognitive functioning. Higher BMI was associated with decreased gray matter volumes in the left orbitofrontal, right inferior frontal, and right precentral gyri, a right posterior region including the parahippocampal, fusiform, and lingual gyri, and right cerebellar regions, as well as increased volumes of white matter in the frontal, temporal, and parietal lobes, even when hypertension was considered. Compared to normal weight women, obese women performed poorer on tests of executive functioning. Smaller gray matter volume in the left orbitofrontal region was associated with lower executive functioning. Additionally, despite the lack of significant group differences in memory and visuomotor speed, gray and white matter volumes predicted performance on these measures. The results provide additional evidence for a negative link between increased body fat and brain functioning in older females. Hum Brain Mapp, 2010. © 2009 Wiley‐Liss, Inc.

Converging evidence suggests that Alzheimer disease (AD) involves insulin signaling impairment. Patients with AD and individuals at risk for AD show reduced glucose metabolism, as indexed by fludeoxyglucose F 18-labeled positron emission tomography (FDG-PET).To determine whether insulin resistance predicts AD-like global and regional glucose metabolism deficits in late middle-aged participants at risk for AD and to examine whether insulin resistance-predicted variation in regional glucose metabolism is associated with worse cognitive performance.This population-based, cross-sectional study included 150 cognitively normal, late middle-aged (mean [SD] age, 60.7 [5.8] years) adults from the Wisconsin Registry for Alzheimer's Prevention (WRAP) study, a general community sample enriched for AD parental history. Participants underwent cognitive testing, fasting blood draw, and FDG-PET at baseline. We used the homeostatic model assessment of peripheral insulin resistance (HOMA-IR). Regression analysis tested the statistical effect of HOMA-IR on global glucose metabolism. We used a voxelwise analysis to determine whether HOMA-IR predicted regional glucose metabolism. Finally, predicted variation in regional glucose metabolism was regressed against cognitive factors. Covariates included age, sex, body mass index, apolipoprotein E ε4 genotype, AD parental history status, and a reference region used to normalize regional uptake.Regional glucose uptake determined using FDG-PET and neuropsychological factors.Higher HOMA-IR was associated with lower global glucose metabolism (β = -0.29; P .01) and lower regional glucose metabolism across large portions of the frontal, lateral parietal, lateral temporal, and medial temporal lobes (P .05, familywise error corrected). The association was especially robust in the left medial temporal lobe (R2 = 0.178). Lower glucose metabolism in the left medial temporal lobe predicted by HOMA-IR was significantly related to worse performance on the immediate memory (β = 0.317; t148 = 4.08; P .001) and delayed memory (β = 0.305; t148 = 3.895; P .001) factor scores.Our results show that insulin resistance, a prevalent and increasingly common condition in developed countries, is associated with significantly lower regional cerebral glucose metabolism, which in turn may predict worse memory performance. Midlife may be a critical period for initiating treatments to lower peripheral insulin resistance to maintain neural metabolism and cognitive function.

Cerebrospinal fluid (CSF) biomarkers T-Tau and Aβ(42) are linked with Alzheimer's disease (AD), yet little is known about the relationship between CSF biomarkers and structural brain alteration in healthy adults. In this study we examined the extent to which AD biomarkers measured in CSF predict brain microstructure indexed by diffusion tensor imaging (DTI) and volume indexed by T1-weighted imaging. Forty-three middle-aged adults with parental family history of AD received baseline lumbar puncture and MRI approximately 3.5 years later. Voxel-wise image analysis methods were used to test whether baseline CSF Aβ(42), total tau (T-Tau), phosphorylated tau (P-Tau) and neurofilament light protein predicted brain microstructure as indexed by DTI and gray matter volume indexed by T1-weighted imaging. T-Tau and T-Tau/Aβ(42) were widely correlated with indices of brain microstructure (mean, axial, and radial diffusivity), notably in white matter regions adjacent to gray matter structures affected in the earliest stages of AD. None of the CSF biomarkers were related to gray matter volume. Elevated P-Tau and P-Tau/Aβ(42) levels were associated with lower recognition performance on the Rey Auditory Verbal Learning Test. Overall, the results suggest that CSF biomarkers are related to brain microstructure in healthy adults with elevated risk of developing AD. Furthermore, the results clearly suggest that early pathological changes in AD can be detected with DTI and occur not only in cortex, but also in white matter.

Introduction Little is still known about the effects of risk factors for Alzheimer's disease (AD) on white matter microstructure in cognitively healthy adults. The purpose of this cross-sectional study was to assess the effect of two well-known risk factors for AD, parental family history and APOE4 genotype. Methods This study included 343 participants from the Wisconsin Registry for Alzheimer's Prevention, who underwent diffusion tensor imaging (DTI). A region of interest analysis was performed on fractional anisotropy maps, in addition to mean, radial, and axial diffusivity maps, aligned to a common template space using a diffeomorphic, tensor-based registration method. The analysis focused on brain regions known to be affected in AD including the corpus callosum, superior longitudinal fasciculus, fornix, cingulum, and uncinate fasciculus. Analyses assessed the impact of APOE4, parental family history of AD, age, and sex on white matter microstructure in late middle-aged participants (aged 47–76 years). Results Both APOE4 and parental family history were associated with microstructural white matter differences. Participants with parental family history of AD had higher FA in the genu of the corpus callosum and the superior longitudinal fasciculus. We observed an interaction between family history and APOE4, where participants who were family history positive but APOE4 negative had lower axial diffusivity in the uncinate fasciculus, and participants who were both family history positive and APOE4 positive had higher axial diffusivity in this region. We also observed an interaction between APOE4 and age, whereby older participants (=65 years of age) who were APOE4 carriers, had higher MD in the superior longitudinal fasciculus and in the portion of the cingulum bundle running adjacent to the cingulate cortex, compared to non-carriers. Older participants who were APOE4 carriers also showed higher radial diffusivity in the genu compared to non-carriers. Across all participants, age had an effect on FA, MD, and axial and radial diffusivities. Sex differences were observed in FA and radial diffusivity. Conclusion APOE4 genotype, parental family history of AD, age, and sex are all associated with microstructural white matter differences in late middle-aged adults. In participants at risk for AD, alterations in diffusion characteristics—both expected and unexpected—may represent cellular changes occurring at the earliest disease stages, but further work is needed. Higher mean, radial, and axial diffusivities were observed in participants who are more likely to be experiencing later stage preclinical pathology, including participants who were both older and carried APOE4, or who were positive for both APOE4 and parental family history of AD., Highlights • Focused on participants (N = 343) in the Wisconsin Registry for Alzheimer's Prevention • Examined effects of Alzheimer's disease risk on brain white matter utilizing DTI • Parental family history was unexpectedly associated with higher fractional anisotropy. • Lower diffusivities in certain risk groups may indicate early disease pathology. • Results have implications for understanding preclinical disease pathology.