The Association between Exposure to Fine Particulate Matter and MRI-Assessed Locus Coeruleus Integrity in the Vietnam Era Twin Study of Aging (VETSA).

BACKGROUND: Increased exposure to ambient air pollution, especially fine particulate matter ≤2.5µm (PM2.5) is associated with poorer brain health and increased risk for Alzheimer's disease (AD) and related dementias. The locus coeruleus (LC), located in the brainstem, is one of the earliest regions affected by tau pathology seen in AD. Its diffuse projections throughout the brain include afferents to olfactory areas that are hypothesized conduits of cerebral particle deposition. Additionally, extensive contact of the LC with the cerebrovascular system may present an additional route of exposure to environmental toxicants. OBJECTIVE: Our aim was to investigate if exposure to PM2.5 was associated with LC integrity in a nationwide sample of men in early old age, potentially representing one pathway through which air pollution can contribute to increased risk for AD dementia. METHODS: We examined the relationship between PM2.5 and in vivo magnetic resonance imaging (MRI) estimates of LC structural integrity indexed by contrast to noise ratio (LCCNR) in 381 men [mean age=67.3; standard deviation (SD)=2.6] from the Vietnam Era Twin Study of Aging (VETSA). Exposure to PM2.5 was taken as a 3-year average over the most recent period for which data were available (average of 5.6 years prior to the MRI scan). We focused on LCCNR in the rostral-middle portion of LC due to its stronger associations with aging and AD than the caudal LC. Associations between PM2.5 exposures and LC integrity were tested using linear mixed effects models adjusted for age, scanner, education, household income, and interval between exposure and MRI. A co-twin control analysis was also performed to investigate whether associations remained after controlling for genetic confounding and rearing environment. RESULTS: Multiple linear regressions revealed a significant association between PM2.5 and rostral-middle LCCNR (ß=-0.16; p=0.02), whereby higher exposure to PM2.5 was associated with lower LCCNR. A co-twin control analysis found that, within monozygotic pairs, individuals with higher PM2.5 exposure showed lower LCCNR (ß=-0.11; p=0.02), indicating associations were not driven by genetic or shared environmental confounds. There were no associations between PM2.5 and caudal LCCNR or hippocampal volume, suggesting a degree of specificity to the rostral-middle portion of the LC. DISCUSSION: Given previous findings that loss of LC integrity is associated with increased accumulation of AD-related amyloid and tau pathology, impacts on LC integrity may represent a potential pathway through which exposure to air pollution increases AD risk. https://doi.org/10.1289/EHP14344.

Using Neuroimaging to Study Cerebral Amyloid Angiopathy and Its Relationship to Alzheimer's Disease.

Cerebral amyloid angiopathy (CAA) is characterized by amyloid-ß aggregation in the media and adventitia of the leptomeningeal and cortical blood vessels. CAA is one of the strongest vascular contributors to Alzheimer's disease (AD). It frequently co-occurs in AD patients, but the relationship between CAA and AD is incompletely understood. CAA may drive AD risk through damage to the neurovascular unit and accelerate parenchymal amyloid and tau deposition. Conversely, early AD may also drive CAA through cerebrovascular remodeling that impairs blood vessels from clearing amyloid-ß. Sole reliance on autopsy examination to study CAA limits researchers' ability to investigate CAA's natural disease course and the effect of CAA on cognitive decline. Neuroimaging allows for in vivo assessment of brain function and structure and can be leveraged to investigate CAA staging and explore its associations with AD. In this review, we will discuss neuroimaging modalities that can be used to investigate markers associated with CAA that may impact AD vulnerability including hemorrhages and microbleeds, blood-brain barrier permeability disruption, reduced cerebral blood flow, amyloid and tau accumulation, white matter tract disruption, reduced cerebrovascular reactivity, and lowered brain glucose metabolism. We present possible areas for research inquiry to advance biomarker discovery and improve diagnostics.

Alzheimer's Related Neurodegeneration Mediates Air Pollution Effects on Medial Temporal Lobe Atrophy.

Exposure to ambient air pollution, especially particulate matter with aerodynamic diameter <2.5 µm (PM2.5) and nitrogen dioxide (NO2), are environmental risk factors for Alzheimer's disease and related dementia. The medial temporal lobe (MTL) is an important brain region subserving episodic memory that atrophies with age, during the Alzheimer's disease continuum, and is vulnerable to the effects of cerebrovascular disease. Despite the importance of air pollution it is unclear whether exposure leads to atrophy of the MTL and by what pathways. Here we conducted a longitudinal study examining associations between ambient air pollution exposure and MTL atrophy and whether putative air pollution exposure effects resembled Alzheimer's disease-related neurodegeneration or cerebrovascular disease-related neurodegeneration. Participants included older women (n = 627; aged 71-87) who underwent two structural brain MRI scans (MRI-1: 2005-6; MRI-2: 2009-10) as part of the Women's Health Initiative Memory Study of Magnetic Resonance Imaging. Regionalized universal kriging was used to estimate annual concentrations of PM2.5 and NO2 at residential locations aggregated to 3-year averages prior to MRI-1. The outcome was 5-year standardized change in MTL volumes. Mediators included voxel-based MRI measures of the spatial pattern of neurodegeneration of Alzheimer's disease (Alzheimer's disease pattern similarity scores [AD-PS]) and whole-brain white matter small-vessel ischemic disease (WM-SVID) volume as a proxy of global cerebrovascular damage. Structural equation models were constructed to examine whether the associations between exposures with MTL atrophy were mediated by the initial level or concurrent change in AD-PS score or WM-SVID while adjusting for sociodemographic, lifestyle, clinical characteristics, and intracranial volume. Living in locations with higher PM2.5 (per interquartile range [IQR]=3.17µg/m3) or NO2 (per IQR=6.63ppb) was associated with greater MTL atrophy (ßPM2.5 = -0.29, 95% confidence interval [CI]=[-0.41,-0.18]; ßNO2 =-0.12, 95%CI=[-0.23,-0.02]). Greater PM2.5 was associated with larger increases in AD-PS (ßPM2.5 = 0.23, 95%CI=[0.12,0.33]) over time, which partially mediated associations with MTL atrophy (indirect effect= -0.10; 95%CI=[-0.15, -0.05]), explaining approximately 32% of the total effect. NO2 was positively associated with AD-PS at MRI-1 (ßNO2=0.13, 95%CI=[0.03,0.24]), which partially mediated the association with MTL atrophy (indirect effect= -0.01, 95% CI=[-0.03,-0.001]). Global WM-SVID at MRI-1 or concurrent change were not significant mediators between exposures and MTL atrophy. Findings support the mediating role of Alzheimer's disease-related neurodegeneration contributing to MTL atrophy associated with late-life exposures to air pollutants. Alzheimer's disease-related neurodegeneration only partially explained associations between exposure and MTL atrophy suggesting the role of multiple neuropathological processes underlying air pollution neurotoxicity on brain aging.

Association between late-life air pollution exposure and medial temporal lobe atrophy in older women.

Background: Ambient air pollution exposures increase risk for Alzheimer's disease (AD) and related dementias, possibly due to structural changes in the medial temporal lobe (MTL). However, existing MRI studies examining exposure effects on the MTL were cross-sectional and focused on the hippocampus, yielding mixed results. Method: To determine whether air pollution exposures were associated with MTL atrophy over time, we conducted a longitudinal study including 653 cognitively unimpaired community-dwelling older women from the Women's Health Initiative Memory Study with two MRI brain scans (MRI-1: 2005-6; MRI-2: 2009-10; Mage at MRI-1=77.3±3.5years). Using regionalized universal kriging models, exposures at residential locations were estimated as 3-year annual averages of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) prior to MRI-1. Bilateral gray matter volumes of the hippocampus, amygdala, parahippocampal gyrus (PHG), and entorhinal cortex (ERC) were summed to operationalize the MTL. We used linear regressions to estimate exposure effects on 5-year volume changes in the MTL and its subregions, adjusting for intracranial volume, sociodemographic, lifestyle, and clinical characteristics. Results: On average, MTL volume decreased by 0.53±1.00cm3 over 5 years. For each interquartile increase of PM2.5 (3.26µg/m3) and NO2 (6.77ppb), adjusted MTL volume had greater shrinkage by 0.32cm3 (95%CI=[-0.43, -0.21]) and 0.12cm3 (95%CI=[-0.22, -0.01]), respectively. The exposure effects did not differ by APOE ε4 genotype, sociodemographic, and cardiovascular risk factors, and remained among women with low-level PM2.5 exposure. Greater PHG atrophy was associated with higher PM2.5 (b=-0.24, 95%CI=[-0.29, -0.19]) and NO2 exposures (b=-0.09, 95%CI=[-0.14, -0.04]). Higher exposure to PM2.5 but not NO2 was also associated with greater ERC atrophy. Exposures were not associated with amygdala or hippocampal atrophy. Conclusion: In summary, higher late-life PM2.5 and NO2 exposures were associated with greater MTL atrophy over time in cognitively unimpaired older women. The PHG and ERC - the MTL cortical subregions where AD neuropathologies likely begin, may be preferentially vulnerable to air pollution neurotoxicity.

White matter hyperintensity volume modifies the association between CSF vascular inflammatory biomarkers and regional FDG-PET along the Alzheimer's disease continuum.

In older adults with abnormal levels of Alzheimer's disease neuropathology, lower cerebrospinal fluid (CSF) vascular endothelial growth factor (VEGF) levels are associated with lower [¹8F]-fluorodeoxyglucose positron emission tomography (FDG-PET) signal, but whether this association is (1) specific to VEGF or broadly driven by vascular inflammation, or (2) modified by vascular risk (e.g., white matter hyperintensities [WMHs]) remains unknown. To address this and build upon our past work, we evaluated whether 5 CSF vascular inflammation biomarkers (vascular cell adhesion molecule 1, VEGF, C-reactive protein, fibrinogen, and von Willebrand factor)-previously associated with CSF amyloid levels-were related to FDG-PET signal and whether WMH volume modified these associations in 158 Alzheimer's Disease Neuroimaging Initiative participants (55-90 years old, 39 cognitively normal, 80 mild cognitive impairment, 39 Alzheimer's disease). We defined regions both by cortical boundary and by the 3 major vascular territories: anterior, middle, and posterior cerebral arteries. We found that WMH volume had interactive effects with CSF biomarkers (VEGF and C-reactive protein) on FDG-PET throughout the cortex in both vascular territories and conventionally defined regions of interest.

Associations of ApoE4 status and DHA supplementation on plasma and CSF lipid profiles and entorhinal cortex thickness.

Apolipoprotein ε allele 4 (APOE4) influences the metabolism of polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA). The entorhinal cortex (EC) in the brain is affected early in Alzheimer's disease and is rich in DHA. The purpose of this study is to identify the effect of APOE4 and DHA lipid species on the EC. Plasma and cerebrospinal fluid (CSF) lipidomic measurements were obtained from the DHA Brain Delivery Pilot, a randomized clinical trial of DHA supplementation (n = 10) versus placebo (n = 12) for six months in nondemented older adults stratified by APOE4 status. Wild-type C57B6/J mice were fed a high or low DHA diet for 6 months followed by plasma and brain lipidomic analysis. Levels of phosphatidylcholine DHA (PC 38:6) and cholesterol ester DHA (CE 22:6) had the largest increases in CSF following supplementation (P < 0.001). DHA within triglyceride (TG) lipids in CSF strongly correlated with corresponding plasma TG lipids, and differed by APOE4, with carriers having a lower increase than noncarriers. Changes in plasma PC DHA had the strongest association with changes in EC thickness in millimeters, independent of APOE4 status (P = 0.007). In mice, a high DHA diet increased PUFAs within brain lipids. Our findings demonstrate an exchange of DHA at the CSF-blood barrier and into the brain within all lipid species with APOE having the strongest effect on DHA-containing TGs. The correlation of PC DHA with EC suggests a functional consequence of DHA accretion in high density lipoprotein for the brain.

Mitochondrial DNA variation in Alzheimer's disease reveals a unique microprotein called SHMOOSE.

Mitochondrial DNA variants have previously associated with disease, but the underlying mechanisms have been largely elusive. Here, we report that mitochondrial SNP rs2853499 associated with Alzheimer's disease (AD), neuroimaging, and transcriptomics. We mapped rs2853499 to a novel mitochondrial small open reading frame called SHMOOSE with microprotein encoding potential. Indeed, we detected two unique SHMOOSE-derived peptide fragments in mitochondria by using mass spectrometry-the first unique mass spectrometry-based detection of a mitochondrial-encoded microprotein to date. Furthermore, cerebrospinal fluid (CSF) SHMOOSE levels in humans correlated with age, CSF tau, and brain white matter volume. We followed up on these genetic and biochemical findings by carrying out a series of functional experiments. SHMOOSE acted on the brain following intracerebroventricular administration, differentiated mitochondrial gene expression in multiple models, localized to mitochondria, bound the inner mitochondrial membrane protein mitofilin, and boosted mitochondrial oxygen consumption. Altogether, SHMOOSE has vast implications for the fields of neurobiology, Alzheimer's disease, and microproteins.

Characterization of Mild Cognitive Impairment and Dementia among Community-Dwelling Mexican Americans and Non-Hispanic Whites.

BACKGROUND: Despite tremendous advancements in the field, our understanding of mild cognitive impairment (MCI) and Alzheimer's disease (AD) among Mexican Americans remains limited. OBJECTIVE: The aim of this study was to characterize MCI and dementia among Mexican Americans and non-Hispanic whites. METHODS: Baseline data were analyzed from n = 1,705 (n = 890 Mexican American; n = 815 non-Hispanic white) participants enrolled in the Health and Aging Brain Study-Health Disparities (HABS-HD). RESULTS: Among Mexican Americans, age (OR = 1.07), depression (OR = 1.09), and MRI-based neurodegeneration (OR = 0.01) were associated with dementia, but none of these factors were associated with MCI. Among non-Hispanic whites, male gender (OR = 0.33), neighborhood deprivation (OR = 1.34), depression (OR = 1.09), and MRI-based neurodegeneration (OR = 0.03) were associated with MCI, while depression (OR = 1.09) and APOEɛ4 genotype (OR = 4.38) were associated with dementia. CONCLUSION: Findings from this study revealed that the demographic, clinical, sociocultural and biomarker characteristics of MCI and dementia are different among Mexican Americans as compared to non-Hispanic whites.

Vascular risk profile and white matter hyperintensity volume among Mexican Americans and non-Hispanic Whites: The HABLE study.

INTRODUCTION: Among vascular risk factors we hypothesized that an increased prevalence of diabetes in Hispanics would be associated with greater white matter hyperintensity (WMH) volume, which may contribute to cognitive decline. METHODS: A total of 1318 participants (60% female; 49% Hispanic, 51% non-Hispanic White; age 66.2 ± 8.9 years) underwent clinical evaluation and brain magnetic resonance imaging (MRI). WMH volume associations were assessed with age, sex, and ethnicity and then with vascular risk factors in a selective regression model. RESULTS: WMH volume was greater with older age (P < .0001), Hispanic ethnicity (P = .02), and female sex (P = .049). WMH volume was best predicted by age, diastolic blood pressure, hypertension history, hemoglobin A1c (HbA1c), white blood cell count, and hematocrit (P < .01 for all). Elevated HbA1c was associated with greater WMH volume among Hispanics (parameter estimate 0.08 ± 0.02, P < .0001) but not non-Hispanic Whites (parameter estimate 0.02 ± 0.04, P = .5). DISCUSSION: WMH volume was greater in Hispanics, which may be partly explained by increased WMH volume related to elevated HbA1c among Hispanics but not non-Hispanic Whites.

Testing a convolutional neural network-based hippocampal segmentation method in a stroke population.

As stroke mortality rates decrease, there has been a surge of effort to study poststroke dementia (PSD) to improve long-term quality of life for stroke survivors. Hippocampal volume may be an important neuroimaging biomarker in poststroke dementia, as it has been associated with many other forms of dementia. However, studying hippocampal volume using MRI requires hippocampal segmentation. Advances in automated segmentation methods have allowed for studying the hippocampus on a large scale, which is important for robust results in the heterogeneous stroke population. However, most of these automated methods use a single atlas-based approach and may fail in the presence of severe structural abnormalities common in stroke. Hippodeep, a new convolutional neural network-based hippocampal segmentation method, does not rely solely on a single atlas-based approach and thus may be better suited for stroke populations. Here, we compared quality control and the accuracy of segmentations generated by Hippodeep and two well-accepted hippocampal segmentation methods on stroke MRIs (FreeSurfer 6.0 whole hippocampus and FreeSurfer 6.0 sum of hippocampal subfields). Quality control was performed using a stringent protocol for visual inspection of the segmentations, and accuracy was measured as volumetric correlation with manual segmentations. Hippodeep performed significantly better than both FreeSurfer methods in terms of quality control. All three automated segmentation methods had good correlation with manual segmentations and no one method was significantly more correlated than the others. Overall, this study suggests that both Hippodeep and FreeSurfer may be useful for hippocampal segmentation in stroke rehabilitation research, but Hippodeep may be more robust to stroke lesion anatomy.

Racial/Ethnic Disparities in Alzheimer's Disease Risk: Role of Exposure to Ambient Fine Particles.

BACKGROUND: Whether racial/ethnic disparities in Alzheimer's disease (AD) risk may be explained by ambient fine particles (PM2.5) has not been studied. METHOD: We conducted a prospective, population-based study on a cohort of Black (n = 481) and White (n = 6 004) older women (aged 65-79) without dementia at enrollment (1995-1998). Cox models accounting for competing risk were used to estimate the hazard ratio (HR) for racial/ethnic disparities in AD (1996-2010) defined by Diagnostic and Statistical Manual of Mental Disorders, 4th edition and the association with time-varying annual average PM2.5 (1999-2010) estimated by spatiotemporal model. RESULTS: Over an average follow-up of 8.3 (±3.5) years with 158 incident cases (21 in Black women), the racial disparities in AD risk (range of adjusted HRBlack women = 1.85-2.41) observed in various models could not be explained by geographic region, age, socioeconomic characteristics, lifestyle factors, cardiovascular risk factors, and hormone therapy assignment. Estimated PM2.5 exposure was higher in Black (14.38 ± 2.21 µg/m3) than in White (12.55 ± 2.76 µg/m3) women, and further adjustment for the association between PM2.5 and AD (adjusted HRPM2.5 = 1.18-1.28) slightly reduced the racial disparities by 2%-6% (HRBlack women = 1.81-2.26). The observed association between PM2.5 and AD risk was ~2 times greater in Black (HRPM2.5 = 2.10-2.60) than in White (HRPM2.5 = 1.07-1.15) women (range of interaction ps: <.01-.01). We found similar results after further adjusting for social engagement (social strain, social support, social activity, living alone), stressful life events, Women's Health Initiative's clinic sites, and neighborhood socioeconomic characteristics. CONCLUSIONS: PM2.5 may contribute to racial/ethnic disparities in AD risk and its associated increase in AD risk was stronger among Black women.

Brain energy failure in dementia syndromes: Opportunities and challenges for glucagon-like peptide-1 receptor agonists.

Medications for type 2 diabetes (T2DM) offer a promising path for discovery and development of effective interventions for dementia syndromes. A common feature of dementia syndromes is an energy failure due to reduced energy supply to neurons and is associated with synaptic loss and results in cognitive decline and behavioral changes. Among diabetes medications, glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) promote protective effects on vascular, microglial, and neuronal functions. In this review, we present evidence from animal models, imaging studies, and clinical trials that support developing GLP-1 RAs for dementia syndromes. The review examines how changes in brain energy metabolism differ in conditions of insulin resistance and T2DM from dementia and underscores the challenges that arise from the heterogeneity of dementia syndromes. The development of GLP-1 RAs as dementia therapies requires a deeper understanding of the regional changes in brain energy homeostasis guided by novel imaging biomarkers.

MRI biomarkers of small vessel disease and cognition: A cross-sectional study of a cognitively normal Mexican American cohort.

BACKGROUND: The current project sought to evaluate the impact that white matter hyperintensities (WMH) have on executive function in cognitively normal Mexican Americans, an underserved population with onset and more rapid progression of dementia. METHODS: Data from 515 participants (360 female) enrolled in the Health and Aging Brain Study: Health Disparities project were analyzed. Participants underwent clinical evaluation, cognitive testing, and a brain MRI. Linear regression was used to predict the effect of total WMH volume on cognitive test scores. Age, sex, and education were entered as covariates. RESULTS: Regression analysis showed that WMH volume significantly predicted executive function. WMH also predicted global cognition and attention scores, although not significantly after adjusting for age. CONCLUSION: In this sample of cognitively normal Mexican Americans, we found that WMH volume was associated with lower scores in a measure of executive function, after accounting for age, sex, and education.

The Health & Aging Brain among Latino Elders (HABLE) study methods and participant characteristics.

INTRODUCTION: Mexican Americans remain severely underrepresented in Alzheimer's disease (AD) research. The Health & Aging Brain among Latino Elders (HABLE) study was created to fill important gaps in the existing literature. METHODS: Community-dwelling Mexican Americans and non-Hispanic White adults and elders (age 50 and above) were recruited. All participants underwent comprehensive assessments including an interview, functional exam, clinical labs, informant interview, neuropsychological testing, and 3T magnetic resonance imaging (MRI) of the brain. Amyloid and tau positron emission tomography (PET) scans were added at visit 2. Blood samples were stored in the Biorepository. RESULTS: Data was examined from n = 1705 participants. Significant group differences were found in medical, demographic, and sociocultural factors. Cerebral amyloid and neurodegeneration imaging markers were significantly different between Mexican Americans and non-Hispanic Whites. DISCUSSION: The current data provide strong support for continued investigations that examine the risk factors for and biomarkers of AD among diverse populations.

Regional relationships between CSF VEGF levels and Alzheimer's disease brain biomarkers and cognition.

Vascular endothelial growth factor (VEGF) is a complex signaling protein that supports vascular and neuronal function. Alzheimer's disease (AD) -neuropathological hallmarks interfere with VEGF signaling and modify previously detected positive associations between cerebral spinal fluid (CSF) VEGF and cognition and hippocampal volume. However, it remains unknown 1) whether regional relationships between VEGF and glucose metabolism and cortical thinning exist, and 2) whether AD-neuropathological hallmarks (CSF Aß, t-tau, p-tau) also modify these relationships. We addressed this in 310 Alzheimer's Disease Neuroimaging Initiative (ADNI) participants (92 cognitively normal, 149 mild cognitive impairment, 69 AD; 215 CSF Aß+, 95 CSF Aß-) with regional cortical thickness and cognition measurements and 158 participants with FDG-PET. In Aß + participants (CSF Aß42 ≤ 192 pg/mL), higher CSF VEGF levels were associated with greater FDG-PET signal in the inferior parietal, and middle and inferior temporal cortices. Abnormal CSF amyloid and tau levels strengthened the positive association between VEGF and regional FDG-PET indices. VEGF also had both direct associations with semantic memory, as well as indirect associations mediated by regional FDG-PET signal to cognition.

Brain delivery of supplemental docosahexaenoic acid (DHA): A randomized placebo-controlled clinical trial.

BACKGROUND: Past clinical trials of docosahexaenoic Acid (DHA) supplements for the prevention of Alzheimer's disease (AD) dementia have used lower doses and have been largely negative. We hypothesized that larger doses of DHA are needed for adequate brain bioavailability and that APOE4 is associated with reduced delivery of DHA and eicosapentaenoic acid (EPA) to the brain before the onset of cognitive impairment. METHODS: 33 individuals were provided with a vitamin B complex (1 mg vitamin B12, 100 mg of vitamin B6 and 800 mcg of folic acid per day) and randomized to 2,152 mg of DHA per day or placebo over 6 months. 26 individuals completed both lumbar punctures and MRIs, and 29 completed cognitive assessments at baseline and 6 months. The primary outcome was the change in CSF DHA. Secondary outcomes included changes in CSF EPA levels, MRI hippocampal volume and entorhinal thickness; exploratory outcomes were measures of cognition. FINDINGS: A 28% increase in CSF DHA and 43% increase in CSF EPA were observed in the DHA treatment arm compared to placebo (mean difference for DHA (95% CI): 0.08 µg/mL (0.05, 0.10), p<0.0001; mean difference for EPA: 0.008 µg/mL (0.004, 0.011), p<0.0001). The increase in CSF EPA in non-APOE4 carriers after supplementation was three times greater than APOE4 carriers. The change in brain volumes and cognitive scores did not differ between groups. INTERPRETATION: Dementia prevention trials using omega-3 supplementation doses equal or lower to 1 g per day may have reduced brain effects, particularly in APOE4 carriers. TRIAL REGISTRATION: NCT02541929. FUNDING: HNY was supported by R01AG055770, R01AG054434, R01AG067063 from the National Institute of Aging and NIRG-15-361854 from the Alzheimer's Association, and MGH by the L. K. Whittier Foundation. This work was also supported by P50AG05142 (HCC) from the National Institutes of Health. Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report.

Effect of APOE Genotype on Plasma Docosahexaenoic Acid (DHA), Eicosapentaenoic Acid, Arachidonic Acid, and Hippocampal Volume in the Alzheimer's Disease Cooperative Study-Sponsored DHA Clinical Trial.

BACKGROUND: Docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and arachidonic acid (AA) play key roles in several metabolic processes relevant to Alzheimer's disease (AD) pathogenesis and neuroinflammation. Carrying the APOEɛ4 allele (APOE4) accelerates omega-3 polyunsaturated fatty acid (PUFA) oxidation. In a pre-planned subgroup analysis of the Alzheimer's Disease Cooperative Study-sponsored DHA clinical trial, APOE4 carriers with mild probable AD had no improvements in cognitive outcomes compared to placebo, while APOE 4 non-carriers showed a benefit from DHA supplementation. OBJECTIVE: We sought to clarify the effect of APOEɛ4/ɛ4 on both the ratio of plasma DHA and EPA to AA, and on hippocampal volumes after DHA supplementation. METHODS: Plasma fatty acids and APOE genotype were obtained in 275 participants randomized to 18 months of DHA supplementation or placebo. A subset of these participants completed brain MRI imaging (n = 86) and lumbar punctures (n = 53). RESULTS: After the intervention, DHA-treated APOEɛ3/ɛ3 and APOEɛ2/ɛ3 carriers demonstrated significantly greater increase in plasma DHA/AA compared to ɛ4/ɛ4 carriers. APOEɛ2/ɛ3 had a greater increase in plasma EPA/AA and less decline in left and right hippocampal volumes compared to compared to ɛ4/ɛ4 carriers. The change in plasma and cerebrospinal fluid DHA/AA was strongly correlated. Greater baseline and increase in plasma EPA/AA was associated with a lower decrease in the right hippocampal volume, but only in APOE 4 non-carriers. CONCLUSION: The lower increase in plasma DHA/AA and EPA/AA in APOEɛ4/ɛ4 carriers after DHA supplementation reduces brain delivery and affects the efficacy of DHA supplementation.

White matter hyperintensities and their relationship to cognition: Effects of segmentation algorithm.

White matter hyperintensities (WMHs) are brain white matter lesions that are hyperintense on fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) scans. Larger WMH volumes have been associated with Alzheimer's disease (AD) and with cognitive decline. However, the relationship between WMH volumes and cross-sectional cognitive measures has been inconsistent. We hypothesize that this inconsistency may arise from 1) the presence of AD-specific neuropathology that may obscure any WMH effects on cognition, and 2) varying criteria for creating a WMH segmentation. Manual and automated programs are typically used to determine segmentation boundaries, but criteria for those boundaries can differ. It remains unclear whether WMH volumes are associated with cognitive deficits, and which segmentation criteria influence the relationships between WMH volumes and clinical outcomes. In a sample of 260 non-demented participants (ages 55-90, 141 males, 119 females) from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we compared the performance of five WMH segmentation methods, by relating the WMH volumes derived using each method to both clinical diagnosis and composite measures of executive function and memory. To separate WMH effects on cognition from effects related to AD-specific processes, we performed analyses separately in people with and without abnormal cerebrospinal fluid amyloid levels. WMH volume estimates that excluded more diffuse, lower-intensity lesions were more strongly correlated with clinical diagnosis and cognitive performance, and only in those without abnormal amyloid levels. These findings may inform best practices for WMH segmentation, and suggest that AD neuropathology may mask WMH effects on clinical diagnosis and cognition.

White matter hypointensities and hyperintensities have equivalent correlations with age and CSF ß-amyloid in the nondemented elderly.

INTRODUCTION: T1- and T2-weighted sequences from MRI often provide useful complementary information about tissue properties. Leukoaraiosis results in signal abnormalities on T1-weighted images, which are automatically quantified by FreeSurfer, but this marker is poorly characterized and is rarely used. We evaluated associations between white matter hyperintensity (WM-hyper) volume from FLAIR and white matter hypointensity (WM-hypo) volume from T1-weighted images and compared their associations with age and cerebrospinal fluid (CSF) ß-amyloid and tau. METHODS: A total of 56 nondemented participants (68-94 years) were recruited and gave informed consent. All participants went through MR imaging on a GE 1.5T scanner and of these 47 underwent lumbar puncture for CSF analysis. WM-hypo was calculated using FreeSurfer analysis of T1 FSPGR 3D, and WM-hyper was calculated with the Lesion Segmentation Toolbox in the SPM software package using T2-FLAIR. RESULTS: WM-hyper and WM-hypo were strongly correlated (r = .81; parameter estimate (p.e.): 1.53 ± 0.15; p < .0001). Age was significantly associated with both WM-hyper (r = .31, p.e. 0.078 ± 0.030, p = .013) and WM-hypo (r = .42, p.e. 0.055 ± 0.015, p < .001). CSF ß-amyloid levels were predicted by WM-hyper (r = .33, p.e. -0.11 ± 0.044, p = .013) and WM-hypo (r = .42, p.e. -0.24 ± 0.073, p = .002). CSF tau levels were not correlated with either WM-hyper (p = .9) or WM-hypo (p = .99). CONCLUSIONS: Strong correlations between WM-hyper and WM-hypo, and similar associations with age, abnormal ß-amyloid, and tau suggest a general equivalence between these two imaging markers. Our work supports the equivalence of white matter hypointensity volumes derived from FreeSurfer for evaluating leukoaraiosis. This may have particular utility when T2-FLAIR is low in quality or absent, enabling analysis of older imaging data sets.