Genomic loci influence patterns of structural covariance in the human brain.

Normal and pathologic neurobiological processes influence brain morphology in coordinated ways that give rise to patterns of structural covariance (PSC) across brain regions and individuals during brain aging and diseases. The genetic underpinnings of these patterns remain largely unknown. We apply a stochastic multivariate factorization method to a diverse population of 50,699 individuals (12 studies and 130 sites) and derive data-driven, multi-scale PSCs of regional brain size. PSCs were significantly correlated with 915 genomic loci in the discovery set, 617 of which are newly identified, and 72% were independently replicated. Key pathways influencing PSCs involve reelin signaling, apoptosis, neurogenesis, and appendage development, while pathways of breast cancer indicate potential interplays between brain metastasis and PSCs associated with neurodegeneration and dementia. Using support vector machines, multi-scale PSCs effectively derive imaging signatures of several brain diseases. Our results elucidate genetic and biological underpinnings that influence structural covariance patterns in the human brain.

Proteomic Indicators of Health Predict Alzheimer's Disease Biomarker Levels and Dementia Risk.

OBJECTIVE: Few studies have comprehensively examined how health and disease risk influence Alzheimer's disease (AD) biomarkers. The present study examined the association of 14 protein-based health indicators with plasma and neuroimaging biomarkers of AD and neurodegeneration. METHODS: In 706 cognitively normal adults, we examined whether 14 protein-based health indices (ie, SomaSignal® tests) were associated with concurrently measured plasma-based biomarkers of AD pathology (amyloid-ß [Aß]42/40 , tau phosphorylated at threonine-181 [pTau-181]), neuronal injury (neurofilament light chain [NfL]), and reactive astrogliosis (glial fibrillary acidic protein [GFAP]), brain volume, and cortical Aß and tau. In a separate cohort (n = 11,285), we examined whether protein-based health indicators associated with neurodegeneration also predict 25-year dementia risk. RESULTS: Greater protein-based risk for cardiovascular disease, heart failure mortality, and kidney disease was associated with lower Aß42/40 and higher pTau-181, NfL, and GFAP levels, even in individuals without cardiovascular or kidney disease. Proteomic indicators of body fat percentage, lean body mass, and visceral fat were associated with pTau-181, NfL, and GFAP, whereas resting energy rate was negatively associated with NfL and GFAP. Together, these health indicators predicted 12, 31, 50, and 33% of plasma Aß42/40 , pTau-181, NfL, and GFAP levels, respectively. Only protein-based measures of cardiovascular risk were associated with reduced regional brain volumes; these measures predicted 25-year dementia risk, even among those without clinically defined cardiovascular disease. INTERPRETATION: Subclinical peripheral health may influence AD and neurodegenerative disease processes and relevant biomarker levels, particularly NfL. Cardiovascular health, even in the absence of clinically defined disease, plays a central role in brain aging and dementia. ANN NEUROL 2024;95:260-273.

Multi-method investigation of factors influencing amyloid onset and impairment in three cohorts.

Alzheimer's disease biomarkers are becoming increasingly important for characterizing the longitudinal course of disease, predicting the timing of clinical and cognitive symptoms, and for recruitment and treatment monitoring in clinical trials. In this work, we develop and evaluate three methods for modelling the longitudinal course of amyloid accumulation in three cohorts using amyloid PET imaging. We then use these novel approaches to investigate factors that influence the timing of amyloid onset and the timing from amyloid onset to impairment onset in the Alzheimer's disease continuum. Data were acquired from the Alzheimer's Disease Neuroimaging Initiative (ADNI), the Baltimore Longitudinal Study of Aging (BLSA) and the Wisconsin Registry for Alzheimer's Prevention (WRAP). Amyloid PET was used to assess global amyloid burden. Three methods were evaluated for modelling amyloid accumulation using 10-fold cross-validation and holdout validation where applicable. Estimated amyloid onset age was compared across all three modelling methods and cohorts. Cox regression and accelerated failure time models were used to investigate whether sex, apolipoprotein E genotype and e4 carriage were associated with amyloid onset age in all cohorts. Cox regression was used to investigate whether apolipoprotein E (e4 carriage and e3e3, e3e4, e4e4 genotypes), sex or age of amyloid onset were associated with the time from amyloid onset to impairment onset (global clinical dementia rating ≥1) in a subset of 595 ADNI participants that were not impaired before amyloid onset. Model prediction and estimated amyloid onset age were similar across all three amyloid modelling methods. Sex and apolipoprotein E e4 carriage were not associated with PET-measured amyloid accumulation rates. Apolipoprotein E genotype and e4 carriage, but not sex, were associated with amyloid onset age such that e4 carriers became amyloid positive at an earlier age compared to non-carriers, and greater e4 dosage was associated with an earlier amyloid onset age. In the ADNI, e4 carriage, being female and a later amyloid onset age were all associated with a shorter time from amyloid onset to impairment onset. The risk of impairment onset due to age of amyloid onset was non-linear and accelerated for amyloid onset age >65. These findings demonstrate the feasibility of modelling longitudinal amyloid accumulation to enable individualized estimates of amyloid onset age from amyloid PET imaging. These estimates provide a more direct way to investigate the role of amyloid and other factors that influence the timing of clinical impairment in Alzheimer's disease.

Skeletal muscle mitochondrial function predicts cognitive impairment and is associated with biomarkers of Alzheimer's disease and neurodegeneration.

INTRODUCTION: Mitochondrial dysfunction is implicated in the pathophysiology of many chronic diseases. Whether it is related to cognitive impairment and pathological markers is unknown. METHODS: We examined the associations of in vivo skeletal muscle mitochondrial function (post-exercise recovery rate of phosphocreatine [kPCr] via magnetic resonance [MR] spectroscopy with future mild cognitive impairment (MCI) or dementia, and with positron emission tomography (PET) and blood biomarkers of Alzheimer's disease [AD] and neurodegeneration (i.e., Pittsburgh Compound-B [PiB] distribution volume ratio [DVR] for amyloid beta [Aß], flortaucipir (FTP) standardized uptake value ratio [SUVR] for tau, Aß42 /40 ratio, phosphorylated tau 181 [p-tau181], neurofilament light chain [NfL], and glial fibrillary acidic protein [GFAP]). RESULTS: After covariate adjustment, each standard deviation (SD) higher kPCr level was associated with 52% lower hazards of developing MCI/dementia, and with 59% lower odds of being PiB positive with specific associations in DVR of frontal, parietal, and temporal regions, and cingulate cortex and pallidum. Higher kPCr level was also associated with lower plasma GFAP. DISCUSSION: In aging, mitochondrial dysfunction may play a vital role in AD pathological changes and neuroinflammation. Highlights Higher in vivo mitochondrial function is related to lower risk of mild cognitive impairment (MCI)/dementia. Higher in vivo mitochondrial function is related to lower amyloid tracer uptake. Higher in vivo mitochondrial function is related to lower plasma neuroinflammation. Mitochondrial dysfunction may play a key role in Alzheimer's disease (AD) and neurodegeneration.

Lower myelin content is associated with more rapid cognitive decline among cognitively unimpaired individuals.

INTRODUCTION: The influence of myelination on longitudinal changes in cognitive performance remains unclear. METHODS: For each participant (N = 123), longitudinal cognitive scores were calculated. Myelin content was probed using myelin water fraction (MWF) or longitudinal relaxation rate (R1 ); both are MRI measures sensitive to myelin, with MWF being specific. RESULTS: Lower MWF was associated with steeper declines in executive function (p < .02 in all regions) and lower R1 was associated with steeper declines in verbal fluency (p < .03 in all regions). Additionally, lower R1 was associated with steeper declines in executive function (p < .02 in all regions) and memory (p < .04 in occipital and cerebral white matter) but did not survive Bonferroni correction. DISCUSSION: We demonstrate significant relationships between myelin content and the rates of change in cognitive performance among cognitively normal individuals. These findings highlight the importance of myelin in cognitive functioning and suggest MWF and R1 as imaging biomarkers to predict cognitive changes.

Longitudinal changes in Alzheimer's-related plasma biomarkers and brain amyloid.

INTRODUCTION: Understanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise Alzheimer's progression assessment strategies. METHODS: We examined the temporal order of changes in plasma amyloid-ß ratio ( A ß 42 / A ß 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ ), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau ratios ( p-tau181 / A ß 42 $\text{p-tau181}/\mathrm{A}{\beta}_{42}$ , p-tau231 / A ß 42 $\text{p-tau231}/\mathrm{A}{\beta}_{42}$ ) relative to 11 C-Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB-/+). Participants (n = 199) were cognitively normal at index visit with a median 6.1-year follow-up. RESULTS: PiB groups exhibited different rates of longitudinal change in A ß 42 / A ß 40 ( ß = 5.41 × 10 - 4 , SE = 1.95 × 10 - 4 , p = 0.0073 ) ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}\ ( {\beta \ = \ 5.41 \times {{10}}^{ - 4},{\rm{\ SE\ }} = \ 1.95 \times {{10}}^{ - 4},\ p\ = \ 0.0073} )$ . Change in brain amyloid correlated with change in GFAP (r = 0.5, 95% CI = [0.26, 0.68]). The greatest relative decline in A ß 42 / A ß 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ (-1%/year) preceded brain amyloid positivity by 41 years (95% CI = [32, 53]). DISCUSSION: Plasma A ß 42 / A ß 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ may begin declining decades prior to brain amyloid accumulation, whereas p-tau ratios, GFAP, and NfL increase closer in time. HIGHLIGHTS Plasma A ß 42 / A ß 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ declines over time among PiB- but does not change among PiB+. Phosphorylated-tau to Aß42 ratios increase over time among PiB+ but do not change among PiB-. Rate of change in brain amyloid is correlated with change in GFAP and neurofilament light chain. The greatest decline in A ß 42 / A ß 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ may precede brain amyloid positivity by decades.

Association of Lifestyle Activities with Functional Brain Connectivity and Relationship to Cognitive Decline among Older Adults.

This study examines the relationship of engagement in different lifestyle activities to connectivity in large-scale functional brain networks, and whether network connectivity modifies cognitive decline, independent of brain amyloid levels. Participants (N = 153, mean age = 69 years, including N = 126 with amyloid imaging) were cognitively normal when they completed resting-state functional magnetic resonance imaging, a lifestyle activity questionnaire, and cognitive testing. They were followed with annual cognitive tests up to 5 years (mean = 3.3 years). Linear regressions showed positive relationships between cognitive activity engagement and connectivity within the dorsal attention network, and between physical activity levels and connectivity within the default-mode, limbic, and frontoparietal control networks, and global within-network connectivity. Additionally, higher cognitive and physical activity levels were independently associated with higher network modularity, a measure of functional network specialization. These associations were largely independent of APOE4 genotype, amyloid burden, global brain atrophy, vascular risk, and level of cognitive reserve. Moreover, higher connectivity in the dorsal attention, default-mode, and limbic networks, and greater global connectivity and modularity were associated with reduced cognitive decline, independent of APOE4 genotype and amyloid burden. These findings suggest that changes in functional brain connectivity may be one mechanism by which lifestyle activity engagement reduces cognitive decline.

Bile acid synthesis, modulation, and dementia: A metabolomic, transcriptomic, and pharmacoepidemiologic study.

BACKGROUND: While Alzheimer disease (AD) and vascular dementia (VaD) may be accelerated by hypercholesterolemia, the mechanisms underlying this association are unclear. We tested whether dysregulation of cholesterol catabolism, through its conversion to primary bile acids (BAs), was associated with dementia pathogenesis. METHODS AND FINDINGS: We used a 3-step study design to examine the role of the primary BAs, cholic acid (CA), and chenodeoxycholic acid (CDCA) as well as their principal biosynthetic precursor, 7α-hydroxycholesterol (7α-OHC), in dementia. In Step 1, we tested whether serum markers of cholesterol catabolism were associated with brain amyloid accumulation, white matter lesions (WMLs), and brain atrophy. In Step 2, we tested whether exposure to bile acid sequestrants (BAS) was associated with risk of dementia. In Step 3, we examined plausible mechanisms underlying these findings by testing whether brain levels of primary BAs and gene expression of their principal receptors are altered in AD. Step 1: We assayed serum concentrations CA, CDCA, and 7α-OHC and used linear regression and mixed effects models to test their associations with brain amyloid accumulation (N = 141), WMLs, and brain atrophy (N = 134) in the Baltimore Longitudinal Study of Aging (BLSA). The BLSA is an ongoing, community-based cohort study that began in 1958. Participants in the BLSA neuroimaging sample were approximately 46% male with a mean age of 76 years; longitudinal analyses included an average of 2.5 follow-up magnetic resonance imaging (MRI) visits. We used the Alzheimer's Disease Neuroimaging Initiative (ADNI) (N = 1,666) to validate longitudinal neuroimaging results in BLSA. ADNI is an ongoing, community-based cohort study that began in 2003. Participants were approximately 55% male with a mean age of 74 years; longitudinal analyses included an average of 5.2 follow-up MRI visits. Lower serum concentrations of 7α-OHC, CA, and CDCA were associated with higher brain amyloid deposition (p = 0.041), faster WML accumulation (p = 0.050), and faster brain atrophy mainly (false discovery rate [FDR] p = <0.001-0.013) in males in BLSA. In ADNI, we found a modest sex-specific effect indicating that lower serum concentrations of CA and CDCA were associated with faster brain atrophy (FDR p = 0.049) in males.Step 2: In the Clinical Practice Research Datalink (CPRD) dataset, covering >4 million registrants from general practice clinics in the United Kingdom, we tested whether patients using BAS (BAS users; 3,208 with ≥2 prescriptions), which reduce circulating BAs and increase cholesterol catabolism, had altered dementia risk compared to those on non-statin lipid-modifying therapies (LMT users; 23,483 with ≥2 prescriptions). Patients in the study (BAS/LMT) were approximately 34%/38% male and with a mean age of 65/68 years; follow-up time was 4.7/5.7 years. We found that BAS use was not significantly associated with risk of all-cause dementia (hazard ratio (HR) = 1.03, 95% confidence interval (CI) = 0.72-1.46, p = 0.88) or its subtypes. We found a significant difference between the risk of VaD in males compared to females (p = 0.040) and a significant dose-response relationship between BAS use and risk of VaD (p-trend = 0.045) in males.Step 3: We assayed brain tissue concentrations of CA and CDCA comparing AD and control (CON) samples in the BLSA autopsy cohort (N = 29). Participants in the BLSA autopsy cohort (AD/CON) were approximately 50%/77% male with a mean age of 87/82 years. We analyzed single-cell RNA sequencing (scRNA-Seq) data to compare brain BA receptor gene expression between AD and CON samples from the Religious Orders Study and Memory and Aging Project (ROSMAP) cohort (N = 46). ROSMAP is an ongoing, community-based cohort study that began in 1994. Participants (AD/CON) were approximately 56%/36% male with a mean age of 85/85 years. In BLSA, we found that CA and CDCA were detectable in postmortem brain tissue samples and were marginally higher in AD samples compared to CON. In ROSMAP, we found sex-specific differences in altered neuronal gene expression of BA receptors in AD. Study limitations include the small sample sizes in the BLSA cohort and likely inaccuracies in the clinical diagnosis of dementia subtypes in primary care settings. CONCLUSIONS: We combined targeted metabolomics in serum and amyloid positron emission tomography (PET) and MRI of the brain with pharmacoepidemiologic analysis to implicate dysregulation of cholesterol catabolism in dementia pathogenesis. We observed that lower serum BA concentration mainly in males is associated with neuroimaging markers of dementia, and pharmacological lowering of BA levels may be associated with higher risk of VaD in males. We hypothesize that dysregulation of BA signaling pathways in the brain may represent a plausible biologic mechanism underlying these results. Together, our observations suggest a novel mechanism relating abnormalities in cholesterol catabolism to risk of dementia.

The Brain Chart of Aging: Machine-learning analytics reveals links between brain aging, white matter disease, amyloid burden, and cognition in the iSTAGING consortium of 10,216 harmonized MR scans.

INTRODUCTION: Relationships between brain atrophy patterns of typical aging and Alzheimer's disease (AD), white matter disease, cognition, and AD neuropathology were investigated via machine learning in a large harmonized magnetic resonance imaging database (11 studies; 10,216 subjects). METHODS: Three brain signatures were calculated: Brain-age, AD-like neurodegeneration, and white matter hyperintensities (WMHs). Brain Charts measured and displayed the relationships of these signatures to cognition and molecular biomarkers of AD. RESULTS: WMHs were associated with advanced brain aging, AD-like atrophy, poorer cognition, and AD neuropathology in mild cognitive impairment (MCI)/AD and cognitively normal (CN) subjects. High WMH volume was associated with brain aging and cognitive decline occurring in an ≈10-year period in CN subjects. WMHs were associated with doubling the likelihood of amyloid beta (Aß) positivity after age 65. Brain aging, AD-like atrophy, and WMHs were better predictors of cognition than chronological age in MCI/AD. DISCUSSION: A Brain Chart quantifying brain-aging trajectories was established, enabling the systematic evaluation of individuals' brain-aging patterns relative to this large consortium.

Lasting consequences of concussion on the aging brain: Findings from the Baltimore Longitudinal Study of Aging.

Studies suggest that concussions may be related to increased risk of neurodegenerative diseases, such as Chronic Traumatic Encephalopathy and Alzheimer's Disease. Most neuroimaging studies show effects of concussions in frontal and temporal lobes of the brain, yet the long-term impacts of concussions on the aging brain have not been well studied. We examined neuroimaging data from 51 participants (mean age at first imaging visit=65.1 ± 11.23) in the Baltimore Longitudinal Study of Aging (BLSA) who reported a concussion in their medical history an average of 23 years prior to the first imaging visit, and compared them to 150 participants (mean age at first imaging visit=66.6 ± 10.97) with no history of concussion. Participants underwent serial structural MRI over a mean of 5.17±6.14 years and DTI over a mean of 2.92±2.22 years to measure brain structure, as well as 15O-water PET over a mean of 5.33±2.19 years to measure brain function. A battery of neuropsychological tests was also administered over a mean of 11.62±7.41 years. Analyses of frontal and temporal lobe regions were performed to examine differences in these measures between the concussion and control groups at first imaging visit and in change over time. Compared to those without concussion, participants with a prior concussion had greater brain atrophy in temporal lobe white matter and hippocampus at first imaging visit, which remained stable throughout the follow-up visits. Those with prior concussion also showed differences in white matter microstructure using DTI, including increased radial and axial diffusivity in the fornix/stria terminalis, anterior corona radiata, and superior longitudinal fasciculus at first imaging visit. In 15O-water PET, higher resting cerebral blood flow was seen at first imaging visit in orbitofrontal and lateral temporal regions, and both increases and decreases were seen in prefrontal, cingulate, insular, hippocampal, and ventral temporal regions with longitudinal follow-up. There were no significant differences in neuropsychological performance between groups. Most of the differences observed between the concussed and non-concussed groups were seen at the first imaging visit, suggesting that concussions can produce long-lasting structural and functional alterations in temporal and frontal regions of the brain in older individuals. These results also suggest that many of the reported short-term effects of concussion may still be apparent later in life.

Association of peripheral inflammatory markers with connectivity in large-scale functional brain networks of non-demented older adults.

BACKGROUND: Systemic inflammation has emerged as a risk factor for cognitive decline and Alzheimer's disease, but inflammation's effect on distributed brain networks is unclear. We examined the relationship between peripheral inflammatory markers and subsequent functional connectivity within five large-scale cognitive networks and evaluated the modifying role of cortical amyloid and APOE ε4 status. METHODS: Blood levels of soluble tumor necrosis factor-alpha receptor-1 and interleukin 6 were assessed in 176 participants (at baseline mean age: 65 (SD 9) years; 63% women; 85% cognitively normal, 15% mild cognitive impairment (MCI)) and were combined to derive an Inflammatory Index. Approximately six years later, participants underwent resting-state functional magnetic resonance imaging to quantify functional connectivity; a subset of 137 participants also underwent 11C Pittsburgh compound-B (PiB) PET imaging to assess cortical amyloid burden. RESULTS: Using linear regression models adjusted for demographic characteristics and cardiovascular risk factors, a higher Inflammatory Index was associated with lower connectivity within the Default Mode (ß = -0.013; 95% CI: -0.023, -0.003) and the Dorsal Attention Networks (ß = -0.017; 95% CI: -0.028, -0.006). The strength of these associations did not vary by amyloid status (positive/negative). However, there was a significant interaction between Inflammatory Index and APOE ε4 status, whereby ε4-positive participants with a higher Inflammatory Index demonstrated lower connectivity. Inflammatory Index was unrelated to connectivity within other large-scale cognitive networks (Control, Limbic, and Salience/Ventral Attention networks). CONCLUSION: Peripheral pro-inflammatory signaling in older adults without dementia, especially among APOE ε4-positive individuals, is associated with altered connectivity within two large-scale cognitive networks.

Brain Oxygen Extraction by Using MRI in Older Individuals: Relationship to Apolipoprotein E Genotype and Amyloid Burden.

Background Apolipoprotein E4 (APOE4) is a major genetic risk factor for late-onset Alzheimer disease. However, the mechanisms by which APOE4 affects the brain, underpinning this risk, have not been fully elucidated. Purpose To investigate the influence of APOE4 on global cerebral oxygen extraction fraction (OEF) and possible mediation through amyloid burden by using MRI-based brain oxygen extraction technique. Materials and Methods Participants were enrolled from a longitudinal prospective study, the Biomarkers for Older Controls at Risk for Dementia study (data collected from January 2015 to December 2017), of whom 35% (50 of 143 participants) were APOE4 carriers. OEF was measured by using a T2-relaxation-under-spin-tagging MRI technique with a 3.0-T MRI system. PET acquired with carbon 11-labeled Pittsburgh compound B tracer was available in 119 participants to measure amyloid burden. Cognitive performance was assessed by using domain-specific composite scores including executive function, episodic memory, visual-spatial processing, and language. Linear regression analysis was performed to investigate the relationship between APOE4, OEF, and amyloid burden. The association between OEF and cognitive function was studied for the entire study cohort and separately for the APOE4 carriers and noncarriers. Results A total of 143 cognitively healthy individuals (mean age 6 standard deviation, 69.1 years 6 8.2; 57 men and 86 women) were studied. APOE4 genetic status was associated with lower OEF (noncarriers, 41.1% 6 5.8; one E4 allele, 40.1% 6 4.9; two E4 alleles, 36.7% 6 4.5; P = .03). Furthermore, among APOE4 carriers, lower OEF correlated with lower executive function scores (b = 0.079 z score for each percent change in OEF; P = .03). Amyloid burden and OEF were independently associated with APOE4 but were not associated with one another, suggesting that the effect of APOE4 on OEF is not mediated by amyloid. Conclusion MRI-based brain oxygen extraction shows that cognitively healthy carriers of the apolipoprotein E4 gene manifest diminished brain oxygen extraction capacity independent of amyloid burden. ©RSNA, 2019 Online supplemental material is available for this article.

Effects of amyloid pathology and neurodegeneration on cognitive change in cognitively normal adults.

Understanding short-term cognitive decline in relation to Alzheimer's neuroimaging biomarkers in early stages of the development of neuropathology and neurodegeneration will inform participant recruitment and monitoring strategies in clinical trials aimed at prevention of cognitive impairment and dementia. We assessed associations among neuroimaging measures of cerebral amyloid pathology, a hallmark Alzheimer's neuropathology, hippocampal atrophy, and prospective cognition among 171 cognitively normal Baltimore Longitudinal Study of Aging participants (baseline age 56-95 years, 48% female, 562 cognitive assessments, 3.7 years follow-up). We categorized each individual based on dichotomous amyloid pathology (A) and hippocampal neurodegeneration (N) status at baseline: A-N-, A+N-, A-N+, A+N+. We conducted linear mixed effects analyses to assess cross-sectional and longitudinal trends in cognitive test z-scores by amyloid and neurodegeneration group. To investigate the effects of amyloid dose and degree of hippocampal atrophy, we assessed the associations of continuous mean cortical amyloid level and hippocampal volume with cognitive performance among individuals with detectable amyloid pathology at baseline. Individuals with amyloidosis or hippocampal atrophy had steeper longitudinal declines in verbal episodic memory and learning compared to those with neither condition (A+N- versus A-N-: ß = - 0.069, P = 0.017; A-N+ versus A-N-: ß = - 0.081, P = 0.025). Among individuals with hippocampal atrophy, amyloid positivity was associated with steeper declines in verbal memory (ß = - 0.123, P = 0.015), visual memory (ß = - 0.121, P = 0.036), language (ß = - 0.144, P = 0.0004), and mental status (ß = - 0.242, P = 0.002). Similarly, among individuals with amyloidosis, hippocampal atrophy was associated with steeper declines in verbal memory (ß = - 0.135, P = 0.004), visual memory (ß = - 0.141, P = 0.010), language (ß = - 0.108, P = 0.006), and mental status (ß = - 0.165, P = 0.022). Presence of both amyloidosis and hippocampal atrophy was associated with greater declines than would be expected by their additive contributions in visual memory (ß = - 0.139, P = 0.036), language (ß = - 0.132, P = 0.005), and mental status (ß = - 0.170, P = 0.049). Neither amyloidosis nor hippocampal atrophy was predictive of declines in executive function, processing speed, or visuospatial ability. Among individuals with amyloidosis, higher baseline amyloid level was associated with lower concurrent visual memory, steeper declines in language, visuospatial ability, and mental status, whereas greater hippocampal atrophy was associated with steeper declines in category fluency. Our results suggest that both amyloid pathology and neurodegeneration have disadvantageous, in part synergistic, effects on prospective cognition. These cognitive effects are detectable early among cognitively normal individuals with amyloidosis, who are in preclinical stages of Alzheimer's disease according to research criteria. Our findings highlight the importance of early intervention to target both amyloidosis and atrophy to preserve cognitive function before further damage occurs.

A multivariate nonlinear mixed effects model for longitudinal image analysis: Application to amyloid imaging.

It is important to characterize the temporal trajectories of disease-related biomarkers in order to monitor progression and identify potential points of intervention. These are especially important for neurodegenerative diseases, as therapeutic intervention is most likely to be effective in the preclinical disease stages prior to significant neuronal damage. Neuroimaging allows for the measurement of structural, functional, and metabolic integrity of the brain at the level of voxels, whose volumes are on the order of mm(3). These voxelwise measurements provide a rich collection of disease indicators. Longitudinal neuroimaging studies enable the analysis of changes in these voxelwise measures. However, commonly used longitudinal analysis approaches, such as linear mixed effects models, do not account for the fact that individuals enter a study at various disease stages and progress at different rates, and generally consider each voxelwise measure independently. We propose a multivariate nonlinear mixed effects model for estimating the trajectories of voxelwise neuroimaging biomarkers from longitudinal data that accounts for such differences across individuals. The method involves the prediction of a progression score for each visit based on a collective analysis of voxelwise biomarker data within an expectation-maximization framework that efficiently handles large amounts of measurements and variable number of visits per individual, and accounts for spatial correlations among voxels. This score allows individuals with similar progressions to be aligned and analyzed together, which enables the construction of a trajectory of brain changes as a function of an underlying progression or disease stage. We apply our method to studying cortical ß-amyloid deposition, a hallmark of preclinical Alzheimer's disease, as measured using positron emission tomography. Results on 104 individuals with a total of 300 visits suggest that precuneus is the earliest cortical region to accumulate amyloid, closely followed by the cingulate and frontal cortices, then by the lateral parietal cortex. The extracted progression scores reveal a pattern similar to mean cortical distribution volume ratio (DVR), an index of global brain amyloid levels. The proposed method can be applied to other types of longitudinal imaging data, including metabolism, blood flow, tau, and structural imaging-derived measures, to extract individualized summary scores indicating disease progression and to provide voxelwise trajectories that can be compared between brain regions.

Individual estimates of age at detectable amyloid onset for risk factor assessment.

INTRODUCTION: Individualized estimates of age at detectable amyloid-beta (Aß) accumulation, distinct from amyloid positivity, allow for analysis of onset age of Aß accumulation as an outcome measure to understand risk factors. METHODS: Using longitudinal Pittsburgh compound B (PiB) positron emission tomography data from Baltimore Longitudinal Study of Aging, we estimated the age at which each PiB+ individual began accumulating Aß. We used survival analysis methods to quantify risk of accumulating Aß and differences in onset age of Aß accumulation in relation to APOE ε4 status and sex among 36 APOE ε4 carriers and 83 noncarriers. RESULTS: Age at onset of Aß accumulation for the APOE ε4- and ε4+ groups was 73.1 and 60.7, respectively. APOE ε4 positivity conferred a threefold risk of accumulating Aß after adjusting for sex and education. DISCUSSION: Estimation of onset age of amyloid accumulation may help gauge treatment efficacy in interventions to delay symptom onset in Alzheimer's disease.

Deformation field correction for spatial normalization of PET images.

Spatial normalization of positron emission tomography (PET) images is essential for population studies, yet the current state of the art in PET-to-PET registration is limited to the application of conventional deformable registration methods that were developed for structural images. A method is presented for the spatial normalization of PET images that improves their anatomical alignment over the state of the art. The approach works by correcting the deformable registration result using a model that is learned from training data having both PET and structural images. In particular, viewing the structural registration of training data as ground truth, correction factors are learned by using a generalized ridge regression at each voxel given the PET intensities and voxel locations in a population-based PET template. The trained model can then be used to obtain more accurate registration of PET images to the PET template without the use of a structural image. A cross validation evaluation on 79 subjects shows that the proposed method yields more accurate alignment of the PET images compared to deformable PET-to-PET registration as revealed by 1) a visual examination of the deformed images, 2) a smaller error in the deformation fields, and 3) a greater overlap of the deformed anatomical labels with ground truth segmentations.

Extreme deep white matter hyperintensity volumes are associated with African American race.

BACKGROUND: African Americans (AAs) have a higher prevalence of extreme ischemic white matter hyperintensities (WMHs) on magnetic resonance imaging (MRI) than do European Americans (EAs) based on the Cardiovascular Health Study (CHS) score. Ischemic white matter disease, limited to the deep white matter, may be biologically distinct from disease in other regions and may reflect a previously observed trend toward an increased risk of subcortical lacunar infarcts in AAs. We hypothesized that extreme deep WMH volume (DWMV) or periventricular volume (PV) may also have a higher prevalence in AAs. Thus, we studied extreme CHS scores and extreme DWMV and PV in a healthy population enriched for cardiovascular disease risk factors. METHODS: We imaged the brains of 593 subjects who were first-degree relatives of probands with early onset coronary disease prior to 60 years of age. WMHs were manually delineated on 3-tesla cranial MRI by a trained radiology reader; the location and volume of lesions were characterized using automated software. DWMV and PV were measured directly with automated software, and the CHS score was determined by a neuroradiologist. Volumes were characterized as being in the upper 25% versus lower 75% of total lesion volume. Volumes in the upper versus the remaining quartiles were examined for AA versus EA race using multiple logistic regression (generalized estimating equations adjusted for family relatedness) and adjusted for major vascular disease risk factors including age ≥55 years versus <55, sex, current smoking, obesity, hypertension, diabetes and low-density lipoprotein >160 mg/dl. RESULTS: Participants were 58% women and 37% AAs, with a mean age of 51.5 ± 11.0 years (range, 29-74 years). AAs had significantly higher odds of having extreme DWMVs (odds ratio, OR, 1.8; 95% confidence interval, CI, 1.2-2.9; p = 0.0076) independently of age, sex, hypertension and all other risk factors. AAs also had significantly higher odds of having extreme CHS scores ≥3 (OR, 1.3; 95% CI, 1.1-3.6; p = 0.025). Extreme PV was not significantly associated with AA race (OR, 1.3; 95% CI, 0.81-2.1; p = 0.26). CONCLUSIONS: AAs from families with early-onset cardiovascular disease are more likely to have extreme DWMVs (a subclinical form of cerebrovascular disease) and an extreme CHS score, but not extreme PV, independently of age and other cardiovascular disease risk factors. These findings suggest that this AA population is at an increased risk for DWMV and may be at an increased risk for future subcortical stroke. Longitudinal studies are required to see if DWMV is predictive of symptomatic subcortical strokes in this population.

Trajectories of Alzheimer disease-related cognitive measures in a longitudinal sample.

BACKGROUND: The delineation of the relative temporal trajectories of specific cognitive measures associated with Alzheimer's disease (AD) is important for evaluating preclinical markers and monitoring disease progression. METHODS: We characterized the temporal trajectories of measures of verbal episodic memory, short-term visual memory, and mental status using data from 895 participants in the Baltimore Longitudinal Study of Aging. RESULTS: The California Verbal Learning Test (CVLT) immediate recall was the first measure to decline, followed by CVLT delayed recall. However, further along the disease progression scale, CVLT delayed recall and visual memory changed more rapidly than CVLT immediate recall. CONCLUSIONS: Our findings reconcile reports of early changes in immediate recall with greater reliance on delayed recall performance in clinical settings. Moreover, the utility of cognitive markers in evaluating AD progression depends on the stage of cognitive decline, suggesting that optimal endpoints in therapeutic trials may vary across different stages of the disease process.

Differences in Daily Physical Activity by Alzheimer's Risk Markers Among Older Adults.

BACKGROUND: Daily physical activity patterns differ by Alzheimer's disease (AD) status and might signal cognitive risk. It is critical to understand whether patterns are disrupted early in the AD pathological process. Yet, whether established AD risk markers (ß-amyloid [Aß] or apolipoprotein E-ε4 [APOE-ε4]) are associated with differences in objectively measured activity patterns among cognitively unimpaired older adults is unclear. METHODS: Wrist accelerometry, brain Aß (+/-), and APOE-ε4 genotype were collected in 106 (Aß) and 472 (APOE-ε4) participants (mean age 76 [standard deviation{SD}: 8.5) or 75 [SD: 9.2] years, 60% or 58% women) in the Baltimore Longitudinal Study of Aging. Adjusted linear and function-on-scalar regression models examined whether Aß or APOE-ε4 status was cross-sectionally associated with activity patterns (amount, variability, or fragmentation) overall and by time of day, respectively. Differences in activity patterns by combinations of Aß and APOE-ε4 status were descriptively examined (n = 105). RESULTS: There were no differences in any activity pattern by Aß or APOE-ε4 status overall. Aß+ was associated with lower total amount and lower within-day variability of physical activity overnight and early evening, and APOE-ε4 carriers had higher total amount of activity in the evening and lower within-day variability of activity in the morning. Diurnal curves of activity were blunted among those with Aß+ regardless of APOE-ε4 status, but only when including older adults with mild cognitive impairment/dementia. CONCLUSIONS: Aß+ in cognitively unimpaired older adults might manifest as lower amount and variability of daily physical activity, particularly during overnight/evening hours. Future research is needed to examine changes in activity patterns in larger samples and by other AD biomarkers.

Evaluating a novel 24-hour rest/activity rhythm marker of preclinical ß-amyloid deposition.

STUDY OBJECTIVES: To compare sleep and 24-hour rest/activity rhythms (RARs) between cognitively normal older adults who are ß-amyloid-positive (Aß+) or Aß- and replicate a novel time-of-day-specific difference between these groups identified in a previous exploratory study. METHODS: We studied 82 cognitively normal participants from the Baltimore Longitudinal Study of Aging (aged 75.7 ±â€…8.5 years, 55% female, 76% white) with wrist actigraphy data and Aß+ versus Aß- status measured by [11C] Pittsburgh compound B positron emission tomography. RARs were calculated using epoch-level activity count data from actigraphy. We used novel, data-driven function-on-scalar regression analyses and standard RAR metrics to cross-sectionally compare RARs between 25 Aß+ and 57 Aß- participants. RESULTS: Compared to Aß- participants, Aß+ participants had higher mean activity from 1:00 p.m. to 3:30 p.m. when using less conservative pointwise confidence intervals (CIs) and from 1:30 p.m. to 2:30 p.m. using more conservative, simultaneous CIs. Furthermore, Aß+ participants had higher day-to-day variability in activity from 9:00 a.m. to 11:30 a.m. and lower variability from 1:30 p.m. to 4:00 p.m. and 7:30 p.m. to 10:30 p.m. according to pointwise CIs, and lower variability from 8:30 p.m. to 10:00 p.m. using simultaneous CIs. There were no Aß-related differences in standard sleep or RAR metrics. CONCLUSIONS: Findings suggest Aß+ older adults have higher, more stable day-to-day afternoon/evening activity than Aß- older adults, potentially reflecting circadian dysfunction. Studies are needed to replicate our findings and determine whether these or other time-of-day-specific RAR features have utility as markers of preclinical Aß deposition and if they predict clinical dementia and agitation in the afternoon/evening (i.e. "sundowning").