Biomedical subjects

Susan M Resnick

Publications and source records attributed to Susan M Resnick.

At least 19 recordsLinked to original sources

PubMed2026

Sex-specific biological aging clocks across organs and omics.

Sex differentially shapes aging, neurodevelopment and neurodegenerative diseases such as Alzheimer's disease (AD). However, most biological aging clocks (artificial intelligence-predicted age minus chronological age) were trained on sex-pooled samples and implicitly assume sex invariance.Here we developed 38 sex-specific biological aging clocks across 15 organ systems. We first demonstrate the importance of sex-stratified training for constructing sex-specific healthy normative references and then reveal marked divergence between female and male clocks. Key genetic parameters and Mendelian randomization results indicate that organ-specific aging liability and its relationships to cardiometabolic, endocrine and mental traits are configured differently in females and males. Proteomic analyses identify distinct, organ-resolved synaptic, immune, vascular and metabolic networks that differentially track female and male biological aging. In longitudinal survival analyses, sex-specific clocks predict whole-body systemic diseases and all-cause mortality in a sex-dependent and organ-dependent manner. Further analyses reveal sex-dependent associations between the brain aging clock and cognitive decline trajectory during a preclinical AD clinical trial. Sex-stratified clocks may offer distinct value by defining biological age against sex-appropriate normative references and revealing sex-dependent genetic, molecular and clinical signatures that pooled models may obscure. Meanwhile, sex-pooled and sex-interaction approaches remain valuable, as human aging and disease also share fundamental biological similarities between females and males. Together, these findings reveal sex-specific biological aging signatures in aging, AD and systemic health, highlighting the need for explicitly sex-stratified modeling approaches.

Journal Article↗

PubMed2026

Epigenetic Clocks of Biological Aging and Cognitively Healthy Longevity: The Women's Health Initiative Memory Study.

BACKGROUND: Little is known about whether epigenetic age acceleration (EAA) clocks are capable of predicting exceptional longevity with or without preserved cognitive function. METHODS: We examined 5844 women from the Women's Health Initiative Memory Study. Fifteen epigenetic clocks were measured at baseline (1996-1999). Longevity outcomes were defined as: 1) survival to age 90 with preserved cognition (n = 1726, 29.5%); or 2) survival to age 90 with cognitive impairment (n = 956, 16.4%); vs. 3) death before age 90 (n = 2611, 44.7%). Logistic regression models examined associations between the 15 clocks and survival to age 90 (vs. death before age 90), adjusting for covariates. Multinomial logistic regression models examined associations with survival to age 90 without cognitive impairment and survival to age 90 with cognitive impairment (each vs. death before age 90), also adjusting for covariates. RESULTS: Each standard deviation increase in EAA for the first-generation clocks was associated with 7%-18% reduced odds of survival to age 90 vs. earlier death. Stronger associations were observed for second- and third-generation clocks, including AgeAccelGrim2 (OR = 0.66; 95% CI 0.61-0.71), PCGrimAge (OR = 0.64; 95% CI 0.59-0.69), PCPhenoAge (OR = 0.73; 95% CI 0.68-0.78) and DunedinPACE (OR = 0.77; 95% CI 0.72-0.82). None of the clocks was more strongly associated with survival to age 90 with preserved cognition than with survival to age 90 with cognitive impairment, relative to death before age 90. CONCLUSION: All epigenetic clocks were associated with exceptional longevity, but none were associated with cognitive healthspan. Developing clocks that can differentiate long survival with and without preserved cognitive function is critical.

Healthspan↗

PubMed2026

Genetic modifiers of APOE-ε4-associated cognitive decline.

The APOE-ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease. However, APOE-ε4 is not deterministic, highlighting the need to identify additional genetic and environmental factors. APOE-ε4 has been linked to accelerated cognitive decline, so we sought to investigate genetic factors that modify APOE-ε4-associated cognitive decline. We conduct cross-ancestry APOE-ε4-stratified and interaction GWAS using harmonized cognitive data from 32,778 participants, including 29,354 non-Hispanic White and 3,424 non-Hispanic Black individuals. Our primary outcome is late-life cognition, measured using harmonized composite scores for memory, executive function, and language, modeled as continuous traits reflecting both normative cognitive aging and disease-related decline. We identify two genome-wide significant loci in APOE-ε4 carriers, reaching genome-wide significance for executive function. These loci also demonstrate nominal associations across the other domains, suggesting broad effects on cognition. In non-carriers, we identify a genome-wide significant association at ITGB8 restricted to executive function, and another locus associated with language. We further link these loci to SEMA6D, GRIN3A, and ITGB8 through expression and methylation databases. Post-GWAS analyses implicate additional genes including SLCO1A2, and DNAH11. Genetic correlation analyses reveal differences by APOE-ε4 status for immune-related traits, suggesting immune-related predispositions may exacerbate cognitive risk in APOE-ε4 carriers.

Humans↗

PubMed2024

Sex and APOE ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging and Alzheimer's disease.

INTRODUCTION: The effects of sex and apolipoprotein E (APOE)-Alzheimer's disease (AD) risk factors-on white matter microstructure are not well characterized. METHODS: Diffusion magnetic resonance imaging data from nine well-established longitudinal cohorts of aging were free water (FW)-corrected and harmonized. This dataset included 4741 participants (age = 73.06 ± 9.75) with 9671 imaging sessions over time. FW and FW-corrected fractional anisotropy (FAFWcorr) were used to assess differences in white matter microstructure by sex and APOE ε4 carrier status. RESULTS: Sex differences in FAFWcorr in projection tracts and APOE ε4 differences in FW limbic and occipital transcallosal tracts were most pronounced. DISCUSSION: There are prominent differences in white matter microstructure by sex and APOE ε4 carrier status. This work adds to our understanding of disparities in AD. Additional work to understand the etiology of these differences is warranted. HIGHLIGHTS: Sex and apolipoprotein E (APOE) ε4 carrier status relate to white matter microstructural integrity. Females generally have lower free water-corrected fractional anisotropy compared to males. APOE ε4 carriers tended to have higher free water than non-carriers.

Humans↗

PubMed2018

Sex-specific genetic predictors of Alzheimer's disease biomarkers.

Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = - 0.03, p = 4.25 × 10-8; β = 0.03, p = 3.97 × 10-8) than males (β = - 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10-10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.

Aged, 80 and over↗

PubMed2006

Detection of prodromal Alzheimer's disease via pattern classification of magnetic resonance imaging.

We report evidence that computer-based high-dimensional pattern classification of magnetic resonance imaging (MRI) detects patterns of brain structure characterizing mild cognitive impairment (MCI), often a prodromal phase of Alzheimer's disease (AD). Ninety percent diagnostic accuracy was achieved, using cross-validation, for 30 participants in the Baltimore Longitudinal Study of Aging. Retrospective evaluation of serial scans obtained during prior years revealed gradual increases in structural abnormality for the MCI group, often before clinical symptoms, but slower increase for individuals remaining cognitively normal. Detecting complex patterns of brain abnormality in very early stages of cognitive impairment has pivotal importance for the detection and management of AD.

Aged↗

PubMed2006

Association between alcohol intake and domain-specific cognitive function in older women.

Moderate levels of alcohol intake may be associated with better cognitive function; however, this relationship may vary between cognitive domains. Women, aged 65-80 years, enrolled in the Women's Health Initiative (WHI) randomized clinical trials of hormone therapy, underwent annual standardized testing for global cognitive function through the ancillary WHI Memory Study (average follow-up of 4.5 years) and domain-specific cognitive function through the WHI Study of Cognitive Aging (average follow-up of 1.7 years). Compared to nondrinkers, women reporting moderate levels of alcohol intake ( or=1 drink/day by 5.7% for verbal knowledge (p < 0.001) and by 5.7% for phonemic fluency (p = 0.004), compared to never-drinkers. Moderate levels of alcohol intake are associated with somewhat better cognition, which may be expressed most strongly in functions related to verbal knowledge and phonemic fluency. However, our observational study cannot rule out confounding associations with unmeasured factors.

Aged↗

PubMed2006

Long-term measures of free testosterone predict regional cerebral blood flow patterns in elderly men.

We previously reported that high circulating free testosterone (T) was associated with better performance on tests of memory, executive function, and spatial ability, and with a reduced risk for Alzheimer's disease. In this study, we report that free T levels, measured on multiple occasions over 14 years, predict regional cerebral blood flow (rCBF) measured by PET in 40 older men. Voxel-based regression, indicated that higher Free T was associated with increased rCBF in the hippocampus bilaterally (extending to the parahippocampal gyrus on the right), anterior cingulate gyrus, and right inferior frontal cortex. Total T concentrations were positively correlated with rCBF in the left putamen, bilateral thalamus, and left inferior frontal cortex and negatively correlated with amygdala rCBF bilaterally. These findings suggest that endogenous T influences brain physiology in regions critical for memory and attention and provide one mechanism through which T may affect cognitive function.

Aged↗

PubMed2006

Effects of combination estrogen plus progestin hormone treatment on cognition and affect.

CONTEXT: Some studies of hormone treatment in postmenopausal women suggest benefits on specific cognitive functions, particularly memory. OBJECTIVE: The objective of this study was to determine whether hormone therapy influences changes in specific cognitive functions and affect in older women. DESIGN: This study was a randomized, double-blind, placebo-controlled clinical trial. SETTING: Participants were women from 14 of 40 clinical centers of the Women's Health Initiative (WHI). PARTICIPANTS: Postmenopausal women (1416) aged 65 yr and older, free of probable dementia, and enrolled in WHI and the WHI Memory Study (WHIMS) trial of combination estrogen and progestin for a mean of 3 yr and followed for a mean of 1.35 yr, were studied. INTERVENTION: Intervention was conjugated equine estrogen (CEE; 0.625 mg) with 2.5 mg medroxyprogesterone acetate (MPA) in one daily tablet (CEE + MPA) or placebo. MAIN OUTCOME MEASURES: Annual rates of change in specific cognitive functions and affect, adjusted for time since randomization, were measured. RESULTS: CEE + MPA had a negative impact on verbal memory (P <or= 0.01) and a trend to a positive impact on figural memory (P = 0.012) over time compared with placebo, but other cognitive domains were not affected. Both effects on memory were evident only after long-term therapy. CEE + MPA did not significantly influence positive affect, negative affect, or depressive symptoms. CONCLUSIONS: The effect of CEE + MPA on cognitive function varies across cognitive domains in older women, reflecting both possible beneficial and detrimental actions of ovarian steroids on the aging brain. Our results extend prior findings about dementia and global cognitive function to age-related changes in specific cognitive functions and suggest directions for future research.

Affect↗

PubMed2006

Impact of Alzheimer's pathology on cognitive trajectories in nondemented elderly.

OBJECTIVE: Some individuals who are asymptomatic for dementia while alive have substantial Alzheimer's disease (AD) neuropathology at autopsy. We investigated whether cognitive trajectories differ between clinically normal elderly individuals with and without AD neuropathology and how they compare with trajectories of clinically impaired individuals before dementia diagnosis. METHODS: Eighty-one elderly participants in the Baltimore Longitudinal Study of Aging (BLSA) were followed prospectively with neurological and neuropsychological assessments before autopsy evaluation at death. Trajectories of cognitive change were estimated for a number of domains using cognitive data before a clinical diagnosis of dementia. RESULTS: Clinically normal elderly individuals with and without AD-type neuropathology have similar cognitive trajectories across different cognitive domains. In contrast, individuals with mild cognitive impairment/AD show steeper rates of longitudinal decline in several aspects of cognition compared with clinically normal elderly individuals regardless of whether the latter have AD neuropathology. Moreover, the cognitive differences between impaired and unimpaired groups can be detected years before a diagnosis of dementia. INTERPRETATION: Clinically normal individuals with and without AD neuropathology do not differ in rates of cognitive decline across a number of cognitive domains. Understanding the factors that protect some individuals with AD pathology from cognitive impairment may contribute to the maintenance of cognitive health in the elderly.

Aged↗

PubMed2005

Cross-sectional and longitudinal analyses of anatomical sulcal changes associated with aging.

Imaging studies of the human brain indicate that the cortex undergoes anatomic changes during the aging process. With the ability to study the human brain in vivo using magnetic resonance imaging, understanding the nature and location of these changes is of increasing interest. In this work, we investigate cross-sectional and longitudinal age effects on the geometric shape and gray matter (GM) volume for regions of interest on the cortical surface. Each of the regions corresponds to the buried cortex surrounding the sulcal spaces and is termed a "sulcal region." The study consists of 35 older adults scanned three times over a 4-year time span. The group includes 19 women and 16 men ranging in ages from 59 to 84 years (mean 70.9, standard deviation 6.2). We analyze 8 sulcal regions-the buried cortex surrounding the left and right central, superior frontal, cingulate, and parietooccipital sulci. We examine surface area, GM thickness, GM volume, sulcal depth, local gyrification index, and measures of curvature. Results indicate cross-sectional age effects in mean thickness, GM volume, sulcal depth, and curvature characteristics of sulcal regions. In addition, we found longitudinal decreases in surface area, mean thickness, GM volume, and sulcal depth measures as well as changes in sulcal curvature.

Aged↗

PubMed2005

Cortical reconstruction using implicit surface evolution: accuracy and precision analysis.

Two different studies were conducted to assess the accuracy and precision of an algorithm developed for automatic reconstruction of the cerebral cortex from T1-weighted magnetic resonance (MR) brain images. Repeated scans of three different brains were used to quantify the precision of the algorithm, and manually selected landmarks on different sulcal regions throughout the cortex were used to analyze the accuracy of the three reconstructed surfaces: inner, central, and pial. We conclude that the algorithm can find these surfaces in a robust fashion and with subvoxel accuracy, typically with an accuracy of one third of a voxel, although this varies with brain region and cortical geometry. Parameters were adjusted on the basis of this analysis in order to improve the algorithm's overall performance.

Algorithms↗

PubMed2005

Age differences in the neural systems supporting human allocentric spatial navigation.

Age-related declines in spatial navigation are well-known in human and non-human species. Studies in non-human species suggest that alteration in hippocampal and other neural circuitry may underlie behavioral deficits associated with aging but little is known about the neural mechanisms of human age-related decline in spatial navigation. The purpose of the present study was to examine age differences in functional brain activation during virtual environment navigation. Voxel-based analysis of activation patterns in young subjects identified activation in the hippocampus and parahippocampal gyrus, retrosplenial cortex, right and left lateral parietal cortex, medial parietal lobe and cerebellum. In comparison to younger subjects, elderly participants showed reduced activation in the hippocampus and parahippocampal gyrus, medial parietal lobe and retrosplenial cortex. Relative to younger participants elderly subjects showed increased activation in anterior cingulate gyrus and medial frontal lobe. These results provide evidence of age specific neural networks supporting spatial navigation and identify a putative neural substrate for age-related differences in spatial memory and navigational skill.

Adult↗

PubMed2005

Program for Assisted Labeling of Sulcal Regions (PALS): description and reliability.

With the improvements in techniques for generating surface models from magnetic resonance (MR) images, it has recently become feasible to study the morphological characteristics of the human brain cortex in vivo. Studies of the entire surface are important for measuring global features, but analysis of specific cortical regions of interest provides a more detailed understanding of structure. We have previously developed a method for automatically segmenting regions of interest from the cortical surface using a watershed transform. Each segmented region corresponds to a cortical sulcus and is thus termed a "sulcal region." In this work, we describe two important augmentations of this methodology. First, we describe a user interface that allows for the efficient labeling of the segmented sulcal regions called the Program for Assisted Labeling of Sulcal Regions (PALS). An additional augmentation allows for even finer divisions on the cortex with a methodology that employs the fast marching technique to track a curve on the cortical surface that is then used to separate segmented regions. After regions of interest have been identified, we compute both the cortical surface area and gray matter volume. Reliability experiments are performed to assess both the long-term stability and short-term repeatability of the proposed techniques. These experiments indicate the proposed methodology gives both highly stable and repeatable results.

Algorithms↗

PubMed2005

Alpha-synuclein lesions in normal aging, Parkinson disease, and Alzheimer disease: evidence from the Baltimore Longitudinal Study of Aging (BLSA).

Alpha-synuclein (alpha-synuclein) lesions are characteristic of idiopathic Parkinson disease (PD) and other alpha-synucleinopathies. To study the frequency of alpha-synuclein lesions in normal aging and how frequently they coexist with lesions of Alzheimer disease (AD), we examined the autopsy brains from normal and demented subjects in the Baltimore Longitudinal Study of Aging (BLSA) (n = 117). We found that the overall frequency of alpha-synuclein lesions was 25%, with 100% in 7 cases of PD, 31.5% in 56 cases with AD lesions, and 8.3% among 36 older control brains. Among brains with AD lesions, the frequency of alpha-synuclein pathology was higher in those with higher scores for neuritic plaques, but not in those with higher scores for neurofibrillary tangles. Our observations indicate that alpha-synuclein lesions are uncommon in aged control subjects. Finally, the coexistence of Abeta amyloid and alpha-synuclein pathology in AD brains suggests that the pathogenic mechanism/s leading to the accumulation of Abeta and alpha-synuclein may be similar.

Aged↗

PubMed2004

Psychological adjustment in children and adults with congenital adrenal hyperplasia.

OBJECTIVE: To determine psychological health in individuals with one form of intersexuality, congenital adrenal hyperplasia (CAH), and its relation to characteristics of the disease and treatment. STUDY DESIGN: Participants (ages 3-31 years) included 72 females and 42 males with CAH, and unaffected relatives (44 females and 69 males). Psychological adjustment was assessed with parent-reports on the Child Behavior Checklist (CBCL) and subject self-reports on the Self-Image Questionnaire for Young Adolescents (SIQYA) or the Multidimensional Personality Questionnaire (MPQ). Information about disease characteristics and genital surgery was obtained from medical records. RESULTS: There were no significant differences between females with CAH and unaffected females on any measure. Psychological adjustment was not significantly associated with genital virilization or age at genital surgery. Males with CAH were not significantly different from unaffected males in childhood, but they showed more negative affect at older ages. CONCLUSIONS: Psychological adjustment is not compromised in females with virilized genitalia who are treated early in life and reared as females. Adjustment does not appear to depend on the characteristics of the disease or its treatment, but sample size and restricted range limit generalizability about adjustment-disease associations.

Adaptation, Psychological↗

PubMed2004

Aging and prefrontal functions: dissociating orbitofrontal and dorsolateral abilities.

This study aimed to determine whether age differentially affects performance on tasks tapping orbitofrontal cortex (OFC) and dorsolateral prefrontal cortex (DLPFC). We administered prefrontal measures to healthy younger ( n=23; age= 28.4+/-5.9, education = 15.7+/-2.6, MMSE=29.5+/-0.6 ) and older participants ( n=20; age=69.1+/-5.0, education =15.5+/-3.4, MMSE =28.9+/-1.5). Groups did not differ on education or mental status, P>0.05. Tasks thought to involve greater OFC processing included the Iowa Gambling Task and Delayed Match and Non-Match to Sample Tasks. Tasks requiring greater DLPFC processing included Petrides' Self-Ordered Pointing, WAIS-R Digit Span Backward, Letter Fluency, and Months Backward from the Boston Revision of WMS-Mental Control. Composite z-scores were calculated for OFC and DLPFC tasks. A 2 x 2 ANOVA revealed a Group x Task interaction: F(1,41) =5.55, P=0.02, and a Group main effect: F(1,41)= 12.16, P=0.001. Follow-up analyses revealed younger adults outperformed older adults on OFC tasks only ( younger = 0.37+/-0.46, older= -0.43+/-0.70; t(41) =4.5, P<0.001 ). Post-hoc analyses of individual tasks confirmed that despite age differences on Petrides' Self-Ordered Pointing, measures requiring relatively greater OFC involvement showed larger effect sizes for age differences. Thus, tasks emphasizing OFC functions appear more sensitive to age effects when directly compared to measures of DLPFC functioning. Reasons for this difference in magnitude may stem from differential aging of prefrontal cortex or differential recruitment of alternative brain regions for successful task completion.

Adult↗

PubMed2004

Morphological classification of brains via high-dimensional shape transformations and machine learning methods.

A high-dimensional shape transformation posed in a mass-preserving framework is used as a morphological signature of a brain image. Population differences with complex spatial patterns are then determined by applying a nonlinear support vector machine (SVM) pattern classification method to the morphological signatures. Significant reduction of the dimensionality of the morphological signatures is achieved via wavelet decomposition and feature reduction methods. Applying the method to MR images with simulated atrophy shows that the method can correctly detect subtle and spatially complex atrophy, even when the simulated atrophy represents only a 5% variation from the original image. Applying this method to actual MR images shows that brains can be correctly determined to be male or female with a successful classification rate of 97%, using the leave-one-out method. This proposed method also shows a high classification rate for old adults' age classification, even under difficult test scenarios. The main characteristic of the proposed methodology is that, by applying multivariate pattern classification methods, it can detect subtle and spatially complex patterns of morphological group differences which are often not detectable by voxel-based morphometric methods, because these methods analyze morphological measurements voxel-by-voxel and do not consider the entirety of the data simultaneously.

Aged↗