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. 2024 Dec 29;46(1):e26794. doi: 10.1002/hbm.26794

Change in transverse relaxation rates (R2 ) and change in cognition for older African Americans

Melissa Lamar 1,2,✉, Konstantinos Arfanakis 1,3,4, Ana W Capuano 1,5, Shengwei Zhang 1, Debra A Fleischman 1,5, S Duke Han 1,6, Victoria N Poole 1,7, Sue E Leurgans 1,5, David A Bennett 1,5, Lisa L Barnes 1,2,5
PMCID: PMC11683048  PMID: 40454627

Abstract

Despite transverse relaxation rate (R2) being one of the fundamental contrasts in MRI, most investigations of brain R2 and cognition have been cross‐sectional and conducted in predominantly non‐Latino White adults. We investigated the profile of R2 as related to cognition in 212 older African Americans (~75 years of age) with longitudinal 3T MRI scans and cognitive test data to determine how changes in R2 are associated with changes in cognition. For each participant, the slopes of global cognitive and five cognitive domain scores were each separately combined with voxel‐specific slopes of R2 in whole brain voxelwise analyses. Participants with less negative rates of R2 change within left basal ganglia and centrum semiovale, bilateral hippocampal complex and temporal gyri, parietooccipital white matter, as well as posterior cingulate displayed less negative slopes in global cognition. Similar associations were seen for regional R2 change and episodic memory (most robustly within bilateral hippocampi) as well as semantic memory (left greater than right hemisphere involvement). Results suggest a relatively wide distribution of regional associations between rates of changes in R2 and changes in global cognition for older African Americans; a profile that became more regionally specific when considering individual cognitive domains. Relative preservation of tissue integrity across grey and white matter, and in key regions associated with specific cognitive domains, is associated with slower cognitive decline for older African Americans. These results may lay the foundation for more directed work to support healthy brain aging in older African Americans.

Keywords: African Americans, episodic memory, global cognition, MRI, R2

This longitudinal study investigated associations between rates of change in R2 and rates of change in cognition over time in 212 older African Americans without dementia. Results for global cognition are shown here (colors depict standardized effect sizes) with regional variations in iron, water, and myelin content associated with domain‐specific cognition discussed in the manuscript.

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Practitioner Points.

  • Most investigations of brain R2 and cognition have been cross‐sectional and conducted in predominantly non‐Latino White adults.

  • We investigated longitudinal 3T brain R2 profiles and changes in cognition in 212 older African Americans (~75 years of age) without dementia at baseline MRI.

  • Results suggest a relatively wide distribution of regional associations between rates of changes in R2 and changes in global cognition; a profile that became more regionally specific when considering individual cognitive domains.

1. INTRODUCTION

The transverse relaxation rate, R2 (the inverse of T2), in magnetic resonance imaging (MRI) is thought to capture additional brain abnormalities beyond that of other Alzheimer's and cerebrovascular‐related neuropathologies. This may be due in part to the fact that changes in R2 represent iron accumulation and demyelinating processes as well as associated neuronal loss and increased water content as noted in MRI to histopathological comparison studies (Besson et al., 1992; Hikita et al., 2005; House et al., 2008). Based on similar comparisons, it is believed that the alterations represented by R2 increase the possibility of oxidant‐mediated tissue damage and loss of oligodendrocytes, as well as increases in astrocytes (House et al., 2008; Quintana et al., 2006). This is in addition to the increased production of amyloid precursor proteins (APP) and the abnormal cleavage process of APP seen with alterations in transverse relaxation rates in post‐mortem comparison studies across diagnostic groups (e.g., Englund et al., 1987; House et al., 2007, 2008; Quintana et al., 2006). Our post‐mortem research incorporating ex‐vivo transverse relaxation rates from brain with Alzheimer's and cerebrovascular‐related neuropathologies in studies of Alzheimer's dementia further support the unique contribution of R2 in this diagnosis (Dawe et al., 2016; Yu, Dawe, Buchman, et al., 2017). Furthermore, we have shown that ex‐vivo R2 accounts for additional variance in global cognition and specific cognitive domains (e.g., episodic memory and perceptual speed) beyond that seen with Alzheimer's and cerebrovascular‐related neuropathologies alone (Dawe et al., 2016, 2018, 2021). Thus, the features captured by R2 in MRI, and by proxy, their downstream effects, contribute unique information to our understanding of the underlying neuropathological mechanisms of brain aging.

Despite this accumulating knowledge from our and others' post‐mortem studies, this work, as well as most ante‐mortem studies of R2 (e.g., Dean et al., 2017; House et al., 2006; Lin et al., 2023), have been conducted in predominantly White participants. Less is known, however, about the profile of R2 and its association with cognition and brain aging for African Americans. This is despite the fact that African American adults are known to have a higher prevalence of many of the risk factors shown to alter R2 in White adults (e.g., hypertension; Laporte et al., 2023). In fact, to our knowledge, no publications exist examining R2 with older African Americans. Thus, a focused study of transverse relaxation rates in relation to cognitive decline within an African American cohort is needed.

We leveraged longitudinal whole brain R2 data from African Americans participating in one of three cohort studies (Barnes et al., 2012; Bennett et al., 2012; Schneider et al., 2009), two of which focused exclusively on older African Americans (Barnes et al., 2012; Schneider et al., 2009). We combined this information with annual longitudinal assessments of cognition to determine whether changes in R2 are associated with changes in global cognition and five cognitive domains (i.e., episodic, semantic, and working memory as well as visuospatial abilities and perceptual speed). We hypothesized that changes in R2 would be associated with changes in global as well as domain‐specific cognitive functions including episodic memory. We further hypothesized that associations between MRI and global cognition would become more circumscribed when investigating specific cognitive domains (e.g., rates of changes in hippocampal R2 would be associated with rates of change in episodic memory). Results of this study may provide a foundation from which to explore targeted interventions to maintain brain integrity and bolster successful brain aging in older African Americans.

2. MATERIALS AND METHODS

2.1. Study population

To be included in the current research, individuals who self‐identified as African American and were participating in one of three cohort studies at the Rush Alzheimer's Disease Center (RADC) were considered. Specifically, the three cohort studies included the Minority Aging Research Study (MARS; Barnes et al., 2012), the Rush African American Clinical Core (AACore; Schneider et al., 2009) and the Rush Memory and Aging Project (MAP; Bennett et al., 2012). Described in detail elsewhere (Barnes et al., 2012; Bennett et al., 2012; Schneider et al., 2009), African American recruitment for these cohorts occurs in a variety of community‐based settings that cater to minoritized seniors in the metropolitan Chicago area and outlying suburbs. All three studies have rolling admission and participants enroll without known dementia, agreeing to annual clinical and cognitive evaluations that are harmonized across studies and performed by examiners blinded to previously collected data. Participants of MAP also agree to brain donation at death; however, brain donation is not required for enrollment in MARS or the AACore. Lastly, 3T MRI was first introduced in 2012 with the aim of biennial scans for those choosing to participate in this neuroimaging sub‐study. The Institutional Review Board of Rush University Medical Center approved these three cohort studies as well as neuroimaging and participants gave written informed consent for all study procedures in accordance with the Declaration of Helsinki.

At the time of these analyses, 1037 participants of MAP, MARS, and AACore had R2 data acquired using 3T MRI and 362 self‐identified as African American. Of the African American participants, 212 had 2 or more 3T MRI scans as required for our longitudinal R2 analyses (average of 2.70 ± 0.87 MRI scans in our analyses; max = 6). None of these 212 participants met criteria for dementia at analytic baseline (i.e., a participant's first valid MRI) based on uniform structured clinical evaluation (Barnes et al., 2012; Bennett et al., 2006) and NINDS/ADRDA criteria (McKhann et al., 1984).

2.2. Image acquisition and processing

High resolution multi‐echo 2D fast spin‐echo (FSE) MRI data were collected on all participants using one of two 3T scanners. While different participants were scanned at one of two scanner sites based on their location, we ensured that scanner site was consistent within participant. Imaging parameters were similar across the two scanners and included a repetition time > 5500 milliseconds (ms), five echoes with echo time (TE) = n × 20 ms, where n = 1–5, acceleration factor = 2, and voxel size = 1.3 × 0.9 × 3 mm3. We generated an R2 map for each scan of each participant by fitting a mono‐exponential decay to the multi‐echo 2D FSE data in each voxel using an algorithm developed in‐house. R2 maps were spatially normalized to the MIITRA atlas space (Wu et al., 2023) using ANTs (Avants et al., 2011). Then the rate of change in R2 was calculated voxelwise from multiple scans of the same participant. When the number of scans was greater than two, the rate of change in R2 was defined as the slope of a linear fit of the longitudinal data in each voxel. Maps of the rate of change in R2 in MIITRA space were smoothed with a Gaussian kernel of FWHM = 3 mm.

2.3. Cognition

Regardless of cohort, all participants underwent the same cognitive evaluation administered in an identical fashion at annual evaluations (Barnes et al., 2012; Bennett et al., 2012; Schneider et al., 2009). Cognitive domains (and the test items included in their construction) consisted of (1) episodic memory (immediate and delayed story recall; word list recall and recognition), (2) semantic memory (confrontational naming; word reading; verbal fluency), (3) working memory (digit span; digit ordering), (4) perceptual speed (Stroop subtests; symbol digit modality; number comparisons), and (5) visuospatial ability (line orientation; progressive matrices). Raw scores were converted to standard z‐scores using the baseline mean and standard deviation (SD) of the entire cohort. The z‐scores of all tests for each domain were then averaged for the five cognitive domain scores. A global cognitive function score was also derived averaging a person's standard scores across all test scores. Psychometric information on these summary scores has been deemed adequate (Wilson et al., 2002) including for the cognitive data of African Americans (Barnes et al., 2016). For the current analyses, global and domain‐specific composite scores from each participant's annual cognitive assessments were combined to create individual unadjusted slope variables for use in the current study.

2.4. Experimental design and statistical analysis

This is a within‐subject longitudinal study. Descriptive summaries of all variables were conducted at study baseline (i.e., first MRI) using SAS/STAT software, Version 9.4 of the SAS System for Linux (SAS Institute, Cary, NC). We conducted separate linear regression models to determine whether the voxelwise rate of change in R2 was associated with rates of change in cognition. Specifically, we examined the relationship between the voxelwise rate of change in R2 and the rate of change in cognition (i.e., unadjusted slopes for global cognition and the five cognitive domains separately) adjusting for scanner site, age at baseline MRI, sex, and education. We ensured the compatibility between MRI and cognitive test data by including cognitive data (collected annually) in a time period beginning 1 cycle (i.e., approximately 1 year) before the first MRI scan to 1 cycle after the last MRI scan as available per participant. This resulted in an average of 4.18 ± 1.06 annual cognitive evaluations (max = 7) and approximately 3 biennial MRI scans (max = 6). Analyses were conducted using FSL PALM (Winkler et al., 2016), assuming different variances across scanners and using two exchangeability blocks (one per scanner). Statistical inference was based on 500 permutations of the data, and tail approximation was used to accelerate the analysis. Associations were considered significant at p < .05, Family‐wise Error (FWE) corrected. The Threshold‐Free Cluster Enhancement (TFCE) method was used to define clusters of significance. Data presented in this article and associated statistical code as well as all data for the aforementioned cohort studies are available at www.radc.rush.edu.

3. RESULTS

3.1. Participant characteristics

Participants were, on average, 75 years old at their first MRI, reported approximately 15 years of education, and were predominantly female (84%). Table 1 has more specific information on these and other variables of interest.

TABLE 1.

Participant characteristics at baseline (N = 212).

Cohort, n of MARS:AACore:MAP 136:66:10
Age, years 75.72 ± 6.14
Sex, n of male: female 34:178
Education, years 15.17 ± 2.95
Scanner Site A:B 63:149
Number of Biennial MRI visits 2.70 ± 0.87
Cognitive performance
Global cognition 0.17 ± 0.50
Episodic memory 0.34 ± 0.59
Semantic memory 0.11 ± 0.68
Working memory 0.03 ± 0.76
Visuospatial ability −0.10 ± 0.79
Perceptual speed 0.13 ± 0.68
Number of annual cognitive visits 4.18 ± 1.06
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Note: Values are mean ± standard deviation unless otherwise noted. Scanner site A, 3 Tesla Siemens Trio; Scanner site B, 3 Tesla Philips Achieva.

3.2. Rate of change in R2 and rate of change in global cognition

In fully adjusted models including terms for scanner, age, sex, and education, the rate of change in R2, that is, the R2 slope, was positively associated with the global cognitive slope (Figure 1). Specifically, the less negative the rate of change in R2 within bilateral hippocampal and parahippocampal regions and surrounding CSF, bilateral precuneus and parieto‐occipital white matter, posterior cingulate, left basal ganglia, left centrum semiovale, inferior/middle temporal gyri, and CSF in the lateral ventricles and multiple sulci, the less negative the global cognitive slope. There were no negative associations between the rate of change in R2 and global cognitive slope.

FIGURE 1.

FIGURE 1

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Associations between less negative rates of change in R2 and less negative rates of change in global cognition over time in fully‐adjusted models that included additional terms for scanner site, age at baseline MRI, sex, and education using TFCE and voxelwise, family wise error correction and p < .05. Standardized effect sizes are shown in color. The skull stripped MIITRA template provides structural reference.

3.3. Rate of change in R2 and rate of change in cognition domains

When considering the five cognitive domains, the rate of change in R2 was associated with the slopes of episodic and semantic memory over time. Specifically, the less negative a rate of relatively widespread change in R2, the less negative slope in episodic memory over time. As seen in Figure 2, although this was a relatively global effect, highlights of R2 involvement include bilateral precuneus and parieto‐occipital white matter, anterior and posterior cingulate, centrum semiovale, superior and medial frontal regions, left basal ganglia, left lingual and left fusiform gyri as well as all major temporal gyri, and the cerebrospinal fluid (CSF) of the lateral ventricles and surrounding multiple sulci and bilateral hippocampal and parahippocampal regions. Not surprisingly, the foci of involvement became more circumscribed to bilateral hippocampi, posterior cingulate and surrounding white matter as well as right parahippocampal and inferior temporal regions at p < .01 (data not shown). There were no negative associations between the rate of change in R2 and slope in episodic memory.

FIGURE 2.

FIGURE 2

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Associations between less negative rates of change in R2 and less negative rates of change in episodic memory over time in fully‐adjusted models that included additional terms for scanner site, age at baseline MRI, sex, and education using TFCE and voxelwise, family wise error correction and p < .05. Standardized effect sizes are shown in color. The skull stripped MIITRA template provides structural reference.

A less negative rate of R2 change was also associated with a less negative slope in semantic memory performance. These associations were most prominent within the left hippocampus, left basal ganglia, bilateral posterior cingulate with CSF involvement in the ventricles and around the hippocampus. This predominantly left‐sided involvement may be seen in Figure 3. There were no negative associations between rate of change in R2 and slope in semantic memory.

FIGURE 3.

FIGURE 3

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Associations between increases in R2 and increases in semantic memory over time in fully‐adjusted models that included additional terms for scanner site, age at baseline MRI, sex, and education using TFCE and voxelwise, family wise error correction and p < .05. Standardized effect sizes are shown in color. The skull stripped MIITRA template provides structural reference.

The rate of change in R2 was not significantly associated with the slope of any other cognitive domain. Additionally, results of fully adjusted regression models using residual slopes for cognition after controlling for age, sex, and education as opposed to unadjusted slopes as outcomes, were relatively unchanged from those reported above.

4. DISCUSSION

In this longitudinal study of over 200 African Americans, we investigated whether rates of change in transverse relaxation associated with rates of change in cognition. We observed that African Americans with less negative rates of change in R2 also showed less negative rates of change, that is, slower rates of decline, in cognitive performance. Specifically, the associated rates of change in R2 and global cognition were located within select subcortical regions (bilateral hippocampi and left basal ganglia), bilateral precuneus and temporal lobe grey matter as well as parieto‐occipital, posterior cingulate, and centrum semiovale white matter. Furthermore, participants with less negative rates of change in R2 predominantly within bilateral hippocampi showed slower rates of decline in episodic memory, while participants with less negative rates of change in R2 within the hippocampus, left basal ganglia, and posterior cingulate showed less negative rates of change in semantic memory. Our results suggest that greater preservation of tissue integrity as measured by R2 across grey and white matter, as well as key subcortical regions associated with specific cognitive domains may be associated with slower cognitive decline for older African Americans.

The present study contributes to the literature in several ways. First, most, if not all ante‐mortem R2 studies to date have been conducted within predominantly if not exclusively non‐Latino White populations (e.g., Dean et al., 2017). Ours is the first to focus an investigation of R2 within an African American population. Furthermore, to our knowledge, most studies have also been cross‐sectional (e.g., House et al., 2006), suggesting that ours may be one of the first to investigate longitudinal rates of change in R2 along with simultaneous rates of change in cognition. Additionally, many previous studies of R2 and cognition have focused on late‐myelinating white matter regions (e.g., Lu et al., 2013) or iron‐rich subcortical structures (e.g., Bartzokis & Tishler, 2000) and fewer still incorporated cognition. Ours expands this literature to include longitudinal study of R2 within a whole brain voxelwise approach to global cognition and five distinct cognitive domains. Furthermore, this study compliments our previous work investigating associations between post‐mortem R2 and ante‐mortem levels of cognition (Dawe et al., 2016, 2018, 2021; Yu, Dawe, Buchman, et al., 2017) by providing an ante‐mortem confirmation and extension of these associations that encompasses simultaneous rates of change within older African Americans.

Most, but not all, current findings relating rates of change in R2 to rates of change in cognition are consistent with previous cross‐sectional studies of associations between transverse relaxation rates and cognition (e.g., House et al., 2006). We (Dawe et al., 2016, 2021) and others (Damulina et al., 2020) have shown that levels of R2 in white matter including occipital white matter are associated with global cognition as well as episodic and semantic memory (Dawe et al., 2021). Additional R2 centrum semiovale involvement in rates of change in global cognition and episodic memory found in the current study suggest that the microstructural stability of white matter regions involving projection, association, as well as commissural fibers contribute to the slower rates of change in cognition. Findings for episodic memory, while generally widespread, were most robust within the hippocampus, in keeping with the importance of this structure for memory (Squire et al., 2004). It implies that, in addition to general neuronal preservation, preservation of myelin—an abundant component of the hippocampus (Soderberg et al., 1992)—is also critical to maintaining the relative health of this brain‐behavior relationship. Rates of change in R2 within the left centrum semiovale and hippocampus, as well as the left basal ganglia, an iron rich subcortical structure (McAllum et al., 2020; Peran et al., 2009), were associated with rates of change in semantic memory and suggest that maintenance of relative homeostasis across iron and myelin levels within these subcortical structures and their white matter connections may be critical to less negative rates of change in semantic memory.

Although there are some studies to suggest that tissue type may have an impact on the direction of the relationships between R2 in grey versus white matter and cognition (Hikita et al., 2005; House et al., 2007), our study is in keeping with other research that suggests reductions in R2 are associated with poorer cognition and cognitive decline (Yu, Dawe, Boyle, et al., 2017). We did not, however, find associations between rates of change in R2 and rates of change in processing speed, a common cross‐sectional associate in ante‐mortem (Bartzokis et al., 2010; Lu et al., 2013) and post‐mortem (Dawe et al., 2016, 2021) studies. Unlike other ante‐mortem studies (e.g., Bartzokis et al., 2010; Lu et al., 2013), we used perceptual speed tasks that required mental as opposed to graphomotor pace. Further, our participants were without dementia at baseline and, by nature of participating in biennial MRI remained relatively healthy both physically and cognitively during their MRI participation, most likely not evidencing advanced neuropathological changes at the time of data collection. More longitudinal work investigating simultaneous change in R2 and various forms of speeded tasks is needed to test our rationale for these conflicting results.

The underlying mechanisms behind the association of less negative rates of change in R2 and slower declines in cognition may provide targets to support maintenance of healthy brain aging in older African Americans more generally. Our R2 findings point toward key myelinated regions (hippocampus and centrum semiovale) as well as customarily iron rich regions of brain (basal ganglia) as those showing associations between less negative rates of R2 change and less negative rates of change in select domains of cognitive functioning. Given that R2 is closely related to water content, our results suggest that lower water content and thus, the preservation of neurons and myelin sheaths may contribute to the preservation of cognition in our analytic sample. Furthermore, variations in demand for iron that lead to regional‐specific patterns in the concentration and distribution of iron (Haacke et al., 2005) may also lead to variations in the region‐specific patterns of association with cognitive domains due, in part, to the fact that iron is essential for oxygen transport and energy metabolism. At elevated levels, however, iron may be deleterious to many brain processes (Ayton et al., 2021). Iron chelators that form a covalent bond with iron may restore iron homeostasis; in fact, select chelators have shown promise in removing iron accumulation and reversing iron‐associated memory impairment in mouse and human interventions, respectively (Wang et al., 2023). Additionally, studies of specific dietary patterns have shown promise in altering not only iron accumulation levels (Zachariou et al., 2021), but in promoting healthy myelin as well as cognition (Bourre, 2006). Additional work is needed before these interventions may be commonplace, however, their success to date bodes well for future large‐scale trials to promote healthy cognitive aging, particularly in older African Americans.

It is important to note that results of this study included rates of change to the transverse relaxation rate of CSF within ventricular and sulcal areas. It is not unreasonable to detect changes in R2 within these spaces; in fact, reports describing changes in R2 within CSF point toward the contribution of glucose in these associations (Daoust et al., 2017). Furthermore, other areas of involvement, including those surrounding the hippocampal complex, appeared to straddle borders of brain tissue and CSF, a nexus within which there are large blood vessels that may also affect R2. Although R2 has been associated with cerebral blood flow, particularly within temporal regions (Bouhrara et al., 2020), partial volume effects may explain at least some of the CSF results.

Limitations of the current work include the fact that our analytic sample, while providing longitudinal data on change in R2 over time, was comprised of individuals 60 years and older. This age restriction naturally excludes a lifespan approach as previously conducted in studies of R2. This, in addition to differences in our analyses (whole brain voxelwise vs region of interest) may limit comparisons with previous studies. Additionally, we did not account for known risk factors beyond participant demographics that may have impacted our results including hypertension (Laporte et al., 2023) and apolipoprotein E (APOE) status—a known modifier of transverse relaxation rates across younger and older, primarily non‐Latino White, adults (Bartzokis et al., 2006, 2007; Triebswetter et al., 2022). Given the dearth of information on changes in R2 and their associations with cognition within African Americans, we chose to focus on understanding basic relationships before considering additional factors. Future work will explore both genetic variations in APOE as well as TREM2 given TREM2 appears to have a more robust effect on brain aging in African Americans than APOE (Logue et al., 2023). Additional future work will employ multi‐exponential R2 relaxometry and also explore recent advances in orientation dependence of transverse relaxation formalism (Pang, 2023) to determine if they may maximize the mechanistic conclusions that may be drawn from our work. The current study, with its multiple strengths including a within race, longitudinal, simultaneous change approach, lays the foundation for these future endeavors.

CONFLICT OF INTEREST STATEMENT

The authors declare no competing financial interests.

ACKNOWLEDGEMENTS

The authors thank all the participants in the Minority Aging Research Study, the Rush Alzheimer's Disease Center (RADC) African American Clinical Core, and the Rush Memory and Aging Project as well as the staff of the RADC. This work was supported by the National Institute on Aging (RF1 AG022018, P30 AG010161, P30AG072975, R01 AG056405, R01 AG055430, and R01 AG062711) and the National Institute of Neurological Disorders and Stroke (UH3 NS100599, UF1NS100599).

Lamar, M. , Arfanakis, K. , Capuano, A. W. , Zhang, S. , Fleischman, D. A. , Han, S. D. , Poole, V. N. , Leurgans, S. E. , Bennett, D. A. , & Barnes, L. L. (2025). Change in transverse relaxation rates (R2 ) and change in cognition for older African Americans. Human Brain Mapping, 46(1), e26794. 10.1002/hbm.26794

DATA AVAILABILITY STATEMENT

The data that support the findings of this study, as well as all data for RADC cohort studies, are available at www.radc.rush.edu.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The data that support the findings of this study, as well as all data for RADC cohort studies, are available at www.radc.rush.edu.

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