Samuel N. Lockhart

PET Imaging of Tau Deposition in the Aging Human Brain

Tau pathology is a hallmark of Alzheimers disease (AD) but also occurs in normal cognitive aging. Using the tau PET agent (18)F-AV-1451, we examined retention patterns in cognitively normal older people in relation to young controls and AD patients. Age and β-amyloid (measured using PiB PET) were differentially associated with tau tracer retention in healthy aging. Older age was related to increased tracer retention in regions of the medial temporal lobe, which predicted worse episodic memory performance. PET detection of tau in other isocortical regions required the presence of cortical β-amyloid and was associated with decline in global cognition. Furthermore, patterns of tracer retention corresponded well with Braak staging of neurofibrillary tau pathology. The present study defined patterns of tau tracer retention in normal aging in relation to age, cognition, and β-amyloid deposition.

Structural Imaging Measures of Brain Aging

During the course of normal aging, biological changes occur in the brain that are associated with changes in cognitive ability. This review presents data from neuroimaging studies of primarily “normal” or healthy brain aging. As such, we focus on research in unimpaired or nondemented older adults, but also include findings from lifespan studies that include younger and middle aged individuals as well as from populations with prodromal or clinically symptomatic disease such as cerebrovascular or Alzheimer’s disease. This review predominantly addresses structural MRI biomarkers, such as volumetric or thickness measures from anatomical images, and measures of white matter injury and integrity respectively from FLAIR or DTI, and includes complementary data from PET and cognitive or clinical testing as appropriate. The findings reveal highly consistent age-related differences in brain structure, particularly frontal lobe and medial temporal regions that are also accompanied by age-related differences in frontal and medial temporal lobe mediated cognitive abilities. Newer findings also suggest that degeneration of specific white matter tracts such as those passing through the genu and splenium of the corpus callosum may also be related to age-related differences in cognitive performance. Interpretation of these findings, however, must be tempered by the fact that comorbid diseases such as cerebrovascular and Alzheimer’s disease also increase in prevalence with advancing age. As such, this review discusses challenges related to interpretation of current theories of cognitive aging in light of the common occurrence of these later-life diseases. Understanding the differences between “Normal” and “Healthy” brain aging and identifying potential modifiable risk factors for brain aging is critical to inform potential treatments to stall or reverse the effects of brain aging and possibly extend cognitive health for our aging society.

Episodic memory function is associated with multiple measures of white matter integrity in cognitive aging

Previous neuroimaging research indicates that white matter injury and integrity, measured respectively by white matter hyperintensities (WMH) and fractional anisotropy (FA) obtained from diffusion tensor imaging (DTI), differ with aging and cerebrovascular disease (CVD) and are associated with episodic memory deficits in cognitively normal older adults. However, knowledge about tract-specific relationships between WMH, FA, and episodic memory in aging remains limited. We hypothesized that white matter connections between frontal cortex and subcortical structures as well as connections between frontal and temporo-parietal cortex would be most affected. In the current study, we examined relationships between WMH, FA and episodic memory in 15 young adults, 13 elders with minimal WMH and 15 elders with extensive WMH, using an episodic recognition memory test for object-color associations. Voxel-based statistics were used to identify voxel clusters where white matter measures were specifically associated with variations in episodic memory performance, and white matter tracts intersecting these clusters were analyzed to examine white matter-memory relationships. White matter injury and integrity measures were significantly associated with episodic memory in extensive regions of white matter, located predominantly in frontal, parietal, and subcortical regions. Template based tractography indicated that white matter injury, as measured by WMH, in the uncinate and inferior longitudinal fasciculi were significantly negatively associated with episodic memory performance. Other tracts such as thalamo-frontal projections, superior longitudinal fasciculus, and dorsal cingulum bundle demonstrated strong negative associations as well. The results suggest that white matter injury to multiple pathways, including connections of frontal and temporal cortex and frontal-subcortical white matter tracts, plays a critical role in memory differences seen in older individuals.

White Matter Hyperintensities and Their Penumbra Lie Along a Continuum of Injury in the Aging Brain

Background and Purpose— Aging is accompanied by clinically silent cerebral white matter injury identified through white matter hyperintensities (WMHs) on fluid-attenuated inversion recovery (FLAIR)– and diffusion tensor imaging–based measures of white matter integrity. The temporal course of FLAIR and diffusion tensor imaging changes within WMHs and their less-injured periphery (ie, their penumbra), however, has not been fully studied. We used longitudinal diffusion tensor imaging and FLAIR to explore these changes. Methods— One hundred fifteen participants, aged 73.7±6.7 years, received clinical evaluations and MRIs on 2 dates. WMHs and fractional anisotropy (FA) maps were produced from FLAIR and diffusion tensor imaging and coregistered to a standardized space. Each distinct WMH was categorized as growing, stagnant, or noncontiguous incident. The penumbra of each WMH was similarly categorized as corresponding to a stagnant, growing, or noncontiguous incident WMH. Linear mixed-effect models were used to assess whether FA and FLAIR measurements changed between baseline and follow-up and differed between tissue categories. Results— Baseline FA differed significantly by tissue category, with the following ordering of categories from highest to lowest FA: penumbra of noncontiguous incident, then stagnant, then growing WMHs; noncontiguous incident, then stagnant, then growing WMHs. Despite differences in baseline values, all tissue categories experienced declines in FA over time. Only noncontiguous incident WMHs showed significant FLAIR signal increases over time, and FLAIR signal significantly decreased in stagnant WMHs. Conclusions— WMHs and their penumbra vary in severity and together span a continuous spectrum of white matter injury that worsens with time. FLAIR fails to capture this continuous injury process fully but does identify a subclass of lesions that seem to improve over time.

Comparison of multiple tau-PET measures as biomarkers in aging and Alzheimer's disease

&NA; The recent development of tau‐specific positron emission tomography (PET) tracers enables in vivo quantification of regional tau pathology, one of the key lesions in Alzheimers disease (AD). Tau PET imaging may become a useful biomarker for clinical diagnosis and tracking of disease progression but there is no consensus yet on how tau PET signal is best quantified. The goal of the current study was to evaluate multiple whole‐brain and region‐specific approaches to detect clinically relevant tau PET signal. Two independent cohorts of cognitively normal adults and amyloid‐positive (A&bgr;+) patients with mild cognitive impairment (MCI) or AD‐dementia underwent [18F]AV‐1451 PET. Methods for tau tracer quantification included: (i) in vivo Braak staging, (ii) regional uptake in Braak composite regions, (iii) several whole‐brain measures of tracer uptake, (iv) regional uptake in AD‐vulnerable voxels, and (v) uptake in a priori defined regions. Receiver operating curves characterized accuracy in distinguishing A&bgr;‐ controls from AD/MCI patients and yielded tau positivity cutoffs. Clinical relevance of tau PET measures was assessed by regressions against cognition and MR imaging measures. Key tracer uptake patterns were identified by a factor analysis and voxel‐wise contrasts. Braak staging, global and region‐specific tau measures yielded similar diagnostic accuracies, which differed between cohorts. While all tau measures were related to amyloid and global cognition, memory and hippocampal/entorhinal volume/thickness were associated with regional tracer retention in the medial temporal lobe. Key regions of tau accumulation included medial temporal and inferior/middle temporal regions, retrosplenial cortex, and banks of the superior temporal sulcus. Our data indicate that whole‐brain tau PET measures might be adequate biomarkers to detect AD‐related tau pathology. However, regional measures covering AD‐vulnerable regions may increase sensitivity to early tau PET signal, atrophy and memory decline. Graphical abstract Figure. No caption available. Highlights10 different tau PET measures were evaluated in 2 independent samples.Global and region‐specific tau measures yielded similar diagnostic accuracies.Correlations to clinical variables were stronger for regional than global measures.Tau deposition showed typical patterns captured by several different approaches.Neocortical tau deposition was greater for early‐ than late‐onset AD cases.

Dynamic PET Measures of Tau Accumulation in Cognitively Normal Older Adults and Alzheimer's Disease Patients Measured Using [18F] THK-5351.

Background [18F]THK5351, a recently-developed positron emission tomography (PET) tracer for measuring tau neurofibrillary tangle accumulation, may help researchers examine aging, disease, and tau pathology in living human brains. We examined THK5351 tracer pharmacokinetics to define an optimal acquisition time for static late images. Methods Primary measurements were calculation of regional values of distribution volume ratios (DVR) and standardized uptake value ratios (SUVR) in 6 healthy older control and 10 Alzheimer’s disease (AD) participants. We examined associations between DVR and SUVR, searching for a 20 min SUVR time window that was stable and comparable to DVR. We additionally examined diagnostic group differences in this 20 min SUVR. Results In healthy controls, [18F]THK5351 uptake was low, with increased temporal relative to frontal binding. In AD, regional uptake was substantially higher than in healthy controls, with temporal exceeding frontal binding. Retention in cerebellar gray matter, which was used as the reference region, was low compared to other regions. Both DVR and SUVR values showed minimal change over time after 40 min. SUVR 20–40, 30–50, and 40–60 min were most consistently correlated with DVR; SUVR 40–60 min, the most stable time window, was used in further analyses. Significant (AD > healthy control) group differences existed in temporoparietal regions, with marginal medial temporal differences. We found high basal ganglia SUVR 40–60 min signal, with no group differences. Conclusions We examined THK5351, a new PET tracer for measuring tau accumulation, and compared multiple analysis methods for quantifying regional tracer uptake. SUVR 40–60 min performed optimally when examining 20 min SUVR windows, and appears to be a practical method for quantifying relative regional tracer retention. The results of this study offer clinical potential, given the usefulness of THK5351-PET as a biomarker of tau pathology in aging and disease.

Reference tissue-based kinetic evaluation of 18F-AV-1451 in aging and dementia

The goal of this paper was to evaluate the in vivo kinetics of the novel tau-specific PET radioligand 18F-AV-1451 in cognitively healthy control (HC) and Alzheimer disease (AD) subjects, using reference region analyses. Methods: 18F-AV-1451 PET imaging was performed on 43 subjects (5 young HCs, 23 older HCs, and 15 AD subjects). Data were collected from 0 to 150 min after injection, with a break from 100 to 120 min. T1-weighted MR images were segmented using FreeSurfer to create 14 bilateral regions of interest (ROIs). In all analyses, cerebellar gray matter was used as the reference region. Nondisplaceable binding potentials (BPNDs) were calculated using the simplified reference tissue model (SRTM) and SRTM2; the Logan graphical analysis distribution volume ratio (DVR) was calculated for 30–150 min (DVR30–150). These measurements were compared with each other and used as reference standards for defining an appropriate 20-min window for the SUV ratio (SUVR). Pearson correlations were used to compare the reference standards to 20-min SUVRs (start times varied from 30 to 130 min), for all values, for ROIs with low 18F-AV-1451 binding (lROIs, mean of BPND + 1 and DVR30–150 < 1.5), and for ROIs with high 18F-AV-1451 binding (hROIs, mean of BPND + 1 and DVR30–150 > 1.5). Results: SRTM2 BPND + 1 and DVR30–150 were in good agreement. Both were in agreement with SRTM BPND + 1 for lROIs but were greater than SRTM BPND + 1 for hROIs, resulting in a nonlinear relationship. hROI SUVRs increased from 80–100 to 120–140 min by 0.24 ± 0.15. The SUVR time interval resulting in the highest correlation and slope closest to 1 relative to the reference standards for all values was 120–140 min for hROIs, 60–80 min for lROIs, and 80–100 min for lROIs and hROIs. There was minimal difference between methods when statistical significance between ADs and HCs was calculated. Conclusion: Despite later time periods providing better agreement between reference standards and SUVRs for hROIs, a good compromise for studying lROIs and hROIs is SUVR80–100. The lack of SUVR plateau for hROIs highlights the importance of precise acquisition time for longitudinal assessment.

Tau and β-amyloid are associated with medial temporal lobe structure, function, and memory encoding in normal aging

Normal aging is associated with a decline in episodic memory and also with aggregation of the β-amyloid (Aβ) and tau proteins and atrophy of medial temporal lobe (MTL) structures crucial to memory formation. Although some evidence suggests that Aβ is associated with aberrant neural activity, the relationships among these two aggregated proteins, neural function, and brain structure are poorly understood. Using in vivo human Aβ and tau imaging, we demonstrate that increased Aβ and tau are both associated with aberrant fMRI activity in the MTL during memory encoding in cognitively normal older adults. This pathological neural activity was in turn associated with worse memory performance and atrophy within the MTL. A mediation analysis revealed that the relationship with regional atrophy was explained by MTL tau. These findings broaden the concept of cognitive aging to include evidence of Alzheimers disease-related protein aggregation as an underlying mechanism of age-related memory impairment. SIGNIFICANCE STATEMENT Alterations in episodic memory and the accumulation of Alzheimers pathology are common in cognitively normal older adults. However, evidence of pathological effects on episodic memory has largely been limited to β-amyloid (Aβ). Because Aβ and tau often cooccur in older adults, previous research offers an incomplete understanding of the relationship between pathology and episodic memory. With the recent development of in vivo tau PET radiotracers, we show that Aβ and tau are associated with different aspects of memory encoding, leading to aberrant neural activity that is behaviorally detrimental. In addition, our results provide evidence linking Aβ- and tau-associated neural dysfunction to brain atrophy.

The role of diffusion tensor imaging in the study of cognitive aging

This chapter gives an overview of the role that diffusion tensor MRI (DTI) can play in the study of cognitive decline that is associated with advancing age. A brief overview of biological injury processes that impinge on the aging brain is provided, and their overall effect on the integrity of neural architecture is described. Cognitive decline associated with aging, and white matter connectivity degradation as a biological substrate for that decline, is then described. We then briefly describe the technology of DTI as a means for in vivo, non-invasive interrogation of white matter connectivity, and relate it to FLAIR, a more traditional MRI method for assessing white matter injury. We then survey the existing findings on relationships between aging-associated neuropathological processes and DTI measurements on one hand; and relationships between DTI measurements and late-life cognitive function on the other. We conclude with a summary of current research directions in relation to DTI studies of cognitive aging.

The Contributions of MRI-Based Measures of Gray Matter, White Matter Hyperintensity, and White Matter Integrity to Late-Life Cognition

BACKGROUND AND PURPOSE: GM volume, WMH volume, and FA are each associated with cognition; however, few studies have detected whether these 3 different types of MR imaging measurements exert independent or additive effects on cognitive performance. To detect their extent of contribution to cognitive performance, we explored the independent and additive contributions of GM atrophy, white matter injury, and white matter integrity to cognition in elderly patients. MATERIALS AND METHODS: Two hundred and 9 elderly patients participated in the study: 97 were CN adults, 65 had MCI, and 47 had dementia. We measured GM on T1-weighted MR imaging, WMH on FLAIR, and FA on DTI, along with psychometrically matched measures of 4 domains of cognitive performance, including semantic memory, episodic memory, executive function, and spatial abilities. RESULTS: As expected, patients with dementia performed significantly more poorly in all 4 cognitive domains, whereas patients with MCI performed generally less poorly than dementia patients, though considerable overlap in performance was present across groups. GM, FA, and WMH each differed significantly between diagnostic groups and were associated with cognitive measures. In multivariate models that included all 3 MR imaging measures (GM, WMH, and FA), GM volume was the strongest determinant of cognitive performance. CONCLUSIONS: These results strongly suggest that MR imaging measures of GM are more closely associated with cognitive function than WM measures across a broad range of cognitive and functional impairment.