Locus coeruleus integrity and left frontoparietal connectivity provide resilience against attentional decline in preclinical alzheimer's disease.

BACKGROUND: Autopsy work reported that neuronal density in the locus coeruleus (LC) provides neural reserve against cognitive decline in dementia. Recent neuroimaging and pharmacological studies reported that left frontoparietal network functional connectivity (LFPN-FC) confers resilience against beta-amyloid (Aß)-related cognitive decline in preclinical sporadic and autosomal dominant Alzheimer's disease (AD), as well as against LC-related cognitive changes. Given that the LFPN and the LC play important roles in attention, and attention deficits have been observed early in the disease process, we examined whether LFPN-FC and LC structural health attenuate attentional decline in the context of AD pathology. METHODS: 142 participants from the Harvard Aging Brain Study who underwent resting-state functional MRI, LC structural imaging, PiB(Aß)-PET, and up to 5 years of cognitive follow-ups were included (mean age = 74.5 ± 9.9 years, 89 women). Cross-sectional robust linear regression associated LC integrity (measured as the average of five continuous voxels with the highest intensities in the structural LC images) or LFPN-FC with Digit Symbol Substitution Test (DSST) performance at baseline. Longitudinal robust mixed effect analyses examined associations between DSST decline and (i) two-way interactions of baseline LC integrity (or LFPN-FC) and PiB or (ii) the three-way interaction of baseline LC integrity, LFPN-FC, and PiB. Baseline age, sex, and years of education were included as covariates. RESULTS: At baseline, lower LFPN-FC, but not LC integrity, was related to worse DSST performance. Longitudinally, lower baseline LC integrity was associated with a faster DSST decline, especially at PiB > 10.38 CL. Lower baseline LFPN-FC was associated with a steeper decline on the DSST but independent of PiB. At elevated PiB levels (> 46 CL), higher baseline LFPN-FC was associated with an attenuated decline on the DSST, despite the presence of lower LC integrity. CONCLUSIONS: Our findings demonstrate that the LC can provide resilience against Aß-related attention decline. However, when Aß accumulates and the LC's resources may be depleted, the functioning of cortical target regions of the LC, such as the LFPN-FC, can provide additional resilience to sustain attentional performance in preclinical AD. These results provide critical insights into the neural correlates contributing to individual variability at risk versus resilience against Aß-related cognitive decline.

Associations Between Self and Study Partner Report of Cognitive Decline With Regional Tau in a Multicohort Study.

BACKGROUND AND OBJECTIVES: Self-reported cognitive decline is an early behavioral manifestation of Alzheimer disease (AD) at the preclinical stage, often believed to precede concerns reported by a study partner. Previous work shows cross-sectional associations with ß-amyloid (Aß) status and self-reported and study partner-reported cognitive decline, but less is known about their associations with tau deposition, particularly among those with preclinical AD. METHODS: This cross-sectional study included participants from the Anti-Amyloid Treatment in Asymptomatic AD/Longitudinal Evaluation of Amyloid Risk and Neurodegeneration studies (N = 444) and the Harvard Aging Brain Study and affiliated studies (N = 231), which resulted in a cognitively unimpaired (CU) sample of individuals with both nonelevated (Aß-) and elevated Aß (Aß+). All participants and study partners completed the Cognitive Function Index (CFI). Two regional tau composites were derived by averaging flortaucipir PET uptake in the medial temporal lobe (MTL) and neocortex (NEO). Global Aß PET was measured in Centiloids (CLs) with Aß+ >26 CL. We conducted multiple linear regression analyses to test associations between tau PET and CFI, covarying for amyloid, age, sex, education, and cohort. We also controlled for objective cognitive performance, measured using the Preclinical Alzheimer Cognitive Composite (PACC). RESULTS: Across 675 CU participants (age = 72.3 ± 6.6 years, female = 59%, Aß+ = 60%), greater tau was associated with greater self-CFI (MTL: ß = 0.28 [0.12, 0.44], p < 0.001, and NEO: ß = 0.26 [0.09, 0.42], p = 0.002) and study partner CFI (MTL: ß = 0.28 [0.14, 0.41], p < 0.001, and NEO: ß = 0.31 [0.17, 0.44], p < 0.001). Significant associations between both CFI measures and MTL/NEO tau PET were driven by Aß+. Continuous Aß showed an independent effect on CFI in addition to MTL and NEO tau for both self-CFI and study partner CFI. Self-CFI (ß = 0.01 [0.001, 0.02], p = 0.03), study partner CFI (ß = 0.01 [0.003, 0.02], p = 0.01), and the PACC (ß = -0.02 [-0.03, -0.01], p < 0.001) were independently associated with MTL tau, but for NEO tau, PACC (ß = -0.02 [-0.03, -0.01], p < 0.001) and study partner report (ß = 0.01 [0.004, 0.02], p = 0.002) were associated, but not self-CFI (ß = 0.01 [-0.001, 0.02], p = 0.10). DISCUSSION: Both self-report and study partner report showed associations with tau in addition to Aß. Additionally, self-report and study partner report were associated with tau above and beyond performance on a neuropsychological composite. Stratification analyses by Aß status indicate that associations between self-reported and study partner-reported cognitive concerns with regional tau are driven by those at the preclinical stage of AD, suggesting that both are useful to collect on the early AD continuum.

Contribution of extracerebral tracer retention and partial volume effects to sex differences in Flortaucipir-PET signal.

Clinically normal females exhibit higher 18F-flortaucipir (FTP)-PET signal than males across the cortex. However, these sex differences may be explained by neuroimaging idiosyncrasies such as off-target extracerebral tracer retention or partial volume effects (PVEs). 343 clinically normal participants (female = 58%; mean[SD]=73.8[8.5] years) and 55 patients with mild cognitive impairment (female = 38%; mean[SD] = 76.9[7.3] years) underwent cross-sectional FTP-PET. We parcellated extracerebral FreeSurfer areas based on proximity to cortical ROIs. Sex differences in cortical tau were then estimated after accounting for local extracerebral retention. We simulated PVE by convolving group-level standardized uptake value ratio means in each ROI with 6 mm Gaussian kernels and compared the sexes across ROIs post-smoothing. Widespread sex differences in extracerebral retention were observed. Although attenuating sex differences in cortical tau-PET signal, covarying for extracerebral retention did not impact the largest sex differences in tau-PET signal. Differences in PVE were observed in both female and male directions with no clear sex-specific bias. Our findings suggest that sex differences in FTP are not solely attributed to off-target extracerebral retention or PVE, consistent with the notion that sex differences in medial temporal and neocortical tau are biologically driven. Future work should investigate sex differences in regional cerebral blood flow kinetics and longitudinal tau-PET.

Association of Pathologic and Volumetric Biomarker Changes With Cognitive Decline in Clinically Normal Adults.

BACKGROUND AND OBJECTIVES: Hippocampal volume (HV) atrophy is a well-known biomarker of memory impairment. However, compared with ß-amyloid (Aß) and tau imaging, it is less specific for Alzheimer disease (AD) pathology. This lack of specificity could provide indirect information about potential copathologies that cannot be observed in vivo. In this prospective cohort study, we aimed to assess the associations among Aß, tau, HV, and cognition, measured over a 10-year follow-up period with a special focus on the contributions of HV atrophy to cognition after adjusting for Aß and tau. METHODS: We enrolled 283 older adults without dementia or overt cognitive impairment in the Harvard Aging Brain Study. In this report, we only analyzed data from individuals with available longitudinal imaging and cognition data. Serial MRI (follow-up duration 1.3-7.0 years), neocortical Aß imaging on Pittsburgh Compound B PET scans (1.9-8.5 years), entorhinal and inferior temporal tau on flortaucipir PET scans (0.8-6.0 years), and the Preclinical Alzheimer Cognitive Composite (3.0-9.8 years) were prospectively collected. We evaluated the longitudinal associations between Aß, tau, volume, and cognition data and investigated sequential models to test the contribution of each biomarker to cognitive decline. RESULTS: We analyzed data from 128 clinically normal older adults, including 72 (56%) women and 56 (44%) men; median age at inclusion was 73 years (range 63-87). Thirty-four participants (27%) exhibited an initial high-Aß burden on PET imaging. Faster HV atrophy was correlated with faster cognitive decline (R2 = 0.28, p < 0.0001). When comparing all biomarkers, HV slope was associated with cognitive decline independently of Aß and tau measures, uniquely accounting for 10% of the variance. Altogether, 45% of the variance in cognitive decline was explained by combining the change measures in the different imaging biomarkers. DISCUSSION: In older adults, longitudinal hippocampal atrophy is associated with cognitive decline, independently of Aß or tau, suggesting that non-AD pathologies (e.g., TDP-43, vascular) may contribute to hippocampal-mediated cognitive decline. Serial HV measures, in addition to AD-specific biomarkers, may help evaluate the contribution of non-AD pathologies that cannot be measured otherwise in vivo.

Kinetic evaluation and assessment of longitudinal changes in reference region and extracerebral [18F]MK-6240 PET uptake.

[18F]MK-6240 meningeal/extracerebral off-target binding may impact tau quantification. We examined the kinetics and longitudinal changes of extracerebral and reference regions. [18F]MK-6240 PET was performed in 24 cognitively-normal and eight cognitively-impaired subjects, with arterial samples in 13 subjects. Follow-up scans at 6.1 ± 0.5 (n = 25) and 13.3 ± 0.9 (n = 16) months were acquired. Extracerebral and reference region (cerebellar gray matter (CerGM)-based, cerebral white matter (WM), pons) uptake were evaluated using standardized uptake values (SUV90-110), spectral analysis, and distribution volume. Longitudinal changes in SUV90-110 were examined. The impact of reference region on target region outcomes, partial volume correction (PVC) and regional erosion were evaluated. Eroded WM and pons showed lower variability, lower extracerebral contamination, and lower longitudinal changes than CerGM-based regions. CerGM-based regions resulted larger cross-sectional effect sizes for group differentiation. Extracerebral signal was high in 50% of subjects and exhibited irreversible kinetics and nonsignificant longitudinal changes over one-year but was highly variable at subject-level. PVC resulted in higher variability in reference region uptake and longitudinal changes. Our results suggest that eroded CerGM may be preferred for cross-sectional, whilst eroded WM or pons may be preferred for longitudinal [18F]MK-6240 studies. For CerGM, erosion was necessary (preferred over PVC) to address the heterogenous nature of extracerebral signal.

Association of Emerging ß-Amyloid and Tau Pathology With Early Cognitive Changes in Clinically Normal Older Adults.

BACKGROUND AND OBJECTIVES: Alzheimer disease (AD) clinical trials are moving earlier in the disease process according to emerging signs of ß-amyloid (Aß) and tau pathology. If early treatment is the right time for intervention, it is critical to find the right test to optimize cognitive outcome measures for clinical trials. We sought to identify cognitive measures associated with the earliest detectable signs of emerging Aß and tau pathology. METHODS: One hundred twelve clinically normal adults with longitudinal Pittsburgh compound B (PiB)-PET, 18F-flortaucipir (FTP)-PET, and cognitive data for ≥7 years were included from the Harvard Aging Brain Study (HABS). Analyses assessed those initially classified as PiB- (less than Centiloid [CL] 20) and then expanded to include PiB+ individuals up to CL40, the approximate threshold beyond which neocortical tau proliferation begins. Separate linear mixed-effects models assessed the effects of emerging global Aß (PiB slope) and tau (baseline FTP level and FTP slope) in the entorhinal and inferior temporal (IT) cortices on multiple cognitive tasks and the Preclinical Alzheimer's Cognitive Composite (PACC) over time. RESULTS: Steeper PiB slopes were associated with declining processing speed (Digit Symbol Substitution Test [DSST], Trail Making Test Part A) in those CL40). DISCUSSION: Early, Aß-mediated cognitive slowing was detected for processing speed measures, while early memory retrieval declines were associated with emerging Aß and tau pathology. Composites of these measures may help determine whether anti-Aß or anti-tau therapies administered at the first signs of pathology might preserve cognitive function. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that in clinically normal older adults, emerging PET-detected AD pathology is associated with declining processing speeds and memory retrieval.

Lower novelty-related locus coeruleus function is associated with Aß-related cognitive decline in clinically healthy individuals.

Animal and human imaging research reported that the presence of cortical Alzheimer's Disease's (AD) neuropathology, beta-amyloid and neurofibrillary tau, is associated with altered neuronal activity and circuitry failure, together facilitating clinical progression. The locus coeruleus (LC), one of the initial subcortical regions harboring pretangle hyperphosphorylated tau, has widespread connections to the cortex modulating cognition. Here we investigate whether LC's in-vivo neuronal activity and functional connectivity (FC) are associated with cognitive decline in conjunction with beta-amyloid. We combined functional MRI of a novel versus repeated face-name paradigm, beta-amyloid-PET and longitudinal cognitive data of 128 cognitively unimpaired older individuals. We show that LC activity and LC-FC with amygdala and hippocampus was higher during novelty. We also demonstrated that lower novelty-related LC activity and LC-FC with hippocampus and parahippocampus were associated with steeper beta-amyloid-related cognitive decline. Our results demonstrate the potential of LC's functional properties as a gauge to identify individuals at-risk for AD-related cognitive decline.

The relationship of functional hippocampal activity, amyloid deposition, and longitudinal memory decline to memory complaints in cognitively healthy older adults.

We evaluated whether self-reports of worse cognition in older adults with normal cognitive function reflected actual memory decline, amyloid pathology, and subtle vulnerabilities in hippocampal function. We measured subjective cognitive decline (SCD) in 156 older participants from the Dallas Lifespan Brain Study. Functional hippocampal activation during encoding, measured with fMRI, and longitudinal memory change that was measured in the four years preceding the SCD measures were used to predict the magnitude of SCD. A subsample (N=105) also underwent 18F-Florbetapir PET imaging that measured amyloid burden. Results showed that increased SCD were associated with greater prior memory decline and amyloid deposition. Importantly, decreased hippocampal activation during encoding was a significant predictor of SCD, particularly in young-old adults below 69 years old, above and beyond prior memory change and amyloid deposition. These results indicate that multiple measures of neural and cognitive dysfunction are simultaneously associated with SCD. Moreover, SCD in younger seniors appears to reflect deficient hippocampal activity that increases their reports of poorer memory, independent of amyloid. This manuscript is part of the Special Issue entitled "Cognitive Neuroscience of Healthy and Pathological Aging" edited by Drs. M. N. Rajah, S. Belleville, and R. Cabeza. This article is part of the Virtual Special Issue titled COGNITIVE NEU-ROSCIENCE OF HEALTHY AND PATHOLOGICAL AGING. The full issue can be found on ScienceDirect at https://www.sciencedirect.com/journal/neurobiology-of-aging/special-issue/105379XPWJP.

Defining the Lowest Threshold for Amyloid-PET to Predict Future Cognitive Decline and Amyloid Accumulation.

INTRODUCTION: As clinical trials move toward earlier intervention, we sought to redefine the ß-amyloid (Aß)-PET threshold based on the lowest point in a baseline distribution that robustly predicts future Aß accumulation and cognitive decline in 3 independent samples of clinically normal individuals. METHODS: Sequential Aß cutoffs were tested to identify the lowest cutoff associated with future change in cognition (Preclinical Alzheimer Cognitive Composite [PACC]) and Aß-PET in clinically normal participants from the Harvard Aging Brain Study (n = 342), Australian Imaging, Biomarker and Lifestyle study of aging (n = 157), and Alzheimer's Disease Neuroimaging Initiative (n = 356). RESULTS: Within samples, cutoffs derived from future Aß-PET accumulation and PACC decline converged on the same inflection point, beyond which trajectories diverged from normal. Across samples, optimal cutoffs fell within a short range (Centiloid 15-18.5). DISCUSSION: These optimized thresholds can help to inform future research and clinical trials targeting early Aß. Threshold convergence raises the possibility of contemporaneous early changes in Aß and cognition. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that among clinically normal individuals a specific Aß-PET threshold is predictive of cognitive decline.

Actual memory as a mediator of the amyloid-subjective cognitive decline relationship.

INTRODUCTION: Amyloid pathology in cognitively normal adults is associated with subjective cognitive decline, potentially reflecting awareness of Alzheimer's-related memory deficits. To clarify the mechanism underlying this relationship, we used mediational analyses to determine the role of depression, anxiety, and actual memory performance. METHODS: To assess amyloid deposition, we imaged 85 cognitively normal adults with florbetapir positron emission tomography imaging. Subjective cognitive decline was measured using a multidimensional instrument that assessed seven subjective memory domains. Mediational measures included assessments of actual memory performance (current and retrospective longitudinal change), depression, and anxiety. RESULTS: The relationship between amyloid and subjective cognitive decline was mediated by poorer memory performance and greater retrospective memory decline, not depression or anxiety. The mediational roles were significant for domains associated with memory function and memory-related anxiety. DISCUSSION: In individuals harboring amyloid, self-reported beliefs of declining memory likely indicate early self-awareness of actual worsening function rather than depression or anxiety.

Regional amyloid accumulation and cognitive decline in initially amyloid-negative adults.

OBJECTIVE: To assess whether global or regional changes in amyloid burden over 4 years predict early declines in episodic memory in initially amyloid-negative adults. METHODS: One hundred twenty-six initially amyloid-negative, cognitively normal participants (age 30-89 years) were included from the Dallas Lifespan Brain Study who completed florbetapir PET and a cognitive battery at baseline and 4-year follow-up. Standardized uptake value ratio (SUVR) change was computed across 8 bilateral regions of interest. Using general linear models, we examined the relationship between change in global and regional SUVR and change in episodic memory, controlling for baseline SUVR, baseline memory, age, sex, education, and APOE status. RESULTS: In initially amyloid-negative adults, we detected a regionally specific relationship between declining episodic memory and increasing amyloid accumulation across multiple posterior cortical regions. In addition, these amyloid-related changes in memory persisted when we focused on middle-aged adults only and after controlling for atrophy in global cortical, hippocampal, and Alzheimer disease signature cortical volume. CONCLUSION: Our results indicate that assessing regional changes in amyloid, particularly in posterior cortical regions, can aid in the early detection of subclinical amyloid-related decline in episodic memory as early as middle age. Future research incorporating tau and other markers of neurodegeneration is needed to clarify the sequence of events that lead to this early, subclinical memory decline.

Longitudinal accrual of neocortical amyloid burden is associated with microstructural changes of the fornix in cognitively normal adults.

The fornix and parahippocampal cingulum are 2 major limbic tracts in the core memory network of the hippocampus. Although these fiber tracts are known to degrade with Alzheimer's disease (AD), little is known about their vulnerability in the asymptomatic phase of AD. In this longitudinal study of cognitively normal adults, we assessed amyloid-beta (Aß) plaques using positron emission tomography and white matter microstructure using diffusion tensor imaging. We found that an increase of neocortical Aß burden over time was associated with an increase of radial diffusivity in the fornix but not in the parahippocampal cingulum. The effect of increasing neocortical Aß burden on the fornix remained significant after controlling for baseline measures, head motion, global brain atrophy, regional Aß burden in the hippocampus, or microstructural changes in the global white matter. In addition, microstructural changes in the fornix were not associated with decline of episodic memory or other cognitive abilities. Our findings suggest that microstructural changes in the fornix may be an early sign in the asymptomatic phase of AD.

Association of Longitudinal Cognitive Decline With Amyloid Burden in Middle-aged and Older Adults: Evidence for a Dose-Response Relationship.

Importance: Presently, the clinical standard for reporting the results of an amyloid positron emission tomography scan is to assign a dichotomous rating of positive or negative for the presence of amyloid. In a 4-year longitudinal study, we investigated whether using a continuous measure of the magnitude of baseline amyloid burden would provide valuable information about the rate of future cognitive decline over the subsequent 4 years compared with a dichotomous measure in middle-aged and older adults. Objective: To examine whether a continuous, dose-response relationship between amyloid burden and cognitive decline was present among middle-aged and older adults. Design, Setting, and Participants: This cohort study included 174 participants from the Dallas Lifespan Brain Study who were 40 to 89 years old at the beginning of the study, were cognitively normal at baseline (a Mini-Mental State Examination score of 26 or higher) with no history of neurological or psychiatric disorders, and had completed amyloid imaging ([18F]-florbetapir) at baseline and cognitive assessments at baseline and a 4-year follow-up. Continuous amyloid burden was measured as the mean cortical standardized uptake value ratio (SUVR) at baseline. Main Outcomes and Measures: Linear mixed models assessed the effect of increasing baseline amyloid over time (SUVR × time interaction) on episodic memory, reasoning, processing speed, vocabulary, and Mini-Mental State Examination performance. Age, sex, education, apolipoprotein ε4, and the random effect of intercepts were included as covariates. Results: The mean (SD) age for all participants (n = 174) was 66.44 (11.74) years, and 65 participants (37%) were men. The primary analyses yielded significant SUVR × time interactions in episodic memory, processing speed, vocabulary, and Mini-Mental State Examination performance, but not in reasoning performance. Higher baseline SUVR projected greater cognitive decline over 4 years. When controlling for variance related to a dichotomized positive/negative classification, most effects on cognition remained. Dichotomized amyloid status alone yielded fewer significant effects of amyloid on cognitive decline than continuous SUVR. Among amyloid-positive participants, increasing baseline SUVR predicted an increasing decline in episodic memory, but other effects on cognition were more limited. Finally, higher baseline amyloid burden among middle-aged adults was related to changes in vocabulary, with the effect driven by 3 apolipoprotein ε4 homozygotes. Conclusions and Relevance: These results suggest that the magnitude of amyloid burden at baseline is associated with the rate of cognitive decline over 4 years and potentially provides important information about the rate of future cognitive decline that is not available from a dichotomous positive/negative categorization.

Discrepancies between fluid and crystallized ability in healthy adults: a behavioral marker of preclinical Alzheimer's disease.

Measures of core cognitive processes (fluid abilities) are highly correlated with measures of knowledge (crystallized abilities) in healthy adults. In early stages of Alzheimer's disease (AD), fluid abilities, however, decline more rapidly than crystallized abilities. We hypothesized that cognitively normal older adults who evidenced lower fluid ability compared with crystallized ability (an ability discrepancy) would show evidence of early AD neuropathology indexed via in vivo measures of amyloid-beta (Aß) deposition and cortical thickness in AD-vulnerable regions. A sample of older adults (n = 112) aged 65 to 89 underwent a cognitive battery, structural magnetic resonance imaging, and a subset (n = 75) also completed positron emission tomography scanning to measure Aß deposition using F-18 Florbetapir. Of this sample, 60 older adults (43 with available positron emission tomography scans) evidenced a discrepancy where fluid ability was lower than crystallized ability. The magnitude of the ability discrepancy was independently associated with a greater Aß deposition and thinner cortex in AD-vulnerable regions, as well as age. The data suggest that such a discrepancy may be a marker of preclinical AD.

Pilot expertise and hippocampal size: associations with longitudinal flight simulator performance.

BACKGROUND: Previous research suggests that the size of the hippocampus can vary in response to intensive training (e.g., during the acquisition of expert knowledge). However, the role of the hippocampus in maintenance of skilled performance is not well understood. The Stanford/Veterans Affairs Aviation MRI Study offers a unique opportunity to observe the interaction of brain structure and multiple levels of expertise on longitudinal flight simulator performance. METHODS: The current study examined the relationship between hippocampal volume and three levels of aviation expertise, defined by pilot proficiency ratings issued by the U.S. Federal Aviation Administration (11). At 3 annual time points, 60 pilots who varied in their level of aviation expertise (ages ranging from 45 to 69 yr) were tested. RESULTS: At baseline, higher expertise was associated with better flight simulator performance, but not with hippocampal volume. Longitudinally, there was an Expertise x Hippocampal volume interaction, in the direction that a larger hippocampus was associated with better performance at higher levels of expertise. DISCUSSION: These results are consistent with the notion that expertise in a cognitively demanding domain involves the interplay of acquired knowledge ('mental schemas') and basic hippocampal-dependent processes.