Poorer aging trajectories are associated with elevated serotonin synthesis capacity.

The dorsal raphe nucleus (DRN) is one of the earliest targets of Alzheimer's disease-related tau pathology and is a major source of brain serotonin. We used [18F]Fluoro-m-tyrosine ([18F]FMT) PET imaging to measure serotonin synthesis capacity in the DRN in 111 healthy adults (18-85 years-old). Similar to reports in catecholamine systems, we found elevated serotonin synthesis capacity in older adults relative to young. To establish the structural and functional context within which serotonin synthesis capacity is elevated in aging, we examined relationships among DRN [18F]FMT net tracer influx (Ki) and longitudinal changes in cortical thickness using magnetic resonance imaging, longitudinal changes in self-reported depression symptoms, and AD-related tau and ß-amyloid (Aß) pathology using cross-sectional [18F]Flortaucipir and [11C]Pittsburgh compound-B PET respectively. Together, our findings point to elevated DRN [18F]FMT Ki as a marker of poorer aging trajectories. Older adults with highest serotonin synthesis capacity showed greatest temporal lobe cortical atrophy. Cortical atrophy was associated with increasing depression symptoms over time, and these effects appeared to be strongest in individuals with highest serotonin synthesis capacity. We did not find direct relationships between serotonin synthesis capacity and AD-related pathology. Exploratory analyses revealed nuanced effects of sex within the older adult group. Older adult females showed the highest DRN synthesis capacity and exhibited the strongest relationships between entorhinal cortex tau pathology and increasing depression symptoms. Together these findings reveal PET measurement of the serotonin system to be a promising marker of aging trajectories relevant to both AD and affective changes in older age.

Rates of ß-amyloid deposition indicate widespread simultaneous accumulation throughout the brain.

Amyloid plaque aggregation is a pathologic hallmark of Alzheimer's disease (AD) that occurs early in the disease. However, little is known about its progression throughout the brain. Using Pittsburgh Compound B (PIB)-PET imaging, we investigated the progression of regional amyloid accumulation in cognitively normal older adults. We found that all examined regions reached their peak accumulation rates 24-28 years after an estimated initiation corresponding to the mean baseline PIB-PET signal in amyloid-negative older adults. We also investigated the effect of increased genetic risk conferred by the apolipoprotein-E ɛ4 allele on rates of amyloid accumulation, as well as the relationship between regional amyloid accumulation and regional tau pathology, another hallmark of AD, measured with Flortaucipir-PET. Carriers of the ɛ4 allele had faster amyloid accumulation in all brain regions. Furthermore, in all regions excluding the temporal lobe, faster amyloid accumulation was associated with greater tau burden. These results indicate that amyloid accumulates near-simultaneously throughout the brain and is associated with higher AD pathology, and that genetic risk of AD is associated with faster amyloid accumulation.

Elevated Dopamine Synthesis as a Mechanism of Cognitive Resilience in Aging.

Aging is associated with declines in multiple components of the dopamine system including loss of dopamine-producing neurons, atrophy of the dopamine system's cortical targets, and reductions in the density of dopamine receptors. Countering these patterns, dopamine synthesis appears to be stable or elevated in older age. We tested the hypothesis that elevation in dopamine synthesis in aging reflects a compensatory response to neuronal loss rather than a nonspecific monotonic shift in older age. We measured individual differences in striatal dopamine synthesis capacity in cognitively normal older adults using [18F]Fluoro-l-m-tyrosine positron emission tomography cross-sectionally and tested relationships with longitudinal reductions in cortical thickness and working memory decline beginning up to 13 years earlier. Consistent with a compensation account, older adults with the highest dopamine synthesis capacity were those with greatest atrophy in posterior parietal cortex. Elevated dopamine synthesis capacity was not associated with successful maintenance of working memory performance overall, but had a moderating effect such that higher levels of dopamine synthesis capacity reduced the impact of atrophy on cognitive decline. Together, these findings support a model by which upregulation of dopamine synthesis represents a mechanism of cognitive resilience in aging.

Tau Accumulation in Clinically Normal Older Adults Is Associated with Hippocampal Hyperactivity.

Animal studies demonstrate that hyperactive neurons facilitate early accumulation and spread of tau and amyloid-ß proteins in the pathological cascade of Alzheimer's disease (AD). Human neuroimaging studies have linked hippocampal hyperactivity to amyloid-ß accumulation, apolipoprotein ε4 (APOE4) and clinical progression from prodromal AD to clinical dementia. The relationship between hippocampal hyperactivity and early AD molecular pathology (amyloid-ß and tau accumulation) before clinical symptoms remains to be elucidated. Here, we studied 120 clinically normal older humans (80 females/40 males) enrolled in the Harvard Aging Brain Study. We measured functional magnetic resonance imaging (fMRI) activity during successful memory encoding and amyloid-ß accumulation with PiB-positron emission tomography imaging. Additionally, we measured tau accumulation using AV1451 PET imaging in a subset of 87 participants. In this subset, we found that inferior temporal tau accumulation was associated with increased fMRI activity in the hippocampus, but showed no clear association with amyloid. Together, the findings support a hypothetical model of the evolution of preclinical AD that place hippocampal hyperactivity concurrent with spread of tau pathology to neocortical regions before clinical impairment.SIGNIFICANCE STATEMENT The circumstances under which the hippocampus becomes hyperactive in preclinical stages of Alzheimer's disease (AD) have thus far remained elusive. Recent advances in positron emission tomography (PET) tracers now enable in vivo characterization of amyloid-ß and tau accumulation. Here, we combine amyloid and tau PET with functional magnetic resonance imaging (fMRI) to examine the association between Alzheimer's disease pathology and memory-related brain activity in clinically normal older adults. We found an association between increased hippocampal activity and tau accumulation in the inferior temporal cortex. These data suggest that the pathogenesis of hippocampal hyperactivity occurs concurrent with the spread of tau pathology from the entorhinal cortex to the neocortex, before the clinical manifestations of Alzheimer's disease.

The relationship between recall of recently versus remotely encoded famous faces and amyloidosis in clinically normal older adults.

INTRODUCTION: Alzheimer's disease (AD) patients exhibit temporally graded memory loss with remote memories remaining more intact than recent memories. It is unclear whether this temporal pattern is observable in clinically normal adults with amyloid pathology (i.e. preclinical AD). METHODS: Participants were asked to recall the names of famous figures most prominent recently (famous after 1990) and remotely (famous from 1960-1980) and were provided with a phonemic cue to ensure that memory failure was not purely due to verbal retrieval weaknesses. In addition, participants identified line drawings of objects. Clinically normal older adults (n = 125) were identified as amyloid ß positive or negative (Aß+/-) using Pittsburgh compound B positron emission tomography. The relationship between Aß+/- and recall of remote and recent famous face-names and objects was examined using repeated measures analyses and general linear models controlling for demographics and media usage. RESULTS: When provided with a phonemic cue, Aß+ participants recalled the names of fewer recent famous faces compared with Aß- participants. However, recall of remote famous face-names and objects did not differ by Aß group. DISCUSSION: Relative sparing of remotely learned information compared with recently learned information is (1) detectable in the preclinical stages of AD and (2) related to amyloid pathology. Both this temporal gradient and assessment of person-centered rather than object-centered semantic information may be particularly meaningful for tracking early memory changes in the AD trajectory.

PET staging of amyloidosis using striatum.

INTRODUCTION: Amyloid positron emission tomography (PET) data are commonly expressed as binary measures of cortical deposition. However, not all individuals with high cortical amyloid will experience rapid cognitive decline. Motivated by postmortem data, we evaluated a three-stage PET classification: low cortical; high cortical, low striatal; and high cortical, high striatal amyloid; hypothesizing this model could better reflect Alzheimer's dementia progression than a model based only on cortical measures. METHODS: We classified PET data from 1433 participants (646 normal, 574 mild cognitive impairment, and 213 AD), explored the successive involvement of cortex and striatum using 3-year follow-up PET data, and evaluated the associations between PET stages, hippocampal volumes, and cognition. RESULTS: Follow-up data indicated that PET detects amyloid first in cortex and then in striatum. Our three-category staging including striatum better predicted hippocampal volumes and subsequent cognition than a three-category staging including only cortical amyloid. DISCUSSION: PET can evaluate amyloid expansion from cortex to subcortex. Using striatal signal as a marker of advanced amyloidosis may increase predictive power in Alzheimer's dementia research.

Association Between Amyloid and Tau Accumulation in Young Adults With Autosomal Dominant Alzheimer Disease.

Importance: It is critically important to improve our ability to diagnose and track Alzheimer disease (AD) as early as possible. Individuals with autosomal dominant forms of AD can provide clues as to which and when biological changes are reliably present prior to the onset of clinical symptoms. Objective: To characterize the associations between amyloid and tau deposits in the brains of cognitively unimpaired and impaired carriers of presenilin 1 (PSEN1) E280A mutation. Design, Setting, and Participants: In this cross-sectional imaging study, we leveraged data from a homogeneous autosomal dominant AD kindred, which allowed us to examine measurable tau deposition as a function of individuals' proximity to the expected onset of dementia. Cross-sectional measures of carbon 11-labeled Pittsburgh Compound B positron emission tomography (PET) and flortaucipir F 18 (previously known as AV 1451, T807) PET imaging were assessed in 24 PSEN1 E280A kindred members (age range, 28-55 years), including 12 carriers, 9 of whom were cognitively unimpaired and 3 of whom had mild cognitive impairment, and 12 cognitively unimpaired noncarriers. Main Outcomes and Measures: We compared carbon 11-labeled Pittsburgh Compound B PET cerebral with cerebellar distribution volume ratios as well as flortaucipir F 18 PET cerebral with cerebellar standardized uptake value ratios in mutation carriers and noncarriers. Spearman correlations characterized the associations between age and mean cortical Pittsburgh Compound B distribution volume ratio levels or regional flortaucipir standardized uptake value ratio levels in both groups. Results: Of the 24 individuals, the mean (SD) age was 38.0 (7.4) years, or approximately 6 years younger than the expected onset of clinical symptoms in carriers. Compared with noncarriers, cognitively unimpaired mutation carriers had elevated mean cortical Pittsburgh Compound B distribution volume ratio levels in their late 20s, and 7 of 9 carriers older than 30 years reached the threshold for amyloidosis (distribution volume ratio level > 1.2). Elevated levels of tau deposition were seen within medial temporal lobe regions in amyloid-positive mutation carriers 6 years before clinical onset of AD in this kindred. Substantial tau deposition in the neocortex was only observed in 1 unimpaired carrier and in those with mild cognitive impairment. ß-Amyloid uptake levels were diffusely elevated in unimpaired carriers approximately 15 years prior to expected onset of mild cognitive impairment. In carriers, higher levels of tau deposition were associated with worse performance on the Mini-Mental State Examination (entorhinal cortex: r = -0.60; P = .04; inferior temporal lobe: r = -0.54; P = .06) and the Consortium to Establish a Registry for Alzheimer Disease Word List Delayed Recall (entorhinal cortex: r = -0.86; P < .001; inferior temporal lobe: r = -0.70; P = .01). Conclusions and Relevance: The present findings add to the growing evidence that molecular markers can characterize biological changes associated with AD in individuals who are still cognitively unimpaired. The findings also suggest that tau PET imaging may be useful as a biomarker to distinguish individuals at high risk to develop the clinical symptoms of AD and to track disease progression.

Interactive versus additive relationships between regional cortical thinning and amyloid burden in predicting clinical decline in mild AD and MCI individuals.

The biological mechanisms that link Beta-amyloid (Aß) plaque deposition, neurodegeneration, and clinical decline in Alzheimer's disease (AD) dementia, have not been completely elucidated. Here we studied whether amyloid accumulation and neurodegeneration, independently or interactively, predict clinical decline over time in a group of memory impaired older individuals [diagnosed with either amnestic mild cognitive impairment (MCI), or mild AD dementia]. We found that baseline Aß-associated cortical thinning across clusters encompassing lateral and medial temporal and parietal cortices was related to higher baseline Clinical Dementia Rating Sum-of-Boxes (CDR-SB). Baseline Aß-associated cortical thinning also predicted CDR-SB over time. Notably, the association between CDR-SB change and cortical thickness values from the right lateral temporo-parietal cortex and right precuneus was driven by individuals with high Aß burden. In contrast, the association between cortical thickness in the medial temporal lobe (MTL) and clinical decline was similar for individuals with high or low Aß burden. Furthermore, amyloid pathology was a stronger predictor for clinical decline than MTL thickness. While this study validates previous findings relating AD biomarkers of neurodegeneration to clinical impairment, here we show that regions outside the MTL may be more vulnerable and specific to AD dementia. Additionally, excluding mild AD individuals revealed that these relationships remained, suggesting that lower cortical thickness values in specific regions, vulnerable to amyloid pathology, predict clinical decline already at the prodromal stage.

The association between tau PET and retrospective cortical thinning in clinically normal elderly.

Tau pathology has been associated with neuronal loss at autopsy, but the temporal evolution of tau pathology and atrophy remains unclear. Here, we investigate the association between cross-sectional AV-1451-PET as a marker of tau pathology and cortical thickness cross-sectionally. We also investigated retrospective rates of cortical thinning over the three years preceding the AV-1451 scan in a clinically normal cohort of 103 older adults from the Harvard Aging Brain Study. Tau measurements were Geometric Transfer Matrix partial volume corrected standardized uptake value ratios (SUVRs) with a cerebellar gray reference region. Thirty-four FreeSurfer-defined cortical regions of interest (ROIs) were used for both thickness and AV-1451 in each hemisphere, with seven additional volumetric ROIs. We examined "local" relationships between AV-1451 and cortical thickness in the same ROI, as well as inferior temporal AV-1451 and all thickness ROIs. All models included baseline age and sex, both interacting with time in retrospective longitudinal models, as covariates. Cross-sectional models controlled for the number of days between the two scans. Cross-sectional local comparisons revealed significant associations between elevated AV-1451 and thinner cortical ROIs predominantly in temporal regions, while analyses associating inferior temporal AV-1451 with all cortical ROIs showed a widespread pattern of significant relationships, which was strongest in temporal and parietal cortices. In our retrospective longitudinal analyses, we saw significant relationships in temporal and parietal regions. Significant local relationships were seen in right superior temporal, middle temporal, temporal pole, and fusiform, as well as the left cuneus and banks of the left superior temporal sulcus. Significant relationships between inferior temporal AV-1451 and faster thinning were observed in right temporal regions (middle temporal and fusiform) and bilateral parahippocampal cortices. We observed significant negative relationships between local and inferior temporal AV-1451 signal and both cross-sectional cortical thickness and rates of thinning in lateral and medial temporal regions. This is an important early step toward elucidating the relationship between tau pathology and retrospective longitudinal atrophy in aging and preclinical AD.

Fluorodeoxyglucose metabolism associated with tau-amyloid interaction predicts memory decline.

OBJECTIVE: The aim of this article was to evaluate in normal older adults and preclinical Alzheimer's disease (AD) the impact of amyloid and regional tauopathy on cerebral glucose metabolism and subsequent memory decline. METHODS: We acquired positron emission tomography using F18 flortaucipir (tau), C11 Pittsburgh compound B (amyloid), and F18 fluorodeoxyglucose (FDG) in 90 clinically normal elderly of the Harvard Aging Brain Study. RESULTS: Posterior cingulate metabolism decreased when both amyloid and neocortical tau were high and predicted subsequent memory decline in a larger sample of normal elderly. In contrast, frontal hypometabolism related to the common age-related entorhinal tauopathy, but this dysfunction was independent of amyloid, and did not predict significant memory decline. Neocortical tauopathy was positively associated with metabolism in individuals with subthreshold amyloid, suggesting that glucose metabolism increases before decreasing in the course of preclinical AD. INTERPRETATION: Our study identified a synergistic effect of amyloid and tau deposits and demonstrated, for the first time, in normal elderly its link to AD-like hypometabolism and to AD-like memory decline. The amyloid effect was observed with tau in neocortex, but not with tau in entorhinal cortex, which is the common site of age-related tauopathy. Entorhinal tau was associated with frontal hypometabolism, but this dysfunction was not associated with memory loss. Ann Neurol 2017;81:583-596.

Phases of Hyperconnectivity and Hypoconnectivity in the Default Mode and Salience Networks Track with Amyloid and Tau in Clinically Normal Individuals.

Alzheimer's disease (AD) is characterized by two hallmark molecular pathologies: amyloid aß1-42 and Tau neurofibrillary tangles. To date, studies of functional connectivity MRI (fcMRI) in individuals with preclinical AD have relied on associations with in vivo measures of amyloid pathology. With the recent advent of in vivo Tau-PET tracers it is now possible to extend investigations on fcMRI in a sample of cognitively normal elderly humans to regional measures of Tau. We modeled fcMRI measures across four major cortical association networks [default-mode network (DMN), salience network (SAL), dorsal attention network, and frontoparietal control network] as a function of global cortical amyloid [Pittsburgh Compound B (PiB)-PET] and regional Tau (AV1451-PET) in entorhinal, inferior temporal (IT), and inferior parietal cortex. Results showed that the interaction term between PiB and IT AV1451 was significantly associated with connectivity in the DMN and salience. The interaction revealed that amyloid-positive (aß+) individuals show increased connectivity in the DMN and salience when neocortical Tau levels are low, whereas aß+ individuals demonstrate decreased connectivity in these networks as a function of elevated Tau-PET signal. This pattern suggests a hyperconnectivity phase followed by a hypoconnectivity phase in the course of preclinical AD.SIGNIFICANCE STATEMENT This article offers a first look at the relationship between Tau-PET imaging with F18-AV1451 and functional connectivity MRI (fcMRI) in the context of amyloid-PET imaging. The results suggest a nonlinear relationship between fcMRI and both Tau-PET and amyloid-PET imaging. The pattern supports recent conjecture that the AD fcMRI trajectory is characterized by periods of both hyperconnectivity and hypoconnectivity. Furthermore, this nonlinear pattern can account for the sometimes conflicting reports of associations between amyloid and fcMRI in individuals with preclinical Alzheimer's disease.

Harvard Aging Brain Study: Dataset and accessibility.

The Harvard Aging Brain Study is sharing its data with the global research community. The longitudinal dataset consists of a 284-subject cohort with the following modalities acquired: demographics, clinical assessment, comprehensive neuropsychological testing, clinical biomarkers, and neuroimaging. To promote more extensive analyses, imaging data was designed to be compatible with other publicly available datasets. A cloud-based system enables access to interested researchers with blinded data available contingent upon completion of a data usage agreement and administrative approval. Data collection is ongoing and currently in its fifth year.

Age-Related Increases in Tip-of-the-tongue are Distinct from Decreases in Remembering Names: A Functional MRI Study.

Tip-of-the-tongue (TOT) experiences increase with age and frequently heighten concerns about memory decline. We studied 73 clinically normal older adults participating in the Harvard Aging Brain Study. They completed a functional magnetic resonance imaging (fMRI) task that required remembering names associated with pictures of famous faces. Older age was associated with more self-reported TOT experiences and a decrease in the percentage of remembered names. However, the percentage of TOT experiences and the percentage of remembered names were not directly correlated. We mapped fMRI activity for recollection of famous names and TOT and examined activity in the hippocampal formation, retrosplenial cortex, and lateral prefrontal cortex. The hippocampal formation was similarly activated in recollection and TOT experiences. In contrast, the retrosplenial cortex was most active for recollection and lateral prefrontal cortex was most active for TOT experiences. Together, the results confirm that age-related increases in TOT experiences are not only solely the consequence of age-related decline in recollection, but also likely reflect functional alterations in the brain networks that support retrieval monitoring and cognitive control. These findings provide behavioral and neuroimaging evidence that age-related TOT experiences and memory failure are partially independent processes.

Heterogeneity in Suspected Non-Alzheimer Disease Pathophysiology Among Clinically Normal Older Individuals.

IMPORTANCE: A substantial proportion of clinically normal (CN) older individuals are classified as having suspected non-Alzheimer disease pathophysiology (SNAP), defined as biomarker negative for ß-amyloid (Aß-) but positive for neurodegeneration (ND+). The etiology of SNAP in this population remains unclear. OBJECTIVE: To determine whether CN individuals with SNAP show evidence of early Alzheimer disease (AD) processes (ie, elevated tau levels and/or increased risk for cognitive decline). DESIGN, SETTING, AND PARTICIPANTS: This longitudinal observational study performed in an academic medical center included 247 CN participants from the Harvard Aging Brain Study. Participants were classified into preclinical AD stages using measures of Aß (Pittsburgh Compound B [PIB]-labeled positron emission tomography) and ND (hippocampal volume or cortical glucose metabolism from AD-vulnerable regions). Classifications included stages 0 (Aß-/ND-), 1 (Aß+/ND-), and 2 (Aß+/ND+) and SNAP (Aß-/ND+). Continuous levels of PiB and ND, tau levels in the medial and inferior temporal lobes, and longitudinal cognition were examined. Data collection began in 2010 and is ongoing. Data were analyzed from 2015 to 2016. MAIN OUTCOMES AND MEASURES: Evidence of amyloid-independent tau deposition and/or cognitive decline. RESULTS: Of the 247 participants (142 women [57.5%]; 105 men [42.5%]; mean age, 74 [range, 63-90] years), 64 (25.9%) were classified as having SNAP. Compared with the stage 0 group, the SNAP group was not more likely to have subthreshold PiB values (higher values within the Aß- range), suggesting that misclassification due to the PiB cutoff was not a prominent contributor to this group (mean [SD] distribution volume ratio, 1.08 [0.05] for the SNAP group; 1.09 [0.05] for the stage 1 group). Tau levels in the medial and inferior temporal lobes were indistinguishable between the SNAP and stage 0 groups (entorhinal cortex, ß = -0.005 [SE, 0.036]; parahippocampal gyrus, ß = -0.001 [SE, 0.027]; and inferior temporal lobe, ß = -0.004 [SE, 0.027]; P ≥ .88) and were lower in the SNAP group compared with the stage 2 group (entorhinal cortex, ß = -0.125 [SE, 0.041]; parahippocampal gyrus, ß = -0.074 [SE, 0.030]; and inferior temporal lobe, ß = -0.083 [SE, 0.031]; P ≤ .02). The stage 2 group demonstrated greater cognitive decline compared with all other groups (stage 0, ß = -0.239 [SE, 0.042]; stage 1, ß = -0.242 [SE, 0.051]; and SNAP, ß = -0.157 [SE, 0.044]; P ≤ .001), whereas the SNAP group showed a diminished practice effect over time compared with the stage 0 group (ß = -0.082 [SE, 0.037]; P = .03). CONCLUSIONS AND RELEVANCE: In this study, clinically normal adults with SNAP did not exhibit evidence of elevated tau levels, which suggests that this biomarker construct does not represent amyloid-independent tauopathy. At the group level, individuals with SNAP did not show cognitive decline but did show a diminished practice effect. SNAP is likely heterogeneous, with a subset of this group at elevated risk for short-term decline. Future refinement of biomarkers will be necessary to subclassify this group and determine the biological correlates of ND markers among Aß- CN individuals.

Temporal T807 binding correlates with CSF tau and phospho-tau in normal elderly.

OBJECTIVE: To better understand cross-sectional relationships between CSF and PET measures of tau pathology, we compared regional and global measures of (18)F-T807 (AV-1451) PET to CSF protein levels of total tau (t-tau), phosphorylated tau (p-tau), and ß-amyloid 1-42 (Aß42). METHODS: T-tau, p-tau, and Aß42 levels were assessed using INNOTEST xMAP immunoassays. Linear regression was used to compare regional and global measures of (18)F-T807 standardized uptake value ratios (SUVR) to CSF protein levels using data from 31 cognitively unimpaired elderly participants in the Harvard Aging Brain study. RESULTS: After controlling for sex and age, total cortical (18)F-T807 binding was significantly correlated with p-tau (partial r = 0.48; p < 0.01) and at trend level with t-tau (partial r = 0.30; p = 0.12). Regional (18)F-T807 measures were more strongly correlated with CSF protein levels than the global measure, with both t-tau and p-tau significantly correlated with (18)F-T807 SUVR in entorhinal, parahippocampal, and inferior temporal cortical regions (partial r = 0.53-0.73). Peak correlations between CSF and PET measures of tau were similar to those between CSF and PET measures of amyloid burden. Finally, we observed significantly higher temporal T807 SUVR in individuals with high amyloid burden. CONCLUSIONS: These data support the link between (18)F-T807 PET and CSF measures of tau pathology. In these cognitively normal individuals with (18)F-T807 binding largely restricted to the temporal lobe, (18)F-T807 SUVR in temporal regions appeared more reflective of CSF t-tau and p-tau than a total cortical measure.