Regional Tau Deposition Research Articles

Association of Apolipoprotein E ɛ4, Educational Level, and Sex With Tau Deposition and Tau-Mediated Metabolic Dysfunction in Older Adults

While amyloidosis is an early event in the Alzheimer disease (AD) biomarker cascade, a complex interplay among the apolipoprotein E (APOE) ɛ4 allele, educational levels, and sex may be associated with an individual's resilience to dementia. To assess whether APOE ɛ4, educational levels, and sex are associated with regional tau deposition and tau-mediated metabolic dysfunction in older adults. Population-based cohort study of individuals aged 65 years and older enrolled between January 1, 2004, and May 1, 2018, in the Mayo Clinic Study of Aging, a prospective longitudinal study of cognitive aging in Olmsted County, Minnesota. The primary outcomes were cross-sectional tau burden and the fluorodeoxyglucose (FDG) to tau ratio (as a measure of tau-mediated metabolic dysfunction) assessed by positron emission tomography for 43 atlas-defined regions, with specific focus on the entorhinal, inferior temporal, and posterior cingulate cortices. Using linear regression, APOE ɛ4 status and years of education were the primary exposure variables, with sex additionally investigated through interaction models. The sample included 325 individuals (173 [53%] male; mean [SD] age, 76.1 [7.2] years; 291 [90%] cognitively unimpaired). Although APOE ɛ4 was nominally associated with higher tau deposition (β = 0.05 [95% CI, 0.02-0.09]; P = .001; Cohen d = 0.40) and lower FDG to tau ratio (β = -0.05 [95% CI, -0.08 to -0.01]; P = .008; Cohen d = 0.33) in the entorhinal cortex, these associations were completely attenuated after controlling for global amyloid burden. Education was not associated with regional tau burden or FDG to tau ratio. In the 3 regions of interest, global amyloid burden accounted for the largest proportion of variance in tau deposition among the candidate variables assessed. In the entorhinal cortex, significant interactions were identified between APOE ɛ4 and global amyloid burden on tau (β = 0.25; SE = 0.06; P < .001) and between sex and tau burden on FDG metabolism (β = 0.10; SE = 0.05; P = .049). These results suggest that (1) tau deposition is most significantly associated with amyloidosis; (2) in the presence of abundant amyloidosis, APOE ɛ4 may be associated with accelerated entorhinal cortex tau deposition; and (3) women may have lower resilience to tau, manifested by a higher degree of metabolic dysfunction in the entorhinal cortex in response to tau pathology.

Association between personality and tau-PET binding in cognitively normal older adults.

Personality traits such as Neuroticism and Conscientiousness are associated with Alzheimer disease (AD) pathophysiology in cognitively normal (CN) and impaired individuals, and may represent potential risk or resilience factors, respectively. This study examined the cross-sectional relationship between personality traits and regional tau deposition using positron emission tomography (PET) in cognitively normal older adults. A cohort of CN (Clinical Dementia Rating (CDR) 0, n= 128) older adults completed the NEO Five-Factor Inventory to assess traits of Neuroticism, Extroversion, Openness, Agreeableness, and Conscientiousness and underwent tau-PET and β-amyloid (Aβ)-PET imaging. We utilized linear regression models, adjusting for age, sex, geriatric depression score, and Aβ to evaluate the association between each of the personality traits and regional tau-PET accumulation. Elevated Neuroticism scores were associated with higher tau-PET accumulation in the amygdala (p= .002), entorhinal cortex (p= .012), and inferior temporal cortex (p= .016), as well as with a composite tau-PET measure (p= .002). In contrast, Extroversion, Openness, Agreeableness, and Conscientiousness were not associated with tau deposition in any of these regions (p's > 0.160). Our results indicate that increased Neuroticism is associated with higher tau pathophysiology in regions known to be vulnerable to AD pathophysiology in CN participants. High Neuroticism scores may therefore serve as a potential risk factor for tau accumulation. Alternatively, personality can change with the onset of AD, thus increased tau levels may affect Neuroticism scores. While future longitudinal studies are needed to determine directionality, our findings suggest early associations between Neuroticism and tau accumulation in CN adults.

P1‐271: CSF GLUCOSE TRACKS BRAAK STAGE TAU DEPOSITION

Type 2 diabetes is a known risk factor for Alzheimer's disease (AD). Tau hyperphosphorylation, a marker of neurodegeneration, occurs in the brain of both type 2 diabetes and AD patients. Furthermore, CSF glucose is strongly associated with CSF total tau protein levels in AD patients. It is not known if CSF glucose is associated with regional tau deposition, however, and if such associations regionally vary depending on AD genetic risk factors, baseline diagnosis, or sex. Data from 142 aged adults was downloaded from the Alzheimer's Disease Neuroimaging Initiative (ADNI). CSF glucose levels were derived from standard lab assays. Fully preprocessed F18-AV-1451 positron emission tomography scans where coregistered to the subject's T1-weighted image in native space. Mean regional uptake in FreeSurfer defined regions was divided by mean uptake in the inferior cerebellum reference region to derive Standardized Uptake Value Ratios (SUVRs). Multiple linear regression regressed CSF glucose against regional AV-1451 SUVR in regions of interest. Due to the large number of cognitive normal subjects scanned (n=103), analyses were restricted to Braak stages 1/2 and 3/4. Interactions between CSF glucose and gender, family history of AD, and beta-amyloid (Aβ) status were also explored. Higher CSF glucose was significantly associated with lower tau deposition in the caudal anterior cingulate gyrus (Braak 4). Moderation analyses showed that only Mild Cognitive Impairment (MCI) and AD participants drove this association. A gender x CSF glucose interaction showed that higher CSF glucose was related to lower hippocampal tau deposition (Braak 2) in women but not men. Finally, for subjects with AD parental history, higher CSF glucose was linked to less regional tau deposition in all Braak stage 3 and 4 regions, particularly the lingual gyrus, fusiform gyrus, and isthmus of cingulate gyrus. Taken together, these results suggest that higher CSF glucose levels may be protective against early tau deposition among women, as well as later tau deposition among subjects with cognitive impairment or a parental history of AD. Future work will examine similar associations with peripheral insulin resistance and moderation by regional amyloid deposition.

Quantitative 18F-AV1451 Brain Tau PET Imaging in Cognitively Normal Older Adults, Mild Cognitive Impairment, and Alzheimer's Disease Patients.

Recent developments of tau Positron Emission Tomography (PET) allows assessment of regional neurofibrillary tangles (NFTs) deposition in human brain. Among the tau PET molecular probes, 18F-AV1451 is characterized by high selectivity for pathologic tau aggregates over amyloid plaques, limited non-specific binding in white and gray matter, and confined off-target binding. The objectives of the study are (1) to quantitatively characterize regional brain tau deposition measured by 18F-AV1451 PET in cognitively normal older adults (CN), mild cognitive impairment (MCI), and AD participants; (2) to evaluate the correlations between cerebrospinal fluid (CSF) biomarkers or Mini-Mental State Examination (MMSE) and 18F-AV1451 PET standardized uptake value ratio (SUVR); and (3) to evaluate the partial volume effects on 18F-AV1451 brain uptake.Methods: The study included total 115 participants (CN = 49, MCI = 58, and AD = 8) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Preprocessed 18F-AV1451 PET images, structural MRIs, and demographic and clinical assessments were downloaded from the ADNI database. A reblurred Van Cittertiteration method was used for voxelwise partial volume correction (PVC) on PET images. Structural MRIs were used for PET spatial normalization and region of interest (ROI) definition in standard space. The parametric images of 18F-AV1451 SUVR relative to cerebellum were calculated. The ROI SUVR measurements from PVC and non-PVC SUVR images were compared. The correlation between ROI 18F-AV1451 SUVR and the measurements of MMSE, CSF total tau (t-tau), and phosphorylated tau (p-tau) were also assessed.Results: 18F-AV1451 prominently specific binding was found in the amygdala, entorhinal cortex, parahippocampus, fusiform, posterior cingulate, temporal, parietal, and frontal brain regions. Most regional SUVRs showed significantly higher uptake of 18F-AV1451 in AD than MCI and CN participants. SUVRs of small regions like amygdala, entorhinal cortex and parahippocampus were statistically improved by PVC in all groups (p < 0.01). Although there was an increasing tendency of 18F-AV-1451 SUVRs in MCI group compared with CN group, no significant difference of 18F-AV1451 deposition was found between CN and MCI brains with or without PVC (p > 0.05). Declined MMSE score was observed with increasing 18F-AV1451 binding in amygdala, entorhinal cortex, parahippocampus, and fusiform. CSF p-tau was positively correlated with 18F-AV1451 deposition. PVC improved the results of 18F-AV-1451 tau deposition and correlation studies in small brain regions.Conclusion: The typical deposition of 18F-AV1451 tau PET imaging in AD brain was found in amygdala, entorhinal cortex, fusiform and parahippocampus, and these regions were strongly associated with cognitive impairment and CSF biomarkers. Although more deposition was observed in MCI group, the 18F-AV-1451 PET imaging could not differentiate the MCI patients from CN population. More tau deposition related to decreased MMSE score and increased level of CSF p-tau, especially in ROIs of amygdala, entorhinal cortex and parahippocampus. PVC did improve the results of tau deposition and correlation studies in small brain regions and suggest to be routinely used in 18F-AV1451 tau PET quantification.

NEW INSIGHTS INTO LONELINESS AND ITS TREATMENT IN OLDER ADULTS: Session 108

Loneliness is a well-studied construct in the social sciences, in the epidemiology of aging and increasingly in gerontology but it is a relatively uncommon focus in psychiatric research. Loneliness is a perceived state of social and emotional isolation that is distinct from objective social isolation. Loneliness is understood to be both a perception and an emotion and may be a form of psychosocial stress. In large population-based studies, there is strong evidence that both loneliness and lower social engagement are independent predictors of accelerated cognitive decline and incident AD dementia. Psychosocial factors influencing loneliness are well known whereas little is known of the neurobiology and pathological correlates of loneliness, particularly in older people. The goal of this session is to illustrate the importance of social function and wellbeing to longitudinal cognition and Alzheimer's disease progression in older adults. The four speakers will provide data from their own research examining associations of loneliness and social engagement to cognition and Alzheimer's disease biomarkers. Dr. Joanna McHugh Power will describe six-year data defining patterns of loneliness and social isolation that are most predictive of semantic memory declines in over 8,000 participants from the Irish Longitudinal Study of Ageing. Dr. Nancy Donovan (Chair) will present a cross-sectional study defining associations of greater loneliness with higher cortical amyloid burden and regional tau deposition in a sample of cognitively normal older adults from the Harvard Aging Brain Study. Kelsey Biddle from Dr. Donovan's group will describe longitudinal data from the Harvard Brain Study examining cortical amyloid deposition, cognition and psychosocial factors that are predictive of decline in social engagement over 3 years among cognitively normal elderly. Dr. Phaedra Bell will present data from a pilot study focusing on lonely older adults to assess the impact of a multimodal intergenerational intervention on ratings of loneliness and mood in these participants. Finally, Dr. McHugh Power (Discussant) will lead the speakers in a panel discussion, along with Q&A involving session attendees.

Sex Differences in the Association of Global Amyloid and Regional Tau Deposition Measured by Positron Emission Tomography in Clinically Normal Older Adults

Mounting evidence suggests that sex differences exist in the pathologic trajectory of Alzheimer disease. Previous literature shows elevated levels of cerebrospinal fluid tau in women compared with men as a function of apolipoprotein E (APOE) ε4 status and β-amyloid (Aβ). What remains unclear is the association of sex with regional tau deposition in clinically normal individuals. To examine sex differences in the cross-sectional association between Aβ and regional tau deposition as measured with positron emission tomography (PET). This is a study of 2 cross-sectional, convenience-sampled cohorts of clinically normal individuals who received tau and Aβ PET scans. Data were collected between January 2016 and February 2018 from 193 clinically normal individuals from the Harvard Aging Brain Study (age range, 55-92 years; 118 women [61%]) who underwent carbon 11-labeled Pittsburgh Compound B and flortaucipir F18 PET and 103 clinically normal individuals from the Alzheimer's Disease Neuroimaging Initiative (age range, 63-94 years; 55 women [51%]) who underwent florbetapir and flortaucipir F 18 PET. A main association of sex with regional tau in the entorhinal cortices, inferior temporal lobe, and a meta-region of interest, which was a composite of regions in the temporal lobe. Associations between sex and global Aβ as well as sex and APOE ε4 on these regions after controlling for age were also examined. The mean (SD) age of all individuals was 74.2 (7.6) years (81 APOE ε4 carriers [31%]; 89 individuals [30%] with high Aβ). There was no clear association of sex with regional tau that was replicated across studies. However, in both cohorts, clinically normal women exhibited higher entorhinal cortical tau than men (meta-analytic estimate: β [male] = -0.11 [0.05]; 95% CI, -0.21 to -0.02; P = .02), which was associated with individuals with higher Aβ burden. A sex by APOE ε4 interaction was not associated with regional tau (meta-analytic estimate: β [male, APOE ε4+] = -0.15 [0.09]; 95% CI, -0.32 to 0.01; P = .07). Early tau deposition was elevated in women compared with men in individuals on the Alzheimer disease trajectory. These findings lend support to a growing body of literature that highlights a biological underpinning for sex differences in Alzheimer disease risk.

Inferior and medial temporal tau and cortical amyloid are associated with daily functional impairment in Alzheimer\u2019s disease

BackgroundA decline in instrumental activities of daily living (IADL) correlates with the progression from mild cognitive impairment (MCI) to Alzheimer’s disease (AD) dementia and has been associated with frontal and parietal hypometabolism, lower cerebrospinal fluid amyloid β1–42, and inferior temporal cortical thinning. Identifying the underlying biomarkers of functional decline will allow for the early identification of individuals at risk of disease progression.ObjectiveTo investigate the association between IADL impairment and in vivo regional cerebral tau and cortical amyloid deposition across clinically normal (CN) elderly, MCI, and AD dementia.MethodsFifty-one CN elderly, 30 MCI, and 9 AD dementia participants of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) underwent assessment of regional tau deposition with flortaucipir (FTP) positron emission tomography (PET). An aggregate of cortical amyloid burden was assessed by florbetapir PET. IADL were assessed using the Functional Activities Questionnaire (FAQ). Tau regions with unadjusted correlations of p ≤ 0.006 (Bonferroni correction) with FAQ were used to evaluate the cross-sectional association between FAQ (dependent variable) and regional cerebral tau deposition, amyloid burden, and tau-amyloid interaction in separate general linear regression models with backward elimination. Covariates included age, American National Adult Reading Test (AMNART) intelligence quotient (IQ), and Rey Auditory Verbal Learning Test (RAVLT) total learning.ResultsUnadjusted correlations between FAQ and tau in the entorhinal cortex (EC) and inferior temporal cortex (IT) survived Bonferroni correction. FAQ was associated with the tau-amyloid interaction, such that in participants with greater amyloid burden, greater IADL impairment was associated with greater regional tau (EC tau × amyloid: partial r (pr) = 0.47, p < 0.001; IT tau × amyloid: pr = 0.54, p < 0.001). Significant associations were found when these regression models were repeated in symptomatic participants alone but not among CN participants.ConclusionsGreater medial and inferior temporal tau and cortical amyloid burden were associated with greater IADL impairment in AD. Further elucidation of the biomarkers underlying the functional decline will allow for the early identification of individual at risk of disease progression.

Corticobasal degeneration.

Corticobasal degeneration (CBD) is a rare neurodegenerative disease characterized by the predominance of pathological 4 repeat tau deposition in various cell types and anatomical regions. Corticobasal syndrome (CBS) is one of the clinical phenotypes associated with CBD pathology, manifesting as a progressive asymmetric akinetic-rigid, poorly levodopa-responsive parkinsonism, with cerebral cortical dysfunction. CBD can manifest as several clinical phenotypes, and similarly, CBS can also have a pathologic diagnosis other than CBD. This chapter discusses the clinical manifestations of pathologically confirmed CBD cases, the current diagnostic criteria, as well as the pathologic and neuroimaging findings of CBD/CBS. At present, therapeutic options for CBD remain symptomatic. Further research is needed to improve the clinical diagnosis of CBD, as well as studies on disease-modifying therapies for this relentlessly progressive neurodegenerative disorder.

Progressive supranuclear palsy.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease characterized pathologically by 4 repeat tau deposition in various cell types and anatomical regions. Richardson's syndrome (RS) is the initially described and one of the clinical phenotypes associated with PSP pathology, characterized by vertical supranuclear gaze paly in particular downwards, postural instability with early falls and subcortical frontal dementia. PSP can manifest as several other clinical phenotypes, including PSP-parkinsonism, -pure akinesia with gait freezing, -frontotemporal dementia, - corticobasal syndrome, - speech/language impairment. RS can also have a pathologic diagnosis other than PSP, including corticobasal degeneration, FTD-TDP-43 and others. New clinical diagnostic criteria take into account this phenotypic variability in an attempt to diagnose the disease earlier, given the current lack of a validated biomarker. At present, therapeutic options for PSP are symptomatic and insufficient. Recent large neuroprotective trials have failed to provide a positive clinical outcome, however, have led to the design of better studies that are ongoing and hold promise for a neuroprotective treatment for PSP.

Subthreshold Amyloid Predicts Tau Deposition in Aging.

Current approaches to the early detection of Alzheimer's disease (AD) rely upon classifying individuals as "positive" or "negative" for biomarkers related to the core pathology of β-amyloid (Aβ). However, the accumulation of Aβ begins slowly, years before biomarkers become abnormal. We used longitudinal [11C] Pittsburgh Compound B PET scanning and neuropsychological assessment to investigate the earliest changes in AD pathology and how it affects memory in cognitively normal older humans (N = 71; mean age 75 years; 35% male). We used [18F] AV-1451 PET scanning at the end of the observation period to measure subsequent tau deposition in a subset of our sample (N = 37). We found evidence for an inverted-U relationship between baseline Aβ levels and Aβ slope in asymptomatic older adults, suggesting a slowing of Aβ accumulation even in cognitively normal adults. In participants who were nominally amyloid negative, both the rate of amyloid accumulation and the baseline levels of Aβ predicted early tau deposition in cortical Braak regions associated with AD. Amyloid measures were only sensitive to memory decline as baseline levels of Aβ increased, suggesting that pathological accumulation occurs before impacting memory. These findings support the necessity of early intervention with amyloid-lowering therapies even in those who are amyloid negative.SIGNIFICANCE STATEMENT The progressive nature of Alzheimer's disease (AD) necessitates the earliest possible detection of pathological or cognitive change if disease progression is to be slowed. We examined cognitively normal older adults in whom AD pathology is starting to develop, with the goal of early detection of AD pathology or cognitive changes. We found amyloid measures to be sensitive early on in predicting subsequent early tau deposition. Further, it appears that rates of amyloid accumulation already begin to slow in preclinical AD, suggesting that it is a relatively late stage of AD progression. Thus, it is crucial to examine older adults early, before amyloid levels have saturated, to intervene to slow disease progression.

BRAIN AEROBIC GLYCOLYSIS AND TAU DEPOSITION WITH [18F]-AV-1451 PET

Our previous studies demonstrated that the aerobic glycolysis (AG, non-oxidative part of brain glucose metabolism), a marker of metabolic functions involved in synaptic plasticity and neuroprotection, declines with age on the whole brain level. This decline is greatest in regions known to accumulate a high density of beta-amyloid plaques in Alzheimer's disease (AD). These observations suggest that there is a substantial age-related loss in metabolic brain reserve supporting synaptic plasticity and neuroprotection that may introduce a selective vulnerability to processes leading to AD pathology and cognitive decline. Neurofibrillary tau pathology is a marker of cell death and dysfunction but little is known about the relationship between regional AG and tau pathology in the human brain in vivo. Our previous tau PET imaging studies with AV-1451 demonstrated tau deposition in several brain regions, including enthorhinal, temporal, lateral occipital, and parietal cortex. Here we present our preliminary evaluation of the relationship between AG, metabolism, blood flow and tau deposition. Thirty five individuals (32 cognitively normal, 15 females, 53–88 years old) underwent PET studies using inhalation of 15O-CO and 15O-O2, and injection of 15O-water, 18F-fluorodeoxyglucose, and [18F]-AV-1451. AG, cerebral metabolic rate of glucose (CMRGlu) and oxygen (CMRO2), cerebral blood flow (CBF), and tau deposition were calculated and corrected for partial volume effects in regions of interest defined using FreeSurfer. Association between AG, CMRGlu, CMRO2, CBF and AV-1451 deposition was evaluated using linear regression models, both unadjusted and adjusted for age and gender. A negative correlation was demonstrated between tau deposition and AG in lateral occipital, inferior and superior parietal cortices, suggesting that higher AG levels are associated with less tau deposition. This association remained significant after adjusting for age and gender for lateral occipital (F1,31=8.632, p=0.006) and superior parietal (F1,31=12.367, p=0.001). Tau deposition correlated to CMRGlu in superior parietal cortex (F1,31=4.856; p=0.035). No correlation was demonstrated between tau deposition and CMRO2 and CBF. Our findings support the hypothesis that in regions known to accumulate AD pathology, higher levels of AG are associated with lower pathological burden, suggesting that high AG promotes resilience to progression of AD pathology.

THE ASSOCIATION BETWEEN PERSONALITY AND TAU PET DEPOSITION IN COGNITIVELY NORMAL OLDER ADULTS: FINDINGS FROM THE KNIGHT ALZHEIMER DISEASE RESEARCH CENTER

Personality traits, such as neuroticism and conscientiousness, are associated with the onset of Alzheimer disease (AD) dementia, and may represent potential risk and resilience factors, respectively. Additionally, neuroticism has been associated with AD-related neuropathology including β-amyloid and neurofibrillary tangles at autopsy. However, the in vivoassociation of personality traits and AD pathophysiology in cognitively normal (CN) individuals remains largely unexamined. This study examined the cross-sectional relationship between personality traits and regional PET tau deposition in CN older adults. Ninety-four CN (Clinical Dementia Rating (CDR) 0) older adults from the Knight Alzheimer Disease Research Center cohort completed the NEO Five-Factor Inventory to assess traits of neuroticism, extroversion, openness, agreeableness, and conscientiousness and underwent [18F]-AV-1451 tau-PET and [18F]-AV-45 β-amyloid-PET imaging. Tau levels were assessed in four regions including the amygdala, entorhinal cortex, inferior temporal cortex, and lateral occipital cortex (Figure 1), which are known to display early tau accumulation in AD. β-amyloid was examined as a composite measure from previously well-defined AD-related regions. We utilized linear regression models, adjusting for age and sex, to evaluate the association between the each of the personality traits and regional tau accumulation. Secondary analyses additionally adjusted for β-amyloid deposition. Elevated neuroticism scores were significantly associated with higher tau accumulation in the amygdala (p=.003), entorhinal cortex (p=.031), and inferior temporal cortex (p<.001) (Figure 2a). In contrast, extroversion, openness, agreeableness, and conscientiousness were not associated with tau deposition for any of these regions (Figure 2b-e). After additionally adjusting for β-amyloid, results remained essentially unchanged (Table 1). Our results indicate that increased neuroticism is associated with higher tau pathophysiology in AD-vulnerable regions in CN participants. These effects were not driven by β-amyloid, suggesting a unique relationship between neuroticism and tau levels. High neuroticism scores are associated with increased levels of stress, which in turn may serve as a potential risk factor for tau accumulation. Alternatively, personality has been shown to change with the onset of AD, thus increased tau levels may affect neuroticism scores. While, future longitudinal studies are needed to determine directionality, our findings suggest early associations between neuroticism and tau accumulation in CN adults. Tau-PET regions of interest. Association between personality traits and tau-PET Covariate adjusted residuals from linear regression models examining the relationship between tau-PET SUVR in the inferior temporal cortex and neuroticism (A), extroversion (B), openness (C), agreeableness (D), and conscientiousness (E).

In vivo quantification of regional tau and β-amyloid deposition in progressive posterior cortical dysfunction due to Alzheimer disease (P6.103)

In vivo quantification of regional tau and β-amyloid deposition in progressive posterior cortical dysfunction due to Alzheimer disease (P6.103)

Regional tau deposition and subregion atrophy of medial temporal structures in early Alzheimer's disease: A combined positron emission tomography/magnetic resonance imaging study

IntroductionMolecular imaging and selective hippocampal subfield atrophy are a focus of recent Alzheimer's disease (AD) research. Here, we investigated correlations between molecular imaging and hippocampal subfields in early AD. MethodsWe investigated 18 patients with early AD and 18 healthy control subjects using 11C-Pittsburgh compound-B (PIB) positron emission tomography (PET) and 18F-THK5351 PET and automatic segmentation of hippocampal subfields with high-resolution T2-weighted magnetic resonance imaging. The PET images were normalized and underwent voxelwise regression analysis with each subregion volumes using SPM12. ResultsAs for 18F-THK5351 PET, the bilateral perirhinal cortex volumes were significantly associated with the ipsilateral or bilateral temporal lobar uptakes, whereas hippocampal subfields showed no correlations. 11C-PIB PET showed relatively broad negative correlation with the right cornu ammonis 3 volumes. DiscussionRegional tau deposition was correlated with extrahippocampal subregional atrophy and not with hippocampal subfields, possibly reflecting different underlying mechanisms of atrophy in early AD. Amyloid might be associated with right cornu ammonis 3 atrophy.

Association between Aβ and tau accumulations and their influence on clinical features in aging and Alzheimer's disease spectrum brains: A [11C]PBB3-PET study

IntroductionAmyloid-β (Aβ) and tau accumulations may occur independently and concurrently as exemplified by primary age-related tauopathy and Alzheimer's disease (AD), respectively. Interactions between Aβ and tau accumulations and their influence on clinical features, however, are still unclear. MethodsAssociations among clinical symptoms, gray-matter volume, regional tau, and Aβ deposition assessed by positron emission tomography with [11C]pyridinyl-butadienyl-benzothiazole 3 (PBB3) and [11C]Pittsburgh compound-B (PiB), were evaluated in 17 AD, 9 mild cognitive impairment due to AD, and 28 PiB(−)-cognitive healthy controls (HCs). ResultsHigh tau burden was associated with aging and low-level education in PiB(−)-HC and AD-spectrum groups, and with high Aβ burden and low-level education in all subjects. It was not Aβ but tau accumulation that showed significant associations with cognitive performance even in PiB(−)-HC. DiscussionThe present study indicated aging and low-level education after Aβ would be enhancers for tau pathology, associated with neurodegeneration and cognitive impairment in healthy and diseased elderly individuals.

Regional tau deposition measured by [18F]THK5317 positron emission tomography is associated to cognition via glucose metabolism in Alzheimer's disease.

BackgroundThe recent development of tau-specific positron emission tomography (PET) tracers has allowed in vivo quantification of regional tau deposition and offers the opportunity to monitor the progression of tau pathology along with cognitive impairment. In this study, we investigated the relationships of cerebral tau deposition ([18F]THK5317-PET) and metabolism ([18F]FDG-PET) with concomitant cognitive function in patients with probable Alzheimer’s disease (AD).MethodsNine patients diagnosed with AD dementia and 11 with prodromal AD (mild cognitive impairment, amyloid-positive on [11C]PiB-PET) were included in this study. All patients underwent PET scans using each tracer, as well as episodic memory and global cognition assessment. Linear models were used to investigate the association of regional [18F]THK5317 retention and [18F]FDG uptake with cognition. The possible mediating effect of local metabolism on the relationship between tau deposition and cognitive performance was investigated using mediation analyses.ResultsSignificant negative associations were found between [18F]THK5317 regional retention, mainly in temporal regions, and both episodic memory and global cognition. Significant positive associations were found between [18F]FDG regional uptake and cognition. The association of [18F]FDG with global cognition was regionally more extensive than that of [18F]THK5317, while the opposite was observed with episodic memory, suggesting that [18F]THK5317 retention might be more sensitive than [18F]FDG regional uptake to early cognitive impairment. Finally, [18F]FDG uptake had a mediating effect on the relationship between [18F]THK5317 retention in temporal regions and global cognition.ConclusionsThese findings suggest a mediating role for local glucose metabolism in the observed association between in vivo tau deposition and concomitant cognitive impairment in AD.Electronic supplementary materialThe online version of this article (doi:10.1186/s13195-016-0204-z) contains supplementary material, which is available to authorized users.

TAU BURDEN IS ASSOCIATED WITH SUBJECTIVE COGNITIVE CONCERNS IN THE CONTEXT OF β-AMYLOID BURDEN IN PRECLINICAL AD

Alzheimer’s disease (AD) is characterized by the deposition of β-amyloid (Aβ) and paired helical filament tau. The relationship of these deposits to the preclinical manifestations of the AD phenotype can now be evaluated in vivo with positron emission tomography (PET). Endorsement of subjective cognitive concerns (SCC) is associated with Aβ in this early phase of the disease trajectory, but until now, a relationship between SCC and regional tau deposition has not been interrogated. We aimed to elucidate the relationship between entorhinal cortical (EC) and inferior temporal (IT) tau, neocortical Aβ and SCC in clinically-normal (CN) older adults. Seventy-three CN (CDR = 0) participants (77yrs (SD=6.2), 58% female, 28% Aβ+, 28% APOEε4 carriers) participating in the Harvard Aging Brain Study underwent T807 (aka AV1451) and PiB PET imaging within 6 months of responding to three SCC questionnaires. An SCC composite was created using z-transformed memory subscales from the Memory Functioning Questionnaire, the Everyday Cognition Scale, and the adapted Structured Telephone Inventory for Dementia Assessment. Greater EC tau was associated with greater SCC (β=0.39, p<.001) after taking into account age, depressive symptoms, sex and education. IT tau was marginally associated (β=0.18, p=.16). After interactions between tau and Aβ were included, no interactive effect of EC tau and Aβ was found on SCC (p=.93), but an IT and Aβ interaction was now marginally associated with greater SCC (p=.07). This is the first study to demonstrate regionally-specific patterns of association between tau burden and SCC. Specifically, EC tau was strongly associated with greater SCC, but the effect was independent of Aβ burden. Increasing IT tau deposition, on the other hand, was related to greater SCC only within the context of increasing Ab burden. As such, both tau and Aβ are associated with SCC and appear to become multiplicative under certain circumstances. It is possible that IT tau-driven SCC reflects individuals likely on the AD trajectory, whereas EC-related SCC captures a range of phenomena including normal aging, in which EC tauopathy is very common. It remains to be seen whether regional tau underlies qualitatively different SCC phenotypes.

LONGITUDINAL CHANGES IN REGIONAL TAU DEPOSITION IN ALZHEIMER'S DISEASE AND OTHER TAUOPATHIES MEASURED BY [18F]-TKH5317 PET IN A MULTI-TRACER DESIGN

LONGITUDINAL CHANGES IN REGIONAL TAU DEPOSITION IN ALZHEIMER'S DISEASE AND OTHER TAUOPATHIES MEASURED BY [18F]-TKH5317 PET IN A MULTI-TRACER DESIGN

IN VIVO QUANTIFICATION OF REGIONAL TAU DEPOSITION IN PATIENTS WITH PROGRESSIVE POSTERIOR CORTICAL DYSFUNCTION

IN VIVO QUANTIFICATION OF REGIONAL TAU DEPOSITION IN PATIENTS WITH PROGRESSIVE POSTERIOR CORTICAL DYSFUNCTION

PREDICTORS OF REGIONAL TAU-PET UPTAKE: MAYO CLINIC STUDY OF AGING

To investigate the effects of age, sex, APOE4, education, and amyloid deposition (via 11C PIB-PET) on the degree of regional tau deposition (via AV1451) in cognitively normal elderly. We identified 168 cognitively normal participants aged 52-94 years in the population-based Mayo Clinic Study of Aging who had undergone APOE4 genotyping, with Tau-PET, and PIB-PET scans available. The subjects identified had a median age of 69, 54% male, 29% APOE4 positive, median education of 16, and median PIB SUVR of 1.34. Regional uptake of Tau-PET was assessed in 46 atlas regions by summarizing the median uptake in each region scaled to the median uptake in the cerebellar crus (SUVR). For each region, we fit a linear regression model with Tau-PET SUVR as the response variable and the following potential predictor variables: global amyloid PET, age, sex, education, and APOE4 genotype. In a preliminary regional correlation analyses of PIB with Tau-PET SUVRs, we found that correlations were driven mainly by global amyloid levels. Therefore, we used global and not regional PIB SUVRs in the models presented here. The results are shown in Figure 1 in which each row represents an independent regional model fit and summarizes the estimated mean (95% confidence interval) difference in tau deposition for each covariate: amyloid PET, age, sex, education, and APOE4. Although effect sizes varied across regions, we found strong evidence that higher levels of amyloid were associated with increased levels of tau after accounting for age, sex, education, and APOE (p<0.01). Except in the pallidum and putamen (p<0.01), age was not independently associated with increased levels of tau. We did not see independent effects of sex, education, or APOE4 (p>0.01) in any of the regions.