Aβ Status Research Articles

Cognitive Profiling Related to Cerebral Amyloid Beta Burden Using Machine Learning Approaches.

Background: Cerebral amyloid beta (Aβ) is a hallmark of Alzheimer’s disease (AD). Aβ can be detected in vivo with amyloid imaging or cerebrospinal fluid assessments. However, these technologies can be both expensive and invasive, and their accessibility is limited in many clinical settings. Hence the current study aims to identify multivariate cost-efficient markers for Aβ positivity among non-demented individuals using machine learning (ML) approaches.Methods: The relationship between cost-efficient candidate markers and Aβ status was examined by analyzing 762 participants from the Alzheimer’s Disease Neuroimaging Initiative-2 cohort at baseline visit (286 cognitively normal, 332 with mild cognitive impairment, and 144 with AD; mean age 73.2 years, range 55–90). Demographic variables (age, gender, education, and APOE status) and neuropsychological test scores were used as predictors in an ML algorithm. Cerebral Aβ burden and Aβ positivity were measured using 18F-florbetapir positron emission tomography images. The adaptive least absolute shrinkage and selection operator (LASSO) ML algorithm was implemented to identify cognitive performance and demographic variables and distinguish individuals from the population at high risk for cerebral Aβ burden. For generalizability, results were further checked by randomly dividing the data into training sets and test sets and checking predictive performances by 10-fold cross-validation.Results: Out of neuropsychological predictors, visuospatial ability and episodic memory test results were consistently significant predictors for Aβ positivity across subgroups with demographic variables and other cognitive measures considered. The adaptive LASSO model using out-of-sample classification could distinguish abnormal levels of Aβ. The area under the curve of the receiver operating characteristic curve was 0.754 in the mild change group, 0.803 in the moderate change group, and 0.864 in the severe change group, respectively.Conclusion: Our results showed that the cost-efficient neuropsychological model with demographics could predict Aβ positivity, suggesting a potential surrogate method for detecting Aβ deposition non-invasively with clinical utility. More specifically, it could be a very brief screening tool in various settings to recruit participants with potential biomarker evidence of AD brain pathology. These identified individuals would be valuable participants in secondary prevention trials aimed at detecting an anti-amyloid drug effect in the non-demented population.

Relevance of the interplay between amyloid and tau for cognitive impairment in early Alzheimer's disease

Amyloid β (Aβ) and tau are key hallmark features of Alzheimer's disease (AD) neuropathology. The interplay of Aβ and tau for cognitive impairment in early AD was examined with cross-sectional analysis, measured by cerebrospinal fluid biomarkers (Aβ1–42, total tau [t-tau], and phosphorylated tau [p-tau181P]), and on cognitive performance by the repeatable battery for assessment of neuropsychological status (RBANS). Participants (n = 246) included cognitively normal (Aβ−), mild cognitively impaired (Aβ−), preclinical AD (Aβ+), and prodromal AD (Aβ+). Overall, cognitive scores (RBANS total scale score) had a moderate negative correlation to t-tau (n = 246; r = −0.434; p < 0.001) and p-tau181P (r = −0.389; p < 0.001). When classified by Aβ status, this correlation to t-tau was applicable only in Aβ+ participants (n = 139; r = −0.451, p < 0.001) but not Aβ− participants (n = 107; r = 0.137, p = 0.16), with identical findings for p-tau. Both tau (p < 0.0001) and interaction of Aβ1–42 with tau (p = 0.006) affected RBANS, but not Aβ1–42 alone. Cognitive/memory performance correlated well with cerebrospinal fluid tau levels across early stages of AD, although the correlation is Aβ dependent.

Cerebrospinal fluid biomarkers of neurodegeneration, synaptic integrity, and astroglial activation across the clinical Alzheimer's disease spectrum

IntroductionWe investigated relations between amyloid-β (Aβ) status, apolipoprotein E (APOE) ε4, and cognition, with cerebrospinal fluid markers of neurogranin (Ng), neurofilament light (NFL), YKL-40, and total tau (T-tau). MethodsWe included 770 individuals with normal cognition, mild cognitive impairment, and Alzheimer's disease (AD)-type dementia from the EMIF-AD Multimodal Biomarker Discovery study. We tested the association of Ng, NFL, YKL-40, and T-tau with Aβ status (Aβ− vs. Aβ+), clinical diagnosis APOE ε4 carriership, baseline cognition, and change in cognition. ResultsNg and T-tau distinguished between Aβ+ from Aβ− individuals in each clinical group, whereas NFL and YKL-40 were associated with Aβ+ in nondemented individuals only. APOE ε4 carriership did not influence NFL, Ng, and YKL-40 in Aβ+ individuals. NFL was the best predictor of cognitive decline in Aβ+ individuals across the cognitive spectrum. DiscussionAxonal degeneration, synaptic dysfunction, astroglial activation, and altered tau metabolism are involved already in preclinical AD. NFL may be a useful prognostic marker.

The influence of β-amyloid on [18F]AV-1451 in semantic variant of primary progressive aphasia.

To compare [18F]AV-1451 uptake in the semantic variant of primary progressive aphasia (svPPA) to Alzheimer dementia, and determine whether increased uptake in svPPA is associated with the presence of β-amyloid (Aβ). Thirty-one participants with svPPA underwent MRI and Pittsburgh compound B-PET scanning, and 17 of these also underwent [18F]AV-1451 tau-PET. A global Pittsburgh compound B standardized uptake value ratio was calculated for all participants, with a cutoff of 1.42 used to define Aβ(+) participants. We assessed region and voxel-level [18F]AV-1451 uptake in the whole svPPA cohort and separately in Aβ(+) and Aβ(-) svPPA groups, compared to 12 Aβ(+) participants with Alzheimer dementia and 170 cognitively normal, Aβ(-) controls. Of the entire cohort of participants with svPPA, 26% were Aβ(+). The Aβ(+) participants were older at scan compared to the Aβ(-) participants. svPPA showed elevated [18F]AV-1451 uptake in anteromedial temporal regions but the degree of uptake was lower than in Alzheimer dementia. After controlling for age, Aβ(+) status in svPPA was associated with significantly higher uptake in all anteromedial and inferior/middle lateral temporal regions, but uptake was still lower than in Alzheimer dementia. Although [18F]AV-1451 uptake is focally elevated in svPPA, the level of uptake is much less than what occurs in Alzheimer dementia and appears to be at least partially related to Aβ. Therefore, it is possible that some of the increased uptake of [18F]AV-1451 in svPPA is related to binding paired helical filament tau.

Identifying Brain Connectivity Using Network-Based Statistics in Amnestic Mild Cognitive Impairment Stratified by β-Amyloid Positivity.

The aim of this study was to identify white matter structural networks of amnestic mild cognitive impairment (aMCI) dichotomized by β amyloid (Aβ) status and compare them using network-based statistics (NBS). Patients underwent whole-brain diffusion-weighted magnetic resonance imaging, detailed neuropsychological test and [18F]-Florbetaben amyloid positron emission tomography. We performed the NBS analysis to compare the whole-brain white matter structural networks extracted from diffusion tensor images. One hundred sixteen participants (Aβ- cognitively normal [CN], n = 35; Aβ- aMCI, n = 42; Aβ+ aMCI, n = 39) were included. There was no subnetwork showing significant difference between Aβ+ aMCI and Aβ- aMCI. However, by comparing each aMCI group with control group, we found that supplementary motor areas were common hub regions. Intriguingly, Aβ+ aMCI showed reduced connectivity mainly in the medial frontal regions, while Aβ- aMCI showed somewhat uniform disruption when compared to CN. Structural network analysis using network-based approach in aMCI may shed light on further understanding of white matter disruption in the prodromal stage of Alzheimer's disease.

Accurate risk estimation of β-amyloid positivity to identify prodromal Alzheimer's disease: Cross-validation study of practical algorithms

IntroductionThe aim was to create readily available algorithms that estimate the individual risk of β-amyloid (Aβ) positivity. MethodsThe algorithms were tested in BioFINDER (n = 391, subjective cognitive decline or mild cognitive impairment) and validated in Alzheimer's Disease Neuroimaging Initiative (n = 661, subjective cognitive decline or mild cognitive impairment). The examined predictors of Aβ status were demographics; cognitive tests; white matter lesions; apolipoprotein E (APOE); and plasma Aβ42/Aβ40, tau, and neurofilament light. ResultsAβ status was accurately estimated in BioFINDER using age, 10-word delayed recall or Mini–Mental State Examination, and APOE (area under the receiver operating characteristics curve = 0.81 [0.77–0.85] to 0.83 [0.79–0.87]). When validated, the models performed almost identical in Alzheimer's Disease Neuroimaging Initiative (area under the receiver operating characteristics curve = 0.80–0.82) and within different age, subjective cognitive decline, and mild cognitive impairment populations. Plasma Aβ42/Aβ40 improved the models slightly. DiscussionThe algorithms are implemented on http://amyloidrisk.com where the individual probability of being Aβ positive can be calculated. This is useful in the workup of prodromal Alzheimer's disease and can reduce the number needed to screen in Alzheimer's disease trials.

Association of Apolipoprotein E ε4 With Transactive Response DNA-Binding Protein 43

Transactive response DNA-binding protein 43 (TDP-43) is associated with Alzheimer disease (AD), progressive hippocampal atrophy, and cognitive decline. The apolipoprotein E (APOE) ε4 allele is strongly associated with β-amyloid (Aβ) aggregation and risk of AD, but its association with TDP-43 is unknown. To determine whether the APOE ε4 allele is a risk factor for TDP-43. This cross-sectional, genetic-histologic study analyzed APOE genotype, TDP-43 status (positive vs negative), Aβ status (positive vs negative), and tau neurofibrillary tangle stage (B0, Braak stage 0; B1, Braak stages I-II; B2, Braak stages III-IV; B3, Braak stage ≥ V). We fit structural equation models to map the association between APOE and TDP-43, Aβ, and tau, accounting for age and hippocampal sclerosis. We identified 751 participants with an AD pathological spectrum diagnosis and completed Aβ, tau, and TDP-43 data who were enrolled in the Mayo Clinic Alzheimer Disease Research Center, Mayo Clinic Alzheimer Disease Patient Registry, or the population based Mayo Clinic Study of Aging and died between May 12, 1999, and December 31, 2015. However, 13 were excluded from the analyses because of missing APOE data, leaving a total of 738 participants. Transactive response DNA-binding protein 43 was the main outcome of interest. We hypothesized that the APOE ε4 allele would be significantly directly and indirectly associated with TDP-43. The 751 study participants were older (median age [interquartile range], 87 years [51-105 years]), 395 (54%) were women, and 324 (44%) were APOE ε4 carriers. The patients died between May 12, 1999, and December 31, 2015. Accounting for age, Aβ, and tau, APOE ε4 had a direct association with TDP-43 (estimate [SE], 0.31 (0.11); P = .01). The association was present among individuals with an intermediate to high likelihood of having AD (neurofibrillary tangle stage B2/B3; n = 604 [81.8%]; estimate [SE], 0.51 [0.11]; P < .001), with a similar trend for those with a low likelihood of having AD (B1; n = 134 [18.2%]; estimate [SE], 0.54 [0.32]; P = .10). We also found an indirect association of APOE ε4 with TDP-43 via Aβ and tau (estimate [SE], 0.34 [0.06]; P < .001), which was similar in magnitude to the direct association and an indirect association of APOE ε4 with hippocampal sclerosis via TDP-43 (estimate [SE], 0.65 [0.26]; P = .01). The study's findings, which mapped a system of risk factors and outcomes, showed that the APOE ε4 allele appears to be a risk factor for TDP-43 independently of Aβ in patients with AD.

Amyloid beta-positive subjects exhibit longitudinal network-specific reductions in spontaneous brain activity.

Amyloid beta (Aβ) deposition and cognitive decline are key features of Alzheimer's disease. The relationship between Aβ status and changes in neuronal function over time, however, remains unclear. We evaluated the effect of baseline Aβ status on reference region spontaneous brain activity (SBA-rr) using resting-state functional magnetic resonance imaging and fluorodeoxyglucose positron emission tomography in patients with mild cognitive impairment. Patients (N= 62, [43 Aβ-positive]) from the Alzheimer's Disease Neuroimaging Initiative were divided into Aβ-positive and Aβ-negative groups via prespecified cerebrospinal fluid Aβ42 or 18F-florbetapir positron emission tomography standardized uptake value ratio cutoffs measured at baseline. We analyzed interaction of biomarker-confirmed Aβ status with SBA-rr change over a 2-year period using mixed-effects modeling. SBA-rr differences between Aβ-positive and Aβ-negative subjects increased significantly over time within subsystems of the default and visual networks. Changes exhibit an interaction with memory performance over time but were independent of glucose metabolism. Results reinforce the value of resting-state functional magnetic resonance imaging in evaluating Alzheimer''s disease progression and suggest spontaneous neuronal activity changes are concomitant with cognitive decline.

Excessive daytime sleepiness and napping in cognitively normal adults: associations with subsequent amyloid deposition measured by PiB PET.

Study objectives To determine the association of excessive daytime sleepiness (EDS) and napping with subsequent brain β-amyloid (Aβ) deposition in cognitively normal persons. Methods We studied 124 community-dwelling participants in the Baltimore Longitudinal Study of Aging Neuroimaging Substudy who completed self-report measures of EDS and napping at our study baseline and underwent [11C] Pittsburgh compound B positron emission tomography (PiB PET) scans of the brain, an average ±standard deviation of 15.7 ± 3.4 years later (range 6.9 to 24.6). Scans with a cortical distribution volume ratio of >1.06 were considered Aβ-positive. Results Participants were aged 60.1 ± 9.8 years (range 36.2 to 82.7) at study baseline; 24.4% had EDS and 28.5% napped. In unadjusted analyses, compared with participants without EDS, those with EDS had more than 3 times the odds of being Aβ+ at follow-up (odds ratio [OR] = 3.37, 95% confidence interval [CI]: 1.44, 7.90, p = 0.005), and 2.75 times the odds after adjustment for age, age2, sex, education, and body mass index (OR = 2.75, 95% CI: 1.09, 6.95, p = 0.033). There was a trend-level unadjusted association between napping and Aβ status (OR = 2.01, 95% CI: 0.90, 4.50, p = 0.091) that became nonsignificant after adjustment (OR = 1.86, 95% CI: 0.73, 4.75, p = 0.194). Conclusions EDS is associated with more than 2.5 times the odds of Aβ deposition an average of 15.7 years later. If common EDS causes (e.g., sleep-disordered breathing, insufficient sleep) are associated with temporally distal AD biomarkers, this could have important implications for AD prevention.

Cerebrospinal fluid phosphorylated tau, visinin-like protein-1, and chitinase-3-like protein 1 in mild cognitive impairment and Alzheimer\u2019s disease

BackgroundVisinin-like protein-1 (VILIP-1) and chitinase-3-like protein 1 (CHI3L1 or YKL-40) in cerebrospinal fluid (CSF) are newly discovered markers indicating neuronal damage and microglial activation, respectively. Phosphorylated tau (p-tau) reflects the neuropathology of Alzheimer’s disease (AD) and is useful as diagnostic markers for AD. However, it is unknown whether these biomarkers have similar or complementary information in AD.MethodsWe stratified 121 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database into cognitively normal (CN), stable mild cognitive impairment (sMCI), progressive MCI (pMCI), and dementia due to AD. Analysis of covariance (ANOVA) and chi-square analyses, Spearman correlation, and logistic regression models were performed to test the demographic, associations between biomarkers, and diagnostic accuracies, respectively. Linear mixed-effects models were used to evaluate the effects of CSF amyloid-β (Aβ) on above biomarkers within diagnostic groups, the combination of diagnostic group and Aβ status as predictor, and CSF biomarkers as predictors of AD features, including cognition measured by Mini–Mental State Examination (MMSE) and brain structure and white matter hyperintensity (WMH) measured by magnetic resonance imaging (MRI).ResultsP-tau, VILIP-1, and YKL-40 were all predictors of AD diagnosis, but combinations of biomarkers did not improve the diagnostic accuracy (AUC 0.924 for p-tau, VILIP-1, and YKL-40) compared to p-tau (AUC 0.922). P-tau and VILIP-1 were highly correlated (r = 0.639, p < 0.001) and strongly associated with Aβ pathology across clinical stages of AD, while YKL-40 was correlated with Aβ pathology in CN and AD groups. VILIP-1 was associated with acceleration of cognitive decline, hippocampal atrophy, and expansion of ventricles in longitudinal analyses. YKL-40 was associated with hippocampal atrophy at baseline and follow-up, while p-tau was only associated with worsening WMH at baseline.ConclusionsCSF levels of p-tau, VILIP-1, and YKL-40 may have utility for discriminating between cognitively normal subjects and patients with AD. Increased levels of both VILIP-1 and YKL-40 may be associated with disease degeneration. These CSF biomarkers should be considered for future assessment in the characterization of the natural history of AD.

Excessive daytime sleepiness and napping in cognitively normal adults: associations with subsequent amyloid deposition measured by PiB PET.

To determine the association of excessive daytime sleepiness (EDS) and napping with subsequent brain β-amyloid (Aβ) deposition in cognitively normal persons. We studied 124 community-dwelling participants in the Baltimore Longitudinal Study of Aging Neuroimaging Substudy who completed self-report measures of EDS and napping at our study baseline and underwent [11C] Pittsburgh compound B positron emission tomography (PiB PET) scans of the brain, an average ±standard deviation of 15.7 ± 3.4 years later (range 6.9 to 24.6). Scans with a cortical distribution volume ratio of >1.06 were considered Aβ-positive. Participants were aged 60.1 ± 9.8 years (range 36.2 to 82.7) at study baseline; 24.4% had EDS and 28.5% napped. In unadjusted analyses, compared with participants without EDS, those with EDS had more than 3 times the odds of being Aβ+ at follow-up (odds ratio [OR] = 3.37, 95% confidence interval [CI]: 1.44, 7.90, p = 0.005), and 2.75 times the odds after adjustment for age, age2, sex, education, and body mass index (OR = 2.75, 95% CI: 1.09, 6.95, p = 0.033). There was a trend-level unadjusted association between napping and Aβ status (OR = 2.01, 95% CI: 0.90, 4.50, p = 0.091) that became nonsignificant after adjustment (OR = 1.86, 95% CI: 0.73, 4.75, p = 0.194). EDS is associated with more than 2.5 times the odds of Aβ deposition an average of 15.7 years later. If common EDS causes (e.g., sleep-disordered breathing, insufficient sleep) are associated with temporally distal AD biomarkers, this could have important implications for AD prevention.

The effect of preclinical Alzheimer's disease on age-related changes in intelligence in cognitively normal older adults

BackgroundIt is possible that estimates of normal age-related decline in intellectual function have been biased negatively by undetected preclinical Alzheimer's disease (AD). This prospective study aimed to determine the nature and magnitude of changes in crystallized and fluid intelligence, as well as their relationship to one another, in normal aging, taking into account the effects of preclinical AD. MethodsCognitively normal older adults (n = 494) aged between 60 and 84 years underwent serial assessment of fluid and crystallized intelligence at 18-month intervals over 72 months and PET neuroimaging for the presence of abnormal amyloid-β (Aβ+; n = 184). The effects of age and Aβ + on changes in fluid and crystallized intelligence were analysed using linear mixed models. An intelligence discrepancy score was developed from linear regression analysis of the extent to which fluid intelligence could be predicted from crystallized intelligence. The predictive validity of the intelligence discrepancy score for Aβ status or clinical disease progression was evaluated. ResultsRelative to the Aβ- group, the Aβ + group showed greater age-related decline on fluid, but not crystallized, intelligence. The intelligence discrepancy score predicted progression to clinically recognized disease (i.e., mild cognitive impairment or dementia), but was unrelated to Aβ status. ConclusionsPreclinical AD is associated with more rapid age-related decline in fluid, but not crystallized, intelligence. Accordingly, a discrepancy between fluid and crystallized intelligence does indicate risk of progression to early AD.

NEUROPSYCHIATRIC BURDEN IS RELATED TO INCREASED AMYLOID BUT NOT TAU DEPOSITION IN COGNITIVELY NORMAL OLDER ADULTS

Neuropsychiatric factors (NPF; e.g. depression, anxiety, apathy) are highly prevalent in older adults and are associated with an increased risk of Alzheimer's disease (AD) (Masters et al, 2015). Recent evidence also linked personality traits (e.g. neuroticism) with progression to AD (Terracciano et al, 2017). The mechanisms by which personality/NPF burden influence AD risk need to be better understood. In cognitively normal older adults at risk of AD, we investigated whether an index of personality/NPF burden was related to AD pathology (amyloid [Aβ] and tau deposition), brain function and cognition. Eighty-two participants (PREVENT-AD study, age=67±5) answered questionnaires assessing personality, perseverative thinking, depression, anxiety, stress and apathy. They underwent Aβ-PET ([18F]NAV4694), tau-PET ([18F]AV1451), resting-state fMRI and cognitive assessment (Repeatable Battery for Assessment of Neuropsychological Status). PET SUVRs were extracted bilaterally from all FreeSurfer Desikan neocortical regions. We used a multivariate approach (partial least squares correlation with permutation tests) to assess which combination of factors was related to Aβ and tau deposition. We then investigated whether this index of personality/NPF burden was related to 1) functional connectivity and 2) cognitive performance in individuals with and without significant AD pathology. Aβ (p=0.003), but not tau (p>0.05) was related to personality/NPF burden. More specifically, a combination of perseverative thinking, neuroticism and apathy was associated with higher Aβ accumulation, predominantly in the AD-signature regions (Fig.1). Higher scores on this personality/NPF component were additionally associated with higher connectivity within the dorsal attention and salience networks in Aβ+ subjects, and lower connectivity in Aβ- subjects (Aβ-status*connectivity: F1,69=5.7-5.2, p=.02-.03 respectively, Fig.2A). Furthermore, higher scores on this personality/NPF component were associated with worse immediate memory (F1,70=4.1, p=.05, Fig.2B), regardless of Aβ status. Relative importance of personality traits and neuropsychiatrie factors (NPF) in relation to regional Aβ accumulation. IA. Loading of each personality traits and NPF score from the component relating personality/NPF with Aβ burden. Traits and factors contributing the most to the model are perseverative thinking, neuroticism and apathy. Confidence intervals are derived from bootstrap resampling. IB. Cortical regions showing higher Aβ SUVR as personality/NPF burden increases. The importance of each region in the model was identified from bootstrap ratios and projected on a brain template. Personality/NPF relationship with brain function (A) and cognition (B) 2A. Functional networks showing a significant interaction of Aβ status by functional connectivity on the personality/NPF burden. 2B. Relationship between personality/NPF burden and immediate memory performance. Our multivariate approach revealed that Aβ burden was increased in cognitively normal individuals at risk of AD showing high levels of perseverative thinking, neuroticism and apathy, which were in turn related to altered brain connectivity and lower cognition. Overall, these results highlight the importance of personality/NPF burden on early AD pathophysiology.

NEUROPSYCHIATRIC BURDEN IS RELATED TO INCREASED AMYLOID BUT NOT TAU DEPOSITION IN LATE MIDDLE-AGED COGNITIVELY NORMAL INDIVIDUALS WITH A FAMILY HISTORY OF ALZHEIMER’S DISEASE

Neuropsychiatric factors (NPF) are highly prevalent throughout the course of Alzheimer's disease (AD) (Masters et al, 2015). Recent evidence also linked neuroticism, a personality trait associated with negative emotional response, with progression to AD (Terracciano et al, 2017). We investigated whether NPF and/or personality traits were related to AD pathology, brain function and cognition in cognitively normal individuals with a family history of AD dementia. Eighty-two participants (PREVENT-AD study, age=67±5) underwent PET scanning. SUVRs values for Aβ ([18F]NAV4694) and tau ([18F]AV1451) were extracted from all FreeSurfer Desikan neocortical regions (grey cerebellum reference region). Resting-state functional connectivity was examined in 13 networks (Power et al, 2011). Cognitive performance was assessed using the RBANS that provides five composite scores: immediate and delayed memory, attention, language, and visuospatial functioning. All participants answered questionnaires assessing personality, perseverative thinking, depression, anxiety, stress and apathy. We used partial least squares correlation with permutation tests to assess which combinations of factors (derived as latent variables), if any, were related to Aβ and tau deposition. We also investigated whether this combination of NPF and personality traits was related to 1) functional connectivity and 2) cognitive performance in individuals with and without AD pathology. One latent variable related NPF and personality traits with Aβ accumulation (p=0.003). Fig.1A displays the weight of each NPF and personality trait to this relationship and Fig.1B, the brain regions presenting higher Aβ burden as a function of this latent variable. Higher scores on this variable were additionally associated with higher brain connectivity within the dorsal attention and salience networks in Aβ+ subjects, and lower connectivity in Aβ- subjects (both interactions p <0.05, Fig.2A). Furthermore, higher scores on this neuropsychiatric component were associated with worse immediate memory (p=0.05, Fig.2B), regardless of Aβ status. No latent variable related NPF/personality traits with tau accumulation. Partial least squares analysis showing the neuropsychiatrie latent variable related to Aβ burden 1A. Loading of each neuropsychiatri factor (NPF) and personality trait to the neuropsychiatri latent variable related with Aβ accumulation. Confidence intervals are derived from bootstrap resampling. 1B. Cortical regions showing higher Aβ SUVR as NPF/personality burden increases. The importance of each region in the model was identified from bootstrap ratios and projected on a brain template. Regression analysis showing the relationship between the neuropsychiatric latent variable with brain function and cognition 2A. Functional network showing an interaction of Aβ status by functional connectivity on neuropsychiatric burden (Salience network interaction F1,69=5.7, p =0.02; dorsal attentional network interaction F 1, 69=5.2, p =0.03). 2B. Association between neuropsychiatric burden and immediate memory performance (Main effect F1,70=4.1, p=0.05). Our multivariate approach revealed that NPF/personality traits, such as perseverative thinking, neuroticism and low agreeableness, were associated with Aβ accumulation, altered brain connectivity and lower cognition. Neuropsychiatric burden might be a consequence of AD pathology, or, because personality traits are relatively stable across lifespan, a risk factor.

Amyloid-β, Tau, and Cognition in Cognitively Normal Older Individuals: Examining the Necessity to Adjust for Biomarker Status in Normative Data.

We investigated whether amyloid-β (Aβ) and tau affected cognition in cognitively normal (CN) individuals, and whether norms for neuropsychological tests based on biomarker-negative individuals would improve early detection of dementia. We included 907 CN individuals from 8 European cohorts and from the Alzheimer's disease Neuroimaging Initiative. All individuals were aged above 40, had Aβ status and neuropsychological data available. Linear mixed models were used to assess the associations of Aβ and tau with five neuropsychological tests assessing memory (immediate and delayed recall of Auditory Verbal Learning Test, AVLT), verbal fluency (Verbal Fluency Test, VFT), attention and executive functioning (Trail Making Test, TMT, part A and B). All test except the VFT were associated with Aβ status and this influence was augmented by age. We found no influence of tau on any of the cognitive tests. For the AVLT Immediate and Delayed recall and the TMT part A and B, we calculated norms in individuals without Aβ pathology (Aβ- norms), which we validated in an independent memory-clinic cohort by comparing their predictive accuracy to published norms. For memory tests, the Aβ- norms rightfully identified an additional group of individuals at risk of dementia. For non-memory test we found no difference. We confirmed the relationship between Aβ and cognition in cognitively normal individuals. The Aβ- norms for memory tests in combination with published norms improve prognostic accuracy of dementia.

PND5 - The Clinical Value of Early Diagnosis Tests for the Long-Term Management of Dementia

A key challenge in early treatment for Alzheimer’s Disease (AD) is identifying the best population for treatment. Genetic tests and imaging technologies are now available to assess the presence of ApoE4 genes or β-amyloid plaques at preclinical stages of AD. Our objective was to assess the utility of these diagnostics for predicting conversion to AD. We simulated disease progression in cognitively normal patients using the AD Archimedes Condition-Event simulator (AD ACE). The AD ACE is constructed using predictive equations for change in disease biomarkers and clinical scales derived primarily from analyses of AD Neuroimaging Initiative (ADNI) data. We compared simulation results over 10 years for 400 patients in each of four patient subgroups (Aβ+/ApoE4+, Aβ+/ApoE4-, Aβ-/ApoE4+, Aβ-/ApoE4-) to evaluate the predictive power of ApoE4 genetic testing versus β-amyloid imaging. Patients with baseline florbetapir PET level ≥ 1.1 for the mcSUVR were considered as Aβ+. Patients with at least one ApoE4 allele were consider ApoE4+. All four patient groups were similar at baseline in terms of their mean age, baseline biomarkers (except β-amyloid level), and cognition scales. Incidence of MCI and AD in the simulation in each subgroup was: Aβ+/ApoE4+ (58%,45%); Aβ+/ApoE4- (57%,39%); Aβ-/ApoE4+ (39%,15%); Aβ-/ApoE4- (35%,13%). Aβ status had moderate power to predict development of MCI, but showed much greater differences in development of AD. While ApoE4 status had minimal incremental information for predicting development of MCI, within the Aβ+ subgroups it retained modest predictive value for the conversion from MCI to AD; 77% of the Aβ+/ApoE4+ subgroup developing MCI converted to AD vs 67% of the Aβ+/ApoE4- subgroup. Amyloid testing was more effective at identifying candidates for an early treatment than ApoE4 status, but ApoE4 can help refine estimates of long-term rates of developing dementia.

Odor Identification Ability Predicts PET Amyloid Status and Memory Decline inOlder Adults.

Odor identification deficits occur in Alzheimer's disease (AD), as measured by the 40-item University of Pennsylvania Smell Identification Test (UPSIT). To determine if UPSIT scores predict amyloid-β (Aβ) status, determined by 11C-Pittsburgh Compound B PET. We also compared UPSIT scores to Aβ status in predicting future memory decline. Subjects were recruited into a longitudinal clinical prediction study. We analyzed data from those who had UPSIT, cognitive testing, PIB PET, and at least 12 months' clinical follow-up. Forty-six amnestic mild cognitive impairment patients and 25 cognitively normal controls were included. Amyloid-positivity was defined as composite PIB standardized uptake value ratio >1.5. Logistic regression and Receiver Operating Characteristic Curve analyses tested the predictive utility of impaired olfaction (defined as UPSIT score <35) and amyloid-positivity for memory decline. High UPSIT scores predicted absence of amyloidosis on PET, with negative predictive value of 100%. Positive predictive value of low UPSIT scores on positive Aβ status was only 41%. Both low UPSIT score (OR = 4.301, 95% CI = 1.248, 14.821, p = 0.021) and positive PET scan (OR = 20.898, 95% CI = 2.222, 196.581, p = 0.008) predicted memory decline. Individuals with high UPSIT scores are less likely to have cerebral amyloidosis or experience memory decline. Therefore, UPSIT has potential as a screening tool to determine utility of Aβ PET in clinical practice or enrollment in clinical trials. Low UPSIT score is a non-specific marker of neurodegeneration that could indicate further workup in patients with memory complaints.

In vivo coupling of tau pathology and cortical thinning in Alzheimer's disease

IntroductionThe deposition of neurofibrillary tangles in neurodegenerative disorders is associated with neuronal loss on autopsy; however, their in vivo associations with atrophy across the continuum of Alzheimer's disease (AD) remain unclear. MethodsWe estimated cortical thickness, tau ([18F]-AV-1451), and amyloid β (Aβ) status ([11C]-PiB) in 47 subjects who were stratified into Aβ− (14 healthy controls and six mild cognitive impairment–Aβ−) and Aβ+ (14 mild cognitive impairment–Aβ+ and 13 AD) groups. ResultsCompared with the Aβ− group, tau was increased in widespread regions whereas cortical thinning was restricted to the temporal cortices. Increased tau binding was associated with cortical thinning in each Aβ group. Locally, regional tau was associated with temporoparietal atrophy. DiscussionThese findings position tau as a promising therapeutic target. Further studies are needed to elucidate the casual relationships between tau pathology and trajectories of atrophy in AD.

Amyloid pathology in the progression to mild cognitive impairment

The objective of this study was to determine the cognitive and functional decline and development of brain injury in individuals progressing from preclinical (β-amyloid positive cognitively normal) to prodromal Alzheimer's disease (AD) (β-amyloid positive mild cognitive impairment [MCI]), and compare this with individuals who progress to MCI in the absence of significant amyloid pathology. Seventy-five cognitively healthy participants who progressed to MCI were followed for 4 years on average and up to 10 years. We tested effects of β-amyloid (Aβ) on measures of cognition, functional status, depressive symptoms, and brain structure and metabolism. Preclinical AD subjects showed greater cognitive decline in multiple domains and increased cerebrospinal fluid phosphorylated tau levels at baseline while Aβ-negative progressors showed increased rates of white matter hyperintensity accumulation and had a greater frequency of depressive symptoms at baseline. Aβ status did not influence patterns of brain atrophy, but preclinical AD subjects showed greater decline of brain metabolism than Aβ-negative progressors. Several unique features separate the transition from preclinical to prodromal AD from other causes of cognitive decline. These features may facilitate early diagnosis and treatment of AD, especially in clinical trials aimed at halting the progression from preclinical to prodromal AD.

Associations Between Tau, β-Amyloid, and Cognition in Parkinson Disease

Multiple disease processes are associated with cognitive impairment in Parkinson disease (PD), including Lewy bodies, cerebrovascular disease, and Alzheimer disease. It remains unknown whether tau pathology relates to cognition in patients with PD without dementia. To compare tau aggregation in patients with PD who are cognitively normal (PD-CN), patients with PD with mild cognitive impairment (PD-MCI), and healthy control participants, and evaluate the relationships between β-amyloid (Aβ), tau, and cognition in patients with PD who did not have dementia. This cross-sectional study recruited 30 patients with Parkinson disease (15 with PD-CN and 15 with PD-MCI) from a tertiary care medical center and research institutions from July 2015 through October 2016. One patient with PD-MCI did not receive a magnetic resonance imaging scan and thus was excluded from all analyses; 29 patients with PD were included in the present study. Participants underwent tau positron emission tomographic (PET) scanning with fluorine 18-labeled AV-1451, Aβ PET scanning with carbon 11-labeled Pittsburgh compound B, magnetic resonance imaging, cognitive testing, and neurologic evaluation. Imaging measures were compared with 49 healthy control participants. Outcomes were tau PET measurements of groups of patients with PD-CN and PD-MCI. We hypothesized that tau aggregation across groups would be related to age and Aβ status. Of the 78 participants, 47 (60%) were female, and the mean (SD) age was 71.1 (6.6) years. Six patients with PD (21%) were Aβ-positive, of whom 1 was mildly cognitively impaired; 23 were Aβ-negative (79%). (Of the 49 healthy controls, 25 were Aβ-negative and 24 Aβ-positive.) Voxelwise contrasts of whole-brain tau PET uptake between patients with PD-CN and patients with PD-MCI, and additionally between all patients with PD and Aβ-negative controls, did not reveal significant differences. Tau PET binding did not differ between patients with PD-MCI and PD-CN in brain regions reflecting Alzheimer disease Braak stages 1/2, 3/4, or 5/6, and did not differ from Aβ-negative healthy older adults. Mean (SD) tau PET binding was significantly elevated in Aβ-positive patients with PD relative to Aβ-negative patients with PD within brain regions reflecting Alzheimer disease Braak stage 3/4 (1.22 [0.07] vs 1.14 [0.07]; P = .03) and Braak stage 5/6 (1.20 [0.07] vs 1.11 [0.08]; P = .02). These findings suggest that patterns of cortical Aβ and tau do not differ in people with PD-CN, people with PD-MCI, and healthy older adults. Age, Aβ, and tau do not differentiate patients with PD-CN and PD-MCI. Tau deposition is related to Aβ status and age in both people with PD and healthy older adults. Cognitive deficits in people with PD without dementia do not appear to reflect measureable Alzheimer disease.