Publications by authors named "William J Jagust"

250 Publications

Hippocampal connectivity with retrosplenial cortex is linked to neocortical tau accumulation and memory function.

J Neurosci 2021 Sep 15. Epub 2021 Sep 15.

Helen Wills Neuroscience Institute, UC Berkeley, Berkeley, United States, 94720.

The mechanisms underlying accumulation of Alzheimer's disease (AD)-related tau pathology outside of the medial temporal lobe (MTL) in older adults are unknown but crucial to understanding cognitive decline. A growing body of evidence from human and animal studies strongly implicates neural connectivity in the propagation of tau in humans, but the pathways of neocortical tau spread and its consequences for cognitive function are not well understood. Using resting state fMRI and tau PET imaging from a sample of 97 male and female cognitively normal older adults, we examined MTL structures involved in medial parietal tau accumulation and associations with memory function. Functional connectivity between hippocampus and retrosplenial cortex, a key region of the medial parietal lobe, was associated with tau in medial parietal lobe. By contrast, connectivity between entorhinal and retrosplenial cortices did not correlate with medial parietal lobe tau. Further, greater hippocampal-retrosplenial connectivity was associated with a stronger correlation between MTL and medial parietal lobe tau. Finally, an interaction between connectivity strength and medial parietal tau was associated with episodic memory performance, particularly in the visuospatial domain. This pattern of tau accumulation thus appears to reflect pathways of neural connectivity, and propagation of tau from entorhinal cortex to medial parietal lobe via the hippocampus may represent a critical process in the evolution of cognitive dysfunction in aging and AD.The accumulation of tau pathology in the neocortex is a fundamental process underlying Alzheimer's disease. Here, we use functional connectivity in cognitively normal older adults to track the accumulation of tau in the medial parietal lobe, a key region for memory processing that is affected early in the progression of AD. We show that the strength of connectivity between the hippocampus and retrosplenial cortex is related to medial parietal tau burden, and that these tau and connectivity measures interact to associate with episodic memory performance. These findings establish the hippocampus as the origin of medial parietal tau and implicate tau pathology in this region as a crucial marker of the beginnings of Alzheimer's disease.
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http://dx.doi.org/10.1523/JNEUROSCI.0990-21.2021DOI Listing
September 2021

Head injury is associated with tau deposition on PET in MCI and AD patients.

Alzheimers Dement (Amst) 2021 24;13(1):e12230. Epub 2021 Aug 24.

Department of Radiology and Imaging Sciences Indiana University School of Medicine Indianapolis Indiana USA.

Introduction: Head injuries (HI) are a risk factor for dementia, but the underlying etiology is not fully known. Understanding whether tau might mediate this relationship is important.

Methods: Cognition and tau deposition were compared between 752 individuals with (impaired, n = 302) or without cognitive impairment (CN, n = 450) with amyloid and [F]flortaucipir positron emission tomography, HI history information, and cognitive testing from the Alzheimer's Disease Neuroimaging Initiative and the Indiana Memory and Aging Study.

Results: Sixty-three (38 CN, 25 impaired) reported a history of HI. Higher neuropsychiatric scores and poorer memory were observed in those with a history of HI. Tau was higher in individuals with a history of HI, especially those who experienced a loss of consciousness (LOC). Results were driven by impaired individuals, especially amyloid beta-positive individuals with history of HI with LOC.

Discussion: These findings suggest biological changes, such as greater tau, are associated with HI in individuals with cognitive impairment. Small effect sizes were observed; thus, further studies should replicate and extend these results.
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http://dx.doi.org/10.1002/dad2.12230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383323PMC
August 2021

Cortical hypometabolism reflects local atrophy and tau pathology in symptomatic Alzheimer's disease.

Brain 2021 Aug 9. Epub 2021 Aug 9.

Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.

Posterior cortical hypometabolism measured with [18F]-Fluorodeoxyglucose (FDG)-PET is a well-known marker of Alzheimer's disease-related neurodegeneration, but its associations with underlying neuropathological processes are unclear. We assessed cross-sectionally the relative contributions of three potential mechanisms causing hypometabolism in the retrosplenial and inferior parietal cortices: local molecular (amyloid and tau) pathology and atrophy, distant factors including contributions from the degenerating medial temporal lobe or molecular pathology in functionally connected regions, and the presence of the apolipoprotein E (APOE) ε4 allele. Two hundred and thirty-two amyloid-positive cognitively impaired patients from two cohorts (University of California, San Francisco, UCSF, and Alzheimer's Disease Neuroimaging Initiative, ADNI) underwent MRI and PET with FDG, amyloid-PET using [11C]-Pittsburgh Compound B, [18F]-Florbetapir, or [18F]-Florbetaben, and [18F]-Flortaucipir tau-PET within one year. Standard uptake value ratios (SUVR) were calculated using tracer-specific reference regions. Regression analyses were run within cohorts to identify variables associated with retrosplenial or inferior parietal FDG SUVR. On average, ADNI patients were older and were less impaired than UCSF patients. Regional patterns of hypometabolism were similar between cohorts, though there were cohort differences in regional gray matter atrophy. Local cortical thickness and tau-PET (but not amyloid-PET) were independently associated with both retrosplenial and inferior parietal FDG SUVR (ΔR2 = .09 to .21) across cohorts in models that also included age and disease severity (local model). Including medial temporal lobe volume improved the retrosplenial FDG model in ADNI (ΔR2 = .04, p = .008) but not UCSF (ΔR2 < .01, p = .52), and did not improve the inferior parietal models (ΔR2s < .01, ps > .37). Interaction analyses revealed that medial temporal volume was more strongly associated with retrosplenial FDG SUVR at earlier disease stages (p = .06 in UCSF, p = .046 in ADNI). Exploratory analyses across the cortex confirmed overall associations between hypometabolism and local tau pathology and thickness and revealed associations between medial temporal degeneration and hypometabolism in retrosplenial, orbitofrontal, and anterior cingulate cortices. Finally, our data did not support hypotheses of a detrimental effect of pathology in connected regions or of an effect of the APOE ε4 allele in impaired participants. Overall, in two independent groups of patients at symptomatic stages of Alzheimer's disease, cortical hypometabolism mainly reflected structural neurodegeneration and tau, but not amyloid, pathology.
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http://dx.doi.org/10.1093/brain/awab294DOI Listing
August 2021

Tau and β-Amyloid Burden Predict Actigraphy-Measured and Self-Reported Impairment and Misperception of Human Sleep.

J Neurosci 2021 Sep 21;41(36):7687-7696. Epub 2021 Jul 21.

Center for Human Sleep Science, Department of Psychology, University of California Berkeley, Berkeley, California 94720

Alzheimer's disease is associated with poor sleep, but the impact of tau and β-amyloid (Aβ) pathology on sleep remains largely unknown. Here, we test the hypothesis that tau and Aβ predict unique impairments in objective and self-perceived human sleep under real-life, free-living conditions. Eighty-nine male and female cognitively healthy older adults received F-FTP-tau and C-PIB-Aβ PET imaging, 7 nights of sleep actigraphy and questionnaire measures, and neurocognitive assessment. Tau burden, but not Aβ, was associated with markedly worse objective sleep. In contrast, Aβ and tau were associated with worse self-reported sleep quality. Of clinical relevance, Aβ burden predicted a unique perceptual mismatch between objective and subject sleep evaluation, with individuals underestimating their sleep. The magnitude of this mismatch was further predicted by worse executive function. Thus, early-stage tau and Aβ deposition are linked with distinct phenotypes of real-world sleep impairment, one that includes a cognitive misperception of their own sleep health. Alzheimer's disease is associated with sleep disruption, often before significant memory decline. Thus, real-life patterns of sleep behavior have the potential to serve as a window into early disease progression. In 89 cognitive healthy older adults, we found that tau burden was associated with worse wristwatch actigraphy-measured sleep quality, and that both tau and β-amyloid were independently predictive of self-reported sleep quality. Furthermore, individuals with greater β-amyloid deposition were more likely to underestimate their sleep quality, and sleep quality underestimation was associated with worse executive function. These data support the role of sleep impairment as a key marker of early Alzheimer's disease, and offer the possibility that actigraphy may be an affordable and scalable tool in quantifying Alzheimer's disease-related behavioral changes.
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http://dx.doi.org/10.1523/JNEUROSCI.0353-21.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8425979PMC
September 2021

Evaluation of [F]-JNJ-64326067-AAA tau PET tracer in humans.

J Cereb Blood Flow Metab 2021 Jul 14:271678X211031035. Epub 2021 Jul 14.

Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.

The [F]-JNJ-64326067-AAA ([F]-JNJ-067) tau tracer was evaluated in healthy older controls (HCs), mild cognitive impairment (MCI), Alzheimer's disease (AD), and progressive supranuclear palsy (PSP) participants. Seventeen subjects (4 HCs, 5 MCIs, 5 ADs, and 3 PSPs) received a [C]-PIB amyloid PET scan, and a tau [F]-JNJ-067 PET scan 0-90 minutes post-injection. Only MCIs and ADs were amyloid positive. The simplified reference tissue model, Logan graphical analysis distribution volume ratio, and SUVR were evaluated for quantification. The [F]-JNJ-067 tau signal relative to the reference region continued to increase to 90 min, indicating the tracer had not reached steady state. There was no significant difference in any bilateral ROIs for MCIs or PSPs relative to HCs; AD participants showed elevated tracer relative to controls in most cortical ROIs (P < 0.05). Only AD participants showed elevated retention in the entorhinal cortex. There was off-target signal in the putamen, pallidum, thalamus, midbrain, superior cerebellar gray, and white matter. [F]-JNJ-067 significantly correlated (p < 0.05) with Mini-Mental State Exam in entorhinal cortex and temporal meta regions. There is clear binding of [F]-JNJ-067 in AD participants. Lack of binding in HCs, MCIs and PSPs suggests [F]-JNJ-067 may not bind to low levels of AD-related tau or 4 R tau.
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http://dx.doi.org/10.1177/0271678X211031035DOI Listing
July 2021

Accuracy of Tau Positron Emission Tomography as a Prognostic Marker in Preclinical and Prodromal Alzheimer Disease: A Head-to-Head Comparison Against Amyloid Positron Emission Tomography and Magnetic Resonance Imaging.

JAMA Neurol 2021 Aug;78(8):961-971

Clinical Memory Research Unit, Lund University, Malmö, Sweden.

Importance: Tau positron emission tomography (PET) tracers have proven useful for the differential diagnosis of dementia, but their utility for predicting cognitive change is unclear.

Objective: To examine the prognostic accuracy of baseline fluorine 18 (18F)-flortaucipir and [18F]RO948 (tau) PET in individuals across the Alzheimer disease (AD) clinical spectrum and to perform a head-to-head comparison against established magnetic resonance imaging (MRI) and amyloid PET markers.

Design, Setting, And Participants: This prognostic study collected data from 8 cohorts in South Korea, Sweden, and the US from June 1, 2014, to February 28, 2021, with a mean (SD) follow-up of 1.9 (0.8) years. A total of 1431 participants were recruited from memory clinics, clinical trials, or cohort studies; 673 were cognitively unimpaired (CU group; 253 [37.6%] positive for amyloid-β [Aβ]), 443 had mild cognitive impairment (MCI group; 271 [61.2%] positive for Aβ), and 315 had a clinical diagnosis of AD dementia (315 [100%] positive for Aβ).

Exposures: [18F]Flortaucipir PET in the discovery cohort (n = 1135) or [18F]RO948 PET in the replication cohort (n = 296), T1-weighted MRI (n = 1431), and amyloid PET (n = 1329) at baseline and repeated Mini-Mental State Examination (MMSE) evaluation.

Main Outcomes And Measures: Baseline [18F]flortaucipir/[18F]RO948 PET retention within a temporal region of interest, MRI-based AD-signature cortical thickness, and amyloid PET Centiloids were used to predict changes in MMSE using linear mixed-effects models adjusted for age, sex, education, and cohort. Mediation/interaction analyses tested whether associations between baseline tau PET and cognitive change were mediated by baseline MRI measures and whether age, sex, and APOE genotype modified these associations.

Results: Among 1431 participants, the mean (SD) age was 71.2 (8.8) years; 751 (52.5%) were male. Findings for [18F]flortaucipir PET predicted longitudinal changes in MMSE, and effect sizes were stronger than for AD-signature cortical thickness and amyloid PET across all participants (R2, 0.35 [tau PET] vs 0.24 [MRI] vs 0.17 [amyloid PET]; P < .001, bootstrapped for difference) in the Aβ-positive MCI group (R2, 0.25 [tau PET] vs 0.15 [MRI] vs 0.07 [amyloid PET]; P < .001, bootstrapped for difference) and in the Aβ-positive CU group (R2, 0.16 [tau PET] vs 0.08 [MRI] vs 0.08 [amyloid PET]; P < .001, bootstrapped for difference). These findings were replicated in the [18F]RO948 PET cohort. MRI mediated the association between [18F]flortaucipir PET and MMSE in the groups with AD dementia (33.4% [95% CI, 15.5%-60.0%] of the total effect) and Aβ-positive MCI (13.6% [95% CI, 0.0%-28.0%] of the total effect), but not the Aβ-positive CU group (3.7% [95% CI, -17.5% to 39.0%]; P = .71). Age (t = -2.28; P = .02), but not sex (t = 0.92; P = .36) or APOE genotype (t = 1.06; P = .29) modified the association between baseline [18F]flortaucipir PET and cognitive change, such that older individuals showed faster cognitive decline at similar tau PET levels.

Conclusions And Relevance: The findings of this prognostic study suggest that tau PET is a promising tool for predicting cognitive change that is superior to amyloid PET and MRI and may support the prognostic process in preclinical and prodromal stages of AD.
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http://dx.doi.org/10.1001/jamaneurol.2021.1858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240013PMC
August 2021

Validation of amyloid PET positivity thresholds in centiloids: a multisite PET study approach.

Alzheimers Res Ther 2021 05 10;13(1):99. Epub 2021 May 10.

Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA, USA.

Background: Inconsistent positivity thresholds, image analysis pipelines, and quantitative outcomes are key challenges of multisite studies using more than one β-amyloid (Aβ) radiotracer in positron emission tomography (PET). Variability related to these factors contributes to disagreement and lack of replicability in research and clinical trials. To address these problems and promote Aβ PET harmonization, we used [F]florbetaben (FBB) and [F]florbetapir (FBP) data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) to derive (1) standardized Centiloid (CL) transformations and (2) internally consistent positivity thresholds based on separate young control samples.

Methods: We analyzed Aβ PET data using a native-space, automated image processing pipeline that is used for PET quantification in many large, multisite AD studies and trials and made available to the research community. With this pipeline, we derived SUVR-to-CL transformations using the Global Alzheimer's Association Interactive Network data; we used reference regions for cross-sectional (whole cerebellum) and longitudinal (subcortical white matter, brain stem, whole cerebellum) analyses. Finally, we developed a FBB positivity threshold using an independent young control sample (N=62) with methods parallel to our existing FBP positivity threshold and validated the FBB threshold using a data-driven approach in ADNI participants (N=295).

Results: The FBB threshold based on the young sample (1.08; 18 CL) was consistent with that of the data-driven approach (1.10; 21 CL), and the existing FBP threshold converted to CL with the derived transformation (1.11; 20 CL). The following equations can be used to convert whole cerebellum- (cross-sectional) and composite- (longitudinal) normalized FBB and FBP data quantified with the native-space pipeline to CL units: [F]FBB: CL = 157.15 × SUVR - 151.87; threshold=1.08, 18 CL [F]FBP: CL = 188.22 × SUVR - 189.16; threshold=1.11, 20 CL [F]FBB: CL = 244.20 × SUVR - 170.80 [F]FBP: CL = 300.66 × SUVR - 208.84 CONCLUSIONS: FBB and FBP positivity thresholds derived from independent young control samples and quantified using an automated, native-space approach result in similar CL values. These findings are applicable to thousands of available and anticipated outcomes analyzed using this pipeline and shared with the scientific community. This work demonstrates the feasibility of harmonized PET acquisition and analysis in multisite PET studies and internal consistency of positivity thresholds in standardized units.
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http://dx.doi.org/10.1186/s13195-021-00836-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111744PMC
May 2021

The changing definition of Alzheimer's disease.

Authors:
William J Jagust

Lancet Neurol 2021 06 29;20(6):414-415. Epub 2021 Apr 29.

Dr William J Jagust, Helen Wills Neuroscience Institute and School of Public Health, University of California, Berkeley, CA 94720-3190, USA. Electronic address:

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http://dx.doi.org/10.1016/S1474-4422(21)00077-6DOI Listing
June 2021

Detection of β-amyloid positivity in Alzheimer's Disease Neuroimaging Initiative participants with demographics, cognition, MRI and plasma biomarkers.

Brain Commun 2021 2;3(2):fcab008. Epub 2021 Feb 2.

San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA.

gold standard for the ante-mortem assessment of brain β-amyloid pathology is currently β-amyloid positron emission tomography or cerebrospinal fluid measures of β-amyloid or the β-amyloid/β-amyloid ratio. The widespread acceptance of a biomarker classification scheme for the Alzheimer's disease continuum has ignited interest in more affordable and accessible approaches to detect Alzheimer's disease β-amyloid pathology, a process that often slows down the recruitment into, and adds to the cost of, clinical trials. Recently, there has been considerable excitement concerning the value of blood biomarkers. Leveraging multidisciplinary data from cognitively unimpaired participants and participants with mild cognitive impairment recruited by the multisite biomarker study of Alzheimer's Disease Neuroimaging Initiative, here we assessed to what extent plasma β-amyloid/β-amyloid, neurofilament light and phosphorylated-tau at threonine-181 biomarkers detect the presence of β-amyloid pathology, and to what extent the addition of clinical information such as demographic data, genotype, cognitive assessments and MRI can assist plasma biomarkers in detecting β-amyloid-positivity. Our results confirm plasma β-amyloid/β-amyloid as a robust biomarker of brain β-amyloid-positivity (area under curve, 0.80-0.87). Plasma phosphorylated-tau at threonine-181 detected β-amyloid-positivity only in the cognitively impaired with a moderate area under curve of 0.67, whereas plasma neurofilament light did not detect β-amyloid-positivity in either group of participants. Clinical information as well as MRI-score independently detected positron emission tomography β-amyloid-positivity in both cognitively unimpaired and impaired (area under curve, 0.69-0.81). Clinical information, particularly ε4 status, enhanced the performance of plasma biomarkers in the detection of positron emission tomography β-amyloid-positivity by 0.06-0.14 units of area under curve for cognitively unimpaired, and by 0.21-0.25 units for cognitively impaired; and further enhancement of these models with an MRI-score of β-amyloid-positivity yielded an additional improvement of 0.04-0.11 units of area under curve for cognitively unimpaired and 0.05-0.09 units for cognitively impaired. Taken together, these multi-disciplinary results suggest that when combined with clinical information, plasma phosphorylated-tau at threonine-181 and neurofilament light biomarkers, and an MRI-score could effectively identify β-amyloid+ cognitively unimpaired and impaired (area under curve, 0.80-0.90). Yet, when the MRI-score is considered in combination with clinical information, plasma phosphorylated-tau at threonine-181 and plasma neurofilament light have minimal added value for detecting β-amyloid-positivity. Our systematic comparison of β-amyloid-positivity detection models identified effective combinations of demographics, , global cognition, MRI and plasma biomarkers. Promising minimally invasive and low-cost predictors such as plasma biomarkers of β-amyloid/β-amyloid may be improved by age and genotype.
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http://dx.doi.org/10.1093/braincomms/fcab008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023542PMC
February 2021

Reduced Repetition Suppression in Aging is Driven by Tau-Related Hyperactivity in Medial Temporal Lobe.

J Neurosci 2021 Apr 17;41(17):3917-3931. Epub 2021 Mar 17.

Helen Wills Neuroscience Institute, University of California, Berkeley, Berkeley, California 94720.

Tau deposition begins in the medial temporal lobe (MTL) in aging and Alzheimer's disease (AD), and MTL neural dysfunction is commonly observed in these groups. However, the association between tau and MTL neural activity has not been fully characterized. We investigated the effects of tau on repetition suppression, the reduction of activity for repeated stimulus presentations compared to novel stimuli. We used task-based functional MRI (fMRI) to assess MTL subregional activity in 21 young adults (YA) and 45 cognitively normal human older adults (OA; total sample: 37 females, 29 males). AD pathology was measured with position emission tomography (PET), using F-Flortaucipir for tau and C-Pittsburgh compound B (PiB) for amyloid-β (Aβ). The MTL was segmented into six subregions using high-resolution structural images. We compared the effects of low tau pathology, restricted to entorhinal cortex and hippocampus (Tau- OA), to high tau pathology, also occurring in temporal and limbic regions (Tau+ OA). Low levels of tau (Tau- OA vs YA) were associated with reduced repetition suppression activity specifically in anterolateral entorhinal cortex (alEC) and hippocampus, the first regions to accumulate tau. High tau pathology (Tau+ vs Tau- OA) was associated with widespread reductions in repetition suppression across MTL. Further analyses indicated that reduced repetition suppression was driven by hyperactivity to repeated stimuli, rather than decreased activity to novel stimuli. Increased activation was associated with entorhinal tau, but not Aβ. These findings reveal a link between tau deposition and neural dysfunction in MTL, in which tau-related hyperactivity prevents deactivation to repeated stimuli, leading to reduced repetition suppression. Abnormal neural activity occurs in the medial temporal lobe (MTL) in aging and Alzheimer's disease (AD). Because tau pathology first deposits in the MTL in aging, this altered activity may be due to local tau pathology, and distinct MTL subregions may be differentially vulnerable. We demonstrate that in older adults (OAs) with low tau pathology, there are focal alterations in activity in MTL subregions that first develop tau pathology, while OAs with high tau pathology have aberrant activity throughout MTL. Tau was associated with hyperactivity to repeated stimulus presentations, leading to reduced repetition suppression, the discrimination between novel and repeated stimuli. Our data suggest that tau deposition is related to abnormal activity in MTL before the onset of cognitive decline.
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http://dx.doi.org/10.1523/JNEUROSCI.2504-20.2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084317PMC
April 2021

Crossed cerebellar diaschisis on F-FDG PET: Frequency across neurodegenerative syndromes and association with C-PIB and F-Flortaucipir.

J Cereb Blood Flow Metab 2021 Sep 10;41(9):2329-2343. Epub 2021 Mar 10.

Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA, USA.

We used F-FDG-PET to investigate the frequency of crossed cerebellar diaschisis (CCD) in 197 patients with various syndromes associated with neurodegenerative diseases. In a subset of 117 patients, we studied relationships between CCD and cortical asymmetry of Alzheimer's pathology (β-amyloid (C-PIB) and tau (F-Flortaucipir)). PET images were processed using MRIs to derive parametric SUVR images and define regions of interest. Indices of asymmetry were calculated in the cerebral cortex, basal ganglia and cerebellar cortex. Across all patients, cerebellar F-FDG asymmetry was associated with reverse asymmetry of F-FDG in the cerebral cortex (especially frontal and parietal areas) and basal ganglia. Based on our operational definition (cerebellar asymmetry >3% with contralateral supratentorial hypometabolism), significant CCD was present in 47/197 (24%) patients and was most frequent in corticobasal syndrome and semantic and logopenic variants of primary progressive aphasia. In β-amyloid-positive patients, mediation analyses showed that F-Flortaucipir cortical asymmetry was associated with cerebellar F-FDG asymmetry, but that cortical F-FDG asymmetry mediated this relationship. Analysis of F-FDG-SUVR values suggested that CCD might also occur in the absence of frank cerebellar F-FDG asymmetry due to symmetrical supratentorial degeneration resulting in a bilateral diaschisis process.
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http://dx.doi.org/10.1177/0271678X211001216DOI Listing
September 2021

Temporal Dynamics of β-Amyloid Accumulation in Aging and Alzheimer Disease.

Neurology 2021 03 6;96(9):e1347-e1357. Epub 2021 Jan 6.

From the Helen Wills Neuroscience Institute, University of California, Berkeley; and Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, CA.

Objective: To understand the time course of β-amyloid (Aβ) deposition in the brain, which is crucial for planning therapeutic trials of Aβ-lowering therapies in Alzheimer disease (AD).

Methods: Two samples of participants from the Alzheimer's Disease Neuroimaging Initiative were studied with [F]Florbetapir (FBP) Aβ PET and followed for up to 9 years. Sample A included 475 cognitively normal (CN) older people and those with mild cognitive impairment (MCI) and AD and sample B included 220 CN Aβ- individuals. We examined the trajectory of FBP over time in sample A and the incidence rate of conversion from negative to positive Aβ PET scans in sample B.

Results: The relationship between time and brain Aβ was sigmoidal, taking 6.4 years to transition from amyloid negative to positive and another 13.9 years to the onset of MCI. Aβ deposition rates began to slow only 3.8 years after reaching the positivity threshold. The incidence rate for scan positivity was 38/1,000 person-years, and factors associated with conversion were age, baseline FBP, and being a female ε4 carrier. Among CN Aβ- individuals, FBP slopes were associated with rates of memory decline and brain tau measured with [F]Flortaucipir PET 5 years after baseline.

Conclusions: Lowering brain Aβ must be accomplished early in the evolution of AD. Transitions of PET scans from Aβ- to Aβ+ should be predictable, and it is reasonable to expect that lowering rates of Aβ even in early stages could produce clinically significant benefits.
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http://dx.doi.org/10.1212/WNL.0000000000011524DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055327PMC
March 2021

Alzheimer Disease Spectrum: Syndrome and Etiology From Clinical and PET Imaging Perspectives.

Neurology 2021 02 22;96(7):299-300. Epub 2020 Dec 22.

From the Department of Neurology (D.S.K.), Mayo Clinic, Rochester MN; and School of Public Health and Helen Wills Neuroscience Institute (W.J.J.), University of California Berkeley.

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http://dx.doi.org/10.1212/WNL.0000000000011415DOI Listing
February 2021

Distinct effects of beta-amyloid and tau on cortical thickness in cognitively healthy older adults.

Alzheimers Dement 2021 07 15;17(7):1085-1096. Epub 2020 Dec 15.

Helen Wills Neuroscience Institute, UC Berkeley, Berkeley, California, USA.

Introduction: Published reports of associations between β-amyloid (Aβ) and cortical integrity conflict. Tau biomarkers may help elucidate the complex relationship between pathology and neurodegeneration in aging.

Methods: We measured cortical thickness using magnetic resonance imaging, Aβ using Pittsburgh compound B positron emission tomography (PiB-PET), and tau using flortaucipir (FTP)-PET in 125 cognitively normal older adults. We examined relationships among PET measures, cortical thickness, and cognition.

Results: Cortical thickness was reduced in PiB+/FTP+ participants compared to the PiB+/FTP- and PiB-/FTP- groups. Continuous PiB associations with cortical thickness were weak but positive in FTP- participants and negative in FTP+. FTP strongly negatively predicted thickness regardless of PiB status. FTP was associated with memory and cortical thickness, and mediated the association of PiB with memory.

Discussion: Past findings linking Aβ and cortical thickness are likely weak due to opposing effects of Aβ on cortical thickness relative to tau burden. Tau, in contrast to Aβ, is strongly related to cortical thickness and memory.
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http://dx.doi.org/10.1002/alz.12249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8203764PMC
July 2021

Evaluation of a visual interpretation method for tau-PET with F-flortaucipir.

Alzheimers Dement (Amst) 2020 28;12(1):e12133. Epub 2020 Nov 28.

Memory and Aging Center University of California, San Francisco San Francisco California USA.

Introduction: Positron emission tomography targeting tau (tau-PET) is a promising diagnostic tool for the identification of Alzheimer's disease (AD). Currently available data rely on quantitative measures, and a visual interpretation method, critical for clinical translation, is needed.

Methods: We developed a visual interpretation method for F-flortaucipir tau-PET and tested it on 274 individuals (cognitively normal controls, patients with mild cognitive impairment [MCI], AD dementia, and non-AD diagnoses). Two readers interpreted F-flortaucipir PET using two complementary indices: a global visual score and a visual distribution pattern.

Results: Global visual scores were reliable, correlated with global cortical F-flortaucipir standardized uptake value ratio (SUVR) and were associated with clinical diagnosis and amyloid status. The AD-like F-flortaucipir pattern had good sensitivity and specificity to identify amyloid-positive patients with AD dementia or MCI.

Discussion: This F-flortaucipir visual rating scheme is associated with SUVR quantification, clinical diagnosis, and amyloid status, and constitutes a promising approach to tau measurement in clinical settings.
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http://dx.doi.org/10.1002/dad2.12133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7699207PMC
November 2020

Association of and Clinical Variability in Alzheimer Disease With the Pattern of Tau- and Amyloid-PET.

Neurology 2021 02 1;96(5):e650-e661. Epub 2020 Dec 1.

From the Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences (R.L.J., A.V.V., O.H.L.-V., L.E., L.I., D.N.S.-M., T.M., Z.A.M., D.C.P., J.P., A.S., M.L.G.-T., H.J.R., B.L.M., G.D.R.), and Department of Radiology and Biomedical Imaging (G.D.R.), University of California, San Francisco; Department of Diagnostic Imaging (O.H.L.-V.), Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; Molecular Biophysics and Integrated Bioimaging Division (S.L.B., M.J., W.J.J., G.D.R.), Lawrence Berkeley National Laboratory; and Helen Wills Neuroscience Institute (W.J.J., G.D.R.), University of California Berkeley.

Objective: To assess whether Alzheimer disease (AD) clinical presentation and relate to the burden and topography of β-amyloid (Aβ) and tau pathologies using in vivo PET imaging.

Methods: We studied 119 Aβ-positive symptomatic patients aged 48-95 years, including 29 patients with logopenic variant primary progressive aphasia (lvPPA) and 21 with posterior cortical atrophy (PCA). Pittsburgh compound B (PiB)-Aβ and flortaucipir (tau)-PET standardized uptake value ratio (SUVR) images were created. General linear models assessed relationships between demographic/clinical variables (phenotype, age), , and PET (including global cortical and voxelwise SUVR values) while controlling for disease severity using the Clinical Dementia Rating Sum of Boxes.

Results: PiB-PET binding showed a widespread cortical distribution with subtle differences across phenotypes and was unrelated to demographic/clinical variables or . Flortaucipir-PET was commonly elevated in temporoparietal regions, but showed marked phenotype-associated differences, with higher binding observed in occipito-parietal areas for PCA, in left temporal and inferior frontal for lvPPA, and in medial temporal areas for other AD. Cortical flortaucipir-PET binding was higher in younger patients across phenotypes ( = -0.63, 95% confidence interval [CI] -0.72, -0.50), especially in parietal and dorsal prefrontal cortices. The presence of was associated with a focal medial temporal flortaucipir-SUVR increase, controlling for all other variables (entorhinal: + 0.310 SUVR, 95% CI 0.091, 0.530).

Conclusions: Clinical phenotypes are associated with differential patterns of tau but not amyloid pathology. Older age and are not only risk factors for AD but also seem to affect disease expression by promoting a more medial temporal lobe-predominant pattern of tau pathology.
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http://dx.doi.org/10.1212/WNL.0000000000011270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884991PMC
February 2021

Diagnostic Accuracy of Amyloid versus F-Fluorodeoxyglucose Positron Emission Tomography in Autopsy-Confirmed Dementia.

Ann Neurol 2021 02 7;89(2):389-401. Epub 2020 Dec 7.

Department of Neurology, Memory and Aging Center, Weill Institute for Neurosciences, University of California, San Francisco, San Francisco, CA, USA.

Objective: The purpose of this study was to compare the diagnostic accuracy of antemortem C-Pittsburgh compound B (PIB) and F-fluorodeoxyglucose (FDG) positron emission tomography (PET) versus autopsy diagnosis in a heterogenous sample of patients.

Methods: One hundred one participants underwent PIB and FDG PET during life and neuropathological assessment. PET scans were visually interpreted by 3 raters blinded to clinical information. PIB PET was rated as positive or negative for cortical retention, whereas FDG scans were read as showing an Alzheimer disease (AD) or non-AD pattern. Neuropathological diagnoses were assigned using research criteria. Majority visual reads were compared to intermediate-high AD neuropathological change (ADNC).

Results: One hundred one participants were included (mean age = 67.2 years, 41 females, Mini-Mental State Examination = 21.9, PET-to-autopsy interval = 4.4 years). At autopsy, 32 patients showed primary AD, 56 showed non-AD neuropathology (primarily frontotemporal lobar degeneration [FTLD]), and 13 showed mixed AD/FTLD pathology. PIB showed higher sensitivity than FDG for detecting intermediate-high ADNC (96%, 95% confidence interval [CI] = 89-100% vs 80%, 95% CI = 68-92%, p = 0.02), but equivalent specificity (86%, 95% CI = 76-95% vs 84%, 95% CI = 74-93%, p = 0.80). In patients with congruent PIB and FDG reads (77/101), combined sensitivity was 97% (95% CI = 92-100%) and specificity was 98% (95% CI = 93-100%). Nine of 24 patients with incongruent reads were found to have co-occurrence of AD and non-AD pathologies.

Interpretation: In our sample enriched for younger onset cognitive impairment, PIB-PET had higher sensitivity than FDG-PET for intermediate-high ADNC, with similar specificity. When both modalities are congruent, sensitivity and specificity approach 100%, whereas mixed pathology should be considered when PIB and FDG are incongruent. ANN NEUROL 2021;89:389-401.
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http://dx.doi.org/10.1002/ana.25968DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856004PMC
February 2021

Regional Tau Effects on Prospective Cognitive Change in Cognitively Normal Older Adults.

J Neurosci 2021 01 20;41(2):366-375. Epub 2020 Nov 20.

Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, California 94720.

Studies suggest that tau deposition starts in the anterolateral entorhinal cortex (EC) with normal aging, and that the presence of β-amyloid (Aβ) facilitates its spread to neocortex, which may reflect the beginning of Alzheimer's disease (AD). Functional connectivity between the anterolateral EC and the anterior-temporal (AT) memory network appears to drive higher tau deposition in AT than in the posterior-medial (PM) memory network. Here, we investigated whether this differential vulnerability to tau deposition may predict different cognitive consequences of EC, AT, and PM tau. Using F-flortaucipir (FTP) and C-Pittsburgh compound-B (PiB) positron emission tomography (PET) imaging, we measured tau and Aβ in 124 cognitively normal human older adults (74 females, 50 males) followed for an average of 2.8 years for prospective cognition. We found that higher FTP in all three regions was individually related to faster memory decline, and that the effects of AT and PM FTP, but not EC, were driven by Aβ+ individuals. Moreover, when we included all three FTP measures competitively in the same model, only AT FTP significantly predicted memory decline. Our data support a model whereby tau, facilitated by Aβ, transits from EC to cortical regions that are most closely associated with the anterolateral EC, which specifically affects memory in the initial stage of AD. Memory also appears to be affected by EC tau in the absence of Aβ, which may be less clinically consequential. These findings may provide clarification of differences between normal aging and AD, and elucidate the transition between the two stages. Tau and β-amyloid (Aβ) are hallmarks of Alzheimer's disease (AD) but are also found in cognitively normal people. It is unclear whether, and how, this early deposition of tau and Aβ may affect cognition in normal aging and the asymptomatic stage of AD. We show that tau deposition in the entorhinal cortex (EC), which is common in advanced age, predicts memory decline in older adults independent of Aβ, likely reflecting normal, age-related memory loss. In contrast, tau in anterior-temporal (AT) regions is most predictive of memory decline in Aβ+ individuals. These data support the idea that tau preferentially spreads to specific cortical regions, likely through functional connections, which plays a primary role in memory decline in the early stage of AD.
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http://dx.doi.org/10.1523/JNEUROSCI.2111-20.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810658PMC
January 2021

Conscientiousness is associated with less amyloid deposition in cognitively normal aging.

Psychol Aging 2020 Nov;35(7):993-999

Lawrence Berkeley National Laboratory.

Little is known about the association between personality and Alzheimer's disease (AD) biomarkers, and existing results are inconsistent. We aimed to determine whether personality was associated with β-amyloid (Aβ) accumulation in cognitively normal aging. One hundred twenty-nine participants were included in this cross-sectional study. Personality was measured with the Big Five Inventory (BFI) and brain Aβ deposition was assessed with [11C] Pittsburgh compound B (PiB)-positron emission tomography (PET) imaging. Conscientiousness scores had a negative association with global PiB distribution volume ratio (DVR) in all participants after adjusting for age, sex, education, and vascular risk factors (β[SE] = -0.19[0.09], 95% confidence interval [CI: -0.35, -0.02], p = .031), while agreeableness, extraversion, neuroticism, and openness had no association with global PiB DVR. Assuming the relative stability of personality traits, these findings suggest that conscientiousness may protect against Aβ accumulation in cognitively normal aging through mechanisms that are as yet unknown. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/pag0000582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8371907PMC
November 2020

18F-flortaucipir PET to autopsy comparisons in Alzheimer's disease and other neurodegenerative diseases.

Brain 2020 12;143(11):3477-3494

Memory and Aging Center, Department of Neurology, University of California, San Francisco, CA, USA.

Few studies have evaluated the relationship between in vivo18F-flortaucipir PET and post-mortem pathology. We sought to compare antemortem 18F-flortaucipir PET to neuropathology in a consecutive series of patients with a broad spectrum of neurodegenerative conditions. Twenty patients were included [mean age at PET 61 years (range 34-76); eight female; median PET-to-autopsy interval of 30 months (range 4-59 months)]. Eight patients had primary Alzheimer's disease pathology, nine had non-Alzheimer tauopathies (progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, and frontotemporal lobar degeneration with MAPT mutations), and three had non-tau frontotemporal lobar degeneration. Using an inferior cerebellar grey matter reference, 80-100-min 18F-flortaucipir PET standardized uptake value ratio (SUVR) images were created. Mean SUVRs were calculated for progressive supranuclear palsy, corticobasal degeneration, and neurofibrillary tangle Braak stage regions of interest, and these values were compared to SUVRs derived from young, non-autopsy, cognitively normal controls used as a standard for tau negativity. W-score maps were generated to highlight areas of increased tracer retention compared to cognitively normal controls, adjusting for age as a covariate. Autopsies were performed blinded to PET results. There was excellent correspondence between areas of 18F-flortaucipir retention, on both SUVR images and W-score maps, and neurofibrillary tangle distribution in patients with primary Alzheimer's disease neuropathology. Patients with non-Alzheimer tauopathies and non-tau frontotemporal lobar degeneration showed a range of tracer retention that was less than Alzheimer's disease, though higher than age-matched, cognitively normal controls. Overall, binding across both tau-positive and tau-negative non-Alzheimer disorders did not reliably correspond with post-mortem tau pathology. 18F-flortaucipir SUVRs in subcortical regions were higher in autopsy-confirmed progressive supranuclear palsy and corticobasal degeneration than in controls, but were similar to values measured in Alzheimer's disease and tau-negative neurodegenerative pathologies. Quantification of 18F-flortaucipir SUVR images at Braak stage regions of interest reliably detected advanced Alzheimer's (Braak VI) pathology. However, patients with earlier Braak stages (Braak I-IV) did not show elevated tracer uptake in these regions compared to young, tau-negative controls. In summary, PET-to-autopsy comparisons confirm that 18F-flortaucipir PET is a reliable biomarker of advanced Braak tau pathology in Alzheimer's disease. The tracer cannot reliably differentiate non-Alzheimer tauopathies and may not detect early Braak stages of neurofibrillary tangle pathology.
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http://dx.doi.org/10.1093/brain/awaa276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719031PMC
December 2020

Longitudinal Cognitive and Biomarker Measurements Support a Unidirectional Pathway in Alzheimer's Disease Pathophysiology.

Biol Psychiatry 2021 04 12;89(8):786-794. Epub 2020 Jul 12.

Helen Wills Neuroscience Institute, University of California, Berkeley, California; Molecular Biophysics and Integrated Bioimaging, Lawrence Berkeley National Laboratory, Berkeley, California.

Background: Amyloid-β (Aβ) likely plays a primary role in Alzheimer's disease pathogenesis, but longitudinal Aβ, tau, and neurodegeneration (A/T/N) measurements in the same individuals have rarely been examined to verify the temporal dynamics of these biomarkers.

Methods: In this study, we investigated the temporal ordering of Aβ, tau, and neurodegeneration using longitudinal biomarkers in nondemented elderly individuals. A total of 395 cognitively unimpaired individuals and 204 individuals with mild cognitive impairment (320 [53%] were female) were classified into 8 A±/T±/N± categories according to the abnormal (+)/normal (-) status of Aβ (F-florbetapir or F-florbetaben) positron emission tomography (PET), F-flortaucipir PET, and adjusted hippocampal volume (aHCV). Follow-up Aβ PET, tau PET, and aHCV measurements at 0.6 to 4.1 years were available for 35% to 63% of the sample. Baseline Aβ, tau, and aHCV were compared between different A/T/N profiles. We investigated the associations of baseline and longitudinal Aβ, tau, and neurodegeneration in relation to one another continuously.

Results: Among T- participants, tau was higher for A+/T-/N- individuals compared with the A-/T-/N- group (p = .02). Among N- participants, neurodegeneration was worse among A+/T+/N- individuals compared with the A-/T-/N- group (p = .001). High baseline Aβ was associated (p < .001) with subsequent tau increase and high baseline tau was associated (p = .002) with subsequent aHCV decrease, whereas high tau and low aHCV at baseline were not associated with subsequent Aβ increase.

Conclusions: These findings define a sequence of pathological events in Alzheimer's disease that support a current model of Alzheimer's disease pathogenesis in which Aβ appears early, followed by deposition of abnormal tau aggregates and subsequent neurodegeneration.
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http://dx.doi.org/10.1016/j.biopsych.2020.06.029DOI Listing
April 2021

Sleep Disturbance Forecasts β-Amyloid Accumulation across Subsequent Years.

Curr Biol 2020 11 3;30(21):4291-4298.e3. Epub 2020 Sep 3.

Center for Human Sleep Science, Department of Psychology, University of California, Berkeley, Berkeley Way West, Berkeley, CA 94720, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, 132 Barker Hall, Berkeley, CA 94720, USA. Electronic address:

Experimental sleep-wake disruption in rodents and humans causally modulates β-amyloid (Aβ) dynamics (e.g., [1-3]). This leads to the hypothesis that, beyond cross-sectional associations, impaired sleep structure and physiology could represent prospective biomarkers of the speed with which Aβ accumulates over time. Here, we test the hypothesis that initial baseline measures of non-rapid eye movement (NREM) sleep slow-wave activity (SWA) and sleep quality (efficiency) provide future forecasting sensitivity to the rate of Aβ accumulation over subsequent years. A cohort of clinically normal older adults was assessed using objective sleep polysomnography in combination with longitudinal tracking of Aβ accumulation with [C]PiB positron emission tomography (PET) imaging. Both the proportion of NREM SWA below 1 Hz and the measure of sleep efficiency predicted the speed (slope) of subsequent Aβ deposition over time, and these associations remained robust when taking into account additional cofactors of interest (e.g., age, sex, sleep apnea). Moreover, these measures were specific, such that no other macro- and microphysiological architecture metrics of sleep demonstrated such sensitivity. Our data support the proposal that objective sleep markers could be part of a set of biomarkers that statistically forecast the longitudinal trajectory of cortical Aβ deposition in the human brain. Sleep may therefore represent a potentially affordable, scalable, repeatable, and non-invasive tool for quantifying of Aβ pathological progression, prior to cognitive symptoms of Alzheimer's disease (AD).
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http://dx.doi.org/10.1016/j.cub.2020.08.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642104PMC
November 2020

Spatial Relationships between Molecular Pathology and Neurodegeneration in the Alzheimer's Disease Continuum.

Cereb Cortex 2021 01;31(1):1-14

Memory and Aging Center, Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94158, USA.

A deeper understanding of the spatial relationships of β-amyloid (Aβ), tau, and neurodegeneration in Alzheimer's disease (AD) could provide insight into pathogenesis and clinical trial design. We included 81 amyloid-positive patients (age 64.4 ± 9.5) diagnosed with AD dementia or mild cognitive impairment due to AD and available 11C-PiB (PIB), 18F-Flortaucipir (FTP),18F-FDG-PET, and 3T-MRI, and 31 amyloid-positive, cognitively normal participants (age 77.3 ± 6.5, no FDG-PET). W-score voxel-wise deviation maps were created and binarized for each imaging-modality (W > 1.64, P < 0.05) adjusting for age, sex, and total intracranial volume (sMRI-only) using amyloid-negative cognitively normal adults. For symptomatic patients, FDG-PET and atrophy W-maps were combined into neurodegeneration maps (ND). Aβ-pathology showed the greatest proportion of cortical gray matter suprathreshold voxels (spatial extent) for both symptomatic and asymptomatic participants (median 94-55%, respectively), followed by tau (79-11%) and neurodegeneration (41-3%). Amyloid > tau > neurodegeneration was the most frequent hierarchy for both groups (79-77%, respectively), followed by tau > amyloid > neurodegeneration (13-10%) and amyloid > neurodegeneration > tau (6-13%). For symptomatic participants, most abnormal voxels were PIB+/FTP+/ND- (median 35%), and the great majority of ND+ voxels (91%) colocalized with molecular pathology. Amyloid spatially exceeded tau and neurodegeneration, with individual heterogeneities. Molecular pathology and neurodegeneration showed a progressive overlap along AD course, indicating shared vulnerabilities or synergistic toxic mechanisms.
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http://dx.doi.org/10.1093/cercor/bhaa184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7727356PMC
January 2021

Normalization of CSF pTau measurement by Aβ improves its performance as a biomarker of Alzheimer's disease.

Alzheimers Res Ther 2020 08 15;12(1):97. Epub 2020 Aug 15.

Helen Wills Neuroscience Institute, University of California, 132 Barker Hall, Berkeley, CA, 94720, USA.

Background: Alzheimer's disease (AD)-related tauopathy can be measured with CSF phosphorylated tau (pTau) and tau PET. We aim to investigate the associations between these measurements and their relative ability to predict subsequent disease progression.

Methods: In 219 cognitively unimpaired and 122 impaired Alzheimer's Disease Neuroimaging Initiative participants with concurrent amyloid-β (Aβ) PET (F-florbetapir or F-florbetaben), F-flortaucipir (FTP) PET, CSF measurements, structural MRI, and cognition, we examined inter-relationships between these biomarkers and their predictions of subsequent FTP and cognition changes.

Results: The use of a CSF pTau/Aβ ratio eliminated positive associations we observed between CSF pTau alone and CSF Aβ in the normal Aβ range likely reflecting individual differences in CSF production rather than pathology. Use of the CSF pTau/Aβ ratio also increased expected associations with Aβ PET, FTP PET, hippocampal volume, and cognitive decline compared to pTau alone. In Aβ+ individuals, abnormal CSF pTau/Aβ only individuals (26.7%) were 4 times more prevalent (p <  0.001) than abnormal FTP only individuals (6.8%). Furthermore, among individuals on the AD pathway, CSF pTau/Aβ mediates the association between Aβ PET and FTP PET accumulation, but FTP PET is more closely linked to subsequent cognitive decline than CSF pTau/Aβ.

Conclusions: Together, these findings suggest that CSF pTau/Aβ may be a superior measure of tauopathy compared to CSF pTau alone, and CSF pTau/Aβ enables detection of tau accumulation at an earlier stage than FTP among Aβ+ individuals.
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http://dx.doi.org/10.1186/s13195-020-00665-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7429887PMC
August 2020

Association of CSF Aβ, amyloid PET, and cognition in cognitively unimpaired elderly adults.

Neurology 2020 10 5;95(15):e2075-e2085. Epub 2020 Aug 5.

From the Helen Wills Neuroscience Institute (T.G., W.J.J., S.M.L.), University of California; Molecular Biophysics and Integrated Bioimaging (T.G., W.J.J., S.M.L.), Lawrence Berkeley National Laboratory, Berkeley, CA; and Department of Pathology and Laboratory Medicine (L.M.S., J.Q.T.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.

Objective: To compare CSF β-amyloid (Aβ) and florbetapir PET measurements in cognitively unimpaired (CU) elderly adults in order to detect the earliest abnormalities and compare their predictive effect for cognitive decline.

Methods: A total of 259 CU individuals were categorized as abnormal (+) or normal (-) on CSF Aβ/Aβ analyzed with mass spectrometry and Aβ PET measured with F-florbetapir. Simultaneous longitudinal measurements of CSF and PET were compared for 39 individuals who were unambiguously Aβ-negative at baseline (CSF-/PET-). We also examined the relationship between baseline CSF/PET group membership and longitudinal changes in CSF Aβ, Aβ PET, and cognition.

Results: The proportions of individuals in each discordant group were similar (8.1% CSF+/PET- and 7.7% CSF-/PET+). Among baseline Aβ-negative (CSF-/PET-) individuals with longitudinal CSF and PET measurements, a larger proportion subsequently worsened on CSF Aβ (odds ratio 4 [95% confidence interval (CI) 1.1, 22.1], = 0.035) than Aβ PET over 3.5 ± 1.0 years. Compared to CSF-/PET- individuals, CSF+/PET- individuals had faster (estimate 0.009 [95% CI 0.005, 0.013], < 0.001) rates of Aβ PET accumulation over 4.4 ± 1.7 years, while CSF-/PET+ individuals had faster (estimate -0.492 [95% CI -0.861, -0.123], = 0.01) rates of cognitive decline over 4.5 ± 1.9 years.

Conclusions: The proportions of discordant PET and CSF Aβ-positive individuals were similar cross-sectionally. However, unambiguously Aβ-negative (CSF-/PET-) individuals are more likely to show subsequent worsening on CSF than PET, supporting the idea that CSF detects the earliest Aβ changes. In discordant cases, only PET abnormality predicted cognitive decline, suggesting that abnormal Aβ PET changes are a later phenomenon in cognitively normal individuals.
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http://dx.doi.org/10.1212/WNL.0000000000010596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7713747PMC
October 2020

Longitudinal structural and metabolic changes in frontotemporal dementia.

Neurology 2020 07 26;95(2):e140-e154. Epub 2020 Jun 26.

From the Memory and Aging Center, Department of Neurology (A.B., G.T., G.M., Y.C., L.I., J.K., A.M.S., M.G.-T., B.L.M., A.L.B., H.J.R., G.D.R.), and Department of Radiology and Biomedical Imaging (G.D.R.), University of California San Francisco; Frontotemporal Disorders Unit (B.C.D.), Department of Neurology, Massachusetts General Hospital, Boston; and Harvard Medical School, Charleston; Department of Neurology (B.F.B., D.S.K.), Mayo Clinic, Rochester, MN; Molecular Biophysics and Integrated Bioimaging Division (W.J.J., G.D.R.), Lawrence Berkeley National Laboratory, CA; and Helen Wills Neuroscience Institute (G.D.R.), University of California Berkeley.

Objective: To compare the sensitivity of structural MRI and F-fludeoxyglucose PET (FDG-PET) to detect longitudinal changes in frontotemporal dementia (FTD).

Methods: Thirty patients with behavioral variant FTD (bvFTD), 7 with nonfluent/agrammatic variant primary progressive aphasia (nfvPPA), 16 with semantic variant primary progressive aphasia (svPPA), and 43 cognitively normal controls underwent 2-4 MRI and FDG-PET scans (total scans/visit = 270) as part of the Frontotemporal Lobar Degeneration Neuroimaging Initiative study. Linear mixed-effects models were carried out voxel-wise and in regions of interest to identify areas showing decreased volume or metabolism over time in patients as compared to controls.

Results: At baseline, patients with bvFTD showed bilateral temporal, dorsolateral, and medial prefrontal atrophy/hypometabolism that extended with time into adjacent structures and parietal lobe. In nfvPPA, baseline atrophy/hypometabolism in supplementary motor cortex extended with time into left greater than right precentral, dorsolateral, and dorsomedial prefrontal cortex. In svPPA, baseline atrophy/hypometabolism encompassed the anterior temporal and medial prefrontal cortex and longitudinal changes were found in temporal, orbitofrontal, and lateral parietal cortex. Across syndromes, there was substantial overlap in the brain regions showing volume and metabolism loss. Even though the pattern of metabolic decline was more extensive, metabolic changes were also more variable and sample size estimates were similar or higher for FDG-PET compared to MRI.

Conclusion: Our findings demonstrated the sensitivity of FDG-PET and structural MRI for tracking disease progression in FTD. Both modalities showed highly overlapping patterns of longitudinal change and comparable sample size estimates to detect longitudinal changes in future clinical trials.
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http://dx.doi.org/10.1212/WNL.0000000000009760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7455324PMC
July 2020

Imaging Tau Pathology-The Next Step.

Authors:
William J Jagust

JAMA Neurol 2020 07;77(7):796-797

Helen Wills Neuroscience Institute and University of California Berkeley School of Public Health, Berkeley.

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http://dx.doi.org/10.1001/jamaneurol.2020.0520DOI Listing
July 2020

Detecting earlier stages of amyloid deposition using PET in cognitively normal elderly adults.

Neurology 2020 04 18;94(14):e1512-e1524. Epub 2020 Mar 18.

From the Helen Wills Neuroscience Institute (T.G., S.M.L., W.J.J.), University of California; and Molecular Biophysics and Integrated Bioimaging (T.G., S.M.L., W.J.J.), Lawrence Berkeley National Laboratory, CA.

Objective: To examine the feasibility of using cross-sectional PET to identify cognitive decliners among β-amyloid (Aβ)-negative cognitively normal (CN) elderly adults.

Methods: We determined the highest Aβ-affected region by ranking baseline and accumulation rates of florbetapir-PET regions in 355 CN elderly adults using F-florbetapir-PET from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The banks of the superior temporal sulcus (BANKSSTS) were found as the highest Aβ-affected region, and Aβ positivity in this region was defined as above the lowest boundary of BANKSSTS standardized uptake value ratio of Aβ+ (ADNI-defined COMPOSITE region) CN individuals. The entire CN cohort was divided as follows: stage 0, BANKSSTS-COMPOSITE-; stage 1, BANKSSTS+COMPOSITE-; and stage 2, BANKSSTS+COMPOSITE+. Linear mixed-effect (LME) models investigated subsequent longitudinal cognitive change, and F-flortaucipir (FTP)-PET was measured 4.8 ± 1.6 years later to track tau deposition.

Results: LME analysis revealed that individuals in stage 1 (n = 64) and stage 2 (n = 99) showed 2.5 ( < 0.05) and 4.8 ( < 0.001) times faster memory decline, respectively, than those in stage 0 (n = 191) over >4 years of mean follow-up. Compared to stage 0, both stage 1 ( < 0.05) and stage 2 ( < 0.001) predicted higher FTP in entorhinal cortex.

Conclusions: Nominally Aβ- CN individuals with high Aβ in BANKSSTS are at increased risk of cognitive decline, probably showing an earlier stage of Aβ deposition. Our findings may help elucidate the association between brain Aβ accumulation and cognition in Aβ- CN cohorts.

Classification Of Evidence: This study provides Class II evidence that in elderly CN individuals those with high PET-identified superior temporal sulcus Aβ burden have an increased risk of cognitive decline.
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http://dx.doi.org/10.1212/WNL.0000000000009216DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251521PMC
April 2020

Neurophysiological signatures in Alzheimer's disease are distinctly associated with TAU, amyloid-β accumulation, and cognitive decline.

Sci Transl Med 2020 03;12(534)

Department Radiology and Biomedical Imaging, University of California, San Francisco, San Francisco, CA 94143, USA.

Neural synchrony is intricately balanced in the normal resting brain but becomes altered in Alzheimer's disease (AD). To determine the neurophysiological manifestations associated with molecular biomarkers of AD neuropathology, in patients with AD, we used magnetoencephalographic imaging (MEGI) and positron emission tomography with amyloid-beta (Aβ) and TAU tracers. We found that alpha oscillations (8 to 12 Hz) were hyposynchronous in occipital and posterior temporoparietal cortices, whereas delta-theta oscillations (2 to 8 Hz) were hypersynchronous in frontal and anterior temporoparietal cortices, in patients with AD compared to age-matched controls. Regional patterns of alpha hyposynchrony were unique in each neurobehavioral phenotype of AD, whereas the regional patterns of delta-theta hypersynchrony were similar across the phenotypes. Alpha hyposynchrony strongly colocalized with TAU deposition and was modulated by the degree of TAU tracer uptake. In contrast, delta-theta hypersynchrony colocalized with both TAU and Aβ depositions and was modulated by both TAU and Aβ tracer uptake. Furthermore, alpha hyposynchrony but not delta-theta hypersynchrony was correlated with the degree of global cognitive dysfunction in patients with AD. The current study demonstrates frequency-specific neurophysiological signatures of AD pathophysiology and suggests that neurophysiological measures from MEGI are sensitive indices of network disruptions mediated by TAU and Aβ and associated cognitive decline. These findings facilitate the pursuit of novel therapeutic approaches toward normalizing network synchrony in AD.
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http://dx.doi.org/10.1126/scitranslmed.aaz4069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138514PMC
March 2020

Modelling prognostic trajectories of cognitive decline due to Alzheimer's disease.

Neuroimage Clin 2020 26;26:102199. Epub 2020 Jan 26.

Department of Psychology, University of Cambridge, Cambridge, United Kingdom. Electronic address:

Alzheimer's disease (AD) is characterised by a dynamic process of neurocognitive changes from normal cognition to mild cognitive impairment (MCI) and progression to dementia. However, not all individuals with MCI develop dementia. Predicting whether individuals with MCI will decline (i.e. progressive MCI) or remain stable (i.e. stable MCI) is impeded by patient heterogeneity due to comorbidities that may lead to MCI diagnosis without progression to AD. Despite the importance of early diagnosis of AD for prognosis and personalised interventions, we still lack robust tools for predicting individual progression to dementia. Here, we propose a novel trajectory modelling approach based on metric learning (Generalised Metric Learning Vector Quantization) that mines multimodal data from MCI patients in the Alzheimer's disease Neuroimaging Initiative (ADNI) cohort to derive individualised prognostic scores of cognitive decline due to AD. We develop an integrated biomarker generation- using partial least squares regression- and classification methodology that extends beyond binary patient classification into discrete subgroups (i.e. stable vs. progressive MCI), determines individual profiles from baseline (i.e. cognitive or biological) data and predicts individual cognitive trajectories (i.e. change in memory scores from baseline). We demonstrate that a metric learning model trained on baseline cognitive data (memory, executive function, affective measurements) discriminates stable vs. progressive MCI individuals with high accuracy (81.4%), revealing an interaction between cognitive (memory, executive functions) and affective scores that may relate to MCI comorbidity (e.g. affective disturbance). Training the model to perform the same binary classification on biological data (mean cortical β-amyloid burden, grey matter density, APOE 4) results in similar prediction accuracy (81.9%). Extending beyond binary classifications, we develop and implement a trajectory modelling approach that shows significantly better performance in predicting individualised rate of future cognitive decline (i.e. change in memory scores from baseline), when the metric learning model is trained with biological (r = -0.68) compared to cognitive (r = -0.4) data. Our trajectory modelling approach reveals interpretable and interoperable markers of progression to AD and has strong potential to guide effective stratification of individuals based on prognostic disease trajectories, reducing MCI patient misclassification, that is critical for clinical practice and discovery of personalised interventions.
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http://dx.doi.org/10.1016/j.nicl.2020.102199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7044529PMC
March 2021
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