Jacob W. Vogel

PET Imaging of Tau Deposition in the Aging Human Brain

Tau pathology is a hallmark of Alzheimers disease (AD) but also occurs in normal cognitive aging. Using the tau PET agent (18)F-AV-1451, we examined retention patterns in cognitively normal older people in relation to young controls and AD patients. Age and β-amyloid (measured using PiB PET) were differentially associated with tau tracer retention in healthy aging. Older age was related to increased tracer retention in regions of the medial temporal lobe, which predicted worse episodic memory performance. PET detection of tau in other isocortical regions required the presence of cortical β-amyloid and was associated with decline in global cognition. Furthermore, patterns of tracer retention corresponded well with Braak staging of neurofibrillary tau pathology. The present study defined patterns of tau tracer retention in normal aging in relation to age, cognition, and β-amyloid deposition.

β-amyloid disrupts human NREM slow waves and related hippocampus-dependent memory consolidation

Independent evidence associates β-amyloid pathology with both non-rapid eye movement (NREM) sleep disruption and memory impairment in older adults. However, whether the influence of β-amyloid pathology on hippocampus-dependent memory is, in part, driven by impairments of NREM slow wave activity (SWA) and associated overnight memory consolidation is unknown. Here we show that β-amyloid burden in medial prefrontal cortex (mPFC) correlates significantly with the severity of impairment in NREM SWA generation. Moreover, reduced NREM SWA generation was further associated with impaired overnight memory consolidation and impoverished hippocampal-neocortical memory transformation. Furthermore, structural equation models revealed that the association between mPFC β-amyloid pathology and impaired hippocampus-dependent memory consolidation was not direct, but instead statistically depended on the intermediary factor of diminished NREM SWA. By linking β-amyloid pathology with impaired NREM SWA, these data implicate sleep disruption as a mechanistic pathway through which β-amyloid pathology may contribute to hippocampus-dependent cognitive decline in the elderly.

Existing Pittsburgh Compound-B positron emission tomography thresholds are too high: statistical and pathological evaluation

Amyloid-β, a hallmark of Alzheimers disease, begins accumulating up to two decades before the onset of dementia, and can be detected in vivo applying amyloid-β positron emission tomography tracers such as carbon-11-labelled Pittsburgh compound-B. A variety of thresholds have been applied in the literature to define Pittsburgh compound-B positron emission tomography positivity, but the ability of these thresholds to detect early amyloid-β deposition is unknown, and validation studies comparing Pittsburgh compound-B thresholds to post-mortem amyloid burden are lacking. In this study we first derived thresholds for amyloid positron emission tomography positivity using Pittsburgh compound-B positron emission tomography in 154 cognitively normal older adults with four complementary approaches: (i) reference values from a young control group aged between 20 and 30 years; (ii) a Gaussian mixture model that assigned each subject a probability of being amyloid-β-positive or amyloid-β-negative based on Pittsburgh compound-B index uptake; (iii) a k-means cluster approach that clustered subjects into amyloid-β-positive or amyloid-β-negative based on Pittsburgh compound-B uptake in different brain regions (features); and (iv) an iterative voxel-based analysis that further explored the spatial pattern of early amyloid-β positron emission tomography signal. Next, we tested the sensitivity and specificity of the derived thresholds in 50 individuals who underwent Pittsburgh compound-B positron emission tomography during life and brain autopsy (mean time positron emission tomography to autopsy 3.1 ± 1.8 years). Amyloid at autopsy was classified using Consortium to Establish a Registry for Alzheimers Disease (CERAD) criteria, unadjusted for age. The analytic approaches yielded low thresholds (standard uptake value ratiolow = 1.21, distribution volume ratiolow = 1.08) that represent the earliest detectable Pittsburgh compound-B signal, as well as high thresholds (standard uptake value ratiohigh = 1.40, distribution volume ratiohigh = 1.20) that are more conservative in defining Pittsburgh compound-B positron emission tomography positivity. In voxel-wise contrasts, elevated Pittsburgh compound-B retention was first noted in the medial frontal cortex, then the precuneus, lateral frontal and parietal lobes, and finally the lateral temporal lobe. When compared to post-mortem amyloid burden, low proposed thresholds were more sensitive than high thresholds (sensitivities: distribution volume ratiolow 81.0%, standard uptake value ratiolow 83.3%; distribution volume ratiohigh 61.9%, standard uptake value ratiohigh 62.5%) for CERAD moderate-to-frequent neuritic plaques, with similar specificity (distribution volume ratiolow 95.8%; standard uptake value ratiolow, distribution volume ratiohigh and standard uptake value ratiohigh 100.0%). A receiver operator characteristic analysis identified optimal distribution volume ratio (1.06) and standard uptake value ratio (1.20) thresholds that were nearly identical to the a priori distribution volume ratiolow and standard uptake value ratiolow. In summary, we found that frequently applied thresholds for Pittsburgh compound-B positivity (typically at or above distribution volume ratiohigh and standard uptake value ratiohigh) are overly stringent in defining amyloid positivity. Lower thresholds in this study resulted in higher sensitivity while not compromising specificity.

Neural compensation in older people with brain amyloid-β deposition

Recruitment of extra neural resources may allow people to maintain normal cognition despite amyloid-β (Aβ) plaques. Previous fMRI studies have reported such hyperactivation, but it is unclear whether increases represent compensation or aberrant overexcitation. We found that older adults with Aβ deposition had reduced deactivations in task-negative regions, but increased activation in task-positive regions related to more detailed memory encoding. The association between higher activity and more detailed memories suggests that Aβ-related hyperactivation is compensatory.

Atrophy Patterns in Early Clinical Stages Across Distinct Phenotypes of Alzheimer’s Disease

Alzheimers disease (AD) can present with distinct clinical variants. Identifying the earliest neurodegenerative changes associated with each variant has implications for early diagnosis, and for understanding the mechanisms that underlie regional vulnerability and disease progression in AD. We performed voxel‐based morphometry to detect atrophy patterns in early clinical stages of four AD phenotypes: Posterior cortical atrophy (PCA, “visual variant,” n = 93), logopenic variant primary progressive aphasia (lvPPA, “language variant,” n = 74), and memory‐predominant AD categorized as early age‐of‐onset (EOAD, <65 years, n = 114) and late age‐of‐onset (LOAD, >65 years, n = 114). Patients with each syndrome were stratified based on: (1) degree of functional impairment, as measured by the clinical dementia rating (CDR) scale, and (2) overall extent of brain atrophy, as measured by a neuroimaging approach that sums the number of brain voxels showing significantly lower gray matter volume than cognitively normal controls (n = 80). Even at the earliest clinical stage (CDR = 0.5 or bottom quartile of overall atrophy), patients with each syndrome showed both common and variant‐specific atrophy. Common atrophy across variants was found in temporoparietal regions that comprise the posterior default mode network (DMN). Early syndrome‐specific atrophy mirrored functional brain networks underlying functions that are uniquely affected in each variant: Language network in lvPPA, posterior cingulate cortex‐hippocampal circuit in amnestic EOAD and LOAD, and visual networks in PCA. At more advanced stages, atrophy patterns largely converged across AD variants. These findings support a model in which neurodegeneration selectively targets both the DMN and syndrome‐specific vulnerable networks at the earliest clinical stages of AD. Hum Brain Mapp 36:4421–4437, 2015.

Effects of Beta-Amyloid on Resting State Functional Connectivity Within and Between Networks Reflect Known Patterns of Regional Vulnerability

Beta-amyloid (Aβ) deposition is one of the hallmarks of Alzheimers disease (AD). However, it is also present in some cognitively normal elderly adults and may represent a preclinical disease state. While AD patients exhibit disrupted functional connectivity (FC) both within and between resting-state networks, studies of preclinical cases have focused primarily on the default mode network (DMN). The extent to which Aβ-related effects occur outside of the DMN and between networks remains unclear. In the present study, we examine how within- and between-network FC are related to both global and regional Aβ deposition as measured by [(11)C]PIB-PET in 92 cognitively normal older people. We found that within-network FC changes occurred in multiple networks, including the DMN. Changes of between-network FC were also apparent, suggesting that regions maintaining connections to multiple networks may be particularly susceptible to Aβ-induced alterations. Cortical regions showing altered FC clustered in parietal and temporal cortex, areas known to be susceptible to AD pathology. These results likely represent a mix of local network disruption, compensatory reorganization, and impaired control network function. They indicate the presence of Aβ-related dysfunction of neural systems in cognitively normal people well before these areas become hypometabolic with the onset of cognitive decline.

Impact of lifestyle dimensions on brain pathology and cognition

Single lifestyle factors affect brain biomarkers and cognition. Here, we addressed the covariance of various lifestyle elements and investigated their impact on positron emission tomography-based β-amyloid (Aβ), hippocampal volume, and cognitive function in aged controls. Lower Aβ burden was associated with a lifestyle comprising high cognitive engagement and low vascular risk, particularly in apolipoprotein E ε4 carriers. Although cognitive function was related to high lifetime cognitive engagement and low vascular risk, Aβ load had no relation to current cognitive function. The covariance between high adult socioeconomic status, high education, and low smoking prevalence predicted better cognitive function and this was mediated by larger hippocampal volume. Our data show that lifestyle is a complex construct composed of associated variables, some of which reflect factors operating over the life span and others which may be developmental. These factors affect brain health via different pathways, which may reinforce one another. Our findings moreover support the importance of an intellectually enriched lifestyle accompanied by vascular health on both cognition and presumed cerebral mediators of cognitive function.

Subjective cognitive decline and β-amyloid burden predict cognitive change in healthy elderly

Objective: To assess in a longitudinal study whether subjective cognitive decline (SCD) and brain β-amyloid (Aβ) contribute unique information to cognitive decline. Methods: One hundred thirty-six healthy elderly from the Berkeley Aging Cohort Study were followed up for a mean of 4 years. SCD and affective measures were generated from the Geriatric Depression Scale (GDS) with factor analysis on data from a larger set of 347 healthy, nondepressed (GDS <11) elderly individuals. Cognition was summarized with previously validated factor scores. Pittsburgh compound B (PiB)-PET scans were acquired to determine the presence (PiB+) or absence (PiB−) of Aβ pathology. Mixed models were used to assess the independent and interactive effects of SCD, affective features, PiB status, and time on cognition, with adjustment for demographic variables. Results: SCD score demonstrated good construct validity compared to an existing measure of subjective memory and was partially explained by several lower-order measurements. Mixed models revealed that SCD interacted with PiB status to predict change in episodic memory and global cognition over time, with adjustment for affective features. PiB+ individuals with more severe SCD demonstrated the steepest cognitive decline. Worse SCD predicted faster decline in working memory independently of PiB status. No such effects were seen for affective scores when adjusted for SCD. Conclusions: PiB+ individuals with SCD are at greatest risk of cognitive decline. Evidence for amyloid alone is not sufficient to indicate risk of rapid cognitive decline in healthy elderly. Effects of GDS on cognitive decline in nondepressed cohorts may be driven by SCD rather than subsyndromal depression.

Are low levels of PiB-PET signal clinically significant?

Sylvia Villeneuve, Helaine St. Amant, Jacob W. Vogel, Shawn Marks, Miranka Wirth, Charles DeCarli, William J. Jagust, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; Helen Wills Neuroscience Institute, University of California, Berkeley, CA, USA; University of California Berkeley, Berkeley, CA, USA; Charit e –Universit€atsmedizin, Berlin, Germany; University of California Davis, Davis, CA, USA. Contact e-mail: villeneuve.sylvia@gmail.com

Distinct [18F]AV1451 retention patterns in clinical variants of Alzheimer’s disease

N 5 4 3 19 Age 64 63 68 79 Sex (m/f) 2/3 1/3 0/3 6/13 MMSE 23 20 22 29 [F]AV1451 SUYr (Tau) Occipital 2.21 1.71 1.65 1.06 Parietal 2.41 2.26 2.20 1.11 Temporal 2.04 2.36 2.12 1.15 Frontal 1.56 1.79 1.36 1.10 MTL 1.47 1.30 1.67 1.18 [E]FDG SUYc (Glucose metabolism) Occipital 1.31 1.89 1.78 1.59 Parietal 1.18 1.43 1.41 1.55 Temporal 1.13 1.25 1.24 1.35 Frontal 1.43 1.53 1.58 1.50 MTL 1.03 1.11 1.09 1.11 [C]PIB DVR (Amyloid) Occipital 1.49 1.65 1.38 1.09 Parietal 1.80 2.17 1.84 1.19 Temporal 1.61 2.02 1.63 1.08 Frontal 1.79 2.28 1.82 1.13 MTL 1.12 1.34 1.21 1.05