Wenzhu Bi

Frequent Amyloid Deposition Without Significant Cognitive Impairment Among the Elderly

OBJECTIVE To characterize the prevalence of amyloid deposition in a clinically unimpaired elderly population, as assessed by Pittsburgh Compound B (PiB) positron emission tomography (PET) imaging, and its relationship to cognitive function, measured with a battery of neuropsychological tests. DESIGN Subjects underwent cognitive testing and PiB PET imaging (15 mCi for 90 minutes with an ECAT HR+ scanner). Logan graphical analysis was applied to estimate regional PiB retention distribution volume, normalized to a cerebellar reference region volume, to yield distribution volume ratios (DVRs). SETTING University medical center. PARTICIPANTS From a community-based sample of volunteers, 43 participants aged 65 to 88 years who did not meet diagnostic criteria for Alzheimer disease or mild cognitive impairment were included. MAIN OUTCOME MEASURES Regional PiB retention and cognitive test performance. RESULTS Of 43 clinically unimpaired elderly persons imaged, 9 (21%) showed evidence of early amyloid deposition in at least 1 brain area using an objectively determined DVR cutoff. Demographic characteristics did not differ significantly between amyloid-positive and amyloid-negative participants, and neurocognitive performance was not significantly worse among amyloid-positive compared with amyloid-negative participants. CONCLUSIONS Amyloid deposition can be identified among cognitively normal elderly persons during life, and the prevalence of asymptomatic amyloid deposition may be similar to that of symptomatic amyloid deposition. In this group of participants without clinically significant impairment, amyloid deposition was not associated with worse cognitive function, suggesting that an elderly person with a significant amyloid burden can remain cognitively normal. However, this finding is based on relatively small numbers and needs to be replicated in larger cohorts. Longitudinal follow-up of these subjects will be required to support the potential of PiB imaging to identify preclinical Alzheimer disease, or, alternatively, to show that amyloid deposition is not sufficient to cause Alzheimer disease within some specified period.

Post-mortem correlates of in vivo PiB-PET amyloid imaging in a typical case of Alzheimer's disease

The positron emission tomography (PET) radiotracer Pittsburgh Compound-B (PiB) binds with high affinity to β-pleated sheet aggregates of the amyloid-β (Aβ) peptide in vitro. The in vivo retention of PiB in brains of people with Alzheimers disease shows a regional distribution that is very similar to distribution of Aβ deposits observed post-mortem. However, the basis for regional variations in PiB binding in vivo, and the extent to which it binds to different types of Aβ-containing plaques and tau-containing neurofibrillary tangles (NFT), has not been thoroughly investigated. The present study examined 28 clinically diagnosed and autopsy-confirmed Alzheimers disease subjects, including one Alzheimers disease subject who had undergone PiB-PET imaging 10 months prior to death, to evaluate region- and substrate-specific binding of the highly fluorescent PiB derivative 6-CN-PiB. These data were then correlated with region-matched Aβ plaque load and peptide levels, [3H]PiB binding in vitro, and in vivo PET retention levels. We found that in Alzheimers disease brain tissue sections, the preponderance of 6-CN-PiB binding is in plaques immunoreactive to either Aβ42 or Aβ40, and to vascular Aβ deposits. 6-CN-PiB labelling was most robust in compact/cored plaques in the prefrontal and temporal cortices. While diffuse plaques, including those in caudate nucleus and presubiculum, were less prominently labelled, amorphous Aβ plaques in the cerebellum were not detectable with 6-CN-PiB. Only a small subset of NFT were 6-CN-PiB positive; these resembled extracellular ‘ghost’ NFT. In Alzheimers disease brain tissue homogenates, there was a direct correlation between [3H]PiB binding and insoluble Aβ peptide levels. In the Alzheimers disease subject who underwent PiB-PET prior to death, in vivo PiB retention levels correlated directly with region-matched post-mortem measures of [3H]PiB binding, insoluble Aβ peptide levels, 6-CN-PiB- and Aβ plaque load, but not with measures of NFT. These results demonstrate, in a typical Alzheimers disease brain, that PiB binding is highly selective for insoluble (fibrillar) Aβ deposits, and not for neurofibrillary pathology. The strong direct correlation of in vivo PiB retention with region-matched quantitative analyses of Aβ plaques in the same subject supports the validity of PiB-PET imaging as a method for in vivo evaluation of Aβ plaque burden.

Amyloid Deposition Begins in the Striatum of Presenilin-1 Mutation Carriers from Two Unrelated Pedigrees

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-β protein is an initiating event in Alzheimers disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n = 5) and symptomatic (n = 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n = 2) were studied with PiB–PET imaging and compared with sporadic AD subjects (n = 12) and controls from the general population (n = 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35–49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.

Basal Cerebral Metabolism May Modulate the Cognitive Effects of Aβ in Mild Cognitive Impairment: An Example of Brain Reserve

Inverse correlations between amyloid-β (Aβ) load measured by Pittsburgh Compound-B (PiB) positron emission tomography (PET) and cerebral metabolism using [18F]fluoro-2-deoxy-d-glucose (FDG) in Alzheimers disease (AD) patients, suggest local Aβ-induced metabolic insults. However, this relationship has not been well studied in mild cognitive impairment (MCI) or amyloid-positive controls. Here, we explored associations of Aβ deposition with metabolism via both region-of-interest-based and voxel-based analyses in amyloid-positive control subjects and patients with MCI or AD. Metabolism in parietal and precuneus cortices of AD patients was negatively correlated with PiB retention locally, and more distantly with PiB retention in frontal cortex. In amyloid-positive controls, no clear patterns in correlations were observed. In MCI patients, there were essentially no significant, negative correlations, but there were frequent significant positive correlations between metabolism and PiB retention. Metabolism in anterior cingulate showed positive correlations with PiB in most brain areas in MCI, and metabolism and PiB retention were positively correlated locally in precuneus/parietal cortex. However, there was no significant increase in metabolism in MCI compared to age-matched controls, negating the possibility that Aβ deposition directly caused reactive hypermetabolism. This suggests that, in MCI, higher basal metabolism could either be exacerbating Aβ deposition or increasing the level of Aβ necessary for cognitive impairment sufficient for the clinical diagnosis of AD. Only after extensive Aβ deposition has been present for longer periods of time does Aβ become the driving force for decreased metabolism in clinical AD and, only in more vulnerable brain regions such as parietal and precuneus cortices.

Chronotype and Diurnal Patterns of Positive Affect and Affective Neural Circuitry in Primary Insomnia

While insomnia is a well‐established risk factor for the initial onset, recurrence or relapse of affective disorders, the specific characteristics of insomnia that confer risk remain unclear. Patients with insomnia with an evening chronotype may be one particularly high‐risk group, perhaps due to alterations in positive affect and its related affective circuitry. We explored this possibility by comparing diurnal patterns of positive affect and the activity of positive affect‐related brain regions in morning‐ and evening‐types with insomnia. We assessed diurnal variation in brain activity via the relative regional cerebral metabolic rate of glucose uptake by using [18F]fluorodeoxyglucose‐positron emission tomography during morning and evening wakefulness. We focused on regions in the medial prefrontal cortex and striatum, which have been consistently linked with positive affect and reward processing. As predicted, chronotypes differed in their daily patterns in both self‐reported positive affect and associated brain regions. Evening‐types displayed diurnal patterns of positive affect characterized by phase delay and smaller amplitude compared with those of morning‐types with insomnia. In parallel, evening‐types showed a reduced degree of diurnal variation in the metabolism of both the medial prefrontal cortex and the striatum, as well as lower overall metabolism in these regions across both morning and evening wakefulness. Taken together, these preliminary findings suggest that alterations in the diurnal activity of positive affect‐related neural structures may underlie differences in the phase and amplitude of self‐reported positive affect between morning and evening chronotypes, and may constitute one mechanism for increased risk of mood disorders among evening‐type insomniacs.

Sparse clustering with resampling for subject classification in PET amyloid imaging studies

Sparse k-means clustering (Sparse_kM) can exclude uninformative variables and yield reliable parsimonious clustering results, especially for p>>n. In this work, Sparse_kM and data resampling were combined to identify variables of greatest interest and define confidence levels for the clustering. The method was evaluated by statistical simulation and applied to PiB PET amyloid imaging data to identify normal control (NC) subjects with (+) or without (−) evidence of amyloid, i.e., PiB(+/−). Simulations. A dataset of n=60 observations (3 groups of 20) and p=500 variables was generated for each simulation run; only 50 variables were truly different across groups. The dataset was resampled 20 times, Sparse_kM was applied to each sample and average variable weights were calculated. Probabilities of cluster membership, also called confidence levels, were computed (n=60). Simulations were performed 250 times. The 50 truly different variables were identified by variable weights that were 13–32 times greater than those for the 450 uninformative variables. Human Data. For the PiB PET dataset, images (ECAT HR+, 10–15 mCi, 90 min) were acquired for 64 cognitively normal subjects (74.1±5.4 yrs). Parametric PiB distribution volume ratio images were generated (Logan method, cerebellum reference) and normalized to the MNI template (SPM8) to produce a dataset of n=64 subjects and p=343,099 voxels/image. The dataset was resampled 10 times and Sparse_kM was applied. An average voxel weight image was computed that indicated cortical areas of greatest interest that included precuneus and frontal cortex; these are key areas linked to early amyloid deposition. Seven of 64 subjects were identified as PiB(+) and 47 as PiB(−) with confidence = 90%, where another subject was PiB(+) at lower confidence (80%) and the other 9 subjects were PiB(−) at confidence in the range of 50–70%. In conclusion, Sparse_kM with resampling can help to establish confidence levels for clustering when p>>n and may be a promising method for revealing informative voxels/spatial patterns that distinguish levels of amyloid load, including that at the transitional amyloid +/− boundary.

Use of pons as a normalizing region for [C-11]PIB PET scans: Effect on subject classification

Background: Negligible levels of fibrillar Abeta deposits in the cerebellum (CER) in sporadic Alzheimer’s disease (AD) supports the use of CER as reference for normalizing regional [C]PiB retention measures. A CER reference, however, may not be ideal for all groups, particularly eoFAD or Down subjects, where significant CER Abeta deposition is a common autopsy finding. For this reason, we examined the suitability of pons (PON) as a reference region.Methods: [C]PiB PETwas performed in 190 subjects (93 Control, 51 MCI, 46 AD) and 46 of these (21 Control, 14, 11 AD) underwent fully quantitative imaging involving 90 min dynamic scanning, arterial input function determination, and estimation of Logan DVR outcomes (ART90). Regional SUVR50-70 retentionmeasureswere determined for all using CER (SUVRCER) and PON (SUVRPON) as reference. For the quantitative subjects, results of the SUVRmethods were compared to ART90. Iterative outlier and k-means clustering approaches were used to classify subjects as PiB positive or negative. Results: CER:plasma ratios reached a plateau of w6 at 30 min, while PON:plasma plateau was slower and more transient, peaking at w12 at 50 min. Across cortical areas, SUVRCER was less biased and more highly correlated with ART90 than SUVRPON. However, both provided similar Cohen’s effect sizes for the distinction of AD and PIB negative Control groups. This is attributable to lower variance in SUVRPON outcomes despite a compressed dynamic range. Using the iterative outlier method, SUVRPON identified significantly more PIB + Cons than SUVRCER (38/93 vs. 27/93), while the overall rate of discordance between SUVRCER and SUVRPON was 12% (23/190). When available, visual interpretation agreed with theSUVRCER classification in 89% of the discordant cases. Use of a k-means clustering algorithm resulted in less discordance between SUVRPON and SUVRCER classification (7%), but classified fewer Control subjects as PiB + compared to the iterative outlier method using both SUVRCER and SUVRPON outcomes (17/ 93 and 21/93, respectively). Conclusions: SUVRPON effectively discriminates amyloid negative controls fromAD subjects andmay be useful when cerebellar data is unavailable or contraindicated. However, the transient kinetics underlying SUVRPON may lead to less reliable subject classification at the PiB + /-interface, relative to SUVRCER.

Trans-cortical correlations of Pittsburgh Compound-B in cognitively normal elderly, MCI and AD: Implications for the natural history of amyloid deposition

Results: Consideration of both baseline and follow-up data provides increased classification accuracies, determined using linear discriminant analysis, compared with those obtained using the baseline data alone. Accuracy increased from 72% to 78% between AD patients and HC, 65% to 68% between aMCI patients and HC, and 58% to 61% between AD and aMCI patients. Conclusions: This work-in-progress follows from the successful application of this regional analysis technique to baseline FDG-PET data from the ADNI, in which the features used for classification include not only the hippocampus, but all those extracted from a subject-specific segmentation consisting of 83 anatomical regions. These early results suggest that the group discrimination achieved using baseline data alone may be further improved by the inclusion of follow-up FDG-PET data.

P2-366: Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees

The amyloid cascade hypothesis suggests that the aggregation and deposition of amyloid-beta protein is an initiating event in Alzheimers disease (AD). Using amyloid imaging technology, such as the positron emission tomography (PET) agent Pittsburgh compound-B (PiB), it is possible to explore the natural history of preclinical amyloid deposition in people at high risk for AD. With this goal in mind, asymptomatic (n = 5) and symptomatic (n = 5) carriers of presenilin-1 (PS1) mutations (C410Y or A426P) that lead to early-onset AD and noncarrier controls from both kindreds (n = 2) were studied with PiB-PET imaging and compared with sporadic AD subjects (n = 12) and controls from the general population (n = 18). We found intense and focal PiB retention in the striatum of all 10 PS1 mutation carriers studied (ages 35-49 years). In most PS1 mutation carriers, there also were increases in PiB retention compared with controls in cortical brain areas, but these increases were not as great as those observed in sporadic AD subjects. The two PS1 mutation carriers with a clinical diagnosis of early-onset AD did not show the typical regional pattern of PiB retention observed in sporadic AD. Postmortem evaluation of tissue from two parents of PS1C410Y subjects in this study confirmed extensive striatal amyloid deposition, along with typical cortical deposition. The early, focal striatal amyloid deposition observed in these PS1 mutation carriers is often is not associated with clinical symptoms.