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author:("klenk, W E.")
1.  Precuneus amyloid burden is associated with reduced cholinergic activity in Alzheimer disease 
Neurology  2011;77(1):39-47.
Objective:
This study examined the relationship between postmortem precuneus cholinergic enzyme activity, Pittsburgh compound B (PiB) binding, and soluble amyloid-β concentration in mild cognitive impairment (MCI) and Alzheimer disease (AD).
Methods:
Choline acetyltransferase (ChAT) activity, [3H]PiB binding, and soluble amyloid-β1–42 (Aβ42) concentration were quantified in precuneus tissue samples harvested postmortem from subjects with no cognitive impairment (NCI), MCI, and mild AD and correlated with their last antemortem Mini-Mental State Examination (MMSE) score and postmortem pathologic evaluation according to the National Institute on Aging–Reagan criteria, recommendations of the Consortium to Establish a Registry for Alzheimer's Disease, and Braak stage.
Results:
Precuneus ChAT activity was lower in AD than in NCI and was comparable between MCI and NCI. Precuneus [3H]PiB binding and soluble Aβ42 levels were elevated in MCI and significantly higher in AD than in NCI. Across all case subjects, reduced ChAT activity was associated with increased [3H]PiB binding, increased soluble Aβ42, lower MMSE score, presence of the APOE*4 allele, and more advanced AD pathology.
Conclusions:
Despite accumulating amyloid burden, cholinergic enzyme activity is stable in the precuneus during prodromal AD. A decline in precuneus ChAT activity occurs only in clinical AD, when PiB binding and soluble Aβ42 levels are substantially elevated compared with those in MCI. Anti-amyloid interventions in MCI case subjects with a positive PiB PET scan may aid in reducing cholinergic deficits and cognitive decline later in the disease process.
doi:10.1212/WNL.0b013e3182231419
PMCID: PMC3127332  PMID: 21700583
2.  Longitudinal cognitive decline is associated with fibrillar amyloid-beta measured by [11C]PiB 
Neurology  2010;74(10):807-815.
Objective:
To investigate whether longitudinal declines in cognition are associated with higher fibrillar amyloid-beta (Aβ) deposition in vivo in individuals without dementia.
Method:
[11C]PiB images were obtained to measure fibrillar Aβ burden in 57 participants without dementia from the Baltimore Longitudinal Study of Aging. Participants (33 men, 24 women) had a mean (SD) age of 78.7 (6.2) years. Six participants (4 men, 2 women) had mild cognitive impairment defined as Clinical Dementia Rating = 0.5. To measure [11C]PiB retention, distribution volume ratios (DVR) for 15 regions of interest were estimated by fitting a simplified reference tissue model to the measured time activity curves. Mixed effects regression was used to predict cognitive trajectories over time using data before and including time of PiB (mean follow-up 10.8 years), with mean cortical DVR, age at baseline, sex, and education as independent predictors. Voxel-based analysis identified local associations.
Results:
[11C]PiB retention was higher in older individuals. Greater declines over time in mental status and verbal learning and memory, but not visual memory, were associated significantly with higher PiB retention. Voxel-based analysis showed significant associations in frontal and lateral temporal regions.
Conclusions:
Higher Aβ deposition is associated with greater longitudinal decline in mental status and verbal memory in the preceding years. The differential association for verbal but not visual memory may reflect the greater reliance of verbal word list learning on prefrontal regions, which show early Aβ deposition. Prospective imaging may help distinguish between individuals with evolving neuropathology who develop accelerated cognitive decline vs those with normal aging.
GLOSSARY
= Alzheimer disease;
= Baltimore Longitudinal Study of Aging;
= Benton Visual Retention Test;
= Clinical Dementia Rating;
= California Verbal Learning Test;
= distribution volume ratio;
= mild cognitive impairment;
= Mini-Mental State Examination;
= regions of interest.
doi:10.1212/WNL.0b013e3181d3e3e9
PMCID: PMC2839197  PMID: 20147655
3.  Anti-Amyloid Effects of Small Molecule Aβ-Binding Agents in PS1/APP Mice 
Aims
One promising approach for treatment of Alzheimer’s disease (AD) is use of anti-amyloid therapies, based on the hypothesis that increases in amyloid-beta (Aβ) deposits in brain are a major cause of AD. Several groups have focused on Aβ immunotherapy with some success. Small molecules derivatives of Congo red have been shown to inhibit Aβ aggregation and protect against Aβ neurotoxicity in vitro. The agents described here are all small molecule Aβ-binding agents (SMAβBA’s) derivatives of Congo red.
Main Methods
Here, we have explored the anti-amyloid properties of these SMAβBA’s in mice doubly transgenic for human prensenilin-1 (PS1) and APP gene mutations that cause early-onset AD. Mice were treated with either methoxy-X04, X:EE:B34 and X:034-3-OMe1. After treatment, brains were examined for Aβ-deposition, using histochemistry, and soluble and insoluble Aβ levels were determined using ELISA.
Key Findings
A range of anti-amyloid activity was observed with these three compounds. PS1/APP mice treated with methoxy-X04 and X:EE:B34 showed decrease in total Aβ load, a decrease in Aβ fibril load, and a decrease in average plaque size. Treatment with methoxy-X04 also resulted in a decrease in insoluble Aβ levels. The structurally similar compound, X:034:3-OMe1, showed no significant effect on any of these measures. The effectiveness of the SMAβBA’s may be related to a combination of binding affinity for Aβ and entry into brain, but other factors appear to apply as well.
Significance
These data suggest that SMAβBA’s may significantly decrease amyloid burden in brain during the pathogenesis of AD and could be useful therapeutics alone, or in combination with immunotherapy.
doi:10.2174/157018009789057526
PMCID: PMC2812908  PMID: 20119496
Alzheimer’s Disease; amyloid β; Congo Red; Methoxy-X04; transgenic mice
4.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Background:
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
Objectives:
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Methods:
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Results:
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Conclusions:
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
GLOSSARY
= Automated Anatomic Labeling;
= Alzheimer disease;
= Alzheimer’s Disease Research Center;
= American version of the National Adult Reading Test;
= analysis of covariance;
= Blessed Dementia Scale;
= cerebral amyloid angiopathy;
= Clinical Dementia Rating;
= Clinical Dementia Rating Sum of Boxes;
= dementia with Lewy bodies;
= distribution volume ratio;
= Cued Selective Reminding Test;
= Free Selective Reminding Test;
= Hoehn and Yahr;
= Massachusetts General Hospital;
= Mini-Mental State Examination;
= normal control;
= neurofibrillary tangle;
= Neuropsychiatric Inventory Questionnaire;
= not significant;
= Parkinson disease;
= Parkinson disease dementia;
= Pittsburgh Compound B;
= region of interest;
= Statistical Parametric Mapping;
= UK Parkinson’s Disease Society Brain Bank Research Center;
= United Parkinson’s Disease Rating Scale;
= Wechsler Adult Intelligence Scale–Revised.
doi:10.1212/01.wnl.0000326146.60732.d6
PMCID: PMC2637553  PMID: 18794492
5.  Imaging amyloid deposition in Lewy body diseases 
Neurology  2008;71(12):903-910.
Background
Extrapyramidal motor symptoms precede dementia in Parkinson disease (PDD) by many years, whereas dementia occurs early in dementia with Lewy bodies (DLB). Despite this clinical distinction, the neuropsychological and neuropathologic features of these conditions overlap. In addition to widespread distribution of Lewy bodies, both diseases have variable burdens of neuritic plaques and neurofibrillary tangles characteristic of Alzheimer disease (AD).
Objectives
To determine whether amyloid deposition, as assessed by PET imaging with the β-amyloid–binding compound Pittsburgh Compound B (PiB), can distinguish DLB from PDD, and to assess whether regional patterns of amyloid deposition correlate with specific motor or cognitive features.
Methods
Eight DLB, 7 PDD, 11 Parkinson disease (PD), 15 AD, and 37 normal control (NC) subjects underwent PiB-PET imaging and neuropsychological assessment. Amyloid burden was quantified using the PiB distribution volume ratio.
Results
Cortical amyloid burden was higher in the DLB group than in the PDD group, comparable to the AD group. Amyloid deposition in the PDD group was low, comparable to the PD and NC groups. Relative to global cortical retention, occipital PiB retention was lower in the AD group than in the other groups. For the DLB, PDD, and PD groups, amyloid deposition in the parietal (lateral and precuneus)/posterior cingulate region was related to visuospatial impairment. Striatal PiB retention in the DLB and PDD groups was associated with less impaired motor function.
Conclusions
Global cortical amyloid burden is high in dementia with Lewy bodies (DLB) but low in Parkinson disease dementia. These data suggest that β-amyloid may contribute selectively to the cognitive impairment of DLB and may contribute to the timing of dementia relative to the motor signs of parkinsonism.
doi:10.1212/01.wnl.0000326146.60732.d6
PMCID: PMC2637553  PMID: 18794492
6.  Impact of Amyloid Imaging on Drug Development in Alzheimer’s Disease 
Nuclear medicine and biology  2007;34(7):809-822.
Imaging agents capable of assessing amyloid-beta (Aβ) content in vivo in the brains of Alzheimer’s disease (AD) subjects likely will be important as diagnostic agents to detect Aβ plaques in the brain, to help test the amyloid cascade hypothesis of AD, and as an aid to assess the efficacy of anti-amyloid therapeutics currently under development and in clinical trials. Positron emission tomography (PET) imaging studies of amyloid deposition in human subjects with several Aβ imaging agents are currently underway. We reported the first PET studies of the carbon-11-labeled thioflavin-T derivative Pittsburgh Compound B ([11C]PiB) in 2004, and this work has subsequently been extended to include a variety of subject groups including AD, mild cognitive impairment (MCI), and healthy controls. The ability to quantify regional Aβ plaque load in the brains of living human subjects has provided a means to begin to apply this technology as a diagnostic agent to detect regional concentrations of Aβ plaques and as a surrogate marker of therapeutic efficacy in anti-amyloid drug trials.
doi:10.1016/j.nucmedbio.2007.06.015
PMCID: PMC2078205  PMID: 17921032
Amyloid imaging; amyloid-beta; Aβ; PiB; Alzheimer’s disease; anti-amyloid therapy

Results 1-6 (6)