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1.  Language performance in postmenopausal women with and without hormone therapy and men 
Aging health  2012;8(6):625-632.
Aims
In the current study, we explored the potential effects of hormone therapy (HT) on language functioning in healthy, postmenopausal women and compared them with men of similar ages.
Materials & methods
Language functioning on tasks of verbal fluency and object naming was examined in 100 participants (mean age: 61.9 years; 33 HT users, 15 HT non-users and 52 men) at baseline and follow-up (mean follow-up time period: 2.6 years).
Results
At baseline, men had higher composite language scores than HT users. However, HT users demonstrated more improvement over time compared with men, whereas HT non-users performed similarly to men, with no improvement over time. Longer duration of HT use was not associated with improved performance on language tests.
Conclusion
These results suggest an association between HT use and better language ability in postmenopausal women.
doi:10.2217/ahe.12.66
PMCID: PMC4332702
cognitive decline; estrogen; hormone therapy; language functioning; postmenopausal women
2.  APOE associated hemispheric asymmetry of entorhinal cortical thickness in aging and Alzheimer’s disease 
Psychiatry research  2013;214(3):10.1016/j.pscychresns.2013.09.006.
Across species structural and functional hemispheric asymmetry is a fundamental feature of the brain. Environmental and genetic factors determine this asymmetry during brain development and modulate its interaction with brain disorders. The e4 allele of the apolipoprotein E gene (APOE-4) is a risk factor for Alzheimer’s disease, associated with regionally specific effects on brain morphology and function during the life span. Furthermore, entorhinal and hippocampal hemispheric asymmetry could be modified by pathology during Alzheimer’s disease development. Using high-resolution magnetic resonance imaging and a cortical unfolding technique we investigated whether carrying the APOE-4 allele influences hemispheric asymmetry in the entorhinal cortex and the hippocampus among patients with Alzheimer’s disease as well as in middle-aged and older cognitively healthy individuals. APOE-4 carriers showed a thinner entorhinal cortex in the left hemisphere when compared with the right hemisphere across all participants. Non-carriers of the allele showed this asymmetry only in the patient group. Cortical thickness in the hippocampus did not vary between hemispheres among APOE-4 allele carriers and non-carriers. The APOE-4 allele modulates hemispheric asymmetry in entorhinal cortical thickness. Among Alzheimer’s disease patients, this asymmetry might be less dependent on the APOE genotype and a more general marker of incipient disease pathology.
doi:10.1016/j.pscychresns.2013.09.006
PMCID: PMC3851589  PMID: 24080518
Entorhinal cortex; Hippocampus; Magnetic resonance imaging; Cortical unfolding; APOE-4 allele
3.  Vascular Risk and FDDNP-PET Influence Cognitive Performance 
Journal of Alzheimer's disease : JAD  2013;35(1):10.3233/JAD-121903.
The relationship of cerebrovascular risk and Alzheimer’s disease (AD) pathology to cognition in pre-dementia has been extensively investigated and is well-established. Cerebrovascular risk can be measured using a Framingham Stroke Risk Profile (FSRP) score, while positron emission tomography (PET) scans with 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl{ethylidene)malononitrile (FDDNP) measure AD neuropathology (i.e., amyloid-β plaques and tau tangles). Here we report results of 75 healthy non-demented subjects (mean age, 63 years) who underwent neuropsychological testing, physical assessments, and FDDNP-PET scans. Controlling for AD family history, education, and APOE4 status in a general linear model, higher FSRP risk and global FDDNP-PET binding were each associated with poorer cognitive functioning. The interaction of FSRP and global FDDNP-PET binding was not significant in the model, indicating that stroke risk and plaque and tangle burden each contributed to worse cognitive performance. Within our healthy volunteers, age, blood pressure, and antihypertensive medication use were vascular risks that contributed significantly to the above findings. These findings suggest that even mild cerebrovascular risk may influence the extent of cognitive dysfunction in pre-dementia, along with amyloid-β and tau burden.
doi:10.3233/JAD-121903
PMCID: PMC3874398  PMID: 23380994
Aging; Alzheimer’s disease; amyloid-µ plaques; FDDNP; Framingham stroke risk profile; mild cognitive impairment; older adults; positron emission tomography; tau tangles
4.  The Memory Fitness Program: Cognitive Effects of a Healthy Aging Intervention 
Context
Age-related memory decline affects a large proportion of older adults. Cognitive training, physical exercise, and other lifestyle habits may help to minimize self-perception of memory loss and a decline in objective memory performance.
Objective
The purpose of this study was to determine whether a 6-week educational program on memory training, physical activity, stress reduction, and healthy diet led to improved memory performance in older adults.
Design
A convenience sample of 115 participants (mean age: 80.9 [SD: 6.0 years]) was recruited from two continuing care retirement communities. The intervention consisted of 60-minute classes held twice weekly with 15–20 participants per class. Testing of both objective and subjective cognitive performance occurred at baseline, preintervention, and postintervention. Objective cognitive measures evaluated changes in five domains: immediate verbal memory, delayed verbal memory, retention of verbal information, memory recognition, and verbal fluency. A standardized metamemory instrument assessed four domains of memory self-awareness: frequency and severity of forgetting, retrospective functioning, and mnemonics use.
Results
The intervention program resulted in significant improvements on objective measures of memory, including recognition of word pairs (t[114] = 3.62, p < 0.001) and retention of verbal information from list learning (t[114] = 2.98, p < 0.01). No improvement was found for verbal fluency. Regarding subjective memory measures, the retrospective functioning score increased significantly following the intervention (t[114] = 4.54, p < 0.0001), indicating perception of a better memory.
Conclusions
These findings indicate that a 6-week healthy lifestyle program can improve both encoding and recalling of new verbal information, as well as self-perception of memory ability in older adults residing in continuing care retirement communities.
doi:10.1097/JGP.0b013e318227f821
PMCID: PMC4255461  PMID: 21765343
Community setting; healthy lifestyle; memory training; older adult
5.  Prediction of Cognitive Decline by Positron Emission Tomography of Brain Amyloid and Tau 
Archives of neurology  2012;69(2):215-222.
Objective
To determine whether 2-(1-{6-[(2-fluorine18–labeled fluoroethyl)methylamino]-2-napthyl}ethylidene) malononitrile ([18F]FDDNP) brain regional values in individuals without dementia predict and correlate with future cognitive change.
Design
Two-year, longitudinal follow-up study.
Setting
A university research institute.
Participants
Volunteer sample of 43 middle-aged and older persons (median age, 64 years), including 21 with mild cognitive impairment (MCI) and 22 with normal aging.
Main Outcome Measures
Longitudinal [18F]FDDNP positron emission tomography (PET) binding values in the medial and lateral temporal, posterior cingulate, parietal, frontal, and global (mean) regions of interest; neuropsychological test battery measuring 5 cognitive domains, including memory, language, attention (and information-processing speed), executive functioning, and visuospatial ability.
Results
For the entire study group (MCI and normal aging), increases in frontal, posterior cingulate, and global binding at follow-up correlated with progression of memory decline (r=−0.32 to −0.37, P=.03 to .01) after 2 years. Moreover, higher baseline [18F]FDDNP binding was associated with future decline in most cognitive domains, including language, attention, executive, and visuospatial abilities (r=−0.31 to −0.56, P=.05 to .002). For the MCI group, frontal and parietal [18F]FDDNP binding yielded the greatest diagnostic accuracy in identifying converters to Alzheimer disease vs nonconverters after 2 years, with an area under the receiver operating characteristic curve of 0.88 (95% CI, 0.72–1.00) compared with 0.68 (95% CI, 0.45–0.91) for medial temporal binding.
Conclusions
[18F]FDDNP PET regional binding patterns are consistent with known neuropathologic patterns of plaque and tangle brain accumulation, spreading from the medial temporal to other neocortical regions as disease progresses. Because binding patterns predict future cognitive decline and increase over time along with clinical decline, [18F]FDDNP PET scanning may have practical utility in identifying people at risk for future cognitive decline and in tracking the effectiveness of novel interventions designed to prevent or delay neurodegeneration and cognitive decline.
doi:10.1001/archneurol.2011.559
PMCID: PMC3623972  PMID: 22332188
6.  Life extension factor klotho enhances cognition 
Cell reports  2014;7(4):1065-1076.
Summary
Aging is the primary risk factor for cognitive decline, an emerging health threat to aging societies worldwide. Whether anti-aging factors such as klotho can counteract cognitive decline is unknown. We show that a life span-extending variant of the human KLOTHO gene, KL-VS, is associated with enhanced cognition in heterozygous carriers. Because this allele increased klotho levels in serum, we analyzed transgenic mice with systemic overexpression of klotho. They performed better than controls in multiple tests of learning and memory. Elevating klotho in mice also enhanced long-term potentiation, a form of synaptic plasticity, and enriched synaptic GluN2B, an NMDA receptor subunit with key functions in learning and memory. Blockade of GluN2B abolished klotho-mediated effects. Surprisingly, klotho effects were evident also in young mice and did not correlate with age in humans, suggesting independence from the aging process. Augmenting klotho or its effects may enhance cognition at different life stages and counteract cognitive decline.
doi:10.1016/j.celrep.2014.03.076
PMCID: PMC4176932  PMID: 24813892
7.  Automated Movement Correction for Dynamic PET/CT Images: Evaluation with Phantom and Patient Data 
PLoS ONE  2014;9(8):e103745.
Head movement during a dynamic brain PET/CT imaging results in mismatch between CT and dynamic PET images. It can cause artifacts in CT-based attenuation corrected PET images, thus affecting both the qualitative and quantitative aspects of the dynamic PET images and the derived parametric images. In this study, we developed an automated retrospective image-based movement correction (MC) procedure. The MC method first registered the CT image to each dynamic PET frames, then re-reconstructed the PET frames with CT-based attenuation correction, and finally re-aligned all the PET frames to the same position. We evaluated the MC method's performance on the Hoffman phantom and dynamic FDDNP and FDG PET/CT images of patients with neurodegenerative disease or with poor compliance. Dynamic FDDNP PET/CT images (65 min) were obtained from 12 patients and dynamic FDG PET/CT images (60 min) were obtained from 6 patients. Logan analysis with cerebellum as the reference region was used to generate regional distribution volume ratio (DVR) for FDDNP scan before and after MC. For FDG studies, the image derived input function was used to generate parametric image of FDG uptake constant (Ki) before and after MC. Phantom study showed high accuracy of registration between PET and CT and improved PET images after MC. In patient study, head movement was observed in all subjects, especially in late PET frames with an average displacement of 6.92 mm. The z-direction translation (average maximum = 5.32 mm) and x-axis rotation (average maximum = 5.19 degrees) occurred most frequently. Image artifacts were significantly diminished after MC. There were significant differences (P<0.05) in the FDDNP DVR and FDG Ki values in the parietal and temporal regions after MC. In conclusion, MC applied to dynamic brain FDDNP and FDG PET/CT scans could improve the qualitative and quantitative aspects of images of both tracers.
doi:10.1371/journal.pone.0103745
PMCID: PMC4128781  PMID: 25111700
8.  Positron Emission Tomography of Brain β-Amyloid and Tau Levels in Adults With Down Syndrome 
Archives of Neurology  2011;68(6):768-774.
Objectives
To determine the neuropathological load in the living brain of nondemented adults with Down syndrome using positron emission tomography with 2-(1-{6-[(2-fluorine 18–labeled fluoroethyl)methylamino]-2-napthyl}ethylidene) malononitrile ([18F]FDDNP) and to assess the influence of age and cognitive and behavioral functioning. For reference, [18F]FDDNP binding values and patterns were compared with those from patients with Alzheimer disease and cognitively intact control participants.
Design
Cross-sectional clinical study.
Participants
Volunteer sample of 19 persons with Down syndrome without dementia (mean age, 36.7 years), 10 patients with Alzheimer disease (mean age, 66.5 years), and 10 controls (mean age, 43.8 years).
Main Outcome Measures
Binding of [18F]FDDNP in brain regions of interest, including the parietal, medial temporal, lateral temporal, and frontal lobes and posterior cingulate gyrus, and the average of all regions (global binding).
Results
The [18F]FDDNP binding values were higher in all brain regions in the Down syndrome group than in controls. Compared with the Alzheimer disease group, the Down syndrome group had higher [18F]FDDNP binding values in the parietal and frontal regions, whereas binding levels in other regions were comparable. Within the Down syndrome group, age correlated with [18F]FDDNP binding values in all regions except the posterior cingulate, and several measures of behavioral dysfunction showed positive correlations with global, frontal, parietal, and posterior cingulate [18F]FDDNP binding.
Conclusions
Consistent with neuropathological findings from postmortem studies, [18F]FDDNP positron emission tomography shows high binding levels in Down syndrome comparable to Alzheimer disease and greater levels than in members of a control group. The positive associations between [18F]FDDNP binding levels and age as well as behavioral dysfunction in Down syndrome are consistent with the age-related progression of Alzheimer-type neuropathological findings in this population.
doi:10.1001/archneurol.2011.104
PMCID: PMC3261613  PMID: 21670401
9.  Modifiable Risk Factors for Alzheimer Disease and Subjective Memory Impairment across Age Groups 
PLoS ONE  2014;9(6):e98630.
Introduction
Previous research has identified modifiable risk factors for Alzheimer's disease (AD) in older adults. Research is limited on the potential link between these risk factors and subjective memory impairment (SMI), which may precede AD and other dementias. Examination of these potential relationships may help identify those at risk for AD at a stage when interventions may delay or prevent further memory problems. The objective of this study was to determine whether risk factors for AD are associated with SMI among different age groups.
Method
Trained interviewers conducted daily telephone surveys (Gallup-Healthways) of a representative community sample of 18,614 U.S. respondents, including 4,425 younger (age 18 to 39 years), 6,365 middle-aged (40 to 59 years), and 7,824 older (60 to 99 years) adults. The surveyors collected data on demographics, lifestyles, and medical information. Less education, smoking, hypertension, diabetes, less exercise, obesity and depression, and interactions among them, were examined for associations with SMI. Weighted logistic regressions and chi-square tests were used to calculate odds ratios and confidence intervals for SMI with each risk factor and pairwise interactions across age groups.
Results
Depression, less education, less exercise, and hypertension were significantly associated with SMI in all three age groups. Several interactions between risk factors were significant in younger and middle-aged adults and influenced their associations with SMI. Frequency of SMI increased with age and number of risk factors. Odds of having SMI increased significantly with just having one risk factor.
Conclusions
These results indicate that modifiable risk factors for AD are also associated with SMI, suggesting that these relationships occur in a broad range of ages and may be targeted to mitigate further memory problems. Whether modifying these risk factors reduces SMI and the eventual incidence of AD and other dementias later in life remains to be determined.
doi:10.1371/journal.pone.0098630
PMCID: PMC4045888  PMID: 24896243
10.  Repeat expansions in the C9ORF72 gene contribute to Alzheimer disease in Caucasians 
Neurobiology of aging  2012;34(5):1519.e5-1519.e12.
Recently, a hexanucleotide repeat expansion in the C9ORF72 gene has been identified to account for a significant portion of Caucasian families affected by frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Given the clinical overlap of FTD with Alzheimer disease (AD), we hypothesized that C9ORF72 expansions may contribute to AD. In Caucasians, we found C9ORF72 expansions in the pathogenic range of FTD/ALS (>30 repeats) at a rate of 0.76% in AD cases versus zero in controls (p=3.3E-03, 1,182 cases, 1,039 controls). In contrast, no large expansions were detected in individuals of African American ethnicity (291 cases, 620 controls). However, in the range of normal variation of C9ORF72 expansions (0–23 repeat copies), we detected significant differences in distribution and mean repeat counts between Caucasians and African Americans. Clinical and pathological reevaluation of identified C9ORF72 expansion carriers revealed nine clinical and/or autopsy confirmed AD and two FTD finial diagnoses. Thus, our results support the notion that large C9ORF72 expansions lead to a phenotypic spectrum of neurodegenerative disease including AD.
doi:10.1016/j.neurobiolaging.2012.10.003
PMCID: PMC3586789  PMID: 23107433
C9ORF72; repeat expansion; Alzheimer Disease; genetic association; repeat-primed PCR; spectrum of neurodegenerative phenotypes
11.  Association of Single-Nucleotide Polymorphisms of the Tau Gene With Late-Onset Parkinson Disease 
Context
The human tau gene, which promotes assembly of neuronal microtubules, has been associated with several rare neurologic diseases that clinically include parkinsonian features. We recently observed linkage in idiopathic Parkinson disease (PD) to a region on chromosome 17q21 that contains the tau gene. These factors make tau a good candidate for investigation as a susceptibility gene for idiopathic PD, the most common form of the disease.
Objective
To investigate whether the tau gene is involved in idiopathic PD.
Design, Setting, and Participants
Among a sample of 1056 individuals from 235 families selected from 13 clinical centers in the United States and Australia and from a family ascertainment core center, we tested 5 single-nucleotide polymorphisms (SNPs) within the tau gene for association with PD, using family-based tests of association. Both affected (n = 426) and unaffected (n = 579) family members were included; 51 individuals had unclear PD status. Analyses were conducted to test individual SNPs and SNP haplotypes within the tau gene.
Main Outcome Measure
Family-based tests of association, calculated using asymptotic distributions.
Results
Analysis of association between the SNPs and PD yielded significant evidence of association for 3 of the 5 SNPs tested: SNP 3, P = .03; SNP 9i, P = .04; and SNP 11, P = .04. The 2 other SNPs did not show evidence of significant association (SNP 9ii, P = .11, and SNP 9iii, P = .87). Strong evidence of association was found with haplotype analysis, with a positive association with one haplotype (P = .009) and a negative association with another haplotype (P = .007). Substantial linkage disequilibrium (P<.001) was detected between 4 of the 5 SNPs (SNPs 3,9i, 9ii, and 11).
Conclusions
This integrated approach of genetic linkage and positional association analyses implicates tau as a susceptibility gene for idiopathic PD.
PMCID: PMC3973175  PMID: 11710889
12.  Psychological Well-Being and Regional Brain Amyloid and Tau in Mild Cognitive Impairment 
Objectives
To determine whether psychological well-being in people with mild cognitive impairment (MCI), a risk state for Alzheimer disease (AD), is associated with in vivo measures of brain pathology.
Methods
Cross-sectional clinical assessments and positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene) malononitrile (FDDNP), a molecule that binds to plaques and tangles, were performed on middle-aged and older adults at a university research institute. Volunteers were aged 40–85 years with MCI (N = 35) or normal cognition (N = 29) without depression or anxiety. Statistical analyses included general linear models, using regional FDDNP-PET binding values as dependent variables and the Vigor-Activity subscale of the Profile of Mood States (POMS) as the independent variable, covarying for age. The POMS is a self-rated inventory of 65 adjectives that describe positive and negative feelings.
Results
Scores on the POMS Vigor-Activity subscale were inversely associated with degree of FDDNP binding in the posterior cingulate cortex (r = −0.35, p = 0.04) in the MCI group but not in the control group.
Conclusion
Psychological well-being, as indicated by self-reports of greater vigor and activity, is associated with lower FDDNP-PET binding in the posterior cingulate cortex, a region involved in emotional regulation, in individuals with MCI but not in those with normal cognition. These findings are consistent with previous work indicating that deposition of brain amyloid plaques and tau tangles may result in noncognitive and cognitive symptoms in persons at risk for AD.
doi:10.1016/j.jagp.2012.09.002
PMCID: PMC3883933  PMID: 23567426
Aging; FDDNP; positron emission tomography; POMS; well-being
13.  Cognitive and Cerebral Metabolic Effects of Celecoxib Versus Placebo in People With Age-Related Memory Loss: Randomized Controlled Study 
Objective
Because anti-inflammatory drugs may delay cognitive decline and influence brain metabolism in normal aging, the authors determined the effects of the cyclooxygenase-2 inhibitor, celecoxib, on cognitive performance and regional cerebral glucose metabolism in nondemented volunteers with mild age-related memory decline.
Design
Randomized, double-blind, placebo-controlled, parallel group trial with 18-months of exposure to study medication.
Setting
University research institute.
Participants
Eighty-eight subjects, aged 40–81 years (mean: 58.7, SD: 8.9 years) with mild self-reported memory complaints but normal memory performance scores were recruited from community physician referrals, media coverage, and advertising. Forty subjects completed the study.
Interventions
Daily celecoxib dose of 200 or 400 mg, or placebo.
Main Outcome Measures
Standardized neuropsychological test battery and statistical parametric mapping (SPM) of FDG-PET scans performed during mental rest.
Results
Measures of cognition showed significant between-group differences in executive functioning (F [1, 30] = 5.06, p = 0.03) and language/semantic memory (F [1, 31] = 6.19, p = 0.02), favoring the celecoxib group compared with the placebo group. Concomitantly, FDG-PET scans demonstrated bilateral metabolic increases in prefrontal cortex in the celecoxib group in the vicinity of Brodmann’s areas 9 and 10, but not in the placebo group. SPM analyses of the PET data pooled by treatment arm corresponded to a 6% increase in activity over pretreatment levels (p = 0.01, after adjustment for multiple comparisons).
Conclusions
These results suggest that daily celecoxib use may improve cognitive performance and increase regional brain metabolism in people with age-associated memory decline.
doi:10.1097/JGP.0b013e31818cd3a4
PMCID: PMC2693408  PMID: 19038899
Cyclooxygenase-2 inhibitor; celecoxib; positron emission tomography; age-related memory complaints
14.  Influence of Cognitive Status, Age, and APOE-4 Genetic Risk on Brain FDDNP Positron-Emission Tomography Imaging in Persons Without Dementia 
Archives of general psychiatry  2009;66(1):81-87.
Context
Amyloid senile plaques and tau neurofibrillary tangles are neuropathological hallmarks of Alzheimer disease that accumulate in the brains of people without dementia years before they develop dementia. Positron emission tomography (PET) scans after intravenous injections of 2-(1-{6-[(2-[F-18]fluoroethyl)(methyl)amino]-2-naphthyl}ethylidene)malononitrile (FDDNP), which binds to plaques and tangles in vitro, demonstrate increased cerebral binding in patients with Alzheimer disease compared with cognitively intact controls. Here we investigated whether known risk factors for Alzheimer disease and dementia are associated with FDDNP-PET binding.
Objective
To determine if impaired cognitive status, older age, apolipoprotein E-4 (APOE-4) genetic risk for Alzheimer disease, family history of dementia, and less education are associated with increased regional cerebral FDDNP-PET binding.
Design
Cross-sectional clinical study.
Setting
A university research institute.
Participants
Volunteer sample of 76 middle-aged and older persons without dementia (mean age, 67 years) including 36 with mild cognitive impairment. Of the 72 subjects with genetic data, 34 were APOE-4 carriers.
Main Outcome Measures
The FDDNP-PET signal in brain regions of interest, including medial and lateral temporal, posterior cingulate, parietal, and frontal.
Results
For all regions studied, cognitive status was associated with increased FDDNP binding (P<.02 to .005). Older age was associated with increased lateral temporal FDDNP binding. Carriers of APOE-4 demonstrated higher frontal FDDNP binding than noncarriers. In the mild cognitive impairment group, age was associated with increased medial and lateral temporal FDDNP binding, and APOE-4 carriers had higher medial temporal binding than noncarriers.
Conclusions
Impaired cognitive status, older age, and APOE-4 carrier status are associated with increased brain FDDNP-PET binding in persons without dementia, consistent with previous clinical and postmortem studies associating these risk factors with amyloid plaque and tau tangle accumulation. Stratifying subject groups according to APOE-4 carrier status, age, and cognitive status may therefore be an informative strategy in future clinical trials using FDDNP-PET.
doi:10.1001/archgenpsychiatry.2008.516
PMCID: PMC2693405  PMID: 19124691
15.  KIAA1462, A Coronary Artery Disease Associated Gene, Is a Candidate Gene for Late Onset Alzheimer Disease in APOE Carriers 
PLoS ONE  2013;8(12):e82194.
Alzheimer disease (AD) is a devastating neurodegenerative disease affecting more than five million Americans. In this study, we have used updated genetic linkage data from chromosome 10 in combination with expression data from serial analysis of gene expression to choose a new set of thirteen candidate genes for genetic analysis in late onset Alzheimer disease (LOAD). Results in this study identify the KIAA1462 locus as a candidate locus for LOAD in APOE4 carriers. Two genes exist at this locus, KIAA1462, a gene associated with coronary artery disease, and “rokimi”, encoding an untranslated spliced RNA The genetic architecture at this locus suggests that the gene product important in this association is either “rokimi”, or a different isoform of KIAA1462 than the isoform that is important in cardiovascular disease. Expression data suggests that isoform f of KIAA1462 is a more attractive candidate for association with LOAD in APOE4 carriers than “rokimi” which had no detectable expression in brain.
doi:10.1371/journal.pone.0082194
PMCID: PMC3861372  PMID: 24349219
16.  Comparative evaluation of Logan and relative-equilibrium graphical methods for parametric imaging of dynamic [18F]FDDNP PET determinations 
NeuroImage  2011;60(1):10.1016/j.neuroimage.2011.12.014.
Logan graphical analysis with cerebellum as reference region has been widely used for the estimation of the distribution volume ratio (DVR) of [18F]FDDNP as a measure of amyloid burden and tau deposition in human brain because of its simplicity and computational ease. However, spurious parametric DVR images may be produced with shorter scanning times and when the noise level is high. In this work, we have characterized a relative-equilibrium-based (RE) graphical method against the Logan analysis for parametric imaging and region-of-interest (ROI) analysis.
Methods
Dynamic [18F]FDDNP PET scans were performed on 9 control subjects and 12 patients diagnosed with Alzheimer’s disease. Using the cerebellum as reference input, regional DVR estimates were derived using both the Logan analysis and the RE plot approach. Effects on DVR estimates obtained at voxel and ROI levels by both graphical approaches using data in different time windows were investigated and compared with the standard values derived using the Logan analysis on a voxel-by-voxel basis for the time window of 35–125 min used in previous studies.
Results
Larger bias and variability were observed for DVR estimates obtained by the Logan graphical analysis at the voxel level when short time windows (85–125 and 45–65 min) were used, because of high noise levels in voxel-wise parametric imaging. However, when the Logan graphical analysis was applied at the ROI level over those short time windows, the DVR estimates did not differ significantly from the standard values derived using the Logan analysis on the voxel level for the time window of 35–125 min, and their bias and variability were remarkably lower. Conversely, the RE plot approach was more robust in providing DVR estimates with less bias and variability even when short time windows were used. The DVR estimates obtained at voxel and ROI levels were consistent. No significant differences were observed in DVR estimates obtained by the RE plot approach for all paired comparisons with the standard values.
Conclusions
The RE plot approach provides less noisy parametric images and gives consistent and reliable regional DVR estimates at both voxel and ROI levels, indicating that it is preferred over the Logan graphical analysis for analyzing [18F]FDDNP PET data.
doi:10.1016/j.neuroimage.2011.12.014
PMCID: PMC3851575  PMID: 22197787
Alzheimer’s disease (AD); Distribution volume ratio (DVR); [18F]FDDNP; Graphical methods; Positron emission tomography (PET)
17.  Prediction of Cognitive Decline Based on Hemispheric Cortical Surface Maps of FDDNP PET 
NeuroImage  2012;61(4):10.1016/j.neuroimage.2012.02.056.
Objectives
A cross-sectional study to establish whether a subject’s cognitive state can be predicted based on regional values obtained from brain cortical maps of FDDNP Distribution Volume Ratio (DVR), which shows the pattern of beta amyloid and neurofibrillary binding, along with those of early summed FDDNP PET images (reflecting the pattern of perfusion) was performed.
Methods
Dynamic FDDNP PET studies were performed in a group of 23 subjects (8 control (NL), 8 Mild Cognitive Impairment (MCI) and 7 Alzheimer’s Disease (AD) subjects). FDDNP DVR images were mapped to the MR derived hemispheric cortical surface map warped into a common space. A set of Regions of Interest (ROI) values of FDDNP DVR and early summed FDDNP PET (0-6 min post tracer injection), were thus calculated for each subject which along with the MMSE score were used to construct a linear mathematical model relating ROI values to MMSE. After the MMSE prediction models were developed, the models’ predictive ability was tested in a non-overlapping set of 8 additional individuals, whose cognitive status was unknown to the investigators who constructed the predictive models.
Results
Among all possible subsets of ROIs, we found that the standard deviation of the predicted MMSE was 1.8 by using only DVR values from medial and lateral temporal and prefrontal regions plus the early summed FDDNP value in the posterior cingulate gyrus. The root mean square prediction error for the eight new subjects was 1.6.
Conclusion
FDDNP scans reflect progressive neuropathology accumulation and can potentially be used to predict the cognitive state of an individual.
doi:10.1016/j.neuroimage.2012.02.056
PMCID: PMC3839850  PMID: 22401755
cortical surface maps; MR; FDDNP PET; MMSE
18.  Influence of Alzheimer Disease Family History and Genetic Risk on Cognitive Performance in Healthy Middle-Aged and Older People 
Objectives
Identification of risk factors for Alzheimer disease (AD) is critical for establishing effective diagnostic and therapeutic strategies. Carrying the ε4 allele of the apolipoprotein E gene (APOE4) and having a family history of the disease are two such factors, with family history risk reflecting additional yet unknown or rarely studied genetic and perhaps nongenetic risks. Our aim was to determine the influence of APOE genotype and family history status on cognitive performance in healthy individuals.
Design
Longitudinal study.
Setting
Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles.
Participants
Seventy-two cognitively healthy middle-aged and older people (mean age ± SD: 62 ± 9 years).
Measurements
Neuropsychological examinations at baseline and after 2 years.
Results
Subjects with a family history of AD had lower baseline scores in processing speed, executive functioning, memory encoding, and delayed memory when compared with those without a family history. The family history risk factor did not influence degree of cognitive decline over time. By contrast, baseline cognitive performance did not vary according to APOE4 carrier status. Non-APOE4 carriers showed improved cognitive performance in the memory domains at follow-up, while performance of APOE4 carriers did not change.
Conclusions
Our data highlight the unique contributions of each risk factor to cognitive performance in healthy people. Both factors should be modeled in neuropsychological assessments of people at risk for AD.
doi:10.1097/JGP.0b013e3182107e6a
PMCID: PMC3816758  PMID: 21849821
Alzheimer disease; family history; APOE genotype
19.  Protein Binding in Patients With Late-Life Depression 
Archives of general psychiatry  2011;68(11):1143-1150.
Context
Depression has been identified as a risk factor and a prodrome of dementia. Common neurobiological mechanisms may underlie this clinical and phenomenologic overlap.
Objective
To examine and compare protein (amyloid and tau) binding in critical brain regions in patients diagnosed as having late-life major depressive disorder (MDD) and healthy control individuals using 2-(1-{6-[(2-[18F]fluoroethyl) (methyl)-amino]-2-naphthyl}ethylidene) malononitrile ([18F]FDDNP) positron emission tomography.
Design
A cross-section neuroimaging study using positron emission tomography.
Setting
University of California, Los Angeles.
Patients
Our samples comprised 20 patients diagnosed as having MDD and 19 healthy control individuals of comparable age, sex, and educational level.
Main Outcome Measure
Relative distribution volume in regions of interest was used as the measure of [18F]FDDNP binding in all study participants.
Results
When compared with controls, [18F]FDDNP binding was significantly higher overall and in the posterior cingulate and lateral temporal regions in the MDD group.
Conclusions
These findings suggest that neuronal injury associated with higher protein load in critical brain regions might provide a mechanism in the pathophysiologic manifestation of MDD in late life and have implications for the therapeutics of depression in elderly individuals.
doi:10.1001/archgenpsychiatry.2011.122
PMCID: PMC3797600  PMID: 22065530
20.  Family History and APOE-4 Genetic Risk in Alzheimer’s Disease 
Neuropsychology review  2012;22(3):298-309.
Identifying risk factors for Alzheimer’s disease, such as carrying the APOE-4 allele, and understanding their contributions to disease pathophysiology or clinical presentation is critical for establishing and improving diagnostic and therapeutic strategies. A first-degree family history of Alzheimer’s disease represents a composite risk factor, which reflects the influence of known and unknown susceptibility genes and perhaps non-genetic risks. There is emerging evidence that investigating family history risk associated effects may contribute to advances in Alzheimer’s disease research and ultimately clinical practice.
doi:10.1007/s11065-012-9193-2
PMCID: PMC3797601  PMID: 22359096
Alzheimer’s disease; APOE Genotype; Family history; Genetic risk; Risk factors; Neuroimaging
21.  Pomegranate Juice Augments Memory and fMRI Activity in Middle-Aged and Older Adults with Mild Memory Complaints 
Despite increasing emphasis on the potential of dietary antioxidants in preventing memory loss and on diet as a precursor of neurological health, rigorous studies investigating the cognitive effects of foods and their components are rare. Recent animal studies have reported memory and other cognitive benefits of polyphenols, found abundantly in pomegranate juice. We performed a preliminary, placebo-controlled randomized trial of pomegranate juice in older subjects with age-associated memory complaints using memory testing and functional brain activation (fMRI) as outcome measures. Thirty-two subjects (28 completers) were randomly assigned to drink 8 ounces of either pomegranate juice or a flavor-matched placebo drink for 4 weeks. Subjects received memory testing, fMRI scans during cognitive tasks, and blood draws for peripheral biomarkers before and after the intervention. Investigators and subjects were all blind to group membership. After 4 weeks, only the pomegranate group showed a significant improvement in the Buschke selective reminding test of verbal memory and a significant increase in plasma trolox-equivalent antioxidant capacity (TEAC) and urolithin A-glucuronide. Furthermore, compared to the placebo group, the pomegranate group had increased fMRI activity during verbal and visual memory tasks. While preliminary, these results suggest a role for pomegranate juice in augmenting memory function through task-related increases in functional brain activity.
doi:10.1155/2013/946298
PMCID: PMC3736548  PMID: 23970941
22.  A post mortem 3-D Brain Hemisphere Cortical Tau and Amyloid–β Pathology Mapping and Quantification as a Validation Method of Neuropathology Imaging 
This work is aimed at correlating pre mortem [F-18]FDDNP PET scan results in a patient with dementia with Lewy bodies (DLB), with cortical neuropathology distribution determined post mortem in three physical dimensions in whole brain coronal sections. Analysis of total Aβ distribution in frontal cortex and posterior cingulate gyrus confirmed its statistically significant correlation with cortical [F-18]FDDNP PET binding values (distribution volume ratios, DVR) (p<0.001, R=0.97, R2=0.94). Neurofibrillary tangle (NFT) distribution correlated significantly with cortical [F-18]FDDNP PET DVR in the temporal lobe (p<0.001, R=0.87, R2=0.76). Linear combination of Aβ and NFT densities was highly predictive of [F-18]FDDNP-PET DVR through all analyzed regions of interest (p<0.0001, R=0.92, R2=0.85), and both densities contributed significantly to the model. Lewy bodies (LB) were present at a much lower level than either Aβ or NFTs and did not significantly contribute to the in vivo signal. [F-18]FDG PET scan results in this patient were consistent with the distinctive DLB pattern of hypometabolism. This work offers a mapping brain model applicable to all imaging probes for verification of imaging results with Aβ and/or tau neuropathology brain distribution using immunohistochemistry, fluorescence microscopy and autoradiography.
doi:10.3233/JAD-122434
PMCID: PMC3688653  PMID: 23568102
[F-18]FDDNP; dementia with Lewy bodies; brain pathology mapping; amyloid and tau immunocytochemistry
23.  PET Imaging of Neuropathology in Tauopathies: Progressive Supranuclear Palsy 
Objective
Currently [F-18]FDDNP is the only PET imaging probe with the ability to visualize hyperphosphorylated tau fibrillar aggregates in living subjects. In this work, we evaluate in vivo [F-18]FDDNP labeling of brain neuropathology, primarily tau fibrillar aggregates, in patients with progressive supranuclear palsy (PSP), a human tauopathy usually lacking β-amyloid deposits.
Methods
Fifteen patients with PSP received [F-18]FDDNP PET scanning. [F-18]FDDNP distribution volume ratios (DVR), in reference to cerebellar gray matter, were determined for cortical and subcortical areas and compared with those of patients with Parkinson’s disease (PD) with short disease duration, and age-matched control subjects without neurodegenerative disorders.
Results
[F-18]FDDNP binding was present in subcortical areas (e.g., striatum, thalamus, subthalamic region, midbrain and cerebellar white matter) regardless of disease severity, with progressive subcortical and cortical involvement as disease severity increased. Brain patterns of [F-18]FDDNP binding were entirely consistent with the known pathology distribution for PSP. High midbrain and subthalamic region [F-18]FDDNP binding was distinctive for PSP subjects and separated them from controls and patients with PD.
Conclusions
These results provide evidence that [F-18]FDDNP is a sensitive in vivo PET imaging probe to map and quantify the dynamic regional localization of tau fibrillar aggregates in PSP. Furthermore, [F-18]FDDNP PET may provide a tool to detect changes in tau pathology distribution either associated with disease progression or as a treatment biomarker for future tau-specific therapies. Patterns of [F-18]FDDNP binding may also be useful in diagnosis early in disease presentation when clinical distinction among neurodegenerative disorders is often difficult.
doi:10.3233/JAD-130032
PMCID: PMC3674205  PMID: 23579330
Key-words: positron emission tomography; FDDNP; progressive supranuclear palsy; Parkinson’s disease; neuropathology; hyperphosphorylated tau aggregates; tauopathy
24.  Geriatric Psychopharmacology 
Western Journal of Medicine  1989;151(3):312-313.
PMCID: PMC1026867  PMID: 18750637
25.  Psychopharmacology of the Aged 
Western Journal of Medicine  1987;147(1):76-77.
PMCID: PMC1025828  PMID: 18750292

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