PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-25 (107)
 

Clipboard (0)
None

Select a Filter Below

Journals
more »
Year of Publication
1.  Amyloid-β assessed by florbetapir F 18 PET and 18-month cognitive decline 
Neurology  2012;79(16):1636-1644.
Objectives:
Florbetapir F 18 PET can image amyloid-β (Aβ) aggregates in the brains of living subjects. We prospectively evaluated the prognostic utility of detecting Aβ pathology using florbetapir PET in subjects at risk for progressive cognitive decline.
Methods:
A total of 151 subjects who previously participated in a multicenter florbetapir PET imaging study were recruited for longitudinal assessment. Subjects included 51 with recently diagnosed mild cognitive impairment (MCI), 69 cognitively normal controls (CN), and 31 with clinically diagnosed Alzheimer disease dementia (AD). PET images were visually scored as positive (Aβ+) or negative (Aβ−) for pathologic levels of β-amyloid aggregation, blind to diagnostic classification. Cerebral to cerebellar standardized uptake value ratios (SUVr) were determined from the baseline PET images. Subjects were followed for 18 months to evaluate changes in cognition and diagnostic status. Analysis of covariance and correlation analyses were conducted to evaluate the association between baseline PET amyloid status and subsequent cognitive decline.
Results:
In both MCI and CN, baseline Aβ+ scans were associated with greater clinical worsening on the Alzheimer's Disease Assessment Scale–Cognitive subscale (ADAS-Cog (p < 0.01) and Clinical Dementia Rating–sum of boxes (CDR-SB) (p < 0.02). In MCI Aβ+ scans were also associated with greater decline in memory, Digit Symbol Substitution (DSS), and Mini-Mental State Examination (MMSE) (p < 0.05). In MCI, higher baseline SUVr similarly correlated with greater subsequent decline on the ADAS-Cog (p < 0.01), CDR-SB (p < 0.03), a memory measure, DSS, and MMSE (p < 0.05). Aβ+ MCI tended to convert to AD dementia at a higher rate than Aβ− subjects (p < 0.10).
Conclusions:
Florbetapir PET may help identify individuals at increased risk for progressive cognitive decline.
doi:10.1212/WNL.0b013e3182661f74
PMCID: PMC3468774  PMID: 22786606
2.  The Alzheimer’s Prevention Initiative composite cognitive test score: Sample size estimates for the evaluation of preclinical Alzheimer’s disease treatments in presenilin 1 E280A mutation carriers 
Objective
There is a need to identify a cognitive composite that is sensitive to tracking preclinical AD decline to be used as a primary endpoint in treatment trials.
Method
We capitalized on longitudinal data, collected from 1995 to 2010, from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the world’s largest known early-onset autosomal dominant AD (ADAD) kindred to identify a composite cognitive test with the greatest statistical power to track preclinical AD decline and estimate the number of carriers age 30 and older needed to detect a treatment effect in the Alzheimer’s Prevention Initiative’s (API) preclinical AD treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of one to seven cognitive tests/sub-tests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a two and five year follow-up period, using data from non-carriers during the same time period to correct for aging and practice effects. Combinations that performed well were then evaluated for robustness across follow-up years, occurrence of selected items within top performing combinations and representation of relevant cognitive domains.
Results
This optimal test combination included CERAD Word List Recall, CERAD Boston Naming Test (high frequency items), MMSE Orientation to Time, CERAD Constructional Praxis and Ravens Progressive Matrices (Set A) with an MSDR of 1.62. This composite is more sensitive than using either the CERAD Word List Recall (MSDR=0.38) or the entire CERAD-Col battery (MSDR=0.76). A sample size of 75 cognitively normal PSEN1-E280A mutation carriers age 30 and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, p=0.05).
Conclusions
We have identified a composite cognitive test score representing multiple cognitive domains that has improved power compared to the most sensitive single test item to track preclinical AD decline in ADAD mutation carriers and evaluate preclinical AD treatments. This API composite cognitive test score will be used as the primary endpoint in the first API trial in cognitively unimpaired ADAD carriers within 15 years of their estimated age at clinical onset. We have independently confirmed our findings in a separate cohort of cognitively healthy older adults who progressed to the clinical stages of late-onset AD, described in a separate report, and continue to refine the composite in independent cohorts and compared with other analytical approaches.
doi:10.4088/JCP.13m08927
PMCID: PMC4331113  PMID: 24816373
composite cognitive score; API; Alzheimer’s Prevention Initiative; E280A; PSEN1; presenilin1; sample size; preclinical; cognitively unimpaired; autosomal dominant; ADAD
3.  Age-at-Onset in Late Onset Alzheimer Disease is Modified by Multiple Genetic Loci 
JAMA neurology  2014;71(11):1394-1404.
Importance
As APOE locus variants contribute to both risk of late-onset Alzheimer disease and differences in age-at-onset, it is important to know if other established late-onset Alzheimer disease risk loci also affect age-at-onset in cases.
Objectives
To investigate the effects of known Alzheimer disease risk loci in modifying age-at-onset, and to estimate their cumulative effect on age-at-onset variation, using data from genome-wide association studies in the Alzheimer’s Disease Genetics Consortium (ADGC).
Design, Setting and Participants
The ADGC comprises 14 case-control, prospective, and family-based datasets with data on 9,162 Caucasian participants with Alzheimer’s occurring after age 60 who also had complete age-at-onset information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single nucleotide polymorphisms (SNPs) most significantly associated with risk at ten confirmed LOAD loci were examined in linear modeling of AAO, and individual dataset results were combined using a random effects, inverse variance-weighted meta-analysis approach to determine if they contribute to variation in age-at-onset. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes.
Main Outcomes and Measures
Age at disease onset abstracted from medical records among participants with late-onset Alzheimer disease diagnosed per standard criteria.
Results
Analysis confirmed association of APOE with age-at-onset (rs6857, P=3.30×10−96), with associations in CR1 (rs6701713, P=7.17×10−4), BIN1 (rs7561528, P=4.78×10−4), and PICALM (rs561655, P=2.23×10−3) reaching statistical significance (P<0.005). Risk alleles individually reduced age-at-onset by 3-6 months. Burden analyses demonstrated that APOE contributes to 3.9% of variation in age-at-onset (R2=0.220) over baseline (R2=0.189) whereas the other nine loci together contribute to 1.1% of variation (R2=0.198).
Conclusions and Relevance
We confirmed association of APOE variants with age-at-onset among late-onset Alzheimer disease cases and observed novel associations with age-at-onset in CR1, BIN1, and PICALM. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on age-at-onset are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on age-at-onset may be significant, additional genetic contributions to age-at-onset are individually likely to be small.
doi:10.1001/jamaneurol.2014.1491
PMCID: PMC4314944  PMID: 25199842
Alzheimer Disease; Alzheimer Disease Genetics; Alzheimer’s Disease - Pathophysiology; Genetics of Alzheimer Disease; Aging
4.  Developing a national strategy to prevent dementia: Leon Thal Symposium 2009 
Among the major impediments to the design of clinical trials for the prevention of Alzheimer's disease (AD), the most critical is the lack of validated biomarkers, assessment tools, and algorithms that would facilitate identification of asymptomatic individuals with elevated risk who might be recruited as study volunteers. Thus, the Leon Thal Symposium 2009 (LTS'09), on October 27–28, 2009 in Las Vegas, Nevada, was convened to explore strategies to surmount the barriers in designing a multisite, comparative study to evaluate and validate various approaches for detecting and selecting asymptomatic people at risk for cognitive disorders/dementia. The deliberations of LTS'09 included presentations and reviews of different approaches (algorithms, biomarkers, or measures) for identifying asymptomatic individuals at elevated risk for AD who would be candidates for longitudinal or prevention studies. The key nested recommendations of LTS'09 included: (1) establishment of a National Database for Longitudinal Studies as a shared research core resource; (2) launch of a large collaborative study that will compare multiple screening approaches and biomarkers to determine the best method for identifying asymptomatic people at risk for AD; (3) initiation of a Global Database that extends the concept of the National Database for Longitudinal Studies for longitudinal studies beyond the United States; and (4) development of an educational campaign that will address public misconceptions about AD and promote healthy brain aging.
doi:10.1016/j.jalz.2010.01.008
PMCID: PMC4298995  PMID: 20298968
Alzheimer's disease; Dementia; Mild cognitive impairment; Prevention; Biomarkers; Diagnosis; Screening; Clinical trials; MCI; Asymptomatic; Risk factors; Registry; Longitudinal studies; Database; PAD2020; Leon Thal Symposium; Treatment; Drug development; Health policy
5.  Symptom onset in autosomal dominant Alzheimer disease 
Neurology  2014;83(3):253-260.
Objective:
To identify factors influencing age at symptom onset and disease course in autosomal dominant Alzheimer disease (ADAD), and develop evidence-based criteria for predicting symptom onset in ADAD.
Methods:
We have collected individual-level data on ages at symptom onset and death from 387 ADAD pedigrees, compiled from 137 peer-reviewed publications, the Dominantly Inherited Alzheimer Network (DIAN) database, and 2 large kindreds of Colombian (PSEN1 E280A) and Volga German (PSEN2 N141I) ancestry. Our combined dataset includes 3,275 individuals, of whom 1,307 were affected by ADAD with known age at symptom onset. We assessed the relative contributions of several factors in influencing age at onset, including parental age at onset, age at onset by mutation type and family, and APOE genotype and sex. We additionally performed survival analysis using data on symptom onset collected from 183 ADAD mutation carriers followed longitudinally in the DIAN Study.
Results:
We report summary statistics on age at onset and disease course for 174 ADAD mutations, and discover strong and highly significant (p < 10−16, r2 > 0.38) correlations between individual age at symptom onset and predicted values based on parental age at onset and mean ages at onset by mutation type and family, which persist after controlling for APOE genotype and sex.
Conclusions:
Significant proportions of the observed variance in age at symptom onset in ADAD can be explained by family history and mutation type, providing empirical support for use of these data to estimate onset in clinical research.
doi:10.1212/WNL.0000000000000596
PMCID: PMC4117367  PMID: 24928124
6.  Subjective Cognitive Decline: Self and Informant Comparisons 
Background
It is unclear whether self or informant-based subjective cognition better distinguishes emotional factors from early stage Alzheimer’s disease (AD).
Methods
447 healthy members of the Arizona Apolipoprotein E (APOE) Cohort and their informants completed both the self and informant paired Multidimensional Assessment of Neurodegenerative Symptoms questionnaire (MANS).
Results
30.6% of members and 26.2% of informants endorsed decline on the MANS. Both self and informant-based decliners had higher scores of psychological distress and slightly lower cognitive scores than nondecliners. Over the next 6.7 years, 20 developed mild cognitive impairment (MCI). Converters were older at entry than nonconverters (63.8[7.0] vs 58.8[7.3] years, p=.003), 85% were APOE e4 carriers (p<.0001), and they self-endorsed decline earlier than informants (58.9[39.2] vs 28.0[40.4] months before MCI; p=.002).
Conclusions
Both self and informant based subjective decline correlated with greater psychological distress, and slightly lower cognitive performance. Those with incident MCI generally self-endorsed decline earlier than informants.
doi:10.1016/j.jalz.2013.01.003
PMCID: PMC3732500  PMID: 23562429
7.  The neuropsychology of normal aging and preclinical Alzheimer’s disease 
Background
An NIA-sponsored workgroup on preclinical Alzheimer’s disease (AD) articulated the need to characterize cognitive differences between normal aging and preclinical AD.
Methods
71 apolipoprotein E (APOE) e4 homozygotes (HMZ), 194 e3/4 heterozygotes (HTZ), and 356 e4 noncarriers (NC) aged 21–87 years who were cognitively healthy underwent neuropsychological testing every two years. Longitudinal trajectories of test scores were compared between APOE subgroups.
Results
There was a significant effect of age on all cognitive domains in both APOE e4 carriers and NC. A significant effect of APOE e4 gene dose was confined to the memory domain and the Dementia Rating Scale. Cross sectional comparisons did not discriminate the groups.
Conclusions
While cognitive aging patterns are similar in APOE e4 carriers and NC, preclinical AD is characterized by a significant e4 gene dose effect that impacts memory and is detectable longitudinally. Preclinical neuropsychological testing strategies should emphasize memory sensitive measures and longitudinal design.
doi:10.1016/j.jalz.2013.01.004
PMCID: PMC3700591  PMID: 23541188
preclinical Alzheimer’s disease; cognitive aging; age-related memory loss; mild cognitive impairment; apolipoprotein E; longitudinal testing
8.  Fibrillar Amyloid Correlates of Preclinical Cognitive Decline 
Background
It is not known whether preclinical cognitive decline is associated with fibrillar β-amyloid (Aβ) deposition irrespective of Apolipoprotein E (APOE) ε4 status.
Methods
From a prospective observational study of 623 cognitively normal individuals, we identified all subjects who showed preclinical decline of at least 2 standard deviations beyond the decline of the entire group in memory or executive function. Fourteen decliners were matched by APOE ε4 gene dose, age, sex, and education with 14 nondecliners. Dynamic Pittsburgh compound B (PiB) positron emission tomography (PET) scans, the Logan method, statistical parametric mapping, and automatically labeled regions of interest were used to characterize and compare cerebral-to-cerebellar PiB distribution volume ratios (DVR), reflecting fibrillar Aβ burden.
Results
At P<.005 (uncorrected), decliners had significantly greater DVR’s in comparison to nondecliners.
Conclusions
Asymptomatic longitudinal neuropsychological decline is associated with subsequent increased fibrillar amyloid deposition, even when controlling for APOE ε4 genotype.
doi:10.1016/j.jalz.2013.01.009
PMCID: PMC3713087  PMID: 23583233
preclinical; Alzheimer’s disease; amyloid imaging; cognitive decline; Apolipoprotein E
9.  Neuropathologic Heterogeneity Does Not Impair Florbetapir-PET Postmortem Correlates 
Neuropathologic heterogeneity is often present within Alzheimer’s disease (AD). We sought to determine if amyloid imaging measures of AD are affected by concurrent pathologies. Thirty-eight clinicopathologically-defined AD and 17 non-demented cases (ND) with quantitative florbetapir F-18 (18F-AV-45) PET imaging during life and histological β-amyloid quantification and neuropathologic examination were assessed. AD cases were divided on the basis of concurrent pathologies, including those with Lewy bodies (N=21), white matter rarefaction (N=27), severe cerebral amyloid angiopathy (N=11), argyrophilic grains (N=5) and TDP-43 inclusions (N=18). Many cases exhibited more than one type of concurrent pathology. The ratio of cortical to cerebellar amyloid imaging signal (SUVr) and immunohistochemical β-amyloid load were analyzed in six cortical regions of interest. All AD subgroups had strong and significant correlations between SUVr and histological β-amyloid measures (p values <0.001). All AD subgroups had significantly greater amyloid measures compared to ND, and mean amyloid measures did not significantly differ between AD subgroups. When comparing AD cases with and without each pathology, AD cases with Lewy bodies had significantly decreased SUVr measures compared to AD cases without (p = 0.002); there were no other paired comparison differences. These findings indicate florbetapir-PET imaging is not confounded by neuropathological heterogeneity within AD.
doi:10.1097/NEN.0000000000000028
PMCID: PMC4037918  PMID: 24335535
argyrophilic grains; autopsy; cerebral amyloid angiopathy; Lewy bodies; plaques; TDP-43; vascular dementia; white matter; leuko-araiosis
10.  Brain Differences in Infants at Differential Genetic Risk for Late-Onset Alzheimer Disease A Cross-sectional Imaging Study 
JAMA neurology  2014;71(1):11-22.
IMPORTANCE
Converging evidence suggests brain structure alterations may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these alterations holds inherent value for the development and evaluation of preventive treatment therapies.
OBJECTIVE
To compare magnetic resonance imaging measurements of white matter myelin water fraction (MWF) and gray matter volume (GMV) in healthy infant carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele, the major susceptibility gene for late-onset AD.
DESIGN, SETTING, AND PARTICIPANTS
Quiet magnetic resonance imaging was performed at an academic research imaging center on 162 healthy, typically developing 2- to 25-month-old infants with no family history of Alzheimer disease or other neurological or psychiatric disorders. Cross-sectional measurements were compared in the APOE ε4 carrier and noncarrier groups. White matter MWF was compared in one hundred sixty-two 2- to 25-month-old sleeping infants (60 ε4 carriers and 102 noncarriers). Gray matter volume was compared in a subset of fifty-nine 6- to 25-month-old infants (23 ε4 carriers and 36 noncarriers), who remained asleep during the scanning session. The carrier and noncarrier groups were matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status.
MAIN OUTCOMES AND MEASURES
Automated algorithms compared regional white matter MWF and GMV in the carrier and noncarrier groups and characterized their associations with age.
RESULTS
Infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P < .05, after correction for multiple comparisons; GMV differences, P < .001, uncorrected for multiple comparisons). Infant ε4 carriers also exhibited an attenuated relationship between MWF and age in posterior white matter regions.
CONCLUSIONS AND RELEVANCE
While our findings should be considered preliminary, this study demonstrates some of the earliest brain changes associated with the genetic predisposition to AD. It raises new questions about the role of APOE in normal human brain development, the extent to which these processes are related to subsequent AD pathology, and whether they could be targeted by AD prevention therapies.
doi:10.1001/jamaneurol.2013.4544
PMCID: PMC4056558  PMID: 24276092
11.  BRAIN ABNORMALITIES IN YOUNG ADULTS AT GENETIC RISK FOR AUTOSOMAL DOMINANT ALZHEIMER’S DISEASE: A CROSS-SECTIONAL STUDY 
The Lancet. Neurology  2012;11(12):1048-1056.
Summary
Background
We previously detected functional brain imaging abnormalities in young adults at genetic risk for late-onset Alzheimer’s disease (AD). Here, we sought to characterize structural and functional magnetic resonance imaging (MRI), cerebrospinal fluid (CSF), and plasma biomarker abnormalities in young adults at risk for autosomal dominant early-onset AD. Biomarker measurements were characterized and compared in presenilin 1 (PSEN1) E280A mutation carriers and non-carriers from the world’s largest known autosomal dominant early-onset AD kindred, more than two decades before the carriers’ estimated median age of 44 at the onset of mild cognitive impairment (MCI) and before their estimated age of 28 at the onset of amyloid-β (Aβ) plaque deposition.
Methods
Biomarker data for this cross-sectional study were acquired in Antioquia, Colombia between July and August, 2010. Forty-four participants from the Colombian Alzheimer’s Prevention Initiative (API) Registry had structural MRIs, functional MRIs during associative memory encoding/novel viewing and control tasks, and cognitive assessments. They included 20 mutation carriers and 24 non-carriers, who were cognitively normal, 18-26 years old and matched for their gender, age, and educational level. Twenty of the participants, including 10 mutation carriers and 10 non-carriers, had lumbar punctures and venipunctures. Primary outcome measures included task-dependent hippocampal/parahippocampal activations and precuneus/posterior cingulate deactivations, regional gray matter reductions, CSF Aβ1-42, total tau and phospho-tau181 levels, and plasma Aβ1-42 levels and Aβ1-42/Aβ1-40 ratios. Structural and functional MRI data were compared using automated brain mapping algorithms and AD-related search regions. Cognitive and fluid biomarkers were compared using Mann-Whitney tests.
Findings
The mutation carrier and non-carrier groups did not differ significantly in their dementia ratings, neuropsychological test scores, or proportion of apolipoprotein E (APOE) ε4 carriers. Compared to the non-carriers, carriers had higher CSF Aβ1-42 levels (p=0·008), plasma Aβ1-42 levels (p=0·01), and plasma Aβ1-42/Aβ1-40 ratios (p=0·001), consistent with Aβ1-42 overproduction. They also had greater hippocampal/parahippocampal activations (as low as p=0·008, after correction for multiple comparisons), less precuneus/posterior cingulate deactivations (as low as p=0·001, after correction), less gray matter in several regions (p-values <0·005, uncorrected, and corrected p=0·008 in the parietal search region), similar to findings in the later preclinical and clinical stages of autosomal dominant and late-onset AD.
Interpretation
Young adults at genetic risk for autosomal dominant AD have functional and structural MRI abnormalities, along with CSF and plasma biomarker findings consistent with Aβ1-42 over-production. While the extent to which the underlying brain changes are progressive or developmental remain to be determined, this study demonstrates the earliest known biomarker changes in cognitively normal people at genetic risk for autosomal dominant AD.
Funding
Banner Alzheimer’s Foundation, Nomis Foundation, Anonymous Foundation, Forget Me Not Initiative, Boston University Department of Psychology, Colciencias (1115-408-20512, 1115-545-31651), National Institute on Aging (R01 AG031581, P30 AG19610, UO1 AG024904, RO1 AG025526, RF1AG041705), National Institute of Neurological Disorders and Stroke (F31-NS078786) and state of Arizona.
doi:10.1016/S1474-4422(12)70228-4
PMCID: PMC4181671  PMID: 23137948
Alzheimer’s disease; biomarkers; preclinical; early-onset; dominantly inherited; MRI; functional MRI; cerebrospinal fluid; plasma; presenilin E280A mutation; amyloid; tau; genetics; prevention
12.  Fat-Free Body Mass but not Fat Mass is Associated with Reduced Gray Matter Volume of Cortical Brain Regions Implicated in Autonomic and Homeostatic Regulation 
NeuroImage  2012;64:712-721.
Obesity has been associated with alterations of both functional and structural aspects of the human central nervous system. In obese individuals both fat mass (FM; primarily consisting of adipose tissue) and fat-free mass (FFM; all non-adipose tissues) are increased and it remains unknown whether these compartments have separate effects on human brain morphology. We used voxel-based morphometry to investigate the relationships between measures of body composition and regional gray matter volume (GMV) in 76 healthy adults with a wide range of adiposity (24F/52M; age 32.1±8.8y; percentage of body fat [PFAT%] 25.5±10.9%; BMI 29.8±8.9). Faf-free mass index (FFMI kg*m-2) showed negative associations in bilateral temporal regions, the bilateral medial and caudolateral OFC, and the left insula. Fat mass index (FMI kg*m-2) showed similar, but less extensive negative associations within temporal cortical regions and the left caudolateral orbitofrontal cortex (OFC). In addition, negative associations were seen for FMI with GMV of the cerebellum. Associations of FFMI with temporal and medial orbitofrontal GMV appeared to be independent of adiposity. No associations were seen between measures of adiposity (i.e. FM and PFAT) and GMV when adjusted for FFM. The majority of regions that we find associated with FFM have been implicated in the regulation of eating behavior and show extensive projections to central autonomic and homeostatic core structures. These data indicate that not adipose tissue or relative adiposity itself, but obesity related increases in absolute tissue mass and particularly FFM may have a more predominant effect on the human brain. This might be explained by the high metabolic demand of FFM and related increases in total energy needs.
doi:10.1016/j.neuroimage.2012.09.005
PMCID: PMC4178061  PMID: 22974975
Fat-free mass; fat mass; obesity; VBM; MRI; gray matter; prefrontal cortex
13.  Genome-Wide Association Meta-analysis of Neuropathologic Features of Alzheimer's Disease and Related Dementias 
PLoS Genetics  2014;10(9):e1004606.
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.
Author Summary
Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study (GWAS), as well as an analysis of known genetic risk loci for AD dementia, using data from 4,914 brain autopsies. Genome-wide significance was observed for 7 genes and pathologic features of AD and related diseases. Twelve of the 22 genetic risk loci for clinically-defined AD dementia were confirmed in our pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for hallmark pathologic features of AD were strongly positive and linear. Our study discovered new genetic associations with specific pathologic features and aligned known genetic risk for AD dementia with specific pathologic changes in a large brain autopsy study of AD and related dementias.
doi:10.1371/journal.pgen.1004606
PMCID: PMC4154667  PMID: 25188341
14.  Postprandial Plasma PYY Concentrations are Associated with Increased Regional Gray Matter Volume and rCBF Declines in Caudate Nuclei – a combined MRI and H215O PET study 
NeuroImage  2011;60(1):592-600.
The anorexigenic gastrointestinal hormone Peptide YY plays an important role in the communication between the gastrointestinal tract and the central nervous system. PYY has been shown to modulate brain activity in regions implicated in reward and food related behavior. Its effects on brain structure however, remain unknown. Voxel-based morphometry was used to investigate the relationship between fasting and postprandial plasma PYY concentrations and regional gray matter volume (GMV). For this analysis twenty adult, non diabetic Caucasians were included (18F/2M, age 31±9 y, percentage of body fat [PFAT] 32±8%) who had volumetric brain magnetic resonance images and underwent H215O positron emission tomographic (PET) measurements of regional cerebral blood flow (rCBF), a marker of local neuronal activity, and measurements of plasma total PYY, prior to (fasting) and following a satiating liquid meal. Voxel-wise analysis revealed a regional positive association between postprandial PYY and gray matter volume bilaterally in the caudate nuclei. These associations remained significant (p<0.05) after small volume correction for multiple comparisons. Based on these findings we investigated whether postprandial PYY is associated with PET measured rCBF of the caudate nucleus. We found a significant negative association between average postprandial caudate rCBF and postprandial plasma PYY concentrations (r=−0.60, p<0.02, age, sex and PFAT adjusted). Average postprandial caudate rCBF was also negatively associated with rCBF in the right medial orbitofrontal cortex and the right hippocampal formation (p<0.05, corrected for multiple comparison). Total PYY is positively associated with gray matter but negatively with postprandial activity in the caudate nuclei while caudate activity is negatively associated with rCBF in prefrontal and paralimbic regions implicated in reward behavior. Thus, PYY may act centrally to modulate eating behavior via striatal networks.
doi:10.1016/j.neuroimage.2011.12.023
PMCID: PMC4152947  PMID: 22206963
PYY; caudate nucleus; striatum; gray matter; VBM; MRI; PET; rCBF
15.  Genetic Susceptibility for Alzheimer’s Disease Neuritic Plaque Pathology 
JAMA neurology  2013;70(9):1150-1157.
Objective
To investigate whether Alzheimer’s disease (AD) susceptibility loci from genome-wide association studies (GWAS) impact neuritic plaque pathology and to additionally identify novel risk loci for this trait.
Design
Candidate analysis of single nucleotide polymorphisms (SNPs) and GWAS in a joint clinicopathologic cohort study, followed by targeted validation in independent neuroimaging cohorts.
Participants and Setting
725 deceased subjects from the Religious Orders and Rush Memory and Aging Project, two prospective, community-based studies of aging; the validation neuroimaging cohort consisted of 114 subjects from multiple clinical and research centers.
Main Outcome Measures
A quantitative measure of neuritic plaque pathologic burden, based on assessments of silver-stained tissue averaged from multiple brain regions. Validation based on β-amyloid load by immunocytochemistry, and replication with fibrillar β-amyloid Positron Emission Tomography (PET) imaging with Pittsburgh Compound B or florbetapir.
Results
Besides the previously reported APOE and CR1 loci, we find that ABCA7 (rs3764650, P=0.02) and CD2AP (rs9349407, P=0.03) AD susceptibility loci are associated with neuritic plaque burden. In addition, among the top results of our GWAS, we discovered a novel variant near the amyloid precursor protein gene (APP, rs2829887) that is associated with neuritic plaques (P=3.3×10−6). This polymorphism was associated with postmortem β-amyloid load, as well as fibrillar β-amyloid in two independent cohorts of adults with normal cognition.
Conclusion
These findings enhance understanding of AD risk factors by relating validated susceptibility alleles to increased neuritic plaque pathology and implicate common genetic variation at the APP locus in the earliest, pre-symptomatic stages of AD.
doi:10.1001/jamaneurol.2013.2815
PMCID: PMC3773291  PMID: 23836404
16.  Biochemical Assessment of Precuneus and Posterior Cingulate Gyrus in the Context of Brain Aging and Alzheimer’s Disease 
PLoS ONE  2014;9(8):e105784.
Defining the biochemical alterations that occur in the brain during “normal” aging is an important part of understanding the pathophysiology of neurodegenerative diseases and of distinguishing pathological conditions from aging-associated changes. Three groups were selected based on age and on having no evidence of neurological or significant neurodegenerative disease: 1) young adult individuals, average age 26 years (n = 9); 2) middle-aged subjects, average age 59 years (n = 5); 3) oldest-old individuals, average age 93 years (n = 6). Using ELISA and Western blotting methods, we quantified and compared the levels of several key molecules associated with neurodegenerative disease in the precuneus and posterior cingulate gyrus, two brain regions known to exhibit early imaging alterations during the course of Alzheimer’s disease. Our experiments revealed that the bioindicators of emerging brain pathology remained steady or decreased with advancing age. One exception was S100B, which significantly increased with age. Along the process of aging, neurofibrillary tangle deposition increased, even in the absence of amyloid deposition, suggesting the presence of amyloid plaques is not obligatory for their development and that limited tangle density is a part of normal aging. Our study complements a previous assessment of neuropathology in oldest-old subjects, and within the limitations of the small number of individuals involved in the present investigation, it adds valuable information to the molecular and structural heterogeneity observed along the course of aging and dementia. This work underscores the need to examine through direct observation how the processes of amyloid deposition unfold or change prior to the earliest phases of dementia emergence.
doi:10.1371/journal.pone.0105784
PMCID: PMC4148328  PMID: 25166759
17.  Variants in triggering receptor expressed on myeloid cells 2 are associated with both behavioral variant frontotemporal lobar degeneration and Alzheimer’s disease 
Neurobiology of aging  2013;34(8):10.1016/j.neurobiolaging.2013.02.016.
Recent evidence suggests that rare genetic variants within the TREM2 gene are associated with increased risk for Alzheimer’s disease. TREM2 mutations are the genetic basis for a condition characterized by polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL) and an early-onset dementia syndrome. TREM2 is important in the phagocytosis of apoptotic neuronal cells by microglia in the brain. Loss of function might lead to an impaired clearance and accumulation of necrotic debris and subsequent neurodegeneration. In this study, we investigated a consanguineous family segregating autosomal recessive behavioral variant FTLD from Antioquia, Colombia. Exome sequencing identified a nonsense mutation in TREM2 (p.Trp198X) segregating with disease. Next, using a cohort of clinically characterized and neuropathologically verified sporadic AD cases and controls we report replication of the AD risk association at rs75932628 within TREM2. These data suggest that mutational burden in TREM2 may serve as a risk factor for neurodegenerative disease in general and that potentially this class of TREM2 variant carriers with dementia should be considered a molecularly distinct form of neurodegenerative disease.
doi:10.1016/j.neurobiolaging.2013.02.016
PMCID: PMC3830921  PMID: 23582655
18.  USHERING IN THE STUDY AND TREATMENT OF PRECLINICAL ALZHEIMER DISEASE 
Nature reviews. Neurology  2013;9(7):371-381.
Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of or completely prevent clinical decline. Here, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how these advances have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research.
doi:10.1038/nrneurol.2013.107
PMCID: PMC4084675  PMID: 23752908
19.  The Receiver Operational Characteristic for Binary Classification with Multiple Indices and Its Application to the Neuroimaging Study of Alzheimer’s Disease 
Given a single index, the receiver operational characteristic (ROC) curve analysis is routinely utilized for characterizing performances in distinguishing two conditions/groups in terms of sensitivity and specificity. Given the availability of multiple data sources (referred to as multi-indices), such as multimodal neuroimaging data sets, cognitive tests, and clinical ratings and genomic data in Alzheimer’s disease (AD) studies, the single-index-based ROC underutilizes all available information. For a long time, a number of algorithmic/analytic approaches combining multiple indices have been widely used to simultaneously incorporate multiple sources. In this study, we propose an alternative for combining multiple indices using logical operations, such as “AND,” “OR,” and “at least n” (where n is an integer), to construct multivariate ROC (multiV-ROC) and characterize the sensitivity and specificity statistically associated with the use of multiple indices. With and without the “leave-one-out” cross-validation, we used two data sets from AD studies to showcase the potentially increased sensitivity/specificity of the multiV-ROC in comparison to the single-index ROC and linear discriminant analysis (an analytic way of combining multi-indices). We conclude that, for the data sets we investigated, the proposed multiV-ROC approach is capable of providing a natural and practical alternative with improved classification accuracy as compared to univariate ROC and linear discriminant analysis.
doi:10.1109/TCBB.2012.141
PMCID: PMC4085147  PMID: 23702553
Alzheimer’s dementia (AD); multiple indices; multiV-ROC; receiver operational characteristic (ROC)
20.  Brain Differences in Infants at Differential Genetic Risk for Late-Onset Alzheimer Disease 
JAMA neurology  2014;71(1):11-22.
IMPORTANCE
Converging evidence suggests brain structure alterations may precede overt cognitive impairment in Alzheimer disease by several decades. Early detection of these alterations holds inherent value for the development and evaluation of preventive treatment therapies.
OBJECTIVE
To compare magnetic resonance imaging measurements of white matter myelin water fraction (MWF) and gray matter volume (GMV) in healthy infant carriers and noncarriers of the apolipoprotein E (APOE) ε4 allele, the major susceptibility gene for late-onset AD.
DESIGN, SETTING, AND PARTICIPANTS
Quiet magnetic resonance imaging was performed at an academic research imaging center on 162 healthy, typically developing 2- to 25-month-old infants with no family history of Alzheimer disease or other neurological or psychiatric disorders. Cross-sectional measurements were compared in the APOE ε4 carrier and noncarrier groups. White matter MWF was compared in one hundred sixty-two 2- to 25-month-old sleeping infants (60 ε4 carriers and 102 noncarriers). Gray matter volume was compared in a subset of fifty-nine 6- to 25-month-old infants (23 ε4 carriers and 36 noncarriers), who remained asleep during the scanning session. The carrier and noncarrier groups were matched for age, gestational duration, birth weight, sex ratio, maternal age, education, and socioeconomic status.
MAIN OUTCOMES AND MEASURES
Automated algorithms compared regional white matter MWF and GMV in the carrier and noncarrier groups and characterized their associations with age.
RESULTS
Infant ε4 carriers had lower MWF and GMV measurements than noncarriers in precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions, areas preferentially affected by AD, and greater MWF and GMV measurements in extensive frontal regions and measurements were also significant in the subset of 2- to 6-month-old infants (MWF differences, P < .05, after correction for multiple comparisons; GMV differences, P < .001, uncorrected for multiple comparisons). Infant ε4 carriers also exhibited an attenuated relationship between MWF and age in posterior white matter regions.
CONCLUSIONS AND RELEVANCE
While our findings should be considered preliminary, this study demonstrates some of the earliest brain changes associated with the genetic predisposition to AD. It raises new questions about the role of APOE in normal human brain development, the extent to which these processes are related to subsequent AD pathology, and whether they could be targeted by AD prevention therapies.
doi:10.1001/jamaneurol.2013.4544
PMCID: PMC4056558  PMID: 24276092
22.  Cortical atrophy in presymptomatic Alzheimer’s disease presenilin 1 mutation carriers 
Background
Sporadic late-onset Alzheimer’s disease (AD) dementia has been associated with a ‘signature’ of cortical atrophy in paralimbic and heteromodal association regions measured with MRI.
Objective
To investigate whether a similar pattern of cortical atrophy is present in presymptomatic presenilin 1 E280A mutation carriers an average of 6 years before clinical symptom onset.
Methods
40 cognitively normal volunteers from a Colombian population with familial AD were included; 18 were positive for the AD-associated presenilin 1 mutation (carriers, mean age=38) whereas 22 were non-carriers. T1-weighted volumetric MRI images were acquired and cortical thickness was measured. A priori regions of interest from our previous work were used to obtain thickness from AD-signature regions.
Results
Compared to non-carriers, presymptomatic presenilin 1 mutation carriers exhibited thinner cortex within the AD-signature summary measure (p<0.008). Analyses of individual regions demonstrated thinner angular gyrus, precuneus and superior parietal lobule in carriers compared to non-carriers, with trend-level effects in the medial temporal lobe.
Conclusion
Results demonstrate that cognitively normal individuals genetically determined to develop AD have a thinner cerebral cortex than non-carriers in regions known to be affected by typical late-onset sporadic AD. These findings provide further support for the hypothesis that cortical atrophy is present in preclinical AD more than 5 years prior to symptom onset. Further research is needed to determine whether this method could be used to characterise the age-dependent trajectory of cortical atrophy in presymptomatic stages of AD.
doi:10.1136/jnnp-2012-303299
PMCID: PMC3632663  PMID: 23134660
23.  Recent Perspectives on APP, Secretases, Endosomal Pathways and How they Influence Alzheimer’s Related Pathological Changes in Down Syndrome 
Down syndrome is one of the most common genetic conditions occurring in one in 700 live births. The trisomy of chromosome 21 causes over-expression of APP which in turn is indicated in the increased production of Aβ associated with AD. This makes DS the most common presenile form of AD exceeding PS1 and PS2 FAD. Since a majority of DS individuals develop dementia, it is important to examine whether DS and sporadic AD share common features, for example, to anticipate shared treatments in the future. Here we explore commonalities and differences for secretases and endosomal pathways in DS and AD.
doi:10.4172/2161-0460.S7-002
PMCID: PMC4000700  PMID: 24782952
Down syndrome; Trisomy; Over-expression
24.  Higher serum glucose levels are associated with cerebral hypometabolism in Alzheimer regions 
Neurology  2013;80(17):1557-1564.
Objective:
To investigate whether higher fasting serum glucose levels in cognitively normal, nondiabetic adults were associated with lower regional cerebral metabolic rate for glucose (rCMRgl) in brain regions preferentially affected by Alzheimer disease (AD).
Methods:
This is a cross-sectional study of 124 cognitively normal persons aged 64 ± 6 years with a first-degree family history of AD, including 61 APOEε4 noncarriers and 63 carriers. An automated brain mapping algorithm characterized and compared correlations between higher fasting serum glucose levels and lower [18F]-fluorodeoxyglucose-PET rCMRgl measurements.
Results:
As predicted, higher fasting serum glucose levels were significantly correlated with lower rCMRgl and were confined to the vicinity of brain regions preferentially affected by AD. A similar pattern of regional correlations occurred in the APOEε4 noncarriers and carriers.
Conclusions:
Higher fasting serum glucose levels in cognitively normal, nondiabetic adults may be associated with AD pathophysiology. Findings suggest that the risk imparted by higher serum glucose levels may be independent of APOEε4 status. This study raises additional questions about the role of the metabolic process in the predisposition to AD and supports the possibility of targeting these processes in presymptomatic AD trials.
doi:10.1212/WNL.0b013e31828f17de
PMCID: PMC3662330  PMID: 23535495
25.  APOE & Neuroenergetics: an Emerging Paradigm in Alzheimer's Disease 
Neurobiology of aging  2012;34(4):1007-1017.
APOE is the major known genetic risk factor for late-onset Alzheimer's disease (AD). While relationships between APOE-encoded apoE and β-amyloid are increasingly well described, mounting evidence supports wide-ranging effects of APOE on the brain. Specifically, APOE appears to impact brain network activity and closely related neuroenergetic functions that may be involved in vulnerability to neurodegenerative pathophysiology. These effects highlight the salience of further investigation into the diverse influences of APOE. Therefore, this article reviews the interplay between APOE and neuroenergetics and proposes areas for further investigation. This research may lead to the identification of novel therapeutic targets for the treatment and/or prevention of AD.
doi:10.1016/j.neurobiolaging.2012.10.011
PMCID: PMC3545040  PMID: 23159550
APOE; apolipoprotein E; mitochondria; neuroenergetics; brain imaging; fMRI; FDG PET; cytochrome oxidase; biomarkers; Alzheimer's disease; energy metabolism; neurodegeneration

Results 1-25 (107)