Faculty Bibliography
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person:ferris01
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352
White matter tract integrity metrics reflect the vulnerability of late-myelinating tracts in Alzheimer's disease
Post-mortem and imaging studies have observed that white matter (WM) degenerates in a pattern inverse to myelin development, suggesting preferential regional vulnerabilities influencing cognitive decline in AD. This study applied novel WM tract integrity (WMTI) metrics derived from diffusional kurtosis imaging (DKI) to examine WM tissue properties in AD within this framework. Using data from amnestic mild cognitive impairment (aMCI, n = 12), AD (n = 14), and normal control (NC; n = 15) subjects, mixed models revealed interaction effects: specific WMTI metrics of axonal density and myelin integrity (i.e. axonal water fraction, radial extra-axonal diffusivity) in late-myelinating tracts (i.e. superior and inferior longitudinal fasciculi) changed in the course of disease, but were stable in the initial stages for early-myelinating tracts (i.e. posterior limb of the internal capsule, cerebral peduncles). WMTI metrics in late-myelinating tracts correlated with semantic verbal fluency, a cognitive function known to decline in AD. These findings corroborate the preferential vulnerability of late-myelinating tracts, and illustrate an application of WMTI metrics to characterizing the regional course of WM changes in AD.
PMCID:3853114
PMID: 24319654
ISSN: 2213-1582
CID: 838022
Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease
Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 x 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.
PMCID:3896259
PMID: 24162737
ISSN: 1061-4036
CID: 948132
Novel White Matter Tract Integrity Metrics Sensitive to Alzheimer Disease Progression
BACKGROUND AND PURPOSE:Along with cortical abnormalities, white matter microstructural changes such as axonal loss and myelin breakdown are implicated in the pathogenesis of Alzheimer disease. Recently, a white matter model was introduced that relates non-Gaussian diffusional kurtosis imaging metrics to characteristics of white matter tract integrity, including the axonal water fraction, the intra-axonal diffusivity, and the extra-axonal axial and radial diffusivities.MATERIALS AND METHODS:This study reports these white matter tract integrity metrics in subjects with amnestic mild cognitive impairment (n = 12), Alzheimer disease (n = 14), and age-matched healthy controls (n = 15) in an effort to investigate their sensitivity, diagnostic accuracy, and associations with white matter changes through the course of Alzheimer disease.RESULTS:With tract-based spatial statistics and region-of-interest analyses, increased diffusivity in the extra-axonal space (extra-axonal axial and radial diffusivities) in several white matter tracts sensitively and accurately discriminated healthy controls from those with amnestic mild cognitive impairment (AUC = 0.82-0.95), while widespread decreased axonal water fraction discriminated amnestic mild cognitive impairment from Alzheimer disease (AUC = 0.84). Additionally, these white matter tract integrity metrics in the body of the corpus callosum were strongly correlated with processing speed in amnestic mild cognitive impairment (r = |0.80-0.82|, P < .001).CONCLUSIONS:These findings have implications for the course and spatial progression of white matter degeneration in Alzheimer disease, suggest the mechanisms by which these changes occur, and demonstrate the viability of these white matter tract integrity metrics as potential neuroimaging biomarkers of the earliest stages of Alzheimer disease and disease progression.
PMCID:3962262
PMID: 23764722
ISSN: 0195-6108
CID: 620202
Developing dementia prevention trials: baseline report of the home-based assessment study
This report describes the baseline experience of the multicenter, Home-Based Assessment study, designed to develop methods for dementia prevention trials using novel technologies for test administration and data collection. Nondemented individuals of 75 years of age or more were recruited and evaluated in-person using established clinical trial outcomes of cognition and function, and randomized to one of 3 assessment methodologies: (1) mail-in questionnaire/live telephone interviews [mail-in/phone (MIP)]; (2) automated telephone with interactive voice recognition; and (3) internet-based computer Kiosk. Brief versions of cognitive and noncognitive outcomes were adapted to each methodology and administered at baseline and repeatedly over a 4-year period. "Efficiency" measures assessed the time from screening to baseline, and staff time required for each methodology. A total of 713 individuals signed consent and were screened; 640 met eligibility and were randomized to one of 3 assessment arms; and 581 completed baseline. Dropout, time from screening to baseline, and total staff time were highest among those assigned to internet-based computer Kiosk. However, efficiency measures were driven by nonrecurring start-up activities suggesting that differences may be mitigated over a long trial. Performance among Home-Based Assessment instruments collected through different technologies will be compared with established outcomes over this 4-year study.
PMCID:3943465
PMID: 23151596
ISSN: 0893-0341
CID: 641432
Evaluation of an 8-item Severe Impairment Battery (SIB-8) vs. the full SIB in moderate to severe Alzheimer's disease patients participating in a donepezil study
AIM: The Severe Impairment Battery (SIB), a reliable cognitive measure for evaluating treatment response in advanced Alzheimer's disease (AD), takes approximately 20 min to administer. A recently derived 8-item version of the S
PMCID:3930878
PMID: 24073978
ISSN: 1742-1241
CID: 2392392
Non-Gaussian diffusion MRI assessment of brain microstructure in mild cognitive impairment and Alzheimer's disease
We report the first application of a novel diffusion-based MRI method, called diffusional kurtosis imaging (DKI), to investigate changes in brain tissue microstructure in patients with mild cognitive impairment (MCI) and AD and in cognitively intact controls. The subject groups were characterized and compared in terms of DKI-derived metrics for selected brain regions using analysis of covariance with a Tukey multiple comparison correction. Receiver operating characteristic (ROC) and binary logistic regression analyses were used to assess the utility of regional diffusion measures, alone and in combination, to discriminate each pair of subject groups. ROC analyses identified mean and radial kurtoses in the anterior corona radiata as the best individual discriminators of MCI from controls, with the measures having an area under the ROC curve (AUC) of 0.80 and 0.82, respectively. The next best discriminators of MCI from controls were diffusivity and kurtosis (both mean and radial) in the prefrontal white matter (WM), with each measure having an AUC between 0.77 and 0.79. Finally, the axial diffusivity in the hippocampus was the best overall discriminator of MCI from AD, having an AUC of 0.90. These preliminary results suggest that non-Gaussian diffusion MRI may be beneficial in the assessment of microstructural tissue damage at the early stage of MCI and may be useful in developing biomarkers for the clinical staging of AD.
PMCID:5347444
PMID: 23602730
ISSN: 0730-725x
CID: 408572
Age and apolipoprotein E genotype influence rate of cognitive decline in nondemented elderly
Objective: This study examined the impact of age and apolipoprotein E (APOE) genotype on the rate of cognitive decline in nondemented elderly participants in a simulated Alzheimer's disease (AD) primary prevention treatment trial carried out by the Alzheimer's Disease Cooperative Study. Method: Cognitive tests were administered at baseline and at four subsequent annual evaluations to 417 nondemented participants (172 men, 245 women) between the ages of 74 and 93 (M = 79.13 +/- 3.34). APOE genotyping was available for 286 of the participants. Results: Four-year decline was evident on measures of orientation, memory, executive function, and language. Faster decline was evident in APOE epsilon4+ (a genetic risk factor for AD; n = 73) than in epsilon4- participants (n = 213), even after controlling for education, gender, ethnicity, and baseline functional and cognitive abilities. This discrepancy increased with age, indicating an Age x Genotype interaction. Conclusion: These results are consistent with population-based studies, and extend the findings to a carefully screened sample that meets inclusion and exclusion criteria for an AD primary prevention trial. The interaction between age and APOE genotype on rate of decline suggests that preclinical disease may be overrepresented in older epsilon4+ individuals. Thus, APOE genotype and age should be considered in the design of AD primary prevention treatment trials. (PsycINFO Database Record (c) 2013 APA, all rights reserved).
PMCID:3831285
PMID: 23876113
ISSN: 0894-4105
CID: 509062
Independent and epistatic effects of variants in VPS10-d receptors on Alzheimer disease risk and processing of the amyloid precursor protein (APP)
Genetic variants in the sortilin-related receptor (SORL1) and the sortilin-related vacuolar protein sorting 10 (VPS10) domain-containing receptor 1 (SORCS1) are associated with increased risk of Alzheimer's disease (AD), declining cognitive function and altered amyloid precursor protein (APP) processing. We explored whether other members of the (VPS10) domain-containing receptor protein family (the sortilin-related VPS10 domain-containing receptors 2 and 3 (SORCS2 and SORCS3) and sortilin (SORT1)) would have similar effects either independently or together. We conducted the analyses in a large Caucasian case control data set (n=11,840 cases, 10,931 controls) to determine the associations between single nucleotide polymorphisms (SNPs) in all the five homologous genes and AD risk. Evidence for interactions between SNPs in the five VPS10 domain receptor family genes was determined in epistatic statistical models. We also compared expression levels of SORCS2, SORCS3 and SORT1 in AD and control brains using microarray gene expression analyses and assessed the effects of these genes on gamma-secretase processing of APP. Several SNPs in SORL1, SORCS1, SORCS2 and SORCS3 were associated with AD. In addition, four specific linkage disequilibrium blocks in SORCS1, SORCS2 and SORCS3 showed additive epistatic effects on the risk of AD (P
PMCID:3669917
PMID: 23673467
ISSN: 2158-3188
CID: 627142
Variants in the ATP-binding cassette transporter (ABCA7), apolipoprotein E 4,and the risk of late-onset Alzheimer disease in African Americans
IMPORTANCE: Genetic variants associated with susceptibility to late-onset Alzheimer disease are known for individuals of European ancestry, but whether the same or different variants account for the genetic risk of Alzheimer disease in African American individuals is unknown. Identification of disease-associated variants helps identify targets for genetic testing, prevention, and treatment. OBJECTIVE: To identify genetic loci associated with late-onset Alzheimer disease in African Americans. DESIGN, SETTING, AND PARTICIPANTS: The Alzheimer Disease Genetics Consortium (ADGC) assembled multiple data sets representing a total of 5896 African Americans (1968 case participants, 3928 control participants) 60 years or older that were collected between 1989 and 2011 at multiple sites. The association of Alzheimer disease with genotyped and imputed single-nucleotide polymorphisms (SNPs) was assessed in case-control and in family-based data sets. Results from individual data sets were combined to perform an inverse variance-weighted meta-analysis, first with genome-wide analyses and subsequently with gene-based tests for previously reported loci. MAIN OUTCOMES AND MEASURES: Presence of Alzheimer disease according to standardized criteria. RESULTS: Genome-wide significance in fully adjusted models (sex, age, APOE genotype, population stratification) was observed for a SNP in ABCA7 (rs115550680, allele = G; frequency, 0.09 cases and 0.06 controls; odds ratio [OR], 1.79 [95% CI, 1.47-2.12]; P = 2.2 x 10(-9)), which is in linkage disequilibrium with SNPs previously associated with Alzheimer disease in Europeans (0.8 < D' < 0.9). The effect size for the SNP in ABCA7 was comparable with that of the APOE 4-determining SNP rs429358 (allele = C; frequency, 0.30 cases and 0.18 controls; OR, 2.31 [95% CI, 2.19-2.42]; P = 5.5 x 10(-47)). Several loci previously associated with Alzheimer disease but not reaching significance in genome-wide analyses were replicated in gene-based analyses accounting for linkage disequilibrium between markers and correcting for number of tests performed per gene (CR1, BIN1, EPHA1, CD33; 0.0005 < empirical P < .001). CONCLUSIONS AND RELEVANCE: In this meta-analysis of data from African American participants, Alzheimer disease was significantly associated with variants in ABCA7 and with other genes that have been associated with Alzheimer disease in individuals of European ancestry. Replication and functional validation of this finding is needed before this information is used in clinical settings.
PMCID:3667653
PMID: 23571587
ISSN: 0098-7484
CID: 627152
Health-Related Resource Use and Costs in Elderly Adults with and without Mild Cognitive Impairment
OBJECTIVES: To assess differences in resource use and cost between older adults with and without mild cognitive impairment (MCI) over time. DESIGN: Multicenter, longitudinal study. SETTING: Sixty-eight Alzheimer's Disease Cooperative Study (ADCS) sites in the United States. PARTICIPANTS: Two hundred fifty-nine individuals diagnosed with MCI and 107 cognitively normal elderly adults followed annually for 3 years. MEASUREMENTS: The Resource Use Instrument (RUI) was used to capture medical and nonmedical care use. Generalized linear latent and mixed models were used to estimate differences in resource use and costs in older adults with and without MCI after controlling for clinical and demographic characteristics. RESULTS: At baseline, average annual direct medical cost per person was substantially higher for participants with MCI ($6,499) than for those without ($2,969) P < .001). Informal care use was also substantially higher (33% vs 8.4%, P < .001). Results from multivariate analyses of longitudinal data show that, after controlling for participant and informant characteristics, direct medical costs were 44% higher for participants with MCI than for those without. Participants with MCI were almost five times as likely to use informal care as those without. Number of medical conditions and older age were associated with higher medical cost. Worse functional and cognitive status, older age, being married, and being female were associated with higher likelihood of informal care use. Having an adult child informant was associated with higher likelihood of using informal care. CONCLUSION: The RUI captured differences in resource use and costs between individuals with and without MCI. Clinicians who care for individuals with MCI should address informal care needs early in the disease course.
PMCID:3928966
PMID: 23414481
ISSN: 0002-8614
CID: 288662
