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1.  Altered Default Mode Network Connectivity in Older Adults with Cognitive Complaints and Amnestic Mild Cognitive Impairment 
Default mode network (DMN) disruption has been reported in Alzheimer’s disease (AD), yet the specific pattern of altered connectivity over the course of prodromal AD remains to be characterized. The aim of this study was to assess DMN connectivity in older adults with informant-verified cognitive complaints (CC) but normal neuropsychological performance compared to individuals with mild cognitive impairment (MCI) and healthy controls (HC). DMN maps were derived from resting-state fMRI using independent component analysis. Group comparisons of DMN connectivity were performed between older adults with MCI (n = 18), CC (n = 23), and HC (n = 16). Both CC and MCI showed decreased DMN connectivity in the right hippocampus compared to HC, with the CC group showing greater connectivity than MCI. These differences survived atrophy correction and correlated with cognitive performance. DMN connectivity appears sensitive to early prodromal neurodegenerative changes associated with AD, notably including pre-MCI individuals with cognitive complaints.
PMCID: PMC3962306  PMID: 23481685
Alzheimer’s disease; cognitive complaints; default mode network; functional connectivity; hippocampus; memory; mild cognitive impairment
2.  Comparing Clinical Profiles in Alzheimer's Disease and Parkinson's Disease Dementia 
Greater understanding of differences in baseline impairment and disease progression in patients with Alzheimer's disease (AD) and Parkinson's disease dementia (PDD) may improve the interpretation of drug effects and the design of future studies.
This was a retrospective analysis of three randomized, double-blind rivastigmine databases (one in PDD, two in AD). Impairment on the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scale, 10-item Neuropsychiatric Inventory (NPI-10) and the ADCS-Clinical Global Impression of Change (CGIC) was compared [standardized difference (Cohen's d), similar if <0.1].
Patients with AD or PDD had similar levels of impairment on the ADAS-cog and NPI-10. Scores on the ADCS-ADL scale (standardized difference = 0.47) and the ADAS-cog memory domain (total, 0.33; items, 0.10-0.58) were higher in AD; PDD patients were more impaired in the language (0.23) and praxis (0.34) domains. AD patients receiving placebo showed greater deterioration on the ADAS-cog (0.14) and improvement on the NPI-10 (0.11) compared with patients with PDD.
Differing patterns of impairment occur in AD and PDD.
PMCID: PMC3808221  PMID: 24174923
Alzheimer's disease; Parkinson's disease dementia; Rivastigmine; Alzheimer's Disease Assessment Scale–cognitive subscale; Alzheimer's Disease Cooperative Study–Activities of Daily Living scale; 10-item Neuropsychiatric Inventory; Alzheimer's Disease Cooperative Study–Clinical Global Impression of Change

3.  Increased β-Amyloid Deposition in Tg-SWDI Transgenic Mouse Brain Following In Vivo Lead Exposure 
Toxicology letters  2012;213(2):211-219.
Previous studies in humans and animals have suggested a possible association between lead (Pb) exposure and the etiology of Alzheimer’s disease (AD). Animals acutely exposed to Pb display an over-expressed amyloid precursor protein (APP) and the ensuing accumulation of beta-amyloid (Aβ) in brain extracellular spaces. This study was designed to examine whether in vivo Pb exposure increased brain concentrations of Aβ, resulting in amyloid plaque deposition in brain tissues. Human Tg-SWDI APP transgenic mice, which genetically over-express amyloid plaques at age of 2-3 months, received oral gavages of 50 mg/kg Pb acetate once daily for 6 wk; a control group of the same mouse strain received the same molar concentration of Na acetate. ELISA results revealed a significant increase of Aβ in the CSF, brain cortex and hippocampus. Immunohistochemistry displayed a detectable increase of amyloid plaques in brains of Pb-exposed animals. Neurobehavioral test using Morris water maze showed an impaired spatial learning ability in Pb-treated mice, but not in C57BL/6 wild type mice with the same age. In vitro studies further uncovered that Pb facilitated Aβ fibril formation. Moreover, the synchrotron X-ray fluorescent studies demonstrated a high level of Pb present in amyloid plaques in mice exposed to Pb in vivo. Taken together, these data indicate that Pb exposure with ensuing elevated Aβ level in mouse brains appears to be associated with the amyloid plaques formation. Pb apparently facilitates Aβ fibril formation and participates in deposition of amyloid plaques.
PMCID: PMC3461595  PMID: 22796588
Lead or Pb; beta-amyloid or Aβ; amyloid plaques; Tg-SWDI mouse; fibril formation; X-ray fluorescence or XRF; hippocampus
4.  Tau Phosphorylation Pathway Genes and Cerebrospinal Fluid Tau Levels in Alzheimer’s Disease 
Alzheimer’s disease (AD) is characterized by the presence in the brain of amyloid plaques, consisting predominately of the amyloid β peptide (Aβ), and neurofibrillary tangles, consisting primarily of tau. Hyper-phosphorylated-tau (p-tau) contributes to neuronal damage, and both p-tau and total-tau (t-tau) levels are elevated in AD cerebrospinal fluid (CSF) compared to cognitively normal controls. Our hypothesis was that increased ratios of CSF phosphorylated-tau levels relative to total-tau levels correlate with regulatory region genetic variation of kinase or phosphatase genes biologically associated with the phosphorylation status of tau. Eighteen SNPs located within 5′ and 3′ regions of 5 kinase and 4 phosphatase genes, as well as two SNPs within regulatory regions of the MAPT gene were chosen for this analysis. The study sample consisted of 101 AD patients and 169 cognitively normal controls. Rs7768046 in the FYN kinase gene and rs913275 in the PPP2R4 phosphatase gene were both associated with CSF p-tau and t-tau levels in AD. These SNPs were also differentially associated with either CSF t-tau (rs7768046) or CSF p-tau (rs913275) relative to t-tau levels in AD compared to controls. These results suggest that rs7768046 and rs913275 both influence CSF tau levels in an AD-associated manner.
PMCID: PMC3626266  PMID: 22927204
5.  Multiple SNPs Within and Surrounding the Apolipoprotein E Gene Influence Cerebrospinal Fluid Apolipoprotein E Protein Levels 
The ε4 allele of the apolipoprotein E gene (APOE) is associated with increased risk and earlier age at onset in late onset Alzheimer’s disease (AD). Other factors, such as expression level of apolipoprotein E protein (apoE), have been postulated to modify the APOE related risk of developing AD. Multiple loci in and outside of APOE are associated with a high risk of AD. The aim of this exploratory hypothesis generating investigation was to determine if some of these loci predict cerebrospinal fluid (CSF) apoE levels in healthy non-demented subjects. CSF apoE levels were measured from healthy non-demented subjects 21–87 years of age (n = 134). Backward regression models were used to evaluate the influence of 21 SNPs, within and surrounding APOE, on CSF apoE levels while taking into account age, gender, APOE ε4 and correlation between SNPs (linkage disequilibrium). APOE ε4 genotype does not predict CSF apoE levels. Three SNPs within the TOMM40 gene, one APOE promoter SNP and two SNPs within distal APOE enhancer elements (ME1 and BCR) predict CSF apoE levels. Further investigation of the genetic influence of these loci on apoE expression levels in the central nervous system is likely to provide new insight into apoE regulation as well as AD pathogenesis.
PMCID: PMC3192652  PMID: 18430993
Apolipoprotein E gene; apolipoprotein E protein; cerebroshinal fluid; enhancer; promoter; SNP
6.  Should the ApoE genotype be a covariate for clinical trials in Alzheimer disease? 
Should the apolipoprotein E (ApoE) genotype be a covariate for clinical trials in Alzheimer disease (AD)? ApoE is a transport protein for lipids, amyloid-beta proteins, and the different phenotypes differentially affect amyloid-beta deposition, neurofibrillary tangle formation, and microglial activation. The ApoE genotype has not affected efficacy in short symptomatic AD trials. ApoE4 has been associated with greater efficacy in at least two mild cognitive impairment studies. Vasogenic edema was more frequent in ApoE4 AD patients treated with a monoclonal antibody to amyloid beta. Since there is evidence that the ApoE genotype may differentially affect disease mechanisms, efficacy, and adverse effects in both AD and mild cognitive impairment trials, the ApoE genotype should be included as a covariate in future studies.
PMCID: PMC2919695  PMID: 20537201
7.  Effectiveness and Tolerability of High-Dose (23 mg/d) Versus Standard-Dose (10 mg/d) Donepezil in Moderate to Severe Alzheimer’s Disease: A 24-Week, Randomized, Double-Blind Study 
Clinical therapeutics  2010;32(7):1234-1251.
Currently approved Alzheimer’s disease (AD) treatments have been reported to provide symptomatic benefit, without proven impact on clinical progression. We hypothesized that the loss of initial therapeutic benefit over time may be mitigated by higher doses of a cholinesterase inhibitor.
The aim of this study was to determine the effectiveness and tolerability of increasing donepezil from 10 to 23 mg/d in patients with moderate to severe AD.
This randomized, double-blind study was conducted at 219 sites in Asia, Europe, Australia, North America, South Africa, and South America from June 6, 2007, to March 27, 2009. Patients aged 45 to 90 years with probable AD, Mini-Mental State Examination score 0 to 20 (moderate to severe impairment), and who were receiving donepezil 10 mg once daily for ≥12 weeks before the start of the study were eligible. Patients (n = 1467) were randomly assigned to receive high-dose donepezil (23 mg once daily) or standard-dose donepezil (10 mg once daily) for 24 weeks. Coprimary effectiveness measures were changes in cognition and global functioning, as assessed using least squares mean changes from baseline (LSM [SE] Δ) scores (last observation carried forward) on the Severe Impairment Battery (SIB; cognition) and the Clinician’s Interview-Based Impression of Change Plus Caregiver Input scale (CIBIC+; global function rating) overall change score (mean [SD]) at week 24. Treatment-emergent adverse events (TEAEs) were assessed using spontaneous patient/caregiver reporting and open-ended questioning; clinical laboratory testing (hematology, biochemistry, and urinalysis panels analyzed by a central laboratory); 12-lead ECG; and physical and neurologic examinations, including vital sign measurements.
The effectiveness analyses included 1371 patients (mean age, 73.8 years; 62.8% female; 73.5% white; weight range, 34.0–138.7 kg). A total of 296 of 981 patients (30.2%) withdrew from the donepezil 23-mg/d group; 87 of 486 patients (17.9%) withdrew from the donepezil 10-mg/d group. At study end (week 24), the LSM (SE) Δ in SIB score was significantly greater with donepezil 23 mg/d than with donepezil 10 mg/d (+2.6 [0.58] vs +0.4 [0.66], respectively; difference, 2.2; P < 0.001). The between-treatment difference in CIBIC+ score was nonsignificant (4.23 [1.07] vs 4.29 [1.07]). In post hoc analysis, LSM Δ in SIB score and CIBIC+ treatment effect at end point were greater with donepezil 23 mg/d than 10 mg/d in patients with more advanced AD compared with less impaired patients (SIB, +1.6 [0.78] vs −1.5 [0.88], respectively [P < 0.001]; CIBIC+, 4.31 [1.09] vs 4.42 [1.10] [P = 0.028]). TEAEs were reported in 710 of 963 patients (73.7%) who received donepezil 23 mg/d and in 300 of 471 patients (63.7%) who received donepezil 10 mg/d. With donepezil 23 mg/d, mild, moderate, and severe TEAEs were reported in 297 (30.8%), 332 (34.5%), and 81 (8.4%) patients, respectively; with donepezil 10 mg/d, these proportions were 147 (31.2%), 119 (25.3%), and 34 (7.2%). The 3 most common severe AEs reported with the 23-mg/d dose were nausea (9 patients [0.9%] vs 1 [0.2%] with the 10-mg/d dose), dizziness (7 [0.7%] vs 1 [0.2%]), and vomiting (6 [0.6%] vs 0). The most commonly reported TEAEs considered probably related to treatment with the 23-mg/d dose were nausea (59 patients [6.1%] vs 9 [1.9%] with the 10-mg/d dose), vomiting (48 [5.0%] vs 4 [0.8%]), and diarrhea (31 [3.2%] vs 7 [1.5%]). Thirteen deaths were reported during the study or within 30 days of study discontinuation (23 mg/d, 8 patients [0.8%]; 10 mg/d, 5 patients [1.1%]); all were considered unrelated to the study medication.
In this study in patients with moderate to severe AD, donepezil 23 mg/d was associated with greater benefits in cognition compared with donepezil 10 mg/d. The between-treatment difference in global functioning was not significant in the overall population. Patients with more advanced AD appeared to benefit from donepezil 23 mg/d on the assessment of global functioning, but this observation requires additional studies for confirmation.
PMCID: PMC3068609  PMID: 20678673
Alzheimer’s disease; cognitive disorders; dementia; randomized controlled clinical trials
8.  Differences in Medication Use in the Alzheimer's Disease Neuroimaging Initiative 
Drugs & aging  2010;27(8):677-686.
The ADNI (Alzheimer's Disease Neuroimaging Initiative) is a large longitudinal study of patients with probable Alzheimer's disease (AD), patients with mild cognitive impairment (MCI) and healthy elderly controls followed for at least 2–3 years. Many participants in the ADNI are being treated with medications, and these may have beneficial or deleterious effects.
The goal of the study was to characterize baseline medication use in the ADNI.
Diagnosis, demographics, medication status, psychometric data and MRI measures of hippocampal volume and entorhinal cortex thickness were obtained for 818 participants from the ADNI cohort. Total number of medications, Beers list (potentially dangerous) medications and AD treatments were also tabulated. ANOVA and logistic regression were used to assess associations between baseline pharmacotherapy and diagnosis, demographics, and selected clinical and MRI variables.
Of the 818 enrolled ADNI participants, 809 were available for analysis in the present study, including 184 patients with AD, 399 patients with MCI and 226 healthy elderly controls. Significant gender differences in recruitment were observed in the MCI group. The average number of medications per participant was 8 (SD 4) and 22% reported treatment with one or more Beers list medications. For symptomatic treatment of MCI or AD, donepezil and memantine were the most commonly reported drugs. As expected, MCI and AD patients with more severe impairment were more likely to be treated. Men received treatment more frequently than women. Older subjects and those with less education were less likely to receive treatment.
AD and MCI participants from the ADNI cohort were being treated with polypharmacy and many were also taking one or more medications with the potential for adverse effects. Off-label use of cholinesterase inhibitors and/or memantine for MCI was common, with more severely affected patients most likely to receive treatment. Differences in the frequency of symptomatic treatment were also observed as a function of age, years of education, gender and disease severity.
PMCID: PMC2951125  PMID: 20658795
9.  Correlation of Clinical Features with Argyrophilic Grains at Autopsy 
Argyrophilic grains (AGs) are a pathologic feature found in association with neurodegenerative disease. Some have suggested that these features may occur as a distinctive condition. We reviewed 80 subjects from our tissue bank with pathologically confirmed AGs and identified their clinical features. We compared these subjects' features to the features of subjects with matched clinical diagnoses but without AGs. Subjects with AGs represented 21.7% of the entire autopsy sample from 1999 through 2005 (80/367). Of AD subjects, 43 /233 had AGs (18.4% of AD subjects); 11 /42 PD-D subjects had AGs (26.1% of PDD subjects); 2 / 9 DLB subjects had AGs (22.2% of DLB subjects); 4 /15 MCI subjects had AGs (26.7% of MCI subjects); and 20 /68 cognitively normal subjects had AGs (29.4% of NC). Subjects with AGs tended to be older but only significantly so in AD. Many co-morbid non-neurological health conditions were seen in cases of AGs without any single predilection emerging. AGs occur in approximately 22% of the entire autopsy cohort and likely are associated with advanced age. No distinctive antemortem clinical features were overrepresented in the AG cases. AGs can occur with or without neurodegenerative conditions and can occur in the absence of significant cognitive decline. AGs are not clearly associated with any single co-morbid health condition.
PMCID: PMC2760041  PMID: 19812464
Argyrophilic grains; dementia; neurodegeneration; neuropathology
10.  Duplication within the SEPT9 gene associated with a founder effect in North American families with hereditary neuralgic amyotrophy 
Human Molecular Genetics  2009;18(7):1200-1208.
Hereditary neuralgic amyotrophy (HNA) is an autosomal dominant disorder associated with recurrent episodes of focal neuropathy primarily affecting the brachial plexus. Point mutations in the SEPT9 gene have been previously identified as the molecular basis of HNA in some pedigrees. However in many families, including those from North America demonstrating a genetic founder haplotype, no sequence mutations have been detected. We report an intragenic 38 Kb SEPT9 duplication that is linked to HNA in 12 North American families that share the common founder haplotype. Analysis of the breakpoints showed that the duplication is identical in all pedigrees, and molecular analysis revealed that the duplication includes the 645 bp exon in which previous HNA mutations were found. The SEPT9 transcript variants that span this duplication contain two in-frame repeats of this exon, and immunoblotting demonstrates larger molecular weight SEPT9 protein isoforms. This exon also encodes for a majority of the SEPT9 N-terminal proline rich region suggesting that this region plays a role in the pathogenesis of HNA.
PMCID: PMC2722193  PMID: 19139049
11.  Phase II safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer's disease 
Archives of neurology  2008;65(8):1031-1038.
Evaluate the safety, tolerability and amyloid beta (Aβ) response to a γ-secretase inhibitor (LY450139) in Alzheimer's disease.
Multi-center, randomized, double-blind, dose-escalation, placebo-controlled trial.
Community based clinical research centers.
51 participants with mild to moderate AD were randomized (placebo=15, 100mg=22, 140mg=14), with 43 completing the treatment phase.
Subjects randomized to LY450139 received 60mg daily for 2 weeks followed by 100mg for 6 weeks, then re-randomized to 100mg or 140mg for 6 additional weeks.
Main Outcome Measures
Primary outcome measures consisted of adverse events, plasma and cerebrospinal fluid Aβ levels, vital signs, electrocardiogram data, and laboratory safety tests. Secondary outcome measures included the ADAS-cognitive subscale and the ADCS-Activities of Daily Living scale.
Group differences were seen in “skin and subcutaneous tissue” complaints (p=0.052). These included 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse-event-related discontinuations, including one report of transient bowel obstruction. Plasma Aβ40 was reduced by 58.2% for the 100mg group and 64.6% for the 140mg group (P<0.001). No significant reduction was seen in CSF Aβ. No group differences were seen in cognitive or functional measures.
LY450139 was generally well tolerated at doses of up to 140mg taken daily for 14 weeks with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Aβ concentrations were consistent with inhibition of γ-secretase.
PMCID: PMC2682361  PMID: 18695053
Alzheimer's disease; amyloid; gamma secretase; clinical trial
12.  In vivo and Postmortem Clinicoanatomical Correlations in Frontotemporal Dementia and Parkinsonism Linked to Chromosome 17 
Neuro-Degenerative Diseases  2008;5(3-4):215-217.
Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) is associated with mutations in the Microtubule-Associated Protein Tau(MAPT) gene or the Progranulin(PGRN) gene. MAPT mutations lead to widespread deposition of hyperphosphorylated tau protein (FTDP-17T). PGRN mutations are associated with ubiquitin- and TDP-43-positive inclusions in the frontotemporal cortex, striatum and hippocampus (FTDP-17U). Despite the differences, FTDP-17T and FTDP-17U share a largely overlapping clinical phenotype.
To determine whether neuroimaging studies may allow an in vivo early differentiation between FTDP-17T and FTDP-17U.
We studied 25 individuals affected with FTDP-17T associated with either the exon 10+3 (24 subjects) or the G335S (1 subject) MAPT mutation, as well as 3 FTDP-17U individuals, who were carriers of the A9D, IVS6-2A>G or R493X PGRN mutation. Neuroimaging studies, obtained along the course of the disease, were compared to the neuropathologic findings.
FTDP-17T cases were associated with symmetric frontotemporal atrophy. Behavioral changes constituted the predominant clinical presentation. Conversely, an asymmetric degenerative process was seen in all 3 PGRN cases, who presented with either corticobasal syndrome (A9D) or frontotemporal dementia and language deterioration (IVS6-2A>G and R493X).
Neuroimaging data, in the early disease stage of FTDP-17, may offer the possibility of an early differentiation of FTDP-17T and FTDP-17U phenotypes, independent of the genetic analysis.
PMCID: PMC2826454  PMID: 18322394
Frontotemporal dementia and parkinsonism linked to chromosome 17; Tau; Ubiquitin; TDP-43; Neuropathology
13.  The tauopathy associated with mutation +3 in intron 10 of Tau: characterization of the MSTD family 
Brain  2007;131(1):72-89.
Multiple system tauopathy with presenile dementia (MSTD) is an inherited disease caused by a (g) to (a) transition at position +3 in intron 10 of Tau. It belongs to the spectrum of frontotemporal dementia and parkinsonism linked to chromosome 17 with mutations in Tau (FTDP-17T). Here we present the longitudinal clinical, neuropsychological, neuroimaging, neuropathological, biochemical and genetic characterization of the MSTD family. Presenting signs were consistent with the behavioural variant of frontotemporal dementia in 17 of 21 patients. Two individuals presented with an atypical form of progressive supranuclear palsy and two others with either severe postural imbalance or an isolated short-term memory deficit. Memory impairment was present at the onset in 15 patients, with word finding difficulties and stereotyped speech also being common. Parkinsonism was first noted 3 years after the onset of symptoms. Neuroimaging showed the most extensive grey matter loss in the hippocampus, parahippocampal gyrus and frontal operculum/insular cortex of the right hemisphere and, to a lesser extent, in the anterior cingulate gyrus, head of the caudate nucleus and the posterolateral orbitofrontal cortex and insular cortex bilaterally. Neuropathologically, progressive nerve cell loss, gliosis and coexistent neuronal and/or glial deposits consisting mostly of 4-repeat tau were present in frontal, cingulate, temporal and insular cortices, white matter, hippocampus, parahippocampus, basal ganglia, selected brainstem nuclei and spinal cord. Tau haplotyping indicated that specific haplotypes of the wild-type allele may act as modifiers of disease presentation. Quantitative neuroimaging has been used to analyse the progression of atrophy in affected individuals and for predicting disease onset in an asymptomatic mutation carrier. This multidisciplinary study provides a comprehensive description of the natural history of disease in one of the largest known families with FTDP-17T.
PMCID: PMC2702832  PMID: 18065436
frontotemporal dementia; progressive supranuclear palsy; hippocampus; voxel-based morphometry; Tau haplotype
14.  Rivastigmine: an open-label, observational study of safety and effectiveness in treating patients with Alzheimer's disease for up to 5 years 
BMC Geriatrics  2005;5:3.
Rivastigmine, a butyl- and acetylcholinesterase inhibitor, is approved for symptomatic treatment of Alzheimer's disease (AD). Data supporting the safety and efficacy of second-generation cholinesterase inhibitors, such as rivastigmine, are available for treatment up to 1 year, with limited data up to 2 1/2 years. The purpose of this report is to present safety and effectiveness data for rivastigmine therapy in patients with mild to moderately severe AD receiving treatment for up to 5 years.
An observational approach was used to study 37 patients with originally mild to moderate AD receiving rivastigmine as a therapy for AD in an open-label extension (ENA713, B352 Study Group, 1998).
The initial trial demonstrated rivastigmine was well-tolerated and effective in terms of cognition, global functioning and activities of daily living. In this open label extension, high-dose rivastigmine therapy was safe and well tolerated over a 5-year period. Two thirds of the participants still enrolled at week 234 were in the original high-dose rivastigmine group during the double-blind phase, suggesting that early therapy may confer some benefit in delaying long-term progression of symptoms.
Long-term cholinesterase inhibition therapy with rivastigmine was well tolerated, with no dropouts due to adverse effects past the initial titration period. Early initiation of treatment, with titration to high-dose therapy, may have an advantage in delaying progression of the illness.
PMCID: PMC548267  PMID: 15659242
15.  Influence of Genetic Variation on Plasma Protein Levels in Older Adults Using a Multi-Analyte Panel 
PLoS ONE  2013;8(7):e70269.
Proteins, widely studied as potential biomarkers, play important roles in numerous physiological functions and diseases. Genetic variation may modulate corresponding protein levels and point to the role of these variants in disease pathophysiology. Effects of individual single nucleotide polymorphisms (SNPs) within a gene were analyzed for corresponding plasma protein levels using genome-wide association study (GWAS) genotype data and proteomic panel data with 132 quality-controlled analytes from 521 Caucasian participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Linear regression analysis detected 112 significant (Bonferroni threshold p = 2.44×10−5) associations between 27 analytes and 112 SNPs. 107 out of these 112 associations were tested in the Indiana Memory and Aging Study (IMAS) cohort for replication and 50 associations were replicated at uncorrected p<0.05 in the same direction of effect as those in the ADNI. We identified multiple novel associations including the association of rs7517126 with plasma complement factor H-related protein 1 (CFHR1) level at p<1.46×10−60, accounting for 40 percent of total variation of the protein level. We serendipitously found the association of rs6677604 with the same protein at p<9.29×10−112. Although these two SNPs were not in the strong linkage disequilibrium, 61 percent of total variation of CFHR1 was accounted for by rs6677604 without additional variation by rs7517126 when both SNPs were tested together. 78 other SNP-protein associations in the ADNI sample exceeded genome-wide significance (5×10−8). Our results confirmed previously identified gene-protein associations for interleukin-6 receptor, chemokine CC-4, angiotensin-converting enzyme, and angiotensinogen, although the direction of effect was reversed in some cases. This study is among the first analyses of gene-protein product relationships integrating multiplex-panel proteomics and targeted genes extracted from a GWAS array. With intensive searches taking place for proteomic biomarkers for many diseases, the role of genetic variation takes on new importance and should be considered in interpretation of proteomic results.
PMCID: PMC3720913  PMID: 23894628
16.  Temporoparietal hypometabolism is common in FTLD and is associated with imaging diagnostic errors 
Archives of neurology  2010;68(3):329-337.
To evaluate the cause of diagnostic errors in the visual interpretation of positron emission tomography scans with 18F-fluorodeoxyglucose (FDG-PET) in patients with frontotemporal lobar degeneration (FTLD) and Alzheimer's disease (AD).
Twelve trained raters unaware of clinical and autopsy information independently reviewed FDG-PET scans and provided their diagnostic impression and confidence of either FTLD or AD. Six of these raters also recorded whether metabolism appeared normal or abnormal in 5 predefined brain regions in each hemisphere – frontal cortex, anterior cingulate cortex, anterior temporal cortex, temporoparietal cortex and posterior cingulate cortex. Results were compared to neuropathological diagnoses.
Academic medical centers
45 patients with pathologically confirmed FTLD (n=14) or AD (n=31)
Raters had a high degree of diagnostic accuracy in the interpretation of FDG-PET scans; however, raters consistently found some scans more difficult to interpret than others. Unanimity of diagnosis among the raters was more frequent in patients with AD (27/31, 87%) than in patients with FTLD (7/14, 50%) (p = 0.02). Disagreements in interpretation of scans in patients with FTLD largely occurred when there was temporoparietal hypometabolism, which was present in 7 of the 14 FTLD scans and 6 of the 7 lacking unanimity. Hypometabolism of anterior cingulate and anterior temporal regions had higher specificities and positive likelihood ratios for FTLD than temporoparietal hypometabolism had for AD.
Temporoparietal hypometabolism in FTLD is common and may cause inaccurate interpretation of FDG-PET scans. An interpretation paradigm that focuses on the absence of hypometabolism in regions typically affected in AD before considering FTLD is likely to misclassify a significant portion of FTLD scans. Anterior cingulate and/or anterior temporal hypometabolism indicates a high likelihood of FTLD, even when temporoparietal hypometabolism is present. Ultimately, the accurate interpretation of FDG-PET scans in patients with dementia cannot rest on the presence or absence of a single region of hypometabolism, but must take into account the relative hypometabolism of all brain regions.
PMCID: PMC3058918  PMID: 21059987

Results 1-16 (16)