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Background and ObjectivesThe goal of this work was to investigate the neuroimaging correlates of the Stages of Objective Memory Impairment (SOMI) system operationalized with the Free and Cued Selective Reminding Test (FCSRT), a widely used episodic memory measure.MethodsThe FCSRT begins with a study phase in which items (e.g., grapes) are identified in response to unique semantic cues (e.g., fruit) that are used in the test phase to prompt recall of items not retrieved by free recall. There are 3 test trials of the 16 items (maximum 48). Data from 4,484 cognitively unimpaired participants from the Anti-Amyloid Treatment in Asymptomatic Alzheimer's (A4) study were used. All participants had amyloid PET imaging, and a subset of 1,262 β-amyloid (Aβ)–positive had structural MRIs. We compared the Aβ mean cortical standardized uptake value ratio (SUVR) and volumetric measures of hippocampus, parahippocampal gyrus, entorhinal cortex, and inferior temporal cortex between the 5 SOMI stages.ResultsParticipants had a mean age of 71.3 (SD 4.6) years; 40.6% were male; and 34.6% were APOE ε4 positive. Half had no memory impairment; the other half had retrieval deficits, storage limitations, or both. Analysis of covariance in the entire sample while controlling for age, sex, education, and APOE ε4 showed that individuals in higher SOMI stages had higher global amyloid SUVR (p < 0.001). Both SOMI-4 and -3 subgroups had higher amyloid SUVR than SOMI-0 and SOMI-1 subgroups. Individuals in higher SOMI stages had smaller hippocampal volume (p = 0.003), entorhinal cortex (p < 0.05), and inferior temporal lobes (p < 0.05), but there was no difference between parahippocampal gyrus volume of different SOMI stages. Pairwise comparison of SOMI subgroups showed that the SOMI-4, -3, and -2 subgroups had smaller hippocampal volume than the SOMI-0 and -1 subgroup. The SOMI-4 subgroup had significantly smaller entorhinal cortex and smaller inferior temporal lobe compared to all other groups.DiscussionPresence of Alzheimer disease pathology is closely related to memory impairment according to SOMI stages in the cognitively unimpaired sample of A4. Results from structural MRIs suggest that memory storage impairment (SOMI-3 and -4) is present when there is widespread medial temporal lobe atrophy.Trial Registration InformationClinicalTrials.gov identifier: NCT02008357.Classification of EvidenceThis study provides Class I evidence that, in normal older individuals, higher stages of memory impairment assessed with FCSRT were associated with higher amyloid imaging burden and lower volume of hippocampus, entorhinal cortex, and inferior temporal lobes.

Objective: To determine whether vitamin E would slow the progression of cognitive deterioration and dementia in aging persons with Down syndrome (DS). Methods: A randomized, double-blind controlled clinical trial was conducted at 21 clinical sites, and researchers trained in research procedures recruited adults with DS older than 50 years to participate. Participants were randomly assigned to receive 1,000 IU of vitamin E orally twice daily for 3 years or identical placebo. The primary outcome was change on the Brief Praxis Test (BPT). Secondary outcomes included incident dementia and measures of clinical global change, cognition, function, and behavior. Results: A total of 337 individuals were randomized, 168 to vitamin E and 169 to placebo. Both groups demonstrated deterioration on the BPT with no difference between drug and placebo. At baseline, 26% were diagnosed with dementia and there was an overall rate of incident dementia of 11%/year with no difference between groups. There was no effect on the secondary outcome measures. Though numerically higher in the treatment group, there was no difference in the number of adverse events ( p = 0.079) and deaths ( p = 0.086) between groups. Conclusions: Vitamin E did not slow the progression of cognitive deterioration in older individuals with DS. Classification of evidence: This study provides Class II evidence that vitamin E does not significantly slow the progression of cognitive deterioration in aging persons with DS.

ObjectiveTo study longitudinal relationships between type 2 diabetes mellitus (T2DM), cortical thickness, and cognitive function in older people with normal cognition, mild cognitive impairment, and Alzheimer disease (AD).MethodsThe sample was derived from the Alzheimer's Disease Neuroimaging Initiative cohort who underwent brain MRI and cognitive tests annually for 5 years. Presence of T2DM was based on fasting blood glucose ≥7.0mml/L or the use of glucose-lowering agents. We used latent growth curve modeling to explore longitudinal relationships between T2DM, cortical thickness, and cognitive function, adjusting for relevant covariates and testing for interactions.ResultsThere were 124 people with T2DM (mean age 75.5 years, SD 6.2) and 693 without T2DM (mean age 75.1 years, SD 6.9) with at least 1 MRI available. AD and lower cortical thickness at study entry was associated with a lower chance of having a MRI available at each follow-up phase (all p < 0.001). T2DM was associated with lower baseline cortical thickness (p = 0.01). We found no direct effect of T2DM on decline in cortical thickness or cognitive function, but there was an indirect pathway linking T2DM and cognitive decline via baseline cortical thickness (β = −0.17, p = 0.022). There was an interaction between T2DM and education whereby the negative effect of T2DM on baseline cortical thickness was reduced in those with greater education (β = 0.34, p = 0.037). These associations changed minimally when adjusted for baseline cognitive diagnosis.ConclusionsIn an older cohort with low cerebrovascular disease burden, T2DM contributes to cognitive decline via neurodegeneration. Prior brain and cognitive reserve may protect against this effect.

The negative results of the IV immunoglobulin trial in mild to moderate Alzheimer disease (AD) dementia1 raised a number of questions for the AD immunotherapy field. Do naturally occurring antibodies have advantages over monoclonal antibodies; if so, how can the advantages be leveraged? What dose and frequency is necessary for benefit? What stage of the AD continuum is optimal for pooled immunoglobulin therapy?

Objective To examine safety, tolerability, and efficacy of PF-04494700, an inhibitor of the receptor for advanced glycation end products (RAGE), in mild to moderate Alzheimer disease (AD). Methods Double-blind, placebo-controlled trial at 40 academic centers (United States). Subjects with AD and Mini-Mental State Examination score 14-26 were randomized to PF-04494700 60 mg/day × 6 days, then 20 mg daily (high dose); 15 mg/day × 6 days, then 5 mg daily (low dose); or placebo, for 18 months. Clinical and laboratory measures were used to evaluate safety and tolerability. The primary efficacy measure was the Alzheimer's Disease Assessment Scale-cognitive (ADAS-cog). Secondary measures assessed clinical stage, function, behavior, MRI, and CSF biomarkers. Results A total of 399 subjects were randomized. In a prespecified interim analysis, when 50% of subjects had completed the 6-month visit, the high dose was associated with confusion, falls, and greater ADAS-cog decline and was discontinued. A second prespecified analysis compared low-dose and placebo groups for futility and safety approximately 12 months after all subjects were randomized. This analysis met criteria for futility, and treatment was discontinued. There were no safety concerns in the low-dose group. Analyses including post-futility data showed decreased decline on the ADAS-cog in the low-dose group at month 18. Other clinical and biomarker measures showed no differences between low-dose treatment and placebo. Conclusions PF-04494700 at 20 mg/d was associated with increased adverse events and cognitive decline. At 5 mg/d, PF-04494700 had a good safety profile. A potential benefit for this low dose on the ADAS-cog is not conclusive, because of high dropout and discontinuation rates subsequent to the interim analyses. Classification of evidence This study provides Class I evidence that in patients with AD high-dose PF-04494700 increased cognitive decline at 6 months and Class IV evidence that low-dose PF-04494700 slowed cognitive decline at 18 months.

Objective:We tested biweekly infusions of IV immunoglobulin (IVIg) as a possible treatment for mild to moderate Alzheimer disease (AD) dementia.Methods:In a phase 3, double-blind, placebo-controlled trial, we randomly assigned 390 participants with mild to moderate AD to receive placebo (low-dose albumin) or IVIg (Gammagard Liquid; Baxalta, Bannockburn, IL) administered IV at doses of 0.2 or 0.4 g/kg every 2 weeks for 18 months. The primary cognitive outcome was change from baseline to 18 months on the 11-item cognitive subscale of the Alzheimer's Disease Assessment Scale; the primary functional outcome was 18-month change on the Alzheimer's Disease Cooperative Study–Activities of Daily Living Inventory. Safety and tolerability data, as well as serial MRIs and plasma samples, were collected throughout the study from all enrolled participants.Results:No beneficial effects were observed in the dual primary outcome measures for the 2 IVIg doses tested. Significant decreases in plasma Aβ42 (but not Aβ40) levels were observed in IVIg-treated participants. Analysis of safety data showed no difference between IVIg and placebo in terms of the rate of occurrence of amyloid-related imaging abnormalities (brain edema or microhemorrhage). IVIg-treated participants had more systemic reactions (chills, rashes) but fewer respiratory infections than participants receiving placebo.Conclusions:Participants with mild to moderate AD showed good tolerability of treatment with low-dose human IVIg for 18 months but did not show beneficial effects on cognition or function relative to participants who received placebo.Clinicaltrials.gov identifier:NCT00818662.Classification of evidence:This study provides Class II evidence that IVIg infusions performed every 2 weeks do not improve cognition or function at 18 months in patients with mild to moderate AD.

Background: Lowering cholesterol is associated with reduced CNS amyloid deposition and increased dietary cholesterol increases amyloid accumulation in animal studies. Epidemiologic data suggest that use of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) may decrease the risk of Alzheimer disease (AD) and a single-site trial suggested possible benefit in cognition with statin treatment in AD, supporting the hypothesis that statin therapy is useful in the treatment of AD. Objective: To determine if the lipid-lowering agent simvastatin slows the progression of symptoms in AD. Methods: This randomized, double-blind, placebo-controlled trial of simvastatin was conducted in individuals with mild to moderate AD and normal lipid levels. Participants were randomly assigned to receive simvastatin, 20 mg/day, for 6 weeks then 40 mg per day for the remainder of 18 months or identical placebo. The primary outcome was the rate of change in the Alzheimer’s Disease Assessment Scale–cognitive portion (ADAS-Cog). Secondary outcomes measured clinical global change, cognition, function, and behavior. Results: A total of 406 individuals were randomized: 204 to simvastatin and 202 to placebo. Simvastatin lowered lipid levels but had no effect on change in ADAS-Cog score or the secondary outcome measures. There was no evidence of increased adverse events with simvastatin treatment. Conclusion: Simvastatin had no benefit on the progression of symptoms in individuals with mild to moderate AD despite significant lowering of cholesterol. Classification of evidence: This study provides Class I evidence that simvastatin 40 mg/day does not slow decline on the ADAS-Cog. Neurology ® 2011;77:556–563

Objectives: CSF levels of Aβ 1-42 , t-tau, and p-tau 181p are potential early diagnostic markers for probable Alzheimer disease (AD). The influence of genetic variation on these markers has been investigated for candidate genes but not on a genome-wide basis. We report a genome-wide association study (GWAS) of CSF biomarkers (Aβ 1-42 , t-tau, p-tau 181p , p-tau 181p /Aβ 1-42 , and t-tau/Aβ 1-42 ). Methods: A total of 374 non-Hispanic Caucasian participants in the Alzheimer9s Disease Neuroimaging Initiative cohort with quality-controlled CSF and genotype data were included in this analysis. The main effect of single nucleotide polymorphisms (SNPs) under an additive genetic model was assessed on each of 5 CSF biomarkers. The p values of all SNPs for each CSF biomarker were adjusted for multiple comparisons by the Bonferroni method. We focused on SNPs with corrected p p −8 ) and secondarily examined SNPs with uncorrected p values less than 10 −5 to identify potential candidates. Results: Four SNPs in the regions of the APOE , LOC100129500, TOMM40 , and EPC2 genes reached genome-wide significance for associations with one or more CSF biomarkers. SNPs in CCDC134 , ABCG2 , SREBF2 , and NFATC4 , although not reaching genome-wide significance, were identified as potential candidates. Conclusions: In addition to known candidate genes, APOE , TOMM40 , and one hypothetical gene LOC100129500 partially overlapping APOE ; one novel gene, EPC2 , and several other interesting genes were associated with CSF biomarkers that are related to AD. These findings, especially the new EPC2 results, require replication in independent cohorts.

Objective: To compare the annual change in MRI and CSF biomarkers in cognitively normal (CN), amnestic mild cognitive impairment (aMCI), and Alzheimer disease (AD). Comparisons were based on intergroup discrimination, correlation with concurrent cognitive/functional changes, relationships to APOE genotype, and sample sizes for clinical trials.Methods: We used data from the Alzheimer's Disease Neuroimaging Initiative study consisting of CN, aMCI, and AD cohorts with both baseline and 12-month follow-up CSF and MRI. The annual change in CSF (total-tau [t-tau], Aβ1-42) and MRI (change in ventricular volume) was obtained in 312 subjects (92 CN, 149 aMCI, 71 AD).Results: There was no significant average annual change in either CSF biomarker in any clinical group except t-tau in CN; moreover, the annual change did not differ by clinical group in pairwise comparisons. In contrast, annual increase in ventricular volume increased in the following order, AD > aMCI > CN, and differences were significant between all clinical groups in pairwise comparisons. Ventricular volume increase correlated with concurrent worsening on cognitive/functional indices in aMCI and AD whereas evidence of a similar correlation with change in CSF measures was unclear. The annual changes in MRI differed by APOE ε4 status overall and among aMCI while annual changes in CSF biomarkers did not. Estimated sample sizes for clinical trials are notably less for MRI than the CSF or clinical measures.Conclusions: Unlike the CSF biomarkers evaluated, changes in serial structural MRI are correlated with concurrent change on general cognitive and functional indices in impaired subjects, track with clinical disease stage, and are influenced by APOE genotype.

Objective: To compare volumetric MRI of whole brain and medial temporal lobe structures to clinical measures for predicting progression from amnestic mild cognitive impairment (MCI) to Alzheimer disease (AD). Methods: Baseline MRI scans from 129 subjects with amnestic MCI were obtained from participants in the Alzheimer9s Disease Cooperative Study group9s randomized, placebo-controlled clinical drug trial of donepezil, vitamin E, or placebo. Measures of whole brain, ventricular, hippocampal, and entorhinal cortex volumes were acquired. Participants were followed with clinical and cognitive evaluations until formal criteria for AD were met, or completion of 36 months of follow-up. Logistic regression modeling was done to assess the predictive value of all MRI measures, risk factors such as APOE genotype, age, family history of AD, education, sex, and cognitive test scores for progression to AD. Least angle regression modeling was used to determine which variables would produce an optimal predictive model, and whether adding MRI measures to a model with only clinical measures would improve predictive accuracy. Results: Of the four MRI measures evaluated, only ventricular volumes and hippocampal volumes were predictive of progression to AD. Maximal predictive accuracy using only MRI measures was obtained by hippocampal volumes by themselves (60.4%). When clinical variables were added to the model, the predictive accuracy increased to 78.8%. Use of MRI measures did not improve predictive accuracy beyond that obtained by cognitive measures alone. APOE status, MRI, or demographic variables were not necessary for the optimal predictive model. This optimal model included the Delayed 10-word list recall, New York University Delayed Paragraph Recall, and the Alzheimer9s Disease Assessment Scale–Cognitive Subscale total score. Conclusion: In moderate stages of amnestic mild cognitive impairment, common cognitive tests provide better predictive accuracy than measures of whole brain, ventricular, entorhinal cortex, or hippocampal volumes for assessing progression to Alzheimer disease.

Objective:To examine the variability in performance among placebo groups in randomized controlled trials for mild cognitive impairment (MCI).Methods:Placebo group data were obtained from 2 National Institute on Aging (NIA) MCI randomized controlled trials, the Alzheimer's Disease Cooperative Study (ADCS) MCI trial and the Alzheimer's Disease Neuroimaging Initiative (ADNI), which is a simulated clinical trial, in addition to industry-sponsored clinical trials involving rivastigmine, galantamine, rofecoxib, and donepezil. The data were collated for common measurement instruments. The performance of the placebo participants from these studies was tracked on the Alzheimer's Disease Assessment Scale–cognitive subscale, Mini-Mental State Examination, and Clinical Dementia Rating–sum of boxes, and for progression on these measures to prespecified clinical study endpoints. APOE status, where available, was also analyzed for its effects.Results:The progression to clinical endpoints varied a great deal among the trials. The expected performances were seen for the participants in the 2 NIA trials, ADCS and ADNI, with generally worsening of performance over time; however, the industry-sponsored trials largely showed stable or improved performance in their placebo participants. APOE4 carrier status influenced results in an expected fashion on the study outcomes, including rates of progression and cognitive subscales.Conclusions:In spite of apparently similar criteria for MCI being adopted by the 7 studies, the implementation of the criteria varied a great deal. Several explanations including instruments used to characterize participants and variability among study populations contributed to the findings.

Background As a potential disease-modifying treatment for Alzheimer disease (AD), 3-amino-1-propanesulfonic acid (3APS) is a compound that binds to amyloid beta (Abeta), a toxic protein known to aggregate, leading to amyloid plaque deposition in the brain. Methods We assessed the safety, tolerability, and pharmacokinetic/pharmacodynamic effect of 3APS in a randomized, double-blind, placebo-controlled Phase II study in which 58 subjects with mild-to-moderate AD were randomly assigned to receive placebo or 3APS 50, 100, or 150 mg BID for 3 months. At the end of the double-blind phase, 42 of these subjects entered an open-label phase in which they received 3APS 150 mg BID for 17 months. Assessments included plasma and CSF 3APS concentrations, CSF levels of Abeta (Abeta(40) and Abeta(42)), and total tau, as well as cognitive (Alzheimer's Disease Assessment Scale-cognitive subscale, Mini-Mental State Examination) and clinical (Clinical Dementia Rating scale-Sum of Boxes) measures. Results 3APS had no significant impact on vital signs or laboratory test values. The most frequent side effects were nausea, vomiting, and diarrhea, which were intermittent and mild to moderate in severity. Seven 3APS-treated subjects discontinued because of side effects (all causalities) over the course of the study, and there were no 3APS-related serious adverse events. 3APS crossed the blood-brain barrier, and dose-dependently reduced CSF Abeta(42) levels after 3 months of treatment. There were no psychometric score differences between groups over the 3-month double-blind period. Conclusion Long-term administration of 3-amino-1-propanesulfonic acid is safe, tolerated and reduces CSF Abeta(42) levels in patients with mild-to-moderate Alzheimer disease.

Objective: A randomized, placebo-controlled, double-blind, multicenter 52-week phase 2 trial of resveratrol in individuals with mild to moderate Alzheimer disease (AD) examined its safety and tolerability and effects on biomarker (plasma Ab40 and Ab42, CSF Ab40, Ab42, tau, and phospho-tau 181) and volumetric MRI outcomes (primary outcomes) and clinical outcomes (secondary outcomes). Methods: Participants (n 5 119) were randomized to placebo or resveratrol 500 mg orally once daily (with dose escalation by 500-mg increments every 13 weeks, ending with 1,000 mg twice daily). Brain MRI and CSF collection were performed at baseline and after completion of treatment. Detailed pharmacokinetics were performed on a subset (n 5 15) at baseline and weeks 13, 26, 39, and 52. Results: Resveratrol and its major metabolites were measurable in plasma and CSF. The most common adverse events were nausea, diarrhea, and weight loss. CSF Ab40 and plasma Ab40 levels declined more in the placebo group than the resveratrol-treated group, resulting in a significant difference at week 52. Brain volume loss was increased by resveratrol treatment compared to placebo. Conclusions: Resveratrol was safe and well-tolerated. Resveratrol and its major metabolites penetrated the blood–brain barrier to have CNS effects. Further studies are required to interpret the biomarker changes associated with resveratrol treatment. Classification of evidence: This study provides Class II evidence that for patients with AD resveratrol is safe, well-tolerated, and alters some AD biomarker trajectories. The study is rated Class II because more than 2 primary outcomes were designated. Neurology® 2015;85:1–9 GLOSSARY 3G-RES 5 3-O-glucuronidated-resveratrol; 4G-RES 5 4-O-glucuronidated-resveratrol; AD 5 Alzheimer disease; ADAScog 5 Alzheimer’s Disease Assessment Scale–cognitive; ADCS 5 Alzheimer’s Disease Cooperative Study; ADCS-ADL 5 Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale; AE 5 adverse event; BMI 5 body mass index; CDRSOB 5 Clinical Dementia Rating-sum of boxes; Cmax 5 maximal plasma concentration; DMSO 5 dimethyl sulfoxide; ITT 5 intention-to-treat; MMRM 5 mixed-model repeated-measures; MMSE 5 Mini-Mental State Examination; NPI 5 Neuropsychiatric Inventory; S-RES 5 3-sulfated-resveratrol; SAE 5 serious adverse event.

Objective: Alzheimer disease (AD) dementia clinical trials require 2 participants: a patient and a study partner. We assessed the prevalence of study partner types and how these types associate with patient-related outcome measures. Methods: Retrospective analyses of 6 Alzheimer's Disease Cooperative Study (ADCS) randomized clinical trials were conducted. Study partners were categorized as spouse, adult child, or other. Prevalence of study partner type and associations between study partner type and trial outcomes including study completion and placebo decline on the Mini-Mental State Examination, the Alzheimer's Disease Assessment Scalecognitive subscale, the Clinical Dementia Rating scale Sum of the Boxes score, and the ADCSActivities of Daily Living were examined. Results: More participants (67%) enrolled with spouses than adult children (26%) or other study partners (7%). Participants with spouse partners had a lower dropout rate (25%) than those with adult child (32%) or other study partners (34%); only the difference vs others was statistically significant. Participants with adult child and other partners randomized to placebo performed worse at baseline than those with spouse partners on the ADCS Activities of Daily Living (p=0.04), but were not different at 18 months. There were no differences at baseline for the Mini-Mental State Examination, Clinical Dementia Rating scale Sum of the Boxes score, or Alzheimer's Disease Assessment Scalecognitive subscale. In multivariate models of the rates of change over time among placebo participants, no differences among study partner groups reached statistical significance. Conclusions: Patients with nonspouse caregivers less frequently participate in AD dementia trials. Increased enrollment of AD patients with nonspouse caregivers may require additional recruitment and retention strategies. © 2013 American Academy of Neurology.

Objective: To investigate predictors of missing data in a longitudinal study of Alzheimer disease (AD). Methods: The Alzheimer9s Disease Neuroimaging Initiative (ADNI) is a clinic-based, multicenter, longitudinal study with blood, CSF, PET, and MRI scans repeatedly measured in 229 participants with normal cognition (NC), 397 with mild cognitive impairment (MCI), and 193 with mild AD during 2005–2007. We used univariate and multivariable logistic regression models to examine the associations between baseline demographic/clinical features and loss of biomarker follow-ups in ADNI. Results: CSF studies tended to recruit and retain patients with MCI with more AD-like features, including lower levels of baseline CSF Aβ 42 . Depression was the major predictor for MCI dropouts, while family history of AD kept more patients with AD enrolled in PET and MRI studies. Poor cognitive performance was associated with loss of follow-up in most biomarker studies, even among NC participants. The presence of vascular risk factors seemed more critical than cognitive function for predicting dropouts in AD. Conclusion: The missing data are not missing completely at random in ADNI and likely conditional on certain features in addition to cognitive function. Missing data predictors vary across biomarkers and even MCI and AD groups do not share the same missing data pattern. Understanding the missing data structure may help in the design of future longitudinal studies and clinical trials in AD.

Objective: To determine whether elderly normal APOE E2 ( APOE 2) carriers exhibit slower rates of hippocampal atrophy and memory decline compared to APOE 3/3 carriers. We also determined whether APOE 2 carriers have less Alzheimer pathology as reflected by CSF biomarkers. Methods: We included longitudinal data from 134 cognitively normal individuals (27 APOE 2/2 or E 2/3, 107 APOE 3/3) from the Alzheimer9s Disease Neuroimaging Initiative, a prospective cohort study. A linear mixed-effects model was used to determine how APOE 2 affected rates of hippocampal atrophy and cognitive change over time. In a subsample of 72 individuals who also underwent CSF analysis, an ordinary least-squares regression was used to determine whether CSF β-amyloid (Aβ), total tau, and phosphorylated tau-181 (p-tau) differed by APOE 2 status. Results: APOE 2 carriers demonstrated slower rates of hippocampal atrophy ( p = 0.004). The mean rate of hippocampal atrophy among APOE 2 carriers was −33 mm 3 /year (95% confidence interval −65 to +0.4), or −0.5%/year, compared to −86 mm 3 /year (95% confidence interval −102 to −71), or −1.3%/year, in the APOE 3/3 group. No differences in the rates of episodic memory ( p = 0.23) or overall cognitive change ( p = 0.90) were detected. In the CSF subsample, APOE 2 carriers had higher levels of CSF Aβ ( p = 0.01), lower p-tau ( p = 0.02), and marginally lower tau ( p = 0.12). Conclusion: A slower rate of hippocampal atrophy in normal APOE 2 carriers is consistent with the lower risk of Alzheimer disease in these individuals. We hypothesize that the slower atrophy rate is related to decreased preclinical Alzheimer pathology.

Objective: A variety of measurements have been individually linked to decline in mild cognitive impairment (MCI), but the identification of optimal markers for predicting disease progression remains unresolved. The goal of this study was to evaluate the prognostic ability of genetic, CSF, neuroimaging, and cognitive measurements obtained in the same participants. Methods: APOE e4 allele frequency, CSF proteins (Aβ 1-42 , total tau, hyperphosphorylated tau [p-tau 181p ]), glucose metabolism (FDG-PET), hippocampal volume, and episodic memory performance were evaluated at baseline in patients with amnestic MCI (n = 85), using data from a large multisite study (Alzheimer9s Disease Neuroimaging Initiative). Patients were classified as normal or abnormal on each predictor variable based on externally derived cutoffs, and then variables were evaluated as predictors of subsequent conversion to Alzheimer disease (AD) and cognitive decline (Alzheimer9s Disease Assessment Scale–Cognitive Subscale) during a variable follow-up period (1.9 ± 0.4 years). Results: Patients with MCI converted to AD at an annual rate of 17.2%. Subjects with MCI who had abnormal results on both FDG-PET and episodic memory were 11.7 times more likely to convert to AD than subjects who had normal results on both measures ( p ≤ 0.02). In addition, the CSF ratio p-tau 181p /Aβ 1-42 (β = 1.10 ± 0.53; p = 0.04) and, marginally, FDG-PET predicted cognitive decline. Conclusions: Baseline FDG-PET and episodic memory predict conversion to AD, whereas p-tau 181p /Aβ 1-42 and, marginally, FDG-PET predict longitudinal cognitive decline. Complementary information provided by these biomarkers may aid in future selection of patients for clinical trials or identification of patients likely to benefit from a therapeutic intervention.

Background: Nonsteroidal anti-inflammatory drugs (NSAID) may be useful in the treatment of AD. Clinical and laboratory experience with nimesulide, an NSAID with preferential cyclooxygenase-2 inhibition, suggests that it may be a good candidate for AD therapy. Methods: This pilot study investigated the clinical feasibility of nimesulide treatment in AD. Forty persons with probable AD, most of whom were taking cholinesterase inhibitors, were enrolled in a randomized, controlled, parallel-group trial designed to assess tolerability and short-term cognitive/behavioral effects of nimesulide. In the initial 12-week double-blind phase, participants were treated with nimesulide 100 mg by mouth twice daily or matching placebo; during the second 12-week phase all participants received active drug. Participants who tolerated the drug well and perceived benefit were invited to continue open-label nimesulide treatment. Results: Short-term therapy with nimesulide, compared with placebo, had no significant effect on total assessment scores of measures of cognition, clinical status, activities of daily living, affect, and behavior. Long-term therapy was well tolerated for periods exceeding 2 years. Conclusion: These findings support the feasibility of nimesulide therapy in AD; assessment of efficacy will require a larger, long-term treatment study.

The concept of mild cognitive impairment (MCI) presents quandaries on several levels. Is it a clearly defined syndrome? A stage of Alzheimer disease (AD)? The prodromal phase preceding AD? The prodromal stage before any dementia? What is the relationship between memory impairment and involvement of other cognitive domains? Should accurate diagnosis move beyond subjective and objective evidence of cognitive impairment, to allow consideration of genetic susceptibility to AD or imaging and biochemical evidence of amyloidosis? Whatever MCI is, it is surely a prevalent, important clinical problem. In the therapeutic age of AD that began 15 years ago, more individuals seek evaluation at early stages of impairment. The clinician may be uncertain of the best label (though MCI often seems preferable to very early AD; it is less foreboding, more palatable, gentler), but a number of interventions seem appropriate and are widely practiced. The most important is education of patient and family regarding the risks, appropriate safety measures (limiting or halting driving, limiting some responsibilities, providing supervision), and planning (occupational, health, financial, legal, care). Clinicians commonly offer general recommendations …

As a result of advances in the understanding of neurodegenerative mechanism in Alzheimer's disease, several strategies for the development of disease-modifying treatment are being investigated. Nerve growth factor and other neurotrophins may improve neuronal survival, although targeted delivery remains an obstacle. Modulation of protein processing has the potential to decrease the formation of plaques and tangles. Pharmacologic reduction of oxidative stress and destructive inflammation may slow the rate of neurodegeneration. Continued research into basic mechanisms, along with therapeutic trials of promising drugs, are improving the likelihood that it will soon be possible to slow the progression of this disease.

Objective: We studied the validity of self- versus informant-reported ratings of everyday functional impairment in older adults by 1) examining if differences across raters varied by diagnostic group (normal, early-Mild Cognitive Impairment (MCI), late-MCI, dementia), and 2) whether there were differences in how self- versus informant-rated functional impairment related to objective measures of cognition, disease severity (hippocampal volume) and genetic risk (ApoE4 status). Background Measuring the impact of cognitive impairment on daily life may provide a simple and efficient way to help identify those with MCI or dementia. Additionally, the presence of functional impairment is associated with faster subsequent cognitive decline. However, it is unclear to what degree self-reported everyday function is accurate. Design/Methods: Participants were part of the Alzheimer9s Disease Neuroimaging Initiative (ADNI). Everyday function was measured using the Everyday Cognition questionnaire (ECog), which was completed by participants and their informants. Results: Differences between raters varied by diagnostic group: participants with dementia rated themselves as less functionally impaired compared to informant ratings; conversely, normals and early-MCI participants rated themselves as more impaired compared to informant ratings. There was no difference in self- vs. informant-reported functional impairment in the late-MCI group. In the sample as a whole, informant-based ECog scores were strongly associated with objective neuropsychological scores (rs = .41-.60), and were related to genetic status and hippocampal volume. Self-report ECog scores were less strongly related to neuropsychological performance (rs = .19-.30) and were not significantly associated with ApoE4 status or hippocampal volume. Conclusions: Older adults with early and late MCI do not appear to underestimate their level of functional impairment compared to informant ratings, whereas individuals with dementia do underestimate their functional impairment. However, as a whole, informant ratings show closer agreement with neuropsychological performance and to other measures of disease including genetic risk for AD and hippocampal atrophy. Supported by: Data collection and sharing for this project was funded by the Alzheimer9s Disease Neuroimaging Initiative (ADNI) (National Institutes of Health Grant U01 AG024904). ADNI is funded by the National Institute on Aging, the National Institute of Biomedical Imaging and Bioengineering, and through generous contributions from the following: Abbott; Alzheimer9s Association; Alzheimer9s Drug Discovery Foundation; Amorfix Life Sciences Ltd.; AstraZeneca; Bayer HealthCare; BioClinica, Inc.; Biogen Idec Inc.; Bristol-Myers Squibb Company; Eisai Inc.; Elan Pharmaceuticals Inc.; Eli Lilly and Company; F. Hoffmann-La Roche Ltd and its affiliated company Genentech, Inc.; GE Healthcare; Innogenetics, N.V.; Janssen Alzheimer Immunotherapy Research & Development, LLC.; Johnson & Johnson Pharmaceutical Research & Development LLC.; Medpace, Inc.; Merck & Co., Inc.; Meso Scale Diagnostics, LLC.; Novartis Pharmaceuticals Corporation; Pfizer Inc.; Servier; Synarc Inc.; and Takeda Pharmaceutical Company. The Canadian Institutes of Health Research is providing funds to support ADNI clinical sites in Canada. Private sector contributions are facilitated by the Foundation for the National Institutes of Health (www.fnih.org). The grantee organization is the Northern California Institute for Research and Education, and the study is coordinated by the Alzheimer9s Disease Cooperative Study at the University of California, San Diego. ADNI data are disseminated by the Laboratory for Neuro Imaging at the University of California, Los Angeles. This research was also supported by NIH grants P30 AG010129, K01 AG030514, and the Dana Foundation. Disclosure: Dr. Farias has nothing to disclose. Dr. Saito has nothing to disclose. Dr. Harvey has received personal compensation in an editorial capacity for the Journal of Alzheimer Disease and Associated Disorders. Dr. Aisen has received personal compensation for activities wtih Neurochem, Pfizer, Merck, Roche, Amgen, Medivation, Pamlab, Adlyfe, Eisai, GlaxoSmithKline, Lilly, Daiichi,Elan, Wyeth, Avid, Novartis, Martek, Bristol Myers Squibb, Schering Plough as a consultant. Dr. Aisen holds stock and/or stock options for Medivation.Dr. Aisen has received research support from TransTech Pharma, Pfizer, Baxter, Merck, Lilly, Myriad, Elan and Neurochem. Dr. Petersen has received personal compensation for activities with Pfizer, Inc., Janssen Alzheimer9s Immunotherapy, Elan Pharmaceuticals, and GE Healthcare.

Background Laboratory and epidemiologic studies suggest that anti-inflammatory/immunosuppressive therapy may be useful in the treatment of AD. In preliminary studies, a regimen of low to moderate dose prednisone was found to suppress peripheral inflammatory markers without adverse effects in subjects with AD. Methods We conducted a randomized, placebo-controlled multicenter trial to determine whether prednisone treatment slowed the rate of cognitive decline in AD. The active treatment regimen consisted of an initial dose of 20 mg of prednisone daily for 4 weeks tapered to a maintenance dose of 10 mg daily for 1 year, followed by gradual withdrawal during an additional 16 weeks. The primary outcome measure was the 1-year change in the cognitive subscale of the AD Assessment Scale. Results A total of 138 subjects were randomized to the drug and placebo groups. There was no difference in cognitive decline between the prednisone and placebo treatment groups in the primary intent-to-treat analysis, or in a secondary analysis considering completers only. Subjects treated with prednisone showed behavioral decline compared with those in the placebo group. Conclusion A low-dose regimen of prednisone is not useful in the treatment of AD.

To the Editor: We read with interest the report of Barned et al [1] concerning the frequency of antinuclear antibodies (ANA) in multiple sclerosis. The authors conducted a retrospective review of 563 charts and examined the results of serologic testing, if obtained (34.7% of relapsing-remitting and 17.7% of chronic progressive patients were so tested). Positive ANA were seen in …