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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.

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.

We analyzed the baseline and 3-year T1-weighted magnetic resonance imaging data of 110 amnestic mild cognitive impairment (MCI) participants with minimal hippocampal atrophy at baseline from the Alzheimer's Disease Cooperative Study group MCI Donepezil/Vitamin E trial. Forty-six subjects converted to Alzheimer disease (AD) (MCIc), whereas 64 remained stable (MCInc). We used the radial distance technique to examine the differences in lateral ventricle shape and size between MCIc and MCInc and the associations between ventricular enlargement and cognitive decline. MCIc group had significantly larger frontal and right body/occipital horns relative to MCInc at baseline and significantly larger bilateral frontal, body/occipital, and left temporal horns at follow-up. Global cognitive decline measured with AD Assessment scale cognitive subscale and Mini-Mental State Examination and decline in activities of daily living (ADL) were associated with posterior lateral ventricle enlargement. Decline in AD Assessment scale cognitive subscale and ADL were associated with left temporal and decline in Mini-Mental State Examination with right temporal horn enlargement. After correction for baseline hippocampal volume, decline in ADL showed a significant association with right frontal horn enlargement. Executive decline was associated with right frontal and left temporal horn enlargement.

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

Objective To evaluate the safety and tolerability of PF-04494700, an oral inhibitor of receptor for advanced glycation end products, in patients with mild-to-moderate dementia of the Alzheimer type. Methods Patients aged 50 years and older who met the National Institute of Neurological and Communicative Diseases and Stroke/Alzheimer's Disease and Related Disorders Association criteria for Alzheimer disease with an Mini-Mental State Examination (MMSE) score between 12 and 26 (inclusive) were randomized to 10 weeks of double-blind treatment with either a 10 mg "low dose" of PF-04494700 (after a 6-d loading dose of 30 mg/d), a 20 mg "high dose" of PF-04494700 (after a loading dose of 60 mg/d), or placebo. Safety measures included adverse events, laboratory tests, vital signs, and 12-lead electrocardiogram. Results Twenty-seven patients received PF-04494700 30/co mg (female: 63%; mean age: 74.6 y; mean MMSE: 21.1), 28 patients received PF-04494700 60/20 mg (female: 57%; mean age: 76.6 y; mean MMSE: 21.6), and 12 patients received placebo (female: 67%; mean age: 74.1 y; mean MMSE: 19.2). A higher proportion of patients completed 10 weeks of double-blind treatment on both the "low-dose" regimen of PF-04494700 (88.9%) and the "high-dose" regimen (85.7%) than patients who were on placebo (66.7%). Discontinuation owing to adverse events and incidence of severe adverse events, respectively, were lower in the "low-dose" regimen (7.4%, 11.1%) and the "high-dose" regimen (3.6%, 10.7%) compared with placebo (25.0%, 16.7%). There were no clinically meaningful differences in vital signs, laboratory test results, or mean electrocardiogram parameters in patients treated with PF-04494700. PF-04494700 had no consistent effect on plasma levels of β-amyloid, inflammatory biomarkers, or secondary cognitive outcomes. Conclusions Ten weeks of treatment with PF-04494700 was safe and well tolerated in patients with mild-to-moderate Alzheimer disease, indicating the feasibility of a larger long-term efficacy trial.

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.

To determine if a self-selected group of participants who enroll in an imaging substudy of Alzheimer disease (AD) clinical trials is representative of the overall study sample.Baseline data from 2 ongoing AD clinical trials with 402 and 313 randomized participants were analyzed. Magnetic resonance imaging substudy enrollers (166 participants in trial 1 and 161 participants in trial 2) and nonenrollers were compared on baseline demographic, medical and clinical characteristics separately for the 2 trials.In both trials, enrollers were statistically similar to nonenrollers on most demographic and clinical measures. One study sample showed that enrollers had lower cognitive scores at baseline when compared with nonenrollers: lower Mini Mental State Examination scores (20.15+/-3.6 vs. 21.04+/-3.6, P=0.02), and higher Alzheimer's Disease Assessment Scale-cognitive domain scores (24.99+/-8.5 vs. 23.03+/-9.3, P=0.03); however, the difference was not considered clinically important and was not observed in the second trial.The groups of individuals who agreed to participate in the imaging substudies of AD trials were remarkably comparable to the comparison groups at baseline on a wide range of demographic and clinical measures; there seems to be a minimal effect of self-selection bias. The results indicate that it may be reasonable to generalize findings in an imaging substudy to the complete the study population.

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.

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.

Anti-inflammatory drugs may be useful in the treatment of Alzheimer disease (AD). In preparation for therapeutic trials, we conducted pilot feasibility studies of hydroxychloroquine alone and in combination with colchicine in subjects with AD. A total of 20 subjects with probable AD were treated with hydroxychloroquine 200 mg twice daily for 11 weeks, or hydroxychloroquine 200 mg twice daily plus colchicine 0.6 mg twice daily for 12 weeks; subjects were monitored for adverse medical, cognitive, or behavioral effects. Neither regimen caused adverse effects on cognitive or behavioral assessment scores. There were no significant side effects in subjects receiving hydroxychloroquine alone; 2 subjects receiving the two drugs together experienced diarrhea. We conclude that these regimens of anti-inflammatory therapy are well tolerated in subjects with AD, indicating the feasibility of large-scale therapeutic trials of these agents.

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 …

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 …