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1.  Arguing Against the Proposed Definition Changes of PD 
As members of the Lewy Body Dementia Association Scientific Advisory Council, we aim to address some of the issues raised in the article entitled, "Time to redefine PD? Introductory statement of the MDS Task Force on the definition of Parkinson's disease." In particular, we suggest that the one-year rule distinguishing Parkinson’s disease dementia from dementia with Lewy bodies is worth maintaining because it serves an important purpose in clinical practice, in clinical and basic science research, and in helping the lay community understand the complexity of these different clinical phenotypes. Furthermore, we believe that adding an additional diagnostic label, “PD (dementia with Lewy bodies subtype)”, will confuse rather than clarify the distinction between dementia with Lewy bodies and PD or PD dementia, and will not improve management or expedite therapeutic development. We present arguments supporting our contentions.
doi:10.1002/mds.26721
PMCID: PMC5168716  PMID: 27492190
2.  Cerebrospinal Fluid Particles in Alzheimer Disease and Parkinson Disease 
Human cerebrospinal fluid (CSF) contains diverse lipid particles, including lipoproteins that are distinct from their plasma counterparts and contain apolipoprotein (apo) E isoforms, apoJ, and apoAI, and extracellular vesicles, which can be detected by annexin V binding. The aim of this study was to develop a method to quantify CSF particles and evaluate their relationship to aging and neurodegenerative diseases. We used a flow cytometric assay to detect annexin V-, apoE-, apoAI-, apoJ- and amyloid (A) β42-positive particles in CSF from 131 research volunteers who were neurologically normal or had mild cognitive impairment (MCI), Alzheimer disease (AD) dementia, or Parkinson disease. APOE ε4/ε4 participants had CSF apoE-positive particles that were more frequently larger but at an 88% lower level vs. those in APOE ε3/ε3 or APOE ε3/ε4 patients; this finding was reproduced in conditioned medium from mouse primary glial cell cultures with targeted replacement of apoE. CSF apoE-positive and β-amyloid (Aβ42)-positive particle concentrations were persistently reduced one-third to one-half in middle and older age subjects; apoAI-positive particle concentration progressively increased approximately 2-fold with age. Both apoAI-positive and annexin V-positive CSF particle levels were reduced one-third to one-half in CSF of MCI and/or AD dementia patients vs. age-matched controls. Our approach provides new methods to investigate CNS lipid biology in relation to neurodegeneration and perhaps develop new biomarkers for diagnosis or treatment monitoring.
doi:10.1097/NEN.0000000000000207
PMCID: PMC4471879  PMID: 26083568
Alzheimer disease; Biomarkers; Cerebrospinal fluid; Cognitive impairment; Neurodegenerative disease; Parkinson disease
3.  “Missed” Mild Cognitive Impairment: High False-Negative Error Rate Based on Conventional Diagnostic Criteria 
Mild cognitive impairment (MCI) is typically diagnosed using subjective complaints, screening measures, clinical judgment, and a single memory score. Our prior work has shown that this method is highly susceptible to false-positive diagnostic errors. We examined whether the criteria also lead to “false-negative” errors by diagnostically reclassifying 520 participants using novel actuarial neuropsychological criteria. Results revealed a false-negative error rate of 7.1%. Participants’ neuropsychological performance, cerebrospinal fluid biomarkers, and rate of decline provided evidence that an MCI diagnosis is warranted. The impact of “missed” cases of MCI has direct relevance to clinical practice, research studies, and clinical trials of prodromal Alzheimer's disease.
doi:10.3233/JAD-150986
PMCID: PMC4879874  PMID: 27031477
Alzheimer's disease; mild cognitive impairment; misclassification; misdiagnosis; neuropsychology
4.  Aggregate effects of vascular risk factors on cerebrovascular changes in autopsy-confirmed Alzheimer’s disease 
We examined the relationships of ante-mortem vascular risk factors to post-mortem cerebrovascular and AD pathologies. Eighty-four AD patients underwent assessment of vascular risk (blood pressure, cholesterol, smoking, cardiovascular disease, diabetes, atrial fibrillation, transient ischemic attack [TIA] or stroke) and later underwent brain autopsy. Given our aim to examine mild cerebrovascular changes (CVC), individuals were excluded if autopsy revealed large stroke. The most common forms of CVC were circle of Willis atherosclerosis followed by arteriosclerosis, lacunes, and microinfarcts. Excluding history of TIA/clinical stroke, individual vascular risk factors were not associated with CVC. However, the presence of multiple vascular risk factors was associated with CVC. Further, presence of CVC was associated with lower Braak and Braak stage. Findings highlight the importance of aggregate risk in the vascular contribution to dementia. Interventions designed to maintain cerebrovascular health may represent important opportunities for preventing or delaying dementia, even when AD is the dominant pathology.
doi:10.1016/j.jalz.2013.12.025
PMCID: PMC4287462  PMID: 25022538
Alzheimer’s disease; vascular risk; cerebrovascular disease
5.  Subtle Cognitive Decline and Biomarker Staging in Preclinical Alzheimer’s Disease 
The NIA-AA criteria for “preclinical” Alzheimer’s disease (AD) propose a staging method in which AD biomarkers follow an invariable temporal sequence in accordance with the amyloid cascade hypothesis. However, recent findings do not align with the proposed temporal sequence and “subtle cognitive decline,” which has not been definitively operationalized, may occur earlier than suggested in preclinical AD. We aimed to define “subtle cognitive decline” using sensitive and reliable neuropsychological tests, and to examine the number and sequence of biomarker abnormalities in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). 570 cognitively normal ADNI participants were classified based on NIA-AA criteria and separately based on the number of abnormal biomarkers/cognitive markers associated with preclinical AD that each individual possessed. Results revealed that neurodegeneration alone was 2.5 times more common than amyloidosis alone at baseline. For those who demonstrated only one abnormal biomarker at baseline and later progressed to mild cognitive impairment/AD, neurodegeneration alone was most common, followed by amyloidosis alone or subtle cognitive decline alone, which were equally common. Findings suggest that most individuals do not follow the temporal order proposed by NIA-AA criteria. We provide an operational definition of subtle cognitive decline that captures both cognitive and functional decline. Additionally, we offer a new approach for staging preclinical AD based on number of abnormal biomarkers, without regard to their temporal order of occurrence. This method of characterizing preclinical AD is more parsimonious than the NIA-AA staging system and does not presume that all patients follow a singular invariant expression of the disease.
doi:10.3233/JAD-150128
PMCID: PMC4634634  PMID: 26402771
Alzheimer’s disease; Alzheimer’s Disease Neuroimaging Initiative; amyloid; biomarkers; cerebrospinal fluid; dementia; neurodegeneration; neuropsychology; preclinical Alzheimer’s disease; subtle cognitive decline
6.  Plasma exosomal α-synuclein is likely CNS-derived and increased in Parkinson’s disease 
Acta neuropathologica  2014;128(5):639-650.
Extracellular α-synuclein is important in the pathogenesis of Parkinson disease (PD) and also as a potential biomarker when tested in the cerebrospinal fluid (CSF). The performance of blood plasma or serum α-synuclein as a biomarker has been found to be inconsistent and generally ineffective, largely due to the contribution of peripherally derived α-synuclein. In this study, we discovered, via an intracerebroventricular injection of radiolabeled α-synuclein into mouse brain, that CSF α-synuclein was readily transported to blood, with a small portion being contained in exosomes that are relatively specific to the central nervous system (CNS). Consequently, we developed a technique to evaluate the levels of α-synuclein in these exosomes in individual plasma samples. When applied to a large cohort of clinical samples (267 PD, 215 controls), we found that in contrast to CSF α-synuclein concentrations, which are consistently reported to be lower in PD patients compared to controls, the levels of plasma exosomal α-synuclein were substantially higher in PD patients, suggesting an increased efflux of the protein to the peripheral blood of these patients. Furthermore, although no association was observed between plasma exosomal and CSF α-synuclein, a significant correlation between plasma exosomal α-synuclein and disease severity (r=0.176, p=0.004) was observed, and the diagnostic sensitivity and specificity achieved by plasma exosomal α-synuclein were comparable to those determined by CSF α-synuclein. Further studies are clearly needed to elucidate the mechanism involved in the transport of CNS α-synuclein to the periphery, which may lead to a more convenient and robust assessment of PD clinically.
doi:10.1007/s00401-014-1314-y
PMCID: PMC4201967  PMID: 24997849
Parkinson disease; exosome; α-synuclein; biomarker; plasma
7.  Influence of lifestyle modifications on age-related free radical injury to brain 
JAMA neurology  2014;71(9):1150-1154.
Importance
The Healthy Brain Initiative seeks to optimize brain health as we age. Free radical injury is an important effector of molecular and cellular stress in aging brain that derives from multiple sources.
Objective
Identify potentially modifiable risk factors associated with increased markers of brain oxidative stress.
Design, Setting, and Participants
Our study consisted of 320 research volunteers (178 women) aged 21 to 100 years old who were medically healthy and cognitively normal.
Measures
Free radical injury to brain was assessed using cerebrospinal fluid (CSF) F2-isoprostanes (IsoPs) and correlated with age, gender, race, cigarette smoking, body mass index (BMI), inheritance of the ε4 allele of apolipoprotein E gene (APOE), and cerebrospinal fluid biomarkers of Alzheimer’s disease (AD).
Results
CSF F2-IsoP concentration increased with age by approximately 10% from age 45 to 71 years in medically healthy cognitively normal adults. CSF F2-IsoP concentration increased by an average of >10% for every 5 kg/m2 increase in BMI. Current smokers had approximately three-fold greater effect than age on CSF F2-IsoPs. Women had greater average CSF F2-IsoP concentration than men at all ages after adjusting for other factors. Neither CSF AD biomarkers nor inheritance of APOE ε4 allele were associated with CSF F2-IsoP concentration in this group of medically healthy cognitively normal adults. Association between CSF F2-IsoP concentrations and race was not significant after controlling for effect of current smoking status.
Conclusions & Relevance
Our results are consistent with an age-related increase in free radical injury in human brain, and uniquely suggest that this form of injury may be greater in women than in men. Our results also highlighted two lifestyle modifications that would have even greater impact on suppressing free radical injury to brain than would suppressing processes of aging. These results inform efforts to achieve success in the Healthy Brain Initiative.
doi:10.1001/jamaneurol.2014.1428
PMCID: PMC4160350  PMID: 25048271
8.  Modulation of Aβ42 in vivo by γ-secretase modulator in primates and humans 
Introduction
Ibuprofen is one of the nonsteroidal anti-inflammatory drugs that have been shown to selectively lower pathogenic amyloid beta-peptide (Aβ)42 without impairing overall γ-secretase activity in vitro. This γ-secretase modulator (GSM) activity has been hypothesized to contribute to the reduction in risk of developing Alzheimer’s disease in chronic users of nonsteroidal anti-inflammatory drugs. However, it is unclear whether ibuprofen, within therapeutic dosing range, demonstrates GSM activity in humans. In this study, we evaluated the effects of ibuprofen and a second-generation GSM, GSM-1, on Aβ levels in cerebrospinal fluid and plasma of young nonhuman primates and humans.
Methods
Five to seven conscious cynomolgus monkeys (Macaca fascicularis) were nontreated or treated with 30 mg/kg GSM-1 or 50 or 100 mg/kg ibuprofen and the plasma and cerebrospinal fluid were sampled at −8, 0 (baseline or right before treatment), 2, 4, 6, 8, 12, and 24 h postdosing. In addition, sixteen healthy human subjects were randomly assigned to receive either placebo or 800 mg ibuprofen given by intravenous administration and plasma were collected at 0 (before drug infusion), 0.5, 1, 2, 4, 6, 8, 10, and 24 h after dosing.
Results
A single dose of GSM-1 (30 mg/kg) decreased the ratio of Aβ42 to Aβ40 to 60 % in plasma and the ratio of Aβ42 to total Aβ to 65 % in cerebrospinal fluid from baseline to postdosing in monkeys. However, no significant changes were detected following ibuprofen treatment at 100 mg/kg. Consistent with the results from nonhuman primates, ibuprofen did not alter plasma Aβ levels in human volunteers after a single 800 mg dose.
Conclusions
GSM-1 exerted potent lowering of the ratio of Aβ42 to Aβ40 in nonhuman primates but the hypothesized GSM activity of ibuprofen could not be demonstrated in nonhuman primates and humans after acute dosing.
doi:10.1186/s13195-015-0137-y
PMCID: PMC4523931  PMID: 26244059
9.  Cross-sectional and longitudinal relationships between cerebrospinal fluid biomarkers and cognitive function in subjects without cognitive impairment from across the adult lifespan 
JAMA neurology  2014;71(6):742-751.
Importance
Age-related cognitive decline among older individuals with normal cognition is a complex trait that potentially derives from processes of aging, inherited vulnerabilities, environmental factors, and common latent diseases that can progress to cause dementia, viz., Alzheimer’s disease (AD) and vascular brain injury (VBI).
Objective
Here we used CSF biomarkers to gain insight into this complex trait.
Design, Setting, Participants
Secondary analyses of an academic multicenter cross sectional (n=315) and longitudinal (n=158) study of five neuropsychological tests (Immediate Recall, Delayed Recall, Trails A, Trails B, Category Fluency) in cognitively normal individuals aged 21 to 100 years.
Main Outcome Measure(s)
to investigate the association of these test results with age, gender, level of education, inheritance of the ε4 allele of the apolipoprotein E gene (APOE), and cerebrospinal fluid (CSF) concentrations of Aβ42 and tau (biomarkers of AD) as well as F2-isoprostanes (IsoPs; measures of free radical injury).
Results
Age and education were broadly predictive of cross sectional cognitive performance: of the genetic and CSF measures, only greater CSF F2-IsoP concentration was significantly associated with poorer executive function (adjusted R2 up to 0.31). Longitudinal measures of cognitive abilities, except Category Fluency, also were associated broadly with age; of the genetic and CSF measures, only lower baseline CSF Aβ42 concentration was associated with longitudinal measures of immediate and delayed recall (marginal R2 up to 0.31).
Conclusions and Relevance
Our results suggest that age and level of education accounted for a substantial minority of variance in cross sectional or longitudinal cognitive test performance in this large group of cognitively normal adults. Latent AD and other diseases that produce free radical injury, like VBI, accounted for a small amount of variation in cognitive test performance across the adult human life span. Likely, additional genetic and environmental factors contribute substantially to age-related cognitive decline.
doi:10.1001/jamaneurol.2014.445
PMCID: PMC4051849  PMID: 24756381
10.  Antioxidants for Alzheimer Disease 
Archives of neurology  2012;69(7):836-841.
Objective
To evaluate whether antioxidant supplements presumed to target specific cellular compartments affected cerebrospinal fluid (CSF) biomarkers.
Design
Double-blind, placebo-controlled clinical trial.
Setting
Academic medical centers.
Participants
Subjects with mild to moderate Alzheimer disease.
Intervention
Random assignment to treatment for 16 weeks with 800 IU/d of vitamin E (α-tocopherol) plus 500 mg/d of vitamin C plus 900 mg/d of α-lipoic acid (E/C/ALA); 400 mg of coenzyme Q 3 times/d; or placebo.
Main Outcome Measures
Changes from baseline to 16 weeks in CSF biomarkers related to Alzheimer disease and oxidative stress, cognition (Mini-Mental State Examination), and function (Alzheimer’s Disease Cooperative Study Activities of Daily Living Scale).
Results
Seventy-eight subjects were randomized; 66 provided serial CSF specimens adequate for biochemical analyses. Study drugs were well tolerated, but accelerated decline in Mini-Mental State Examination scores occurred in the E/C/ALA group, a potential safety concern. Changes in CSF Aβ42, tau, and P-tau181 levels did not differ between the 3 groups. Cerebrospinal fluid F2-isoprostane levels, an oxidative stress biomarker, decreased on average by 19% from baseline to week 16 in the E/C/ALA group but were unchanged in the other groups.
Conclusions
Antioxidants did not influence CSF biomarkers related to amyloid or tau pathology. Lowering of CSF F2-isoprostane levels in the E/C/ALA group suggests reduction of oxidative stress in the brain. However, this treatment raised the caution of faster cognitive decline, which would need careful assessment if longer-term clinical trials are conducted.
Trial Registration
clinicaltrials.gov Identifier: NCT00117403
PMCID: PMC3661272  PMID: 22431837
11.  Pulse Pressure in Relation to Tau-Mediated Neurodegeneration, Cerebral Amyloidosis, and Progression to Dementia in Very Old Adults 
JAMA neurology  2015;72(5):546-553.
IMPORTANCE
Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzheimer dementia but the mechanism responsible for this association remains unclear.
OBJECTIVES
To determine the relationship between pulse pressure and cerebral spinal fluid biomarker profiles of preclinical Alzheimer disease, investigate whether observed relationships are stronger in adults with more advanced arterial age (≥80 years of age), and examine the relationship between pulse pressure and progression to dementia.
DESIGN, SETTING, AND PARTICIPANTS
In this retrospective cohort study, 877 participants without dementia (55–91 years of age) from the Alzheimer’s Disease Neuroimaging Initiative underwent baseline health assessment, including blood pressure assessment and lumbar puncture for determination of cerebral spinal fluid phosphorylated tau (P-tau) and β-amyloid 1–42. Participants have been followed up longitudinally since 2005. The last date of examination was October 15, 2013. Clinical follow-up between 6 and 96 months tracked progression to dementia.
MAIN OUTCOMES AND MEASURES
Regression and analysis of covariance analyses investigated relationships between pulse pressure and distinct cerebral spinal fluid biomarker profiles. Very old participants (80 years or older) were compared with younger participants (55–79 years of age) on clinical measures and pulse pressure × age group interactions were investigated. Survival analysis examined the effect of baseline pulse pressure on progression to dementia. Covariates were age, sex, apolipoprotein E genotype, body mass index, vascular risk factors, and antihypertensive medication use.
RESULTS
Individuals with a P-tau-positive biomarker profile exhibited mean (SD) elevated pulse pressure regardless of age (62.0 [15.6]mmHg for a P-tau-positive biomarker vs 57.4 [14.0]mmHg for P-tau-negative biomarker; P = .04). In very old participants, a further increase in pulse pressure was observed in those exhibiting both P-tau elevation and β-amyloid 1–42 reduction vs either biomarkers alone (69.7 [16.0]mmHg for both positive biomarkers vs 63.18 [13.0]mmHg for P-tau alone vs 60.1 [16.4]mmHg for β-amyloid 1–42 alone vs 56.6 [14.5]mmHg for negative biomarkers; P = .003). Those with higher baseline pulse pressure progressed to dementia more rapidly (95%CI, 1.000–1.048; P = .05; hazard ratio = 1.024). Systolic pressure exhibited similar relationships with Alzheimer disease biomarkers and progression to dementia in the very old subgroup (P < .05) but showed no associations in the young old subgroup (P > .10). Diastolic pressure was reduced in young old participants with isolated phosphorylated tau elevation (P = .04).
CONCLUSIONS AND RELEVANCE
Pulse pressure, an index of vascular aging, was associated with neurodegenerative change prior to the onset of dementia across a broad age range. Among those with more advanced age, higher pulse pressure was also associated with cerebral amyloidosis in the presence of neurodegeneration and more rapid progression to dementia. Diastolic contributions to these biomarker associations were limited to young old participants whereas systolic contributions were found only in very old participants.
doi:10.1001/jamaneurol.2014.4477
PMCID: PMC4428938  PMID: 25822631
12.  Improved Statistical Power of Alzheimer Clinical Trials by Item-Response Theory: Proof of Concept by Application to the Activities of Daily Living Scale 
Discovery of effective treatment for Alzheimer disease (AD) depends upon the availability of outcome measures that exhibit good sensitivity to rates of longitudinal decline on global functional performance. The Alzheimer’s Disease Cooperative Study-Activities of Daily Living inventory (ADCS-ADL) is a frequently used functional endpoint in clinical trials for AD that assesses patient functional ability on the basis of informant ratings of patient performance on a variety of everyday tasks. Previous research has shown that the items comprising the ADCS-ADL are sensitive to characteristic longitudinal trajectories in AD. However, standard procedures for combining information from individual items into an overall test score may not make full use of the information provided by informant responses. The current study explored an application of item-response theory (IRT) techniques to the calculation of test scores on the ADCS-ADL. Using data from 2 ADCS clinical trials on mild-to-moderate AD patients we found that IRT based scoring increased sensitivity to change in functional ability and improved prospective statistical power of the ADCS-ADL as an outcome measure in clinical trials.
doi:10.1097/WAD.0b013e318265bcc1
PMCID: PMC4362713  PMID: 22874658
statistical power; sample size; clinical trial; item-response theory; activities of daily living; Alzheimer’s disease
13.  Pulse pressure is associated with Alzheimer biomarkers in cognitively normal older adults 
Neurology  2013;81(23):2024-2027.
Objective:
The current study examined the association between pulse pressure (PP) and CSF-based biomarkers for Alzheimer disease, including β-amyloid 1–42 (Aβ1–42) and phosphorylated tau (P-tau) protein, in cognitively normal older adults.
Methods:
One hundred seventy-seven cognitively normal, stroke-free older adult participants (aged 55–100 years) underwent blood pressure assessment for determination of PP (systolic − diastolic blood pressure) and lumbar puncture for measurement of CSF Aβ1–42 and P-tau. Pearson correlations and multiple linear regression, controlling for age, sex, APOE genotype, and body mass index, evaluated the relationship between PP and Alzheimer disease biomarkers.
Results:
PP elevation was associated with increased P-tau (r = 0.23, p = 0.002), reduced Aβ1–42 (r = −0.19, p = 0.01), and increased P-tau to Aβ1–42 ratio (r = 0.27, p < 0.001). After controlling for covariates, PP remained associated with P-tau (β = 0.18, p = 0.0196) and P-tau to Aβ1–42 ratio (β = 0.0016, p < 0.001) but was no longer associated with Aβ1–42 (β = −0.1, p = 0.35). Post hoc multivariate analyses indicated that increased PP was associated with all biomarkers in younger participants (aged 55–70 years) (Aβ1–42: p = 0.050; P-tau: p = 0.003; P-tau to Aβ ratio: p = 0.0007) but not older participants (aged 70–100 years).
Conclusions:
PP elevation is associated with increased CSF P-tau and decreased Aβ1–42 in cognitively normal older adults, suggesting that pulsatile hemodynamics may be related to amyloidosis and tau-related neurodegeneration. The relationship between PP and CSF biomarkers is age-dependent and observed only in participants in the fifth and sixth decades of life.
doi:10.1212/01.wnl.0000436935.47657.78
PMCID: PMC3854831  PMID: 24225352
14.  Cerebrospinal fluid norepinephrine and cognition in subjects across the adult age span 
Neurobiology of aging  2013;34(10):2287-2292.
Adequate central nervous system noradrenergic activity enhances cognition, but excessive noradrenergic activity may have adverse effects on cognition. Previous studies have also demonstrated that noradrenergic activity is higher in older than younger adults. We aimed to determine relationships between cerebrospinal fluid (CSF) norepinephrine (NE) concentration and cognitive performance by using data from a CSF bank that includes samples from 258 cognitively normal participants aged 21–100 years. After adjusting for age, gender, education, and ethnicity, higher CSF NE levels (units of 100 pg/mL) are associated with poorer performance on tests of attention, processing speed, and executive function (Trail Making A: regression coefficient 1.5, standard error [SE] 0.77, p = 0.046; Trail Making B: regression coefficient 5.0, SE 2.2, p = 0.024; Stroop Word-Color Interference task: regression coefficient 6.1, SE 2.0, p = 0.003). Findings are consistent with the earlier literature relating excess noradrenergic activity with cognitive impairment.
doi:10.1016/j.neurobiolaging.2013.04.007
PMCID: PMC3706572  PMID: 23639207
Noradrenergic system; Norepinephrine; Cognition; Aging
15.  Subjective Cognitive Complaints Contribute to Misdiagnosis of Mild Cognitive Impairment 
Subjective cognitive complaints are a criterion for the diagnosis of mild cognitive impairment (MCI), despite their uncertain relationship to objective memory performance in MCI. We aimed to examine self-reported cognitive complaints in subgroups of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) MCI cohort to determine whether they are a valuable inclusion in the diagnosis of MCI or, alternatively, if they contribute to misdiagnosis. Subgroups of MCI were derived using cluster analysis of baseline neuropsychological test data from 448 ADNI MCI participants. Cognitive complaints were assessed via the Everyday Cognition (ECog) questionnaire, and discrepancy scores were calculated between self- and informant-report. Cluster analysis revealed Amnestic and Mixed cognitive phenotypes as well as a third Cluster-Derived Normal subgroup (41.3%), whose neuropsychological and cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarker profiles did not differ from a “robust” normal control group. This cognitively intact phenotype of MCI participants overestimated their cognitive problems relative to their informant, whereas Amnestic MCI participants with objective memory impairment underestimated their cognitive problems. Underestimation of cognitive problems was associated with positive CSF AD biomarkers and progression to dementia. Overall, there was no relationship between self-reported cognitive complaints and objective cognitive functioning, but significant correlations were observed with depressive symptoms. The inclusion of self-reported complaints in MCI diagnostic criteria may cloud rather than clarify diagnosis and result in high rates of misclassification of MCI. Discrepancies between self- and informant-report demonstrate that overestimation of cognitive problems is characteristic of normal aging while underestimation may reflect greater risk for cognitive decline.
doi:10.1017/S135561771400068X
PMCID: PMC4172502  PMID: 25156329
Mild cognitive impairment; Awareness; Cluster analysis; Diagnostic errors; Neuropsychology; Dementia; Alzheimer disease
16.  C9orf72 Hexanucleotide Repeat Expansion and Guam Amyotrophic Lateral Sclerosis–Parkinsonism-Dementia Complex 
JAMA neurology  2013;70(6):742-745.
Importance
High-prevalence foci of amyotrophic lateral sclerosis (ALS) and parkinsonism-dementia complex (PDC) exist in Japanese on the Kii Peninsula of Japan and in the Chamorros of Guam. Clinical and neuropathologic similarities suggest that the disease in these 2 populations may be related. Recent findings showed that some of the Kii Peninsula ALS cases had pathogenic C9orf72 repeat expansions, a genotype that causes ALS in Western populations.
Objectives
To perform genotyping among Guam residents to determine if the C9orf72 expanded repeat allele contributes to ALS-PDC in this population and to evaluate LRRK2 for mutations in the same population.
Design and Setting Case-control series from neurodegenerative disease research programs on Guam that screened residents for ALS, PDC, and dementia.
Participants Study participants included 24 with ALS and 22 with PDC and 43 older control subjects with normal cognition ascertained between 1956 and 2006. All but one participant were Chamorro, the indigenous people of Guam. A single individual of white race/ethnicity with ALS was ascertained on Guam during the study.
Main Outcomes and Measures Participants were screened for C9orf72 hexanucleotide repeat length. Participants with repeat numbers in great excess of 30 were considered to have pathogenic repeat expansions. LRRK2 was screened for point mutations by DNA sequencing.
Results We found a single individual with an expanded pathogenic hexanucleotide repeat. This individual of white race/ethnicity with ALS was living on Guam at the time of ascertainment but had been born in the United States. All Chamorro participants with ALS and PDC and control subjects had normal repeats, ranging from 2 to 17 copies. No pathogenic LRRK2 mutations were found.
Conclusions and Relevance Unlike participants with ALS from the Kii Peninsula, C9orf72 expansions do not cause ALS-PDC in Chamorros. Likewise, LRRK2 mutations do not cause Guam ALS-PDC.
doi:10.1001/jamaneurol.2013.1817
PMCID: PMC3771869  PMID: 23588498
17.  Effect of TTP488 in patients with mild to moderate Alzheimer’s disease 
BMC Neurology  2014;14:12.
Background
TTP488, an antagonist at the Receptor for Advanced Glycation End products, was evaluated as a potential treatment for patients with mild-to-moderate Alzheimer’s disease (AD). A previous report describes decreased decline in ADAS-cog (delta = 3.1, p = 0.008 at 18 months, ANCOVA with multiple imputation), relative to placebo, following a 5 mg/day dose of TTP488. Acute, reversible cognitive worsening was seen with a 20 mg/day dose. The present study further evaluates the efficacy of TTP488 by subgroup analyses based on disease severity and concentration effect analysis.
Methods
399 patients were randomized to one of two oral TTP488 doses (60 mg for 6 days followed by 20 mg/day; 15 mg for 6 days followed by 5 mg/day) or placebo for 18 months. Pre-specified primary analysis, using an ITT population, was on the ADAS-cog11. Secondary analyses included as a key secondary variable the Clinical Dementia Rating-Sum of Boxes (CDR-SB), and another secondary variable of the ADCS-ADL.
Results
On-treatment analysis demonstrated numerical differences favoring 5 mg/day over placebo, with nominal significance at Month 18 (delta = 2.7, p = 0.03). Patients with mild AD, whether defined by MMSE or ADAS-cog, demonstrated significant differences favoring 5 mg/day on ADAS-cog and trends on CDR-sb and ADCS-ADL at Month 18. TTP488 plasma concentrations of 7.6-16.8 ng/mL were associated with a decreased decline in ADAS-cog over time compared to placebo. Worsening on the ADAS-cog relative to placebo was evident at 46.8-167.0 ng/mL.
Conclusions
Results of these analyses support further investigation of 5 mg/day in future Phase 3 trials in patients with mild AD.
doi:10.1186/1471-2377-14-12
PMCID: PMC4021072  PMID: 24423155
18.  Temporal Sequence Learning in Healthy Aging and Amnestic Mild Cognitive Impairment 
Experimental aging research  2013;39(4):371-381.
Background/Study Context
Temporal sequence learning is a critical aspect of episodic memory that may be dependent on the temporal and frontal lobes. Since amnestic mild cognitive impairment (aMCI) and normal aging may result in changes within the temporal and frontal lobes, the present study investigated temporal sequence learning in patients with aMCI, cognitively normal older adults, and young adults.
Methods
On each trial of a temporal sequence task, circles appeared one at a time at the end of each arm of a computerized radial 8-arm maze. Participants were asked to reproduce the temporal sequence by placing numbered circles (1-8) on the arms of the 8-arm maze. Participants were presented with the same fixed sequence on each trial until the sequence was replicated without any errors, or until 15 trials were presented.
Results
Individuals with aMCI required significantly more trials to learn the temporal sequence compared to older adults (p <. 05). Older adults required significantly more trials to learn the sequence than young adults (p <. 05). Older adults and individuals with aMCI committed significantly more Trial 1 errors (p <. 05) than young adults; however, there were no significant differences between the aMCI and older adult groups on Trial 1.
Conclusion
The results suggest that temporal sequence learning deficits are detectable in aMCI. These deficits may disrupt a number of cognitive processes, such as episodic memory, that are important for the execution of daily activities. The results suggest that although temporal sequence learning declines with normal aging, this decline is greater in individuals who have a diagnosis of aMCI and are at higher risk for developing AD.
doi:10.1080/0361073X.2013.808122
PMCID: PMC3736698  PMID: 23875836
19.  Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases 
Coppola, Giovanni | Chinnathambi, Subashchandrabose | Lee, Jason JiYong | Dombroski, Beth A. | Baker, Matt C. | Soto-Ortolaza, Alexandra I. | Lee, Suzee E. | Klein, Eric | Huang, Alden Y. | Sears, Renee | Lane, Jessica R. | Karydas, Anna M. | Kenet, Robert O. | Biernat, Jacek | Wang, Li-San | Cotman, Carl W. | DeCarli, Charles S. | Levey, Allan I. | Ringman, John M. | Mendez, Mario F. | Chui, Helena C. | Le Ber, Isabelle | Brice, Alexis | Lupton, Michelle K. | Preza, Elisavet | Lovestone, Simon | Powell, John | Graff-Radford, Neill | Petersen, Ronald C. | Boeve, Bradley F. | Lippa, Carol F. | Bigio, Eileen H. | Mackenzie, Ian | Finger, Elizabeth | Kertesz, Andrew | Caselli, Richard J. | Gearing, Marla | Juncos, Jorge L. | Ghetti, Bernardino | Spina, Salvatore | Bordelon, Yvette M. | Tourtellotte, Wallace W. | Frosch, Matthew P. | Vonsattel, Jean Paul G. | Zarow, Chris | Beach, Thomas G. | Albin, Roger L. | Lieberman, Andrew P. | Lee, Virginia M. | Trojanowski, John Q. | Van Deerlin, Vivianna M. | Bird, Thomas D. | Galasko, Douglas R. | Masliah, Eliezer | White, Charles L. | Troncoso, Juan C. | Hannequin, Didier | Boxer, Adam L. | Geschwind, Michael D. | Kumar, Satish | Mandelkow, Eva-Maria | Wszolek, Zbigniew K. | Uitti, Ryan J. | Dickson, Dennis W. | Haines, Jonathan L. | Mayeux, Richard | Pericak-Vance, Margaret A. | Farrer, Lindsay A. | Ross, Owen A. | Rademakers, Rosa | Schellenberg, Gerard D. | Miller, Bruce L. | Mandelkow, Eckhard | Geschwind, Daniel H.
Human Molecular Genetics  2012;21(15):3500-3512.
Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease. We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects.
Tau p.A152T significantly increases the risk for both FTD-s (n = 2139, OR = 3.0, CI: 1.6–5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3–4.2, P = 0.004) compared with 9047 controls. Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers. However, there is a pronounced increase in the formation of tau oligomers. Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation. These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.
doi:10.1093/hmg/dds161
PMCID: PMC3392107  PMID: 22556362
20.  Common genetic variants in the CLDN2 and PRSS1-PRSS2 loci alter risk for alcohol-related and sporadic pancreatitis 
Whitcomb, David C. | LaRusch, Jessica | Krasinskas, Alyssa M. | Klei, Lambertus | Smith, Jill P. | Brand, Randall E. | Neoptolemos, John P. | Lerch, Markus M. | Tector, Matt | Sandhu, Bimaljit S. | Guda, Nalini M. | Orlichenko, Lidiya | Alkaade, Samer | Amann, Stephen T. | Anderson, Michelle A. | Baillie, John | Banks, Peter A. | Conwell, Darwin | Coté, Gregory A. | Cotton, Peter B. | DiSario, James | Farrer, Lindsay A. | Forsmark, Chris E. | Johnstone, Marianne | Gardner, Timothy B. | Gelrud, Andres | Greenhalf, William | Haines, Jonathan L. | Hartman, Douglas J. | Hawes, Robert A. | Lawrence, Christopher | Lewis, Michele | Mayerle, Julia | Mayeux, Richard | Melhem, Nadine M. | Money, Mary E. | Muniraj, Thiruvengadam | Papachristou, Georgios I. | Pericak-Vance, Margaret A. | Romagnuolo, Joseph | Schellenberg, Gerard D. | Sherman, Stuart | Simon, Peter | Singh, Vijay K. | Slivka, Adam | Stolz, Donna | Sutton, Robert | Weiss, Frank Ulrich | Wilcox, C. Mel | Zarnescu, Narcis Octavian | Wisniewski, Stephen R. | O'Connell, Michael R. | Kienholz, Michelle L. | Roeder, Kathryn | Barmada, M. Michael | Yadav, Dhiraj | Devlin, Bernie | Albert, Marilyn S. | Albin, Roger L. | Apostolova, Liana G. | Arnold, Steven E. | Baldwin, Clinton T. | Barber, Robert | Barnes, Lisa L. | Beach, Thomas G. | Beecham, Gary W. | Beekly, Duane | Bennett, David A. | Bigio, Eileen H. | Bird, Thomas D. | Blacker, Deborah | Boxer, Adam | Burke, James R. | Buxbaum, Joseph D. | Cairns, Nigel J. | Cantwell, Laura B. | Cao, Chuanhai | Carney, Regina M. | Carroll, Steven L. | Chui, Helena C. | Clark, David G. | Cribbs, David H. | Crocco, Elizabeth A. | Cruchaga, Carlos | DeCarli, Charles | Demirci, F. Yesim | Dick, Malcolm | Dickson, Dennis W. | Duara, Ranjan | Ertekin-Taner, Nilufer | Faber, Kelley M. | Fallon, Kenneth B. | Farlow, Martin R. | Ferris, Steven | Foroud, Tatiana M. | Frosch, Matthew P. | Galasko, Douglas R. | Ganguli, Mary | Gearing, Marla | Geschwind, Daniel H. | Ghetti, Bernardino | Gilbert, John R. | Gilman, Sid | Glass, Jonathan D. | Goate, Alison M. | Graff-Radford, Neill R. | Green, Robert C. | Growdon, John H. | Hakonarson, Hakon | Hamilton-Nelson, Kara L. | Hamilton, Ronald L. | Harrell, Lindy E. | Head, Elizabeth | Honig, Lawrence S. | Hulette, Christine M. | Hyman, Bradley T. | Jicha, Gregory A. | Jin, Lee-Way | Jun, Gyungah | Kamboh, M. Ilyas | Karydas, Anna | Kaye, Jeffrey A. | Kim, Ronald | Koo, Edward H. | Kowall, Neil W. | Kramer, Joel H. | Kramer, Patricia | Kukull, Walter A. | LaFerla, Frank M. | Lah, James J. | Leverenz, James B. | Levey, Allan I. | Li, Ge | Lin, Chiao-Feng | Lieberman, Andrew P. | Lopez, Oscar L. | Lunetta, Kathryn L. | Lyketsos, Constantine G. | Mack, Wendy J. | Marson, Daniel C. | Martin, Eden R. | Martiniuk, Frank | Mash, Deborah C. | Masliah, Eliezer | McKee, Ann C. | Mesulam, Marsel | Miller, Bruce L. | Miller, Carol A. | Miller, Joshua W. | Montine, Thomas J. | Morris, John C. | Murrell, Jill R. | Naj, Adam C. | Olichney, John M. | Parisi, Joseph E. | Peskind, Elaine | Petersen, Ronald C. | Pierce, Aimee | Poon, Wayne W. | Potter, Huntington | Quinn, Joseph F. | Raj, Ashok | Raskind, Murray | Reiman, Eric M. | Reisberg, Barry | Reitz, Christiane | Ringman, John M. | Roberson, Erik D. | Rosen, Howard J. | Rosenberg, Roger N. | Sano, Mary | Saykin, Andrew J. | Schneider, Julie A. | Schneider, Lon S. | Seeley, William W. | Smith, Amanda G. | Sonnen, Joshua A. | Spina, Salvatore | Stern, Robert A. | Tanzi, Rudolph E. | Trojanowski, John Q. | Troncoso, Juan C. | Tsuang, Debby W. | Valladares, Otto | Van Deerlin, Vivianna M. | Van Eldik, Linda J. | Vardarajan, Badri N. | Vinters, Harry V. | Vonsattel, Jean Paul | Wang, Li-San | Weintraub, Sandra | Welsh-Bohmer, Kathleen A. | Williamson, Jennifer | Woltjer, Randall L. | Wright, Clinton B. | Younkin, Steven G. | Yu, Chang-En | Yu, Lei
Nature genetics  2012;44(12):1349-1354.
Pancreatitis is a complex, progressively destructive inflammatory disorder. Alcohol was long thought to be the primary causative agent, but genetic contributions have been of interest since the discovery that rare PRSS1, CFTR, and SPINK1 variants were associated with pancreatitis risk. We now report two significant genome-wide associations identified and replicated at PRSS1-PRSS2 (1×10-12) and x-linked CLDN2 (p < 1×10-21) through a two-stage genome-wide study (Stage 1, 676 cases and 4507 controls; Stage 2, 910 cases and 4170 controls). The PRSS1 variant affects susceptibility by altering expression of the primary trypsinogen gene. The CLDN2 risk allele is associated with atypical localization of claudin-2 in pancreatic acinar cells. The homozygous (or hemizygous male) CLDN2 genotype confers the greatest risk, and its alleles interact with alcohol consumption to amplify risk. These results could partially explain the high frequency of alcohol-related pancreatitis in men – male hemizygous frequency is 0.26, female homozygote is 0.07.
doi:10.1038/ng.2466
PMCID: PMC3510344  PMID: 23143602
21.  Incidence of New-Onset Seizures in Mild to Moderate Alzheimer Disease 
Archives of neurology  2012;69(3):368-372.
Objective
To estimate the incidence rate and predictors of seizures in patients with mild to moderate Alzheimer disease (AD).
Design
Cohort study of patients with mild to moderate AD in clinical trials. Risk factors for potential seizures were evaluated by stratified descriptive statistics and univariable and multivariable Cox proportional hazards regressions.
Setting
Pooled patient-level data from 10 Alzheimer Disease Cooperative Study clinical trials in mild to moderate AD from 1995 to 2010.
Patients
Three thousand seventy-eight subjects randomized to the treatment or placebo arms of 10 AD clinical trials. Screening Mini-Mental State Examination scores ranged between 10 and 28.
Results
Eighteen seizures were reported in 3078 randomized subjects, with an incidence rate of 484 per 100 000 person-years (95% CI, 287–764). Statistically significant independent risk factors for seizure were younger age (adjusted hazard ratio, 0.80; 95% CI, 0.69–0.93 per every 5 years of age), greater cognitive impairment at baseline (adjusted hazard ratio, 2.79; 95% CI, 1.06–7.33 for Mini-Mental State Examination scores <18 compared with Mini-Mental State Examination scores ≥18), and antipsychotic use at baseline (adjusted hazard ratio, 3.47; 95% CI, 1.33–9.08).
Conclusions
Seizure rates in patients with mild to moderate AD in clinical trials are similar to rates observed in longer observational cohort studies, but they are greater than expected in the general elderly population. Younger age, greater degree of cognitive impairment, and history of antipsychotic use were independent risk factors for new-onset seizures in AD.
doi:10.1001/archneurol.2011.830
PMCID: PMC3622046  PMID: 22410444
22.  TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis 
Lancet neurology  2008;7(5):409-416.
SUMMARY
BACKGROUND
TDP-43 is a major component of the ubiquitinated inclusions that characterise amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) with ubiquitin inclusions (FTLD-U). TDP-43 is an RNA-binding and DNA-binding protein that has many functions and is encoded by the TAR DNA-binding protein gene (TARDBP) on chromosome 1. Our aim was to investigate whether TARDBP is a candidate disease gene for familial ALS that is not associated with mutations in superoxide dismutase 1 (SOD1).
METHODS
TARDBP was sequenced in 259 patients with ALS, FTLD, or both. We used TaqMan-based SNP genotyping to screen for the identifi ed variants in control groups matched to two kindreds of patients for age and ethnic origin. Additional clinical, genetic, and pathological assessments were made in these two families.
FINDINGS
We identified two variants, p.Gly290Ala and p.Gly298Ser, in TARDBP in two familial ALS kindreds and we observed TDP-43 neuropathology in the CNS tissue available from one family. The variants are considered pathogenic mutations because they co-segregate with disease in both families, are absent in ethnically-matched controls, and are associated with TDP-43 neuropathology in several family members.
INTERPRETATION
The p.Gly290Ala and p.Gly298Ser mutations are located in the glycine-rich domain that regulates gene expression and mediates protein-protein interactions; in particular TDP-43 binds to heterogeneous ribonucleoproteins (hnRNPs) via this domain. We postulate that due to the varied and important cellular functions of TDP-43, these mutations may cause neurodegeneration through both gains and losses of function. The finding of TARDBP mutations implicates TDP-43 as an active mediator of neurodegeneration in a novel class of disorders, TDP-43 proteinopathies, a class of disorder that includes ALS and FTLD-U.
doi:10.1016/S1474-4422(08)70071-1
PMCID: PMC3546119  PMID: 18396105
23.  Degree of Bilingualism Predicts Age of Diagnosis of Alzheimer’s Disease in Low-Education but not in Highly-Educated Hispanics 
Neuropsychologia  2011;49(14):3826-3830.
The current study investigated the relationship between bilingual language proficiency and onset of probable Alzheimer’s disease (AD) in 44 Spanish-English bilinguals at the UCSD Alzheimer’s Disease Research Center. Degree of bilingualism along a continuum was measured using Boston Naming Test (BNT) scores in each language. Higher degrees of bilingualism were associated with increasingly later age-of-diagnosis (and age of onset of symptoms), but this effect was driven by participants with low education level (a significant interaction between years of education and bilingualism) most of whom (73%) were also Spanish-dominant. Additionally, only objective measures (i.e., BNT scores), not self-reported degree of bilingualism, predicted age-of-diagnosis even though objective and self-reported measures were significantly correlated. These findings establish a specific connection between knowledge of two languages and delay of AD onset, and demonstrate that bilingual effects can be obscured by interactions between education and bilingualism, and by failure to obtain objective measures of bilingualism. More generally, these data support analogies between the effects of bilingualism and “cognitive reserve” and suggest an upper limit on the extent to which reserve can function to delay dementia.
doi:10.1016/j.neuropsychologia.2011.09.041
PMCID: PMC3223277  PMID: 22001315
24.  Antemortem Pulse Pressure Elevation Predicts Cerebrovascular Disease in Autopsy-Confirmed Alzheimer’s Disease 
Journal of Alzheimer's Disease  2012;30(3):595-603.
Elevated pulse pressure (PP) is associated with cognitive decline and increased risk of Alzheimer’s disease (AD) in older adults, although the mechanisms behind these associations remain unclear. To address this question, we examined whether antemortem late-life PP elevation predicted vascular or AD pathology in autopsy-confirmed AD patients. Sixty-five elderly patients (mean age 74.2 years) clinically diagnosed with possible or probable AD underwent neuropsychological testing and blood pressure examinations. Postmortem histopathological measures of cerebrovascular disease (CVD) and AD neuropathology were later obtained on these same patients. We expected that antemortem PP elevation, but not standard blood pressure measures such as systolic or diastolic blood pressure, would predict the autopsy-based presence of CVD, and possibly AD pathology, in elderly AD patients. Results demonstrated that antemortem PP elevation was associated with the presence and severity of CVD at autopsy. For every 5 mmHg increase in antemortem PP there was an estimated 36% increase in the odds of having CVD at autopsy. Additionally, PP accounted for 12% of variance in CVD severity. No significant associations were present for cerebral amyloid angiopathy or Braak and Braak staging of the severity of AD pathology. Other standard blood pressure measures also did not significantly predict neuropathology. The association between antemortem PP and CVD at autopsy suggests that in older adults with AD, PP elevation may increase the risk of CVD. These findings may have treatment implications since some antihypertensive medications specifically address the pulsatile component of blood pressure (e.g., renin-angiotensin system inhibitors, calcium channel blockers).
doi:10.3233/JAD-2012-111697
PMCID: PMC3370943  PMID: 22451309
Alzheimer’s disease; blood pressure; cerebrovascular disease; pulse pressure
25.  The aging systemic milieu negatively regulates neurogenesis and cognitive function 
Nature  2011;477(7362):90-94.
Summary
In the central nervous system (CNS), aging results in a precipitous decline in adult neural stem/progenitor cells (NPCs) and neurogenesis, with concomitant impairments in cognitive functions1. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise1. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age dependent fashion in mice. Accordingly, exposing a young animal to an old systemic environment, or to plasma from old mice, decreased synaptic plasticity and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines - including CCL11/Eotaxin – whose plasma levels correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and whose levels are increased in plasma and cerebral spinal fluid of healthy aging humans. Finally, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis, and cognitive impairments, observed during aging can be in part attributed to changes in blood-borne factors.
doi:10.1038/nature10357
PMCID: PMC3170097  PMID: 21886162

Results 1-25 (36)