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1.  Influence of lifestyle modifications on age-related free radical injury to brain 
JAMA neurology  2014;71(9):1150-1154.
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.
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.
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).
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.
PMCID: PMC4160350  PMID: 25048271
2.  Modulation of Aβ42 in vivo by γ-secretase modulator in primates and humans 
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.
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.
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.
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.
PMCID: PMC4523931  PMID: 26244059
3.  Diagnostic values of cerebrospinal fluid t-tau and Aβ42 using Meso Scale Discovery assays for Alzheimer’s disease 
Meso Scale Discovery (MSD) recently established electrochemiluminescence-based assays to measure cerebrospinal fluid (CSF) levels of total tau (t-tau) and amyloid beta 1–42 peptide (Aβ42) that can aid in the diagnosis of Alzheimer’s disease (AD). The goal of this investigation is to independently evaluate this platform and establish cut-off values of these biomarkers for AD diagnosis.
To validate the analytical and clinical performance of the MSD t-tau and Aβ42 kits and propose diagnostic cut-off values for the field.
The analytical performance of the CSF t-tau and Aβ42 assays was determined, followed by assessment of diagnostic performance of CSF t-tau, Aβ42 and t-tau/Aβ42 in three clinically characterized cohorts.
Both MSD assays demonstrated consistent and stable analytical performance, as well as resistance to several important pre-analytic variables. Diagnostically, t-tau/Aβ42 performed the best.
Our results independently confirm the analytical and clinical performance of the MSD CSF t-tau and Aβ42 assays. Based on a large, multi-center, clinically diagnosed cohort, we propose for the first time candidate diagnostic cut-offs for MSD measured CSF t-tau, Aβ42 and t-tau/Aβ42. However, these values needs to be refined as more subjects are included and the assays are tested by other laboratories.
PMCID: PMC4517668  PMID: 25613100
Aβ42; tau; cerebrospinal fluid; Alzheimer’s disease; Meso Scale Discovery
4.  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.
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).
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).
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.
PMCID: PMC4051849  PMID: 24756381
5.  Targeted Discovery and Validation of Plasma Biomarkers of Parkinson’s Disease 
Journal of Proteome Research  2014;13(11):4535-4545.
Despite extensive research, an unmet need remains for protein biomarkers of Parkinson’s disease (PD) in peripheral body fluids, especially blood, which is easily accessible clinically. The discovery of such biomarkers is challenging, however, due to the enormous complexity and huge dynamic range of human blood proteins, which are derived from nearly all organ systems, with those originating specifically from the central nervous system (CNS) being exceptionally low in abundance. In this investigation of a relatively large cohort (∼300 subjects), selected reaction monitoring (SRM) assays (a targeted approach) were used to probe plasma peptides derived from glycoproteins previously found to be altered in the CNS based on PD diagnosis or severity. Next, the detected peptides were interrogated for their diagnostic sensitivity and specificity as well as the correlation with PD severity, as determined by the Unified Parkinson’s Disease Rating Scale (UPDRS). The results revealed that 12 of the 50 candidate glycopeptides were reliably and consistently identified in plasma samples, with three of them displaying significant differences among diagnostic groups. A combination of four peptides (derived from PRNP, HSPG2, MEGF8, and NCAM1) provided an overall area under curve (AUC) of 0.753 (sensitivity: 90.4%; specificity: 50.0%). Additionally, combining two peptides (derived from MEGF8 and ICAM1) yielded significant correlation with PD severity, that is, UPDRS (r = 0.293, p = 0.004). The significance of these results is at least two-fold: (1) it is possible to use a targeted approach to identify otherwise very difficult to detect CNS related biomarkers in peripheral blood and (2) the novel biomarkers, if validated in independent cohorts, can be employed to assist with clinical diagnosis of PD as well as monitoring disease progression.
PMCID: PMC4224986  PMID: 24853996
Parkinson’s disease; targeted mass spectrometry; peripheral biomarkers; selected reaction monitoring
6.  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.
Increased pulse pressure associated with age-related arterial stiffening increases risk for Alzheimer dementia but the mechanism responsible for this association remains unclear.
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.
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.
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.
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).
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.
PMCID: PMC4428938  PMID: 25822631
8.  Clinical trial of an inhibitor of RAGE-Aβ interactions in Alzheimer disease 
Neurology  2014;82(17):1536-1542.
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).
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.
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.
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.
PMCID: PMC4011464  PMID: 24696507
9.  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.
PMCID: PMC4362713  PMID: 22874658
statistical power; sample size; clinical trial; item-response theory; activities of daily living; Alzheimer’s disease
10.  Cerebrospinal Fluid α-Synuclein and Lewy Body-Like Symptoms in Normal Controls, Mild Cognitive Impairment, and Alzheimer’s Disease 
Journal of Alzheimer's disease : JAD  2015;43(3):1007-1016.
Reduced cerebrospinal fluid (CSF) α-synuclein has been described in synucleinopathies, including dementia with Lewy bodies (DLB). Common symptoms of DLB include visual hallucinations and visuospatial and executive deficits. Co-occurrence of Lewy body pathology is common in Alzheimer’s disease (AD) patients, but it is unknown if reduced CSF α-synuclein is associated with Lewy body-like symptomatology in AD.
Determine associations between CSF α-synuclein and Lewy body-like symptomatology.
We included 73 controls (NC), 121 mild cognitive impairment (MCI) patients, and 61 AD patients (median follow-up 3.5 years, range 0.6–7.8). We tested associations between baseline CSF α-synuclein and visual hallucinations and (longitudinal) cognition. Models were tested with and without co-varying for CSF total tau (T-tau), which is elevated in AD patients, and believed to reflect neurodegeneration.
Hallucinations were reported in 20% of AD patients, 13% of MCI patients, and 8% of NC. In AD, low CSF α-synuclein was associated with hallucinations. When adjusting for CSF T-tau, low CSF α-synuclein was associated with accelerated decline of executive function (NC, MCI, and AD), memory (MCI and AD), and language (MCI).
The associations of low CSF α-synuclein with hallucinations and poor executive function, which are hallmarks of DLB, indirectly suggest that this biomarker may reflect underlying synuclein pathology. The associations with memory and language in MCI and AD suggests either that reduced CSF α-synuclein also partly reflects global impaired neuronal/synaptic function, or that non-specific overall cognitive deterioration is accelerated in the presence of synuclein related pathology. The findings will require autopsy verification.
PMCID: PMC4350922  PMID: 25125463
Alpha-synuclein; Alzheimer’s disease; cerebrospinal fluid; cognition; hallucinations; tau
11.  Detection of Peri-Synaptic Amyloid-β Pyroglutamate Aggregates in Early Stages of Alzheimer’s Disease and in AβPP Transgenic Mice Using a Novel Monoclonal Antibody 
The neurodegenerative pathology in patients with Alzheimer’s disease (AD) has been associated with the progressive accumulation of aggregated and post-translationally modified amyloid-β (Aβ) species. Among them, recent studies indicate that the pyroglutamate modification of Aβ (pE(3)Aβ) catalyzed by glutaminyl cyclase might play an important role in the pathogenesis of AD. Although the effects of the pyroglutamate modification on Aβ aggregation and toxicity have been investigated, less is known about the distribution of pE(3)Aβ across the spectrum of AD and in the brains of amyloid-β protein precursor (AβPP) transgenic (tg) animals. For this purpose, we generated a novel monoclonal antibody (denominated D129) that specifically recognizes pE(3)Aβ and characterized the patterns of distribution in the postmortem brain samples from AD patients divided by disease stage (Braak stage) and in AβPP tg mice. We found that in early stages of AD and young AβPP tg mice pE(3)Aβ was found in discrete linear and granular aggregates in the neuropil that co-localized with the pre-synaptic protein synaptophysin and was in close opposition to dendrites labeled with MAP2. In later stages of AD and in older AβPP tg mice, pE(3)Aβ was abundant in diffuse and mature plaques. In conclusion, this study suggests that peri-synaptic accumulation of pE(3)Aβ might contribute to early cognitive dysfunction in AD.
PMCID: PMC4350934  PMID: 22064070
ELISA; monoclonal antibody; mThy1-hAβPP tg; synapse; Tg2576
12.  The New Qualitative Scoring MMSE Pentagon Test (QSPT) as a Valid Screening Tool between Autopsy-Confirmed Dementia with Lewy Bodies and Alzheimer's Disease 
Visual-constructional apraxia is a prominent feature of dementia with Lewy bodies (DLB) that might help to clinically distinguish it from Alzheimer's disease (AD). The main goal of this study was to assess performance on the copy intersecting-pentagon item of the Mini-Mental State Examination with the new Qualitative Scoring method for the Pentagon copy Test (QSPT). In order to determine which aspects of the drawings might differentiate DLB from AD, pentagon drawings of autopsy-verified DLB (n = 16) and AD (n = 15) patients were assessed using the QSPT. The qualitative scoring encompasses the assessment of different parameters of the drawing, such as number of angles, distance/intersection, closure/opening, rotation, and closing-in. The QSPT scores were compared between groups using linear analyses and artificial neural network analyses at four different time points. Linear analyses showed that during the first evaluation, number of angles was the only parameter that showed a significant difference between DLB and AD patients. A gradual decline in other parameters and total pentagon score occurred in both groups during subsequent years, with greater decline for the DLB group. The artificial neural network analyses using auto-contractive maps showed that, with disease progression, DLB became related to relatively lower qualitative pentagon scores, whereas AD became related to relatively higher qualitative scores. These findings suggest that the QSPT might be a sensitive measure of visuo-constructive abilities able to differentiate DLB from AD at disease onset and as the diseases progress, but further studies on larger population are necessary in order to establish its clinical relevance.
PMCID: PMC4346244  PMID: 24284368
Alzheimer's disease; autopsy-confirmed; copy of pentagons; dementia with Lewy bodies
13.  Widespread micro-RNA dysregulation in Multiple System Atrophy: disease-related alteration in miR-96 
The European journal of neuroscience  2013;39(6):1026-1041.
MicroRNA (miRNA) are short sequences of RNA that function as post-transcriptional regulators by binding to target mRNA transcripts resulting in translational repression. A number of recent studies have identified miRNA as being involved in neurodegenerative disorders including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). However, the role of miRNA in Multiple System Atrophy (MSA), a progressive neurodegenerative disorder characterized by oligodendroglial accumulation of alpha-synuclein remains unexamined. In this context, this study examined miRNA profiles in MSA cases compared to controls and in transgenic (tg) models of MSA compared to non tg mice.
The results demonstrate a widespread dysregulation of miRNA in MSA cases, which is recapitulated in the murine models. The study employed a cross-disease, cross-species approach to identify miRNA that were either specifically dysregulated in MSA or were commonly dysregulated in neurodegenerative conditions such as AD, Dementia with Lewy bodies, Progressive Supranuclear Palsy and Corticobasal Degeneration or the tg mouse model equivalents of these disorders. Using this approach we identified a number of miRNA that were commonly dysregulated between disorders and those that were disease-specific.
Moreover, we identified miR-96 as being up regulated in MSA. Consistent with the up regulation of miR-96, mRNA and protein levels of members of the solute carrier protein family SLC1A1 and SLC6A6, miR-96 target genes, were down regulated in MSA cases and a tg model of MSA. These results suggest that miR-96 dysregulation may play a role in MSA and its target genes may be involved in the pathogenesis of MSA.
PMCID: PMC4052839  PMID: 24304186
Transgenic; neurodegeneration; mouse; human
14.  Accounting for Functional Loss in Alzheimer’s Disease and Dementia with Lewy Bodies: Beyond Cognition 
The relative contributions of cognitive, motor and behavioral deficits to the impairment of physical or instrumental activities of daily living (ADL) may differ in patients with Dementia with Lewy Bodies (DLB) and Alzheimer’s Disease (AD).
Multiple linear regression analyses were used to identify the amount of variability in physical self-maintenance and instrumental ADL ratings predicted by cognitive, motor, and behavioral indices separately for patients with autopsy-diagnosed DLB (n=39) or AD (n=39).
Motor dysfunction accounted for significant variance in physical ADL in DLB (R2 change=0.17), whereas behavioral (R2 change=0.23) and motor dysfunction (R2 change=0.13) accounted for significant variance in AD. Motor (R2 change=0.32) and cognitive (R2 change=0.10) dysfunction accounted for significant variance in instrumental ADL in DLB, whereas cognitive (R2 change=0.36) and behavioral (R2 change=0.12) dysfunction accounted for significant variance in AD.
Cognitive, motor, and behavioral deficits contribute differently to ADL changes in DLB and AD. Thus, treatments designed to ameliorate a certain aspect of AD or DLB (e.g., cognitive dysfunction) may have a larger impact on everyday function in one disorder than the other.
PMCID: PMC4339266  PMID: 23850331
Dementia with Lewy Bodies; Alzheimer’s Disease; Activities of Daily Living; Cognition; Behavior; Motor Function
15.  Pulse pressure is associated with Alzheimer biomarkers in cognitively normal older adults 
Neurology  2013;81(23):2024-2027.
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.
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.
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).
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.
PMCID: PMC3854831  PMID: 24225352
16.  Abnormal P600 word repetition effect in elderly persons with Preclinical Alzheimer’s disease 
Cognitive neuroscience  2013;4(0):10.1080/17588928.2013.838945.
We sought cognitive event-related potential (ERP) biomarkers of “Preclinical Alzheimer’s disease” (Pre-AD) using an incidental verbal learning paradigm with high sensitivity to prodromal AD. Seven elderly persons, with normal cognition at the time of ERP recordings, but who showed subsequent cognitive decline or AD pathology at autopsy (n=5, mean Braak stage=2.8), were compared to 12 “robust” normal elderly (RNE) who remained cognitively normal (Mfollow-up=9.0 years). EEG was recorded during a word repetition paradigm (semantically congruous (50%) and incongruous target words repeat ~10–140 seconds later). The RNE P600 congruous word repetition ERP effects (New minus Old congruous words) were significantly larger than in Pre-AD (mean amplitudes = 3.28 vs. 0.10 µV, p= 0.04). High group discrimination (84%) was achieved (by a P600 amplitude cutoff of ~1.5 µV). Abnormal P600 word repetition effects in cognitively normal elderly persons may be an important sign of synaptic dysfunction and Preclinical AD.
PMCID: PMC3841188  PMID: 24090465
Mild Cognitive Impairment; EEG; memory; Alzheimer’s disease; Event-related potentials
17.  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.
PMCID: PMC3706572  PMID: 23639207
Noradrenergic system; Norepinephrine; Cognition; Aging
18.  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.
PMCID: PMC4172502  PMID: 25156329
Mild cognitive impairment; Awareness; Cluster analysis; Diagnostic errors; Neuropsychology; Dementia; Alzheimer disease
19.  Neuropsychological Criteria for Mild Cognitive Impairment Improves Diagnostic Precision, Biomarker Associations, and Progression Rates 
We compared two methods of diagnosing mild cognitive impairment (MCI): conventional Petersen/Winblad criteria as operationalized by the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and an actuarial neuropsychological method put forward by Jak and Bondi designed to balance sensitivity and reliability. 1,150 ADNI participants were diagnosed at baseline as cognitively normal (CN) or MCI via ADNI criteria (MCI: n = 846; CN: n = 304) or Jak/Bondi criteria (MCI: n = 401; CN: n = 749), and the two MCI samples were submitted to cluster and discriminant function analyses. Resulting cluster groups were then compared and further examined for APOE allelic frequencies, cerebrospinal fluid (CSF) Alzheimer’s disease (AD) biomarker levels, and clinical outcomes. Results revealed that both criteria produced a mildly impaired Amnestic subtype and a more severely impaired Dysexecutive/Mixed subtype. The neuropsychological Jak/Bondi criteria uniquely yielded a third Impaired Language subtype, whereas conventional Petersen/Winblad ADNI criteria produced a third subtype comprising nearly one-third of the sample that performed within normal limits across the cognitive measures, suggesting this method’s susceptibility to false positive diagnoses. MCI participants diagnosed via neuropsychological criteria yielded dissociable cognitive phenotypes, significant CSF AD biomarker associations, more stable diagnoses, and identified greater percentages of participants who progressed to dementia than conventional MCI diagnostic criteria. Importantly, the actuarial neuropsychological method did not produce a subtype that performed within normal limits on the cognitive testing, unlike the conventional diagnostic method. Findings support the need for refinement of MCI diagnoses to incorporate more comprehensive neuropsychological methods, with resulting gains in empirical characterization of specific cognitive phenotypes, biomarker associations, stability of diagnoses, and prediction of progression. Refinement of MCI diagnostic methods may also yield gains in biomarker and clinical trial study findings because of improvements in sample compositions of ‘true positive’ cases and removal of ‘false positive’ cases.
PMCID: PMC4133291  PMID: 24844687
Alzheimer’s disease; Alzheimer’s Disease Neuroimaging Initiative; biomarker; cluster analysis; dementia; mild cognitive impairment; neuropsychology; progression
20.  Neuropsychiatric Features of Frontal Lobe Dysfunction in Autopsy-Confirmed Patients with Lewy Bodies and “Pure” Alzheimer’s Disease 
To compare patients with autopsy-confirmed Alzheimer’s disease (AD, #14) and Dementia with Lewy bodies (DLB) on the frequency of behaviors related to frontal systems dysfunction and the association of these behaviors with dementia severity.
Cross-sectional survey of longitudinal cohort.
University Alzheimer’s disease research center.
Volunteer sample of 19 DLB and 38 AD participants with autopsy-confirmed diagnoses, similar in age (DLB: 77.3, AD: 77.5), education (15.2, 14.7), and Mini-Mental State Examination (MMSE) score (20.6, 20.5), with impairment ranging from mild deficits to moderate dementia.
The Frontal Systems Behavior Scale (FrSBe)-Family Rating Form assessing patient apathy, disinhibition, and executive dysfunction by a knowledgeable informant.
A two-way analysis of variance with the FrSBe total as the dependent variable revealed a significant MMSE by diagnosis interaction (F(1,53)=9.34, p=.004). Mean FrSBe total for AD patients showed significant impairment across the range of dementia severity, while it was relatively preserved for DLB patients in early stage of disease. The interaction term showed the same pattern for the executive dysfunction (F(1,53)=7.62, p=.008), disinhibition (F(1,53)=4.90, p=.031), and apathy (F(1,53)=9.77, p=.003) subscales.
While frontal behavioral symptoms in AD patients were present regardless of stage of dementia, DLB patients showed significant frontal dysfunction only in later stages. Results suggest that frontal subcortical circuits associated with behaviors assessed by the FrSBe are affected early in AD but not until later stages in DLB. Assessing specific behaviors related to frontal systems, coupled with stage of cognitive decline, may aid in clinical differentiation of AD and DLB.
PMCID: PMC3664517  PMID: 23567425
Dementia with Lewy bodies; Alzheimer’s disease; Frontal systems; Behavioral symptoms
21.  C9orf72 Hexanucleotide Repeat Expansion and Guam Amyotrophic Lateral Sclerosis–Parkinsonism-Dementia Complex 
JAMA neurology  2013;70(6):742-745.
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.
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.
PMCID: PMC3771869  PMID: 23588498
22.  Effect of Knowledge of APOE Genotype on Subjective and Objective Memory Performance in Healthy Older Adults 
The American journal of psychiatry  2014;171(2):201-208.
The knowledge that one carries the apolipoprotein E (APOE) ε4 allele risk factor for Alzheimer’s disease was recently found to have little short-term psychological risk. The authors investigated the impact of knowledge of carrying the risk allele on subjective ratings of memory and objective memory test performance of older adults.
Using a nested case-control design, the authors administered objective verbal and visual memory tests and self-rating scales of memory function to 144 cognitively normal older adults (ages 52–89) with known APOE genotype who knew (ε4+, N=25; ε4−, N=49) or did not know (ε4+, N=25; ε4−, N=45) their genotype and genetic risk for Alzheimer’s disease prior to neuropsychological evaluation.
Significant genotype-by-disclosure interaction effects were observed on several memory rating scales and tests of immediate and delayed verbal recall. Older adults who knew their ε4+ genotype judged their memory more harshly and performed worse on an objective verbal memory test than did ε4+ adults who did not know. In contrast, older adults who knew their ε4− genotype judged their memory more positively than did ε4− adults who did not know, but these groups did not differ in objective memory test performance.
Informing older adults that they have an APOE genotype associated with an increased risk of Alzheimer’s disease can have adverse consequences on their perception of their memory abilities and their performance on objective memory tests. The patient’s knowledge of his or her genotype and risk of Alzheimer’s disease should be considered when evaluating cognition in the elderly.
PMCID: PMC4037144  PMID: 24170170
23.  Interrater reliability of the new criteria for behavioral variant frontotemporal dementia 
Neurology  2013;80(21):1973-1977.
To evaluate the interrater reliability of the new International Behavioural Variant FTD Criteria Consortium (FTDC) criteria for behavioral variant frontotemporal dementia (bvFTD).
Twenty standardized clinical case modules were developed for patients with a range of neurodegenerative diagnoses, including bvFTD, primary progressive aphasia (nonfluent, semantic, and logopenic variant), Alzheimer disease, and Lewy body dementia. Eighteen blinded raters reviewed the modules and 1) rated the presence or absence of core diagnostic features for the FTDC criteria, and 2) provided an overall diagnostic rating. Interrater reliability was determined by κ statistics for multiple raters with categorical ratings.
The mean κ value for diagnostic agreement was 0.81 for possible bvFTD and 0.82 for probable bvFTD (“almost perfect agreement”). Interrater reliability for 4 of the 6 core features had “substantial” agreement (behavioral disinhibition, perseverative/compulsive, sympathy/empathy, hyperorality; κ = 0.61–0.80), whereas 2 had “moderate” agreement (apathy/inertia, neuropsychological; κ = 0.41–0.6). Clinician years of experience did not significantly influence rater accuracy.
The FTDC criteria show promise for improving the diagnostic accuracy and reliability of clinicians and researchers. As disease-altering therapies are developed, accurate differential diagnosis between bvFTD and other neurodegenerative diseases will become increasingly important.
PMCID: PMC3716343  PMID: 23635967
Human platelets can be stimulated by thrombin or ionomycin to secrete soluble truncated amyloid β–protein precursor and particulate membrane fragments which contain C-terminal and N-terminal immunoreactive amyloid β–protein precursor. This suggests a possible circulating source of β–protein in serum which may play a role in the formation of amyloid deposits. The release of soluble amyloid β-protein precursor could be involved in normal platelet physiology.
PMCID: PMC4019003  PMID: 2115331
25.  GWAS of cerebrospinal fluid tau levels identifies novel risk variants for Alzheimer’s disease 
Neuron  2013;78(2):256-268.
Cerebrospinal fluid (CSF) tau, tau phosphorylated at threonine 181 (ptau) and Aβ42 are established biomarkers for Alzheimer’s Disease (AD), and have been used as quantitative traits for genetic analyses. We performed the largest genome-wide association study for cerebrospinal fluid (CSF) tau/ptau levels published to date (n=1,269), identifying three novel genome-wide significant loci for CSF tau and ptau: rs9877502 (P=4.89×10−9 for tau) located at 3q28 between GEMC1 and OSTN, rs514716 (P=1.07×10−8 and P=3.22×10−9 for tau and ptau respectively), located at 9p24.2 within GLIS3 and rs6922617 (P = 3.58×10−8 for CSF ptau) at 6p21.1 within the TREM gene cluster, a region recently reported to harbor rare variants that increase AD risk. In independent datasets rs9877502 showed a strong association with risk for AD, tangle pathology and global cognitive decline (P=2.67×10−4, 0.039, 4.86×10−5 respectively) illustrating how this endophenotype-based approach can be used to identify new AD risk loci.
PMCID: PMC3664945  PMID: 23562540

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