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1.  Plasma Amyloid β as a Predictor of Dementia and Cognitive Decline: A Systematic Review and Meta-analysis 
Archives of neurology  2012;69(7):824-831.
Context
Preclinical prediction of Alzheimer’s disease is important, critical to effective intervention. Plasma levels of amyloid β-peptides have been a principal focus of the growing literature on blood-based biomarkers, but studies to date have varied in design, assay methods and sample size, making it difficult to readily interpret the overall data.
Objective
To conduct a systematic review and meta-analysis of relevant prospective studies in order to determine if plasma amyloid β levels may predict development of dementia, Alzheimer’s disease, and cognitive decline.
Data Sources
Prospective studies published between 1995 and 2011 indexed in the PubMed, EMBASE, and PsycInfo databases were searched.
Study Selection
Selected studies included those measuring at least one relevant plasma amyloid β species (Aβ40, Aβ42, Aβ42:Aβ40 ratio) and reporting an effect estimate for dementia, Alzheimer’s disease, or cognitive change.
Data Extraction
Using a standardized extraction form, appropriate study parameters on subject information, exposure, and outcome were extracted. Random effects models were utilized to generate summary risk ratios and 95% confidence intervals, comparing the bottom versus top quantile for each plasma measure.
Results
Thirteen studies with a total of 10,303 subjects met inclusion criteria for meta-analysis. Lower Aβ42:Aβ40 ratios were significantly associated with development of Alzheimer’s disease (summary RR=1.60, 95% CI=1.04,2.46; p=0.03) and dementia (RR=1.67 95% CI=1.02,2.75; p=0.04). Significant heterogeneity was found for both summary estimates, which could not be explained by participants’ age, sex distribution, the study’s follow-up time, or year of publication. Plasma levels of Aβ40 and Aβ42 alone were not significantly associated with either outcome.
Conclusions
Overall, the literature indicates that plasma Aβ42:Aβ40 ratios predict development of Alzheimer’s disease and dementia. However, significant heterogeneity in the meta-analysis underlines the need for substantial further investigation of plasma amyloid β levels as a preclinical biomarker.
doi:10.1001/archneurol.2011.1841
PMCID: PMC3772635  PMID: 22451159
2.  The SIST-M: Development, reliability and cross-sectional validation of a brief structured Clinical Dementia Rating interview 
Archives of neurology  2011;68(3):343-350.
Background
The Clinical Dementia Rating (CDR) and CDR-Sum-of-Boxes (CDR-SB) can be utilized to grade mild but clinically important cognitive symptoms. However, sensitive clinical interview formats are lengthy.
Objective
To develop a brief instrument for obtaining CDR scores, and to assess its reliability and cross-sectional validity.
Methods
Using legacy data from expanded interviews conducted among 347 community-dwelling, older adults in a longitudinal study, we identified 60 questions about cognitive functioning in daily life–out of a possible 131– using clinical judgment, inter-item correlations, and principal components analysis. Items were selected in one cohort (n=147), and a computer algorithm for generating CDR scores was developed in this same cohort and re-run in a replication cohort (n=200) to evaluate how well the 60 items retained information from the original 131. Then, short interviews based on the 60 items were administered to 50 consecutively-recruited elders, with no or mild cognitive symptoms, at an Alzheimer Disease Research Center. CDR scores based on short interviews were compared with those from independent long interviews.
Results
In the replication cohort, agreement between short and long CDR interviews ranged from κ =0.65–0.79, with κ =0.76 for Memory; κ =0.77 for global CDR; ICC (intra-class correlation coefficient) for CDR-SB=0.89. In the cross-sectional validation, short interview scores were slightly lower than those from long interviews, but good agreement was observed: κ ≥ 0.70 for global CDR and Memory; ICC for CDR-SB=0.73.
Conclusions
The SIST-M is a brief, reliable and sensitive instrument for obtaining CDR scores in persons with symptoms along the spectrum of mild cognitive change.
doi:10.1001/archneurol.2010.375
PMCID: PMC3058542  PMID: 21403019
Alzheimer disease; mild cognitive impairment; Clinical Dementia Rating; instrument; questionnaire; clinical interview
3.  Meta-Analysis confirms CR1, CLU, and PICALM as Alzheimer’s disease risk loci and reveals interactions with APOE genotypes 
Archives of neurology  2010;67(12):1473-1484.
Objectives
To determine whether genotypes at CLU, PICALM, and CR1 confer risk for Alzheimer’s disease (AD) and whether risk for AD associated with these genes is influenced by APOE genotypes.
Design
Association study of AD and CLU, PICALM, CR1 and APOE genotypes.
Setting
Academic research institutions in the United States, Canada, and Israel.
Participants
7,070 AD cases, 3,055 with autopsies, and 8,169 elderly cognitively normal controls, 1,092 with autopsies from 12 different studies, including Caucasians, African Americans, Israeli-Arabs, and Caribbean Hispanics.
Results
Unadjusted, CLU [odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.85 – 0.96 for single nucleotide polymorphism (SNP) rs11136000], CR1 (OR = 1.14, CI = 1.07 – 1.22, SNP rs3818361), and PICALM (OR = 0.89, CI = 0.84 – 0.94, SNP rs3851179) were associated with AD in Caucasians. None were significantly associated with AD in the other ethnic groups. APOE ε4 was significantly associated with AD (ORs from 1.80 to 9.05) in all but one small Caucasian cohort and in the Arab cohort. Adjusting for age, sex, and the presence of at least one APOE ε4 allele greatly reduced evidence for association with PICALM but not CR1 or CLU. Models with the main SNP effect, APOE ε4 (+/−), and an interaction term showed significant interaction between APOE ε4 (+/−) and PICALM.
Conclusions
We confirm in a completely independent dataset that CR1, CLU, and PICALM are AD susceptibility loci in European ancestry populations. Genotypes at PICALM confer risk predominantly in APOE ε4-positive subject. Thus, APOE and PICALM synergistically interact.
doi:10.1001/archneurol.2010.201
PMCID: PMC3048805  PMID: 20697030
4.  Delusions and Hallucinations Are Associated With Worse Outcome in Alzheimer Disease 
Archives of neurology  2005;62(10):1601-1608.
Background
Delusions and hallucinations are common in Alzheimer disease (AD) and there are conflicting reports regarding their ability to predict cognitive decline, functional decline, and institutionalization. According to all previous literature, they are not associated with mortality.
Objective
To examine whether the presence of delusions or hallucinations has predictive value for important outcomes in AD.
Design, Setting, and Participants
A total of 456 patients with AD at early stages (mean Folstein Mini-Mental State Examination [MMSE] score of 21 of 30 at entry) were recruited and followed up semiannually for up to 14 years (mean, 4.5 years) in 5 university-based AD centers in the United States and Europe. Using the Columbia University Scale for Psychopathology in AD (administered every 6 months, for a total of 3266 visit-assessments, average of 7.2 per patient), the presence of delusions and hallucinations was extracted and examined as time-dependent predictors in Cox models. The models controlled for cohort effect, recruitment center, informant status, sex, age, education, a comorbidity index, baseline cognitive and baseline functional performance, behavioral symptoms, and use of neuroleptics and cholinesterase inhibitors.
Main Outcome Measures
Cognitive (Columbia MMSE score of ≤20/57 [approximate Folstein MMSE score of ≤10/30]), functional (Blessed Dementia Rating Scale [parts I and II] score of ≥10), institutionalization equivalent index, and death.
Results
During the full course of follow-up, 38% of patients reached the cognitive, 41% the functional, 54% the institutionalization, and 49% the mortality end point. Delusions were noted for 34% of patients at baseline and 70% at any evaluation. Their presence was associated with increased risk for cognitive (risk ratio [RR], 1.50; 95% confidence interval [CI], 1.07-2.08) and functional decline (RR, 1.41; 95% CI, 1.02-1.94). Hallucinations were present in 7% of patients at initial visit and in 33% at any visit. Their presence was associated with increased risk for cognitive decline (RR, 1.62; 95% CI, 1.06-2.47), functional decline (RR, 2.25; 95% CI, 1.54-2.27), institutionalization (RR, 1.60; 95% CI, 1.13-2.28), and death (RR, 1.49; 95% CI, 1.03-2.14).
Conclusions
Delusions and hallucinations are very common in AD and predict cognitive and functional decline. Presence of hallucinations is also associated with institutionalization and mortality.
doi:10.1001/archneur.62.10.1601
PMCID: PMC3028538  PMID: 16216946
5.  GAB2 as an Alzheimer Disease Susceptibility Gene 
Archives of neurology  2009;66(2):250-254.
Background
Genomewide association (GWA) studies have recently implicated 4 novel Alzheimer disease (AD) susceptibility loci (GAB2, GOLM1, and 2 uncharacterized loci to date on chromosomes 9p and 15q). To our knowledge, these findings have not been independently replicated.
Objective
To assess these GWA findings in 4 large data sets of families affected by AD.
Design
Follow-up of genetic association findings in previous studies.
Setting
Academic research.
Participants
More than 4000 DNA samples from almost 1300 families affected with AD.
Main Outcome Measures
Genetic association analysis testing of 4 GWA signals (rs7101429 [GAB2], rs7019241 [GOLM1], rs10519262 [chromosome 15q], and rs9886784 [chromosome 9p]) using family-based methods.
Results
In the combined analyses, only rs7101429 in GAB2 yielded significant evidence of association with the same allele as in the original GWA study (P = .002). The results are in agreement with recent meta-analyses of this and other GAB2 polymorphisms suggesting approximately a 30% decrease in risk for AD among carriers of the minor alleles. None of the other 3 tested loci showed consistent evidence for association with AD across the investigated data sets.
Conclusions
GAB2 contains genetic variants that may lead to a modest change in the risk for AD. Despite these promising results, more data from independent samples are needed to better evaluate the potential contribution of GAB2 to AD risk in the general population.
doi:10.1001/archneurol.2008.552
PMCID: PMC2841135  PMID: 19204163
6.  Seizures in Alzheimer Disease 
Archives of neurology  2009;66(8):992-997.
Background
Transient symptoms in Alzheimer disease (AD) are frequent and include seizures, syncope, and episodes of inattention or confusion. The incidence of seizures in AD and predictors of which patients with AD might be more predisposed to them is based primarily on retrospective studies and is not well established.
Objective
To determine the incidence and predictors of new-onset unprovoked seizures.
Design
Prospective cohort study.
Setting
Three academic centers.
Patients
Four hundred fifty-three patients with probable AD observed prospectively from mild disease stages since 1992.
Main Outcome Measure
Informant interviews every 6 months included questions about whether the patient had a seizure (convulsion, fainting, or “funny” spell) and whether diagnosis or treatment for epilepsy or seizure was made. Two epileptologists independently retrospectively reviewed all available medical records for 52 patients with positive responses to either of these questions, and using a specific checklist form, events were diagnosed as to whether they were unprovoked seizures (intrarater concordance, κ=0.67). Diagnosis of unprovoked seizures constituted the event in survival analyses. Potential predictors included sex, age, race/ethnicity, educational achievement, duration of illness, baseline cognition and function, depression, medical comorbidities, and time-dependent use of cholinesterase inhibitors and neuroleptic agents, apolipoprotein E genotype, and previous electroencephalographic findings.
Results
Over the course of 3518 visit-assessments (per patient: mean, 7.8; maximum, 27), 7 patients (1.5%) developed seizures. Younger age was associated with higher risk (hazard ratio, 1.23; 95% confidence interval, 1.08–1.41; P=.003 for each additional year of age) of seizure incidence. No other predictor was significant. The overall incidence of seizures was low (418 per 100 000 person-years of observation) although significantly higher than expected for idiopathic unprovoked seizures in similar age ranges of the general population (hazard ratio, 8.06; 95% confidence interval, 3.23–16.61).
Conclusions
Unprovoked seizures are uncommon in AD, but they do occur more frequently than in the general population. Younger age is a risk factor for seizures in AD.
doi:10.1001/archneurol.2009.130
PMCID: PMC2768279  PMID: 19667221
7.  Measuring cerebral atrophy and white matter hyperintensity burden to predict the rate of cognitive decline in Alzheimer disease 
Archives of neurology  2008;65(9):1202-1208.
Objective
Although non-specific, cerebral atrophy and white matter hyperintensities (WMH) are features of the neurodegeneration associated with Alzheimer’s disease (AD). The purpose of the current study was to determine if baseline measurements of cerebral atrophy and WMH predict the rate of future cognitive decline in AD.
Design
Data were drawn from the Predictors Study, a longitudinal study that enrolls mild AD patients and re-asseses them every six months with the Columbia modified Mini Mental State Examination (mMMS; 0–57). MR images were analyzed to determine the severity of WMH (Scheltens Scale) and the degree of atrophy (bicaudate ratio). Generalized estimating equations (GEE) were used to determine whether severity of baseline MRI measurements and their interaction predicted the rate of mMMS decline at subsequent visits.
Setting
Three university-based AD centers in the United States (Predictors Study).
Participants
Eighty-four AD patients from the Predictors Study received structural MRI at baseline and were selected for analysis. They had an average of 6 follow-up evaluations.
Main outcome measure
Cognitive (Columbia modified Mini-Mental State Examination).
Results
Generalized estimating equation models demonstrated that degree of baseline atrophy (β = −0.316, p = 0.036), severity of WMH (β = −0.173, p = 0.028), and their interaction (β = − 6.061, p = 0.018) predicted rate of decline in mMMS scores.
Conclusions
Both degree of cerebral atrophy and severity of WMH are associated with the rapidity of cognitive decline in AD. Atrophy and WMH may interact to have a synergistic effect on future decline, such that AD patients with a high degree of both have a particularly precipitous cognitive course. These findings lend further support to the hypothesis that cerebrovascular pathology contributes to the clinical syndrome of Alzheimer’s disease.
doi:10.1001/archneur.65.9.1202
PMCID: PMC2629007  PMID: 18779424
Alzheimer’s disease; MRI; neuropsychological assessment
8.  Disruptive Behavior as a Predictor in Alzheimer Disease 
Archives of neurology  2007;64(12):1755-1761.
Background
Disruptive behavior is common in Alzheimer disease (AD). There are conflicting reports regarding its ability to predict cognitive decline, functional decline, institutionalization, and mortality.
Objective
To examine whether the presence of disruptive behavior has predictive value for important outcomes in AD.
Design
Using the Columbia University Scale for Psychopathology in Alzheimer Disease (administered every 6 months, for a total of 3438 visit-assessments and an average of 6.9 per patient), the presence of disruptive behavior (wandering, verbal outbursts, physical threats/violence, agitation/restlessness, and sundowning) was extracted and examined as a time-dependent predictor in Cox models. The models controlled for the recruitment cohort, recruitment center, informant status, sex, age, education, a comorbidity index, baseline cognitive and functional performance, and neuroleptic use.
Setting
Five university-based AD centers in the United States and Europe (Predictors Study).
Participants
Four hundred ninety-seven patients with early-stage AD (mean Folstein Mini-Mental State Examination score, 20 of 30 at entry) who were recruited and who underwent semiannual follow-up for as long as 14 (mean, 4.4) years.
Main Outcome Measures
Cognitive (Columbia Mini-Mental State Examination score, ≤ 20 of 57 [approximate Folstein Mini-Mental State Examination score, ≤ 10 of 30]) and functional (Blessed Dementia Rating Scale score, parts I and II, ≥ 10) ratings, institutionalization equivalent index, and death.
Results
At least 1 disruptive behavioral symptom was noted in 48% of patients at baseline and in 83% at any evaluation. Their presence was associated with increased risks of cognitive decline (hazard ratio 1.45 [95% confidence interval (CI), 1.03–2.03]), functional decline (1.66 [95% CI, 1.17–2.36]), and institutionalization (1.47 [95% CI, 1.10–1.97]). Sundowning was associated with faster cognitive decline, wandering with faster functional decline and institutionalization, and agitation/restlessness with faster cognitive and functional decline. There was no association between disruptive behavior and mortality (hazard ratio, 0.94 [95% CI, 0.71–1.25]).
Conclusion
Disruptive behavior is very common in AD and predicts cognitive decline, functional decline, and institutionalization but not mortality.
doi:10.1001/archneur.64.12.1755
PMCID: PMC2690610  PMID: 18071039
9.  Distinct Pools of Aβ in Alzheimer’s Disease Brain: A Clinical-Pathological Study 
Archives of neurology  2008;65(7):906-912.
Objective
Most measures of Aβ are elevated in Alzheimer’s Disease (AD) brain, but correlate inconsistently with disease severity. Since specific forms of Aβ may differentially correlate with clinical features, we segregated Aβ into distinct biochemical pools which may be enriched in biologically-relevant forms of Aβ.
Design
Clinical-pathological correlation
Subjects
27 subjects from a longitudinal study of AD, and 13 age- and gender- matched controls without known history of cognitive impairment or dementia.
Interventions
Temporal and cingulate neocortex were processed using a 4-step extraction, yielding biochemical fractions which are hypothesized to be enriched with proteins from distinct anatomical compartments: Tris (extracellular-soluble), Triton (intracellular), SDS (membrane-associated), Formic Acid (FA) (extracellular-insoluble). Aβ40 and Aβ42 were quantified in each biochemical compartment by ELISA.
Results
Aβ42 from all biochemical compartments was significantly elevated in AD cases vs. controls (p < 0.01). Aβ40 in the Tris and FA fractions were elevated in AD (temporal, p < 0.01; cingulate, p = 0.03), however Triton and SDS Aβ40 were similar in AD and controls. Functional impairment proximal to death correlated with Triton Aβ42 (r = 0.482, p = 0.015) and SDS Aβ42 (r = 0.409, p = 0.042) in temporal cortex. Faster cognitive decline was associated with elevated temporal SDS Aβ42 (p < 0.001) , while slower decline was associated with elevated cingulate FA Aβ42 and SDS Aβ42 (p = 0.02, p = 0.01).
Conclusions
Intracellular and membrane-associated Aβ, especially Aβ42 in temporal neocortex, may be more closely related to AD symptoms than other measured Aβ species.
doi:10.1001/archneur.65.7.906
PMCID: PMC2586606  PMID: 18625856

Results 1-9 (9)