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1.  Cerebrospinal Fluid Aβ and Tau Level Fluctuation in an Older Clinical Cohort 
Archives of Neurology  2012;69(2):246-250.
Objective
To determine whether cerebrospinal fluid (CSF) biomarkers for Alzheimer disease fluctuate significantly over time in a cohort of older, mildly symptomatic individuals.
Design
Biomarker validation in a clinical cohort.
Setting
University hospital inpatient unit.
Participants
Ten patients admitted for CSF drainage for diagnostic purposes.
Main Outcome Measures
The CSF levels of Aβ1–40, Aβ1–42, tau, and phosphorylated tau on threonine 181 (p-tau181) were measured every 6 hours for 24 or 36 hours.
Results
The mean coefficient of variation values for each biomarker assessed in our 10 patients were 5.5% (95% CI, 3.8%–10.0%) for Aβ1–42, 12.2% (9.0%–24.2%) for Aβ1–40, 8.2% (5.7%–15.1%) for total tau, and 11.9% (8.5%–23.0%) for p-tau181. These values are only slightly higher than the variability in the assay. In addition, no significant circadian fluctuation in any Alzheimer disease biomarker was observed given the limitations of our sampling frequency.
Conclusion
In a cohort of elderly patients, little fluctuation in the levels of important Alzheimer disease biomarkers in lumbar CSF is seen as a function of time.
doi:10.1001/archneurol.2011.732
PMCID: PMC3310240  PMID: 22332192
2.  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
3.  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
4.  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
5.  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 1-5 (5)