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1.  Executive Dysfunction in Alzheimer Disease 
Archives of neurology  2004;61(4):556-560.
Executive dysfunction (EDF) is common in Alzheimer disease (AD); however, its relationship to other symptoms is difficult to assess in patients with AD.
To determine the prevalence of EDF and study its relationship to cognitive, functional, and neuropsychiatric symptoms in patients with AD.
Design, Setting, and Patients
A retrospective analysis of data from participants in the English Instruments Protocol of the Alzheimer’s Disease Cooperative Study. Subjects were drawn from a sample of patients evaluated at tertiary referral centers.
A total of 64% of AD patients were classified as having EDF. Patients with EDF performed worse on tests of cognition (P<.001), dementia severity (P<.001), and activities of daily living (P = .01) and had more frequent symptoms of psychosis (P=.03) with greater emergence during the 12-month interval (P=.03) compared with patients with normal executive function. Less than 30% of the variance in executive function performance was explained by cognitive measures.
These findings support the assessment of executive function in persons with AD and the importance of frontal lobe dysfunction in AD.
PMCID: PMC4419376  PMID: 15096405
2.  The Sleep Disorders Inventory: an instrument for studies of sleep disturbance in persons with Alzheimer’s disease 
Journal of sleep research  2003;12(4):331-337.
The Sleep Disorders Inventory (SDI) is an expanded version of one item of the Neuropsychiatric Inventory (NPI). It describes the frequency, severity, and caregiver burden of sleep-disturbed behaviors during a period prior to its administration. We carried out post hoc analyses on baseline responses to the SDI in 104 persons with Alzheimer’s disease (AD) and live-in caregivers who had been recruited for a trial of melatonin in the treatment of sleep disturbance. These patient-participants averaged <7 h of sleep per night, measured by actigraph (sleep disturbance), for the 2–3-week period prior to administration of SDI. Data were from the 2 weeks prior to the baseline visit (SDI, NPI) including actigraph-derived sleep variables and 2 weeks’ worth of sleep quality ratings (SQR) kept in a diary by caregivers, plus Mini-Mental State Examination and activities of daily living assessment at baseline. The prevalence of sleep disorder symptoms ranged from 34% (waking up at night thinking it is daytime) and 82% (getting up during the night). Worse SDI scores were associated with worse cognitive, functional, and behavioral status, but not with sex, age, education or duration of dementia. SDI scores were significantly worse in individuals meeting independently established criteria for a diagnosis of ‘sleep disturbance’ (<6 h total sleep time per night) whereas demographic variables and scores reflecting cognition and function were not significantly different across this grouping. The SDI covers a wide range of sleep behaviors and provides information independent of sleep time and SQR.
PMCID: PMC4418643  PMID: 14633245
alzheimer’s disease; measurement; sleep disturbance
3.  Comorbidity of Psychopathological Domains in Community-Dwelling Persons With Alzheimer’s Disease 
In this post hoc analysis of baseline responses to the CERAD Behavior Rating Scale for Dementia in a clinical trial of interventions for agitation in Alzheimer’s disease (AD), the authors investigated the distribution of, and relationships between, agitation, depression, and psychosis in 148 individuals with AD. Prevalence of depressive symptoms was highest (78.4%), followed by agitation (77.6%) and psychotic symptoms (69.3%); 51.1% of the sample had symptoms in all 3 domains. Cross-sectionally, psychotic symptoms were most closely associated with Mini-Mental State Examination (MMSE) scores, while agitation was less so. Depressive symptoms were relatively consistently prevalent across MMSE levels. After controlling for the presence of agitated symptoms, psychosis and depression were significantly associated, but neither symptoms of psychosis nor of depression were associated with agitation when depression or psychosis, respectively, was controlled for. Significant psychopathological comorbidity should be considered in the design of clinical trials targeting particular psychopathology in this disease population.
PMCID: PMC4418652  PMID: 12801159
psychopathology; Alzheimer’s; comorbidity; psychosis; agitation; depression
4.  A Multicenter, Placebo-controlled Trial of Melatonin for Sleep Disturbance in Alzheimer’s Disease 
Sleep  2003;26(7):893-901.
To determine the safety and efficacy of 2 dose formulations of melatonin for the treatment of insomnia in patients with Alzheimer’s disease.
A multicenter, randomized, placebo-controlled clinical trial of 2 dose formulations of oral melatonin coordinated by the National Institute of Aging-funded Alzheimer’s Disease Cooperative Study. Subjects with Alzheimer’s disease and nighttime sleep disturbance were randomly assigned to 1 of 3 treatment groups: placebo, 2.5-mg slow-release melatonin, or 10-mg melatonin.
Private homes and long-term care facilities.
157 individuals were recruited by 36 Alzheimer’s disease research centers. Subjects with a diagnosis of Alzheimer’s disease were eligible if they averaged less than 7 hours of sleep per night (as documented by wrist actigraphy) and had 2 or more episodes per week of nighttime awakenings reported by the caregiver.
Nocturnal total sleep time, sleep efficiency, wake-time after sleep onset, and day-night sleep ratio during 2- to 3-week baseline and 2-month treatment periods. Sleep was defined by an automated algorithmic analysis of wrist actigraph data.
No statistically significant differences in objective sleep measures were seen between baseline and treatment periods for the any of the 3 groups. Nonsignificant trends for increased nocturnal total sleep time and decreased wake after sleep onset were observed in the melatonin groups relative to placebo. Trends for a greater percentage of subjects having more than a 30-minute increase in nocturnal total sleep time in the 10-mg melatonin group and for a decline in the day-night sleep ratio in the 2.5-mg sustained-release melatonin group, compared to placebo, were also seen. On subjective measures, caregiver ratings of sleep quality showed improvement in the 2.5-mg sustained-release melatonin group relative to placebo. There were no significant differences in the number or seriousness of adverse events between the placebo and melatonin groups.
Based on actigraphy as an objective measure of sleep time, melatonin is not an effective soporific agent in people with Alzheimer’s disease.
PMCID: PMC4418658  PMID: 14655926
5.  Independence of Changes in Behavior From Cognition and Function in Community-Dwelling Persons With Alzheimer's Disease: A Factor Analytic Approach 
The authors’ main objective was to investigate the relationship between changes in psychopathological, cognitive and activity of daily living (ADL) instrument scores over 12 months in community-dwelling persons with Alzheimer's disease (AD). A secondary objective was to evaluate the validity of dividing the Clinical Dementia Rating (CDR), a global dementia staging instrument into cognitive and functional subscores.
Changes in measures of psychopathology, cognition and function between the baseline and 12-month visits were entered into these post hoc analyses of data from a one-year clinical trial to evaluate behavioral, cognitive and functional assessment instruments for use in clinical trials with AD patients. Exploratory factor analysis was used to determine whether there was independence between changes in any of these three domains of interest for this disease population; participants were a cohort of 187 well-characterized, community-dwelling persons with AD.
One-year change in the behavioral symptoms of this cohort of persons with AD was statistically independent from changes in scores on cognitive and functional measures. Some evidence of independence of 12 month changes in cognitive and functional measures was found. Cognitive and functional subscores for the CDR were supported. These findings suggest that changes in behavior and cognition in dementia may have distinct pathophysiologies.
PMCID: PMC4377284  PMID: 15746483
6.  Frequency of behavioral symptoms characterizes agitation in Alzheimer’s disease 
This study describes two well-characterized groups of Alzheimer’s disease (AD) patients with similar levels of cognitive functioning, but with different overall behavioral disturbance levels. We sought to determine the nature of this difference – whether AD patients with higher levels of behavioral disturbance (n = 148) differ from less disturbed AD patients (n = 235) in terms of (a) the range of symptoms exhibited, (b) the frequency of occurrence of these symptoms, or (c) both of these. We defined and operationalized ‘diversity of behaviors’ and ‘frequency’ with respect to the item-level responses on the Cohen-Mansfield agitation inventory (CMAI). We found that, in these two samples of AD patients, differences occurred in the frequency of 10 out of 21 behaviors, rather than in a variety of endorsed behaviors. These 10 behaviors, observed at different frequencies in both groups, may be useful for monitoring change in studies of drugs or behavioral interventions for behavioral disturbance in persons with AD.
PMCID: PMC4373072  PMID: 11571769
Alzheimer’s disease; assessment; agitation; behavioral disturbance
7.  Regression to the Mean: Implications for Clinical Trials of Psychotropic Agents in Dementia 
Current Alzheimer research  2004;1(4):323-328.
Effective drug development depends on understanding and optimizing results from controlled clinical trials. A recent double-blind, randomized, controlled trial of the treatment of agitation in patients with Alzheimer’s disease (AD) found no difference among the four arms of the study: haloperidol, trazodone, behavioral therapy, placebo. The current analysis was undertaken to further investigate the issues bearing on this outcome and to identify better means of detecting psychotropic effects in trials involving patients with AD.
This was post hoc analysis of a clinical trial data set. Patients in the placebo group were divided into responders (25% reduction in symptoms), worseners (25% worsening in baseline agitation scores), and those without a change in symptoms.
Analysis of the trial outcomes demonstrated that the reduction observed in the placebo group was of the same magnitude as predicted by regression to the mean. Patients exhibiting greater improvement had more severe baseline behavioral disturbances. The relatively modest severity of agitation and the low medication doses achieved in the study may have further contributed to the failure to distinguish among treatment groups.
Research design adjustments such as collection of both screening and baseline measures to determine eligibility may limit the effects of regression to the mean on trial outcomes and reduce this challenge to clinical trials.
PMCID: PMC4371726  PMID: 15975061
8.  Investigating Emergent Symptomatology as an Outcome Measure in a Behavioral Study of Alzheimer’s Disease 
These retrospective analyses represent a pilot study of a potential new outcome, expected emergence. The Behavior Rating Scale for Dementia (BRSD) was administered at the baseline and 12-month visits of a multicenter study. The authors computed the rates at which each BRSD symptom emerged over 12 months in normal elderly control subjects (n = 64). These normal rates were then applied as the expected emergent rate (EER) to a population of individuals with Alzheimer’s disease (n = 235). The comparison of expected emergence to observed emergence in Alzheimer’s disease showed interpretable differences. EER assesses whether treatments limit emergence in the target, relative to the standard, population. The ratio of expected to observed emergence provides an intuitively appealing quantification of treatment efficacy and can be used with any instrument that uses categorical or frequency ratings.
PMCID: PMC4371727  PMID: 12154155
9.  Qualifying Change: A Method for Defining Clinically Meaningful Outcomes of Change Score Computation 
To identify clinically meaningful change in longitudinal assessment.
A novel approach that qualifies item-level change over time by the degree to which it is clinically meaningful.
The classification method was tested by applying it to changes over 12 months in the frequency ratings of the items of a behavioral assessment instrument that is used commonly in clinical trials with Alzheimer’s disease (AD) patients.
Responses from a cohort of 235 well characterized, community-dwelling subjects with AD were analyzed by this method.
The approach allowed us to describe the proportions of items that emerged, ceased, worsened, and improved between the baseline and 12-month visits.
One-year change in the behavioral symptoms of persons with AD was used to exemplify the methodology. This approach can be used in other populations and with other measurements and was designed for analyses of clinical trial data. This method uses item-level changes to generate global impressions of clinically meaningful change; it also facilitates the definition of change that can be used in the clinical setting.
PMCID: PMC4367856  PMID: 11083327
follow-up studies; outcome assessment (health care); health status indicators; clinical trials; methods; data interpretation; statistical
10.  Reliability of Monitoring the Clinical Dementia Rating in Multicenter Clinical Trials 
The Clinical Dementia Rating (CDR) is quickly becoming a criterion standard in multicenter clinical trials in Alzheimer disease. An abbreviated version, with formal monitoring for consistency across sites and raters, is currently used in the Alzheimer’s Disease Cooperative Study (ADCS).
To demonstrate the degree of agreement on CDR scoring of clinical monitors working independently from ADCS-CDR worksheets.
Three members of the ADCS who are experienced and highly trained with respect to the CDR independently reviewed the ADCS-CDR worksheets of 15 subjects, assigning box and global CDR scores according to the prescribed algorithm.
The ratings were assigned during a single, 3-hour session in a closed room.
Two clinical monitors and one project director/clinical monitor supervisor.
Main Outcome Measures
Percent agreement, Kendall’s tau-b, and Cohen’s kappa were used to assess the degree of agreement of the raters with the previously established gold standard assessment on global and box scores for the 15 subjects.
Raters, blinded to patient groupings, were in agreement with the Gold Standard global CDR assessment on 87% of ratings. Kappa values indicated good (κ = 0.66, orientation and judgment & problem solving boxes) to excellent (κ = 0.83, global CDR) agreement.
The ADCS-CDR worksheets were reliably and consistently scored by clinical monitors, who may be considered proxy gold standards for CDR assessment.
PMCID: PMC4367865  PMID: 15592134
11.  Spanish Instrument Protocol: New Treatment Efficacy Instruments for Spanish-speaking Patients in Alzheimer Disease Clinical Trials 
To evaluate the feasibility of longitudinal assessment and the psychometric properties of both established and new outcome measures used in clinical trials of patients with dementia in a cohort of Spanish-speaking elders in the United States.
This is a prospectively collected multicenter study comparing patients with Alzheimer disease (AD) (N = 77) and elderly controls (N = 17) who are primary Spanish speakers. Spanish-speaking individuals with AD (SSI AD) were selected to represent predefined categories of impairment as determined by a Mini-Mental State Examination score. Controls were selected to approximately match by age and education (SSI C). Subjects were administered a series of Spanish translations of established outcome measures (Mini-Mental State Examination, Clinical Dementia Rating, Geriatric Dementia Scale), and Functional Assessment Staging (FAST)] and new outcome measures developed for United States in clinical trials to assess cognition, function, behavioral disturbance, and clinical global change. Half of the subjects were assessed at 1 and 2 months to evaluate reliability; all subjects were assessed at 6 and 12 months. Comparisons were made between patients and controls and between the Spanish-speaking cohort and a similar English-speaking cohort.
The 12-month completion rate was 77%, with a trend toward greater impairment in those with full retention. Both established and new measures demonstrated good internal consistency and test-retest reliability in this cohort. All but one measure of cognition demonstrated excellent discriminability between AD subjects and controls. The SSI AD cohort declined significantly on measures of cognition, function, and clinical global change over the 12-month assessment period. The SSI AD and English AD (ESI AD) cohorts declined equivalently on the most common outcomes in clinical trials of AD (delayed recall, clinical global change). Likewise, the most common behavioral changes were also similar in the ESI and SSI groups. However, the annual change was lower in SSI AD than in the ESI AD on several other measures of cognition and function.
These results support the recruitment of Spanish-speaking patients and the use of Spanish language translations for use in the clinical trials for AD.
PMCID: PMC3526370  PMID: 17132967
Alzheimer disease; Spanish language assessment; outcome measures; clinical trials
12.  ADCS Prevention Instrument Project: Pharmacoeconomics: Assessing Health-related Resource Use Among Healthy Elderly 
Alzheimer disease and associated disorders  2006;20(4 Suppl 3):S191-S202.
The Prevention Instrument project of the Alzheimer’s Disease Cooperative Study (ADCS) seeks to develop instruments to assess treatment efficacy including potential economic benefit. The Resource Use Inventory (RUI) is an instrument that has been used to capture resource utilization and costs in populations with Alzheimer disease (AD). However, resource utilization and costs for healthy, cognitively intact elderly as they begin to demonstrate cognitive deterioration are not well understood. In addition, the loss that relates to the subjects’ own time as they transition through cognitive impairment is not well documented.
To evaluate the utility of the RUI in a sample of cognitively intact elderly individuals living in the community and enrolled in AD prevention trials.
The RUI was administered to 644 subjects and their study partners either at home or in the clinic. For half of each sample, 3-month retesting was carried out. The RUI consisted of 9 questions. The first part of the RUI captured subjects’ use of direct medical care (eg, hospitalizations) and nonmedical care (eg, home health aides). The second part of the RUI captured the time caregivers spend providing care to the subjects. The third part of the RUI captured subjects’ participation in volunteer work and employment. The assessment interval for each question was the past 3 months.
The percentage of RUI forms returned incomplete or inaccurate for both in-clinic and at-home groups was extremely low. There were no differences in utilization rates between in-clinic and at-home group for all items in the RUI. Except for use of outpatient procedures, tests, or treatments, there were no differences in utilization rates between subjects who filled out the RUI with the help of their study partners or by themselves. Items in the RUI were sensitive to subjects’ cognitive and functional status and demographic characteristics.
Home-based completion of the RUI by participants in an AD prevention study is feasible, and seems to provide data that are reliable and valid. The instrument will be useful for tracking resource and time use through transition from healthy to cognitive impairment.
PMCID: PMC3229195  PMID: 17135812
Alzheimer disease; primary prevention; assessment measure; resource use; health care utilization; clinical trials
13.  Subtypes of Mild Cognitive Impairment in Older Postmenopausal Women: The Women’s Health Initiative Memory Study 
Mild cognitive impairment (MCI) is a transitional state between normal cognitive functioning and dementia. A proposed MCI typology1 classifies individuals by the type and extent of cognitive impairment, yet few studies have characterized or compared these subtypes. 447 women 65 years of age and older from the Women’s Health Initiative Memory Study2 were classified into the four MCI subgroups and a ‘no impairment’ group and compared on clinical, sociodemographic, and health variables.
82.1% of participants had a cognitive deficit in at least one domain with most (74.3%) having deficits in multiple cognitive domains. Only 4.3% had an isolated memory deficit, while 21.3% had an isolated non-memory deficit. Of the 112 women who met all MCI criteria examined, the most common subtype was amnestic multi-domain MCI (42.8%) followed by non-amnestic multiple domain MCI (26.7%), non-amnestic single domain (24.1%) and amnestic single domain MCI (6.3%). Subtypes were similar with respect to education, health status, smoking, depression and pre- and on-study use of hormone therapy.
Despite the attention it receives in the literature amnestic MCI is the least common type highlighting the importance of identifying and characterizing other non-amnestic and multi-domain subtypes. Further research is needed on the epidemiology of MCI subtypes, clinical and biological differences between them and rates for conversion to dementia.
PMCID: PMC2929315  PMID: 20473134
MCI; women; WHIMS; postmenopausal; cognition; dementia; hormone therapy
14.  3D Comparison of Low, Intermediate, and Advanced Hippocampal Atrophy in MCI 
Human brain mapping  2010;31(5):786-797.
We applied the hippocampal radial atrophy mapping technique to the baseline and follow-up magnetic resonance image data of 169 amnestic mild cognitive impairment (MCI) participants in the imaging arm of the Alzheimer's Disease Cooperative Study MCI Donepezil/Vitamin E trial. Sixty percent of the subjects with none to mild hippocampal atrophy rated with the visual medial temporal atrophy rating scale (MTA score < 2) and 33.8% of the subjects with moderate to severe (MTA ≥ 2) hippocampal atrophy converted to Alzheimer's disease (AD) during 3-year follow-up. MTA ≥ 2 showed a trend for greater left sided hippocampal atrophy versus MTA < 2 groups at baseline (Pcorrected = 0.08). Higher MTA scores were associated with progressive atrophy of the subiculum and the CA1–3 subregions. The MTA < 2 group demonstrated significant bilateral atrophy progression at follow-up (left Pcorrected = 0.008; right Pcorrected = 0.05). Relative to MTA < 2 nonconverters, MTA < 2 converters showed further involvement of the subiculum and CA1 and additional involvement of CA2–3 at follow-up. Right CA1 atrophy was significantly associated with conversion to dementia (for 1 mm greater right CA1 radial distance subjects had 50% reduced hazard for conversion). Greater CA1 and subicular atrophy can be demonstrated early and is predictive of future conversion to AD, whereas CA2–3 involvement becomes more evident as the disease progresses.
PMCID: PMC2938765  PMID: 20143386
mild cognitive impairment; conversion; hippocampal atrophy; medial temporal atrophy; magnetic resonance imaging; imaging biomarker
15.  Cognitive Discrepancies Versus APOE Genotype as Predictors of Cognitive Decline in Normal-Functioning Elderly Individuals: A Longitudinal Study 
Cognitive-discrepancy analysis has been shown to be a useful technique for detecting subtle cognitive deficits in normal-functioning elderly individuals who are genetically at-risk for Alzheimer disease (AD). However, studies that have used cognitive-discrepancy measures to date have used retrospective or cross-sectional designs, and the utility of this approach to predict cognitive decline has not been examined in a prospective investigation.
Longitudinal study.
San Diego, CA, Veterans Administration Hospital.
Twenty-four normal-functioning elderly individuals participated in the study, with 16 subjects exhibiting no change in their Dementia Rating Scale (DRS) scores over an 1-year period (Stable Group), and 8 subjects exhibiting a decline in DRS scores over the 1-year period (Decline group).
A cognitive-discrepancy measure isolating cognitive switching was computed that contrasted performance on a new higher-level task of executive functioning (a Stroop/Switching measure) relative to a composite measure of lower-level Stroop conditions.
a) In the year before their cognitive changes, the Decline group exhibited a significantly larger cognitive-discrepancy (Stroop/Switching versus lower-level Stroop conditions) score compared with a control (Stable) group; and b) the cognitive-discrepancy measure was superior to APOE genotype in predicting DRS decline.
Cognitive-discrepancy analysis isolating a component executive function ability not only seems to be a useful tool for identifying individuals at risk for cognitive deficits, but also shows promise in predicting individuals who may show subtle cognitive decline over time.
PMCID: PMC3050584  PMID: 18448849
Cognitive discrepancies; aging; Alzheimer disease; executive functioning
16.  Periventricular white matter hyperintensities increase the likelihood of progression from amnestic mild cognitive impairment to dementia 
Journal of neurology  2008;255(9):1302-1308.
White matter hyperintensities (WMH) have an effect on cognition and are increased in severity among individuals with amnestic mild cognitive impairment (aMCI). The influence of WMH on progression of aMCI to Alzheimer’s disease (AD) is less clear.
Data were drawn from a three-year prospective, double blind, placebo controlled clinical trial that examined the effect of donepezil or vitamin E on progression from aMCI to AD. WMH from multiple brain regions were scored on MR images obtained at entry into the trial from a subset of 152 study participants using a standardized visual rating scale. Cox proportional hazards models adjusting for age, education and treatment arm were used to investigate the role of WMH on time to progression.
55 of the 152 (36.2 %) aMCI subjects progressed to AD. Only periventricular hyperintensities (PVH) were related to an increased risk of AD within three years (HR = 1.59, 95 % CI = 1.24–2.05, p-value < 0.001). Correcting for medial temporal lobe atrophy or the presence of lacunes did not change statistical significance.
PVH are associated with an increased risk of progression from aMCI to AD. This suggests that PVH, an MRI finding thought to represent cerebrovascular damage, contributes to AD onset in vulnerable individuals independent of Alzheimer pathology.
PMCID: PMC2879405  PMID: 18825439
Alzheimer’s disease; MCI (mild cognitive impairment); MRI; cerebrovascular disease
17.  Visuospatial Deficits Predict Rate of Cognitive Decline in Autopsy-Verified Dementia with Lewy Bodies 
Neuropsychology  2008;22(6):729-737.
Dementia with Lewy Bodies (DLB) is often characterized by pronounced impairment in visuospatial skills, attention, and executive functions. However, the strength of the phenotypic expression of DLB varies and may be weaker in patients with extensive concomitant Alzheimer’s disease (AD). To determine whether strength of the DLB clinical phenotype impacts cognitive decline, visuospatial and language tests were retrospectively used to predict two-year rate of global cognitive decline in 22 autopsy-confirmed DLB patients (21 with concomitant AD) and 44 autopsy-confirmed “pure” AD patients. Generalized Estimating Equations (GEE) revealed a significant interaction such that poor baseline performances on tests of visuospatial skills were strongly associated with a rapid rate of cognitive decline in DLB but not AD (p < .001). No effect of confrontation naming was found. DLB patients with poor visuospatial skills had fewer neurofibrillary tangles and were more likely to experience visual hallucinations than those with better visuospatial skills. These results suggest that the severity of visuospatial deficits in DLB may identify those facing a particularly malignant disease course and may designate individuals whose clinical syndrome is impacted more by Lewy body formation than AD pathology.
PMCID: PMC2587484  PMID: 18999346
Dementia with Lewy bodies; cognitive decline; visuospatial skills; Alzheimer’s disease
18.  Longitudinal MRI findings from the vitamin E and Donepezil treatment study for MCI 
Neurobiology of aging  2007;29(9):1285-1295.
The vitamin E and donepezil trial for the treatment of amnestic mild cognitive impairment (MCI) was conducted at 69 centers in North America; 24 centers participated in an MRI sub study. The objective of this study was to evaluate the effect of treatment on MRI atrophy rates; and validate rate measures from serial MRI as indicators of disease progression in multi center therapeutic trials for MCI. Annual percent change (APC) from baseline to follow-up was measured for hippocampus, entorhinal cortex, whole brain, and ventricle in the 131 subjects who remained in the treatment study and completed technically satisfactory baseline and follow-up scans. Although a non-significant trend toward slowing of hippocampal atrophy rates was seen in APOE ∈4 carriers treated with donepezil; no treatment effect was confirmed for any MRI measure in either treatment group. For each of the four brain atrophy rate measures, APCs were greater in subjects who converted to AD than non-converters, and were greater in APOE ∈4 carriers than non-carriers. MRI APCs and changes in cognitive test performance were uniformly correlated in the expected direction (all p < 0.000). Results of this study support the feasibility of using MRI as an outcome measure of disease progression in multi center therapeutic trials for MCI.
PMCID: PMC2768818  PMID: 17452062
dementia; Alzheimer's disease; mild cognitive impairment; clinical trials; therapeutic trials; MRI; magnetic resonance imaging; serial MRI; longitudinal imaging; brain atrophy; brain atrophy rates
19.  High Dose B Vitamin Supplementation and Cognitive Decline in Alzheimer’s Disease: A Randomized Controlled Trial 
Blood levels of homocysteine may be elevated in Alzheimer’s disease (AD), and hyperhomocysteinemia may contribute to disease pathophysiology by vascular and direct neurotoxic mechanisms. Even in the absence of vitamin deficiency, homocysteine levels can be reduced by administration of high-dose supplements of folic acid and vitamins B6 and B12. Prior studies of B vitamins to reduce homocysteine in AD have not had sufficient size or duration to assess impact on cognitive decline.
To determine the efficacy and safety of B vitamin supplementation in the treatment of AD.
We conducted a multicenter, randomized, double-blind controlled clinical trial of high-dose folate/B6/B12 supplementation in individuals with AD.
The study was conducted between March, 2003 and February, 2007 at clinical research sites of the Alzheimer’s Disease Cooperative Study located throughout the US.
A total of 409 participants (out of 601 screened) with mild to moderate AD (Mini-Mental Status Scores between 14 and 26, inclusive) and normal folic acid, B12 and homocysteine levels were enrolled in this trial; 340 completed the trial on study medication.
Participants were randomly assigned to two groups of unequal size: 60% were treated with daily high-dose supplements (folate 5mg, vitamin B6 25mg, vitamin B12 1 mg), and 40% were treated with identical placebo; the duration of treatment was 18 months.
Main Outcome Measure
The primary outcome measure was the change in the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAScog).
Although the vitamin supplement regimen was effective in reducing homocysteine levels (active −2.42±3.35; placebo -0.86±2.59; p<0.001), it had no beneficial effect on the primary cognitive measure, rate of change in ADAS-Cog over 18 months (placebo: 0.372 point/month vs active: 0.401 point/month, p-value=0.522, CI of rate difference: (−0.06, 0.12), based on the Generalized Estimating Equations (GEE) model), or on any secondary measures. A higher rate of adverse events involving depression was observed in the group treated with vitamin supplements.
This regimen of high dose B vitamin supplements does not slow cognitive decline in individuals with mild to moderate AD.
PMCID: PMC2684821  PMID: 18854539
20.  Phase II safety trial targeting amyloid beta production with a gamma-secretase inhibitor in Alzheimer's disease 
Archives of neurology  2008;65(8):1031-1038.
Evaluate the safety, tolerability and amyloid beta (Aβ) response to a γ-secretase inhibitor (LY450139) in Alzheimer's disease.
Multi-center, randomized, double-blind, dose-escalation, placebo-controlled trial.
Community based clinical research centers.
51 participants with mild to moderate AD were randomized (placebo=15, 100mg=22, 140mg=14), with 43 completing the treatment phase.
Subjects randomized to LY450139 received 60mg daily for 2 weeks followed by 100mg for 6 weeks, then re-randomized to 100mg or 140mg for 6 additional weeks.
Main Outcome Measures
Primary outcome measures consisted of adverse events, plasma and cerebrospinal fluid Aβ levels, vital signs, electrocardiogram data, and laboratory safety tests. Secondary outcome measures included the ADAS-cognitive subscale and the ADCS-Activities of Daily Living scale.
Group differences were seen in “skin and subcutaneous tissue” complaints (p=0.052). These included 3 possible drug rashes and 3 reports of hair color change in the treatment groups. There were 3 adverse-event-related discontinuations, including one report of transient bowel obstruction. Plasma Aβ40 was reduced by 58.2% for the 100mg group and 64.6% for the 140mg group (P<0.001). No significant reduction was seen in CSF Aβ. No group differences were seen in cognitive or functional measures.
LY450139 was generally well tolerated at doses of up to 140mg taken daily for 14 weeks with several findings indicating the need for close clinical monitoring in future studies. Decreases in plasma Aβ concentrations were consistent with inhibition of γ-secretase.
PMCID: PMC2682361  PMID: 18695053
Alzheimer's disease; amyloid; gamma secretase; clinical trial
21.  APOE Genotype Predicts Depression in Women with Alzheimer’s Disease 
The association between the epsilon-4 type allele of apolipoprotein E (APOE ε4) and depression was investigated in 323 AD patients. Patients were divided into two groups based on the presence (n=61) or absence (n=262) of depression as assessed by the DSM-based Diagnostic Interview Schedule. Both subgroups were demographically comparable with regard to age, education, gender, and severity of cognitive impairment. Analysis of the frequency of APOE ε4 alleles between the groups revealed a significantly higher prevalence rate of the APOE ε4 genotype in the depressed group (72% of depressed AD patients carried at least one copy of the ε4 allele) compared to the non-depressed AD patients (58%). This effect was primarily accounted for by women. Specifically, an interaction was revealed wherein women who possessed the APOE ε4 allele were almost 4 times more likely to be depressed in comparison to those who did not carry the allele, and APOE ε4 status did not predict depression among men in our sample. These results are consistent with recent suggestions that the APOE ε4 genotype may be over-represented among women with AD and depression and highlight a need for additional research investigating the links between APOE genotype, mood, and gender.
PMCID: PMC2583456  PMID: 18058831
23.  Ways toward an early diagnosis in Alzheimer’s disease: The Alzheimer’s Disease Neuroimaging Initiative (ADNI) 
With the increasing life expectancy in developed countries, the incidence of Alzheimer’s disease (AD) and thus its socioeconomic impact are growing. Increasing knowledge over the last years about the pathomechanisms involved in AD allow for the development of specific treatment strategies aimed at slowing down or even preventing neuronal death in AD. However, this requires also that (1) AD can be diagnosed with high accuracy, because non-AD dementias would not benefit from an AD-specific treatment; (2) AD can be diagnosed in very early stages when any intervention would be most effective; and (3) treatment efficacy can be reliably and meaningfully monitored. Although there currently is no ideal biomarker that would fulfill all these requirements, there is increasing evidence that a combination of currently existing neuroimaging and cerebrospinal fluid (CSF) and blood biomarkers can provide important complementary information and thus contribute to a more accurate and earlier diagnosis of AD. The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is exploring which combinations of these biomarkers are the most powerful for diagnosis of AD and monitoring of treatment effects.
PMCID: PMC1864941  PMID: 17476317
Positron-emission tomography; Single photon emission tomography; Magnetic resonance imaging; Biochemical biomarker; Genetic biomarker
24.  The Role of Biomarkers in Clinical Trials for Alzheimer Disease 
Biomarkers are likely to be important in the study of Alzheimer disease (AD) for a variety of reasons. A clinical diagnosis of Alzheimer disease is inaccurate even among experienced investigators in about 10% to 15% of cases, and biomarkers might improve the accuracy of diagnosis. Importantly for the development of putative disease-modifying drugs for Alzheimer disease, biomarkers might also serve as indirect measures of disease severity. When used in this way, sample sizes of clinical trials might be reduced, and a change in biomarker could be considered supporting evidence of disease modification. This review summarizes a meeting of the Alzheimer’s Association’s Research Roundtable, during which existing and emerging biomarkers for AD were evaluated. Imaging biomarkers including volumetric magnetic resonance imaging and positron emission tomography assessing either glucose utilization or ligands binding to amyloid plaque are discussed. Additionally, biochemical biomarkers in blood or cerebrospinal fluid are assessed. Currently appropriate uses of biomarkers in the study of Alzheimer disease, and areas where additional work is needed, are discussed.
PMCID: PMC1820855  PMID: 16493230
Alzheimer disease; amyloid beta; cerebrospinal fluid; clinical trials; cytokines; isoprostanes; positron emission tomography; tau; volumetric magnetic resonance imaging
25.  Verbal paired-associate learning by APOE genotype in non-demented older adults: fMRI evidence of a right hemispheric compensatory response◆ 
Neurobiology of aging  2006;28(2):238-247.
Previous studies of episodic memory report a greater extent of blood-oxygenation-level-dependent (BOLD) response in non-demented older adults with the apolipoprotein E epsilon-4 (APOE ε4) allele than in those without the allele. We conducted a functional MRI study to investigate whether APOE genotype is related to brain response to verbal paired-associate encoding and consolidation, particularly in the right hemisphere, among non-demented older adults. Structurally segmented volumes and BOLD response were measured in 13 non-ε4 and 12 ε4 subjects. The ε4 group displayed greater activation than the non-ε4 group in multiple right hemisphere regions for previously encoded word pairs relative to fixation. Activation within manually outlined hippocampal regions of interest also displayed genotype-specific dissociations consistent with whole brain analyses. Furthermore, this differential BOLD response occurred in the presence of equivalent behavioral and neuropsychological performances as well as comparable hippocampal and overall structural segmentation volumes between groups. Results implicate a widely distributed and interconnected network of right hemisphere brain regions that may be involved in compensating for APOE ε4-related deficiencies associated with verbal episodic memory encoding and consolidation.
PMCID: PMC1705815  PMID: 16434125
Verbal paired-associate encoding; Hippocampus; Apolipoprotein E; BOLD; Episodic memory; Non-demented older adults

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