Optimizing ADAS-Cog Worksheets: A Survey of Clinical Trial Rater s' Perceptions.

BACKGROUND: The Alzheimer's Disease Assessment Scale-Cognitive subscale (ADASCog) remains the most widely used test of longitudinal cognitive functioning in Alzheimer's disease (AD) clinical trials. Unlike most neuropsychological tests, the ADAS-Cog source documentation worksheets are not uniform across clinical trials, and vary by document layout, inclusion of administration and/or scoring instructions, and documentation of subtest scoring (e.g., recording correct versus incorrect scores), among other differences. Many ADAS-Cog test administrators (raters) participate in multiple AD trials and switching between different ADAS-Cog worksheets may increase the likelihood of administration and/or scoring mistakes that lessen the reliability of the instrument. An anonymous online survey sought raters' experiences with ADAS-Cog worksheets and their opinions on the design and content of the worksheets. RESULTS: Results of the survey indicated preference for structure and standardization of the ADASCog worksheets, which has been considered in the development of a standard ADAS-Cog source document by the Alzheimer's Disease Cooperative Study (ADCS) Working Group.

Sex and post-menopause hormone therapy effects on hippocampal volume and verbal memory.

Many studies suggest sex differences in memory and hippocampal size, and that hormone therapy (HT) may positively affect these measures in women; however, the parameters of HT use that most likely confer benefits are debated. We evaluated the impact of sex and postmenopausal HT use on verbal learning and memory and hippocampal size in 94 cognitively intact women and 49 men. Using analysis of covariance that controlled for age and education, women had better total word learning and delayed verbal memory performance than men. HT analyses showed that non-HT users performed similarly to men, while HT users performed better than men in Delayed Memory regardless of whether use was current or in the past. Women had larger hippocampal volumes than men regardless of whether they were HT users. Using univariate linear models, we assessed group differences in the predictive value of hippocampal volumes for verbal learning and memory. Hippocampal size significantly predicted memory performance for men and non-HT users, but not for HT users. This lack of relationship between hippocampal size and verbal learning and memory performance in HT users suggests HT use may impact memory through extra-hippocampal neural systems.

Neuropathological findings of PSP in the elderly without clinical PSP: possible incidental PSP?

AIMS: We aimed to describe cases with incidental neuropathological findings of progressive supranuclear palsy (PSP) from the Banner Sun Health Research Institute Brain and Body Donation Program. METHODS: We performed a retrospective review of 277 subjects with longitudinal motor and neuropsychological assessments who came to autopsy. The mean Gallyas-positive PSP features grading for subjects with possible incidental neuropathological PSP was compared to those of subjects with clinically manifest disease. RESULTS: There were 5 cases with histopathological findings suggestive of PSP, but no parkinsonism, dementia or movement disorder during life. Cognitive evaluation revealed 4 of the 5 cases to be cognitively normal; one case had amnestic mild cognitive impairment (MCI) in her last year of life. The mean age at death of the 5 cases was 88.9 years (range 80-94). All 5 individuals had histopathologic microscopic findings suggestive of PSP. Mean Gallyas-positive PSP features grading was significantly lower in subjects with possible incidental neuropathological PSP than subjects with clinical PSP, particularly in the subthalamic nucleus. CONCLUSIONS: We present 5 patients with histopathological findings suggestive of PSP, without clinical PSP, dementia or parkinsonism during life. These incidental neuropathological PSP findings may represent the early or pre-symptomatic stage of PSP. The mean Gallyas-positive PSP features grading was significantly lower in possible incidental PSP than in clinical PSP, thus suggesting that a threshold of pathological burden needs to be reached within the typically affected areas in PSP before clinical signs and symptoms appear.

The Alzheimer's questionnaire: a proof of concept study for a new informant-based dementia assessment.

The aim of this pilot study is to determine the feasibility and clinical utility of a brief, informant-based screening questionnaire for Alzheimer's disease (AD) that can be administered in a primary care setting. The Alzheimer's Questionnaire (AQ) was administered to the informants of 188 patients in 3 dementia clinics (50 cognitively normal, 69 mild cognitive impairment (MCI), 69 AD). Total score for the AQ is based upon the sum of clinical symptom items in which the informant responds as being present. Clinical symptoms which are known to be highly predictive of the clinical AD diagnosis are given greater weight in the total AQ score. The mean time of administration of the AQ was 2.6 ± 0.6 minutes. Sensitivity and specificity were found to be high for detecting both AD (98.55, 96.00) and MCI (86.96, 94.00) with ROC curves yielding AUC values of 0.99 and 0.95, respectively. This pilot study indicates that the AQ is a brief, sensitive measure for detecting both MCI and AD and could be easily implemented in a primary care setting.

Cholesterol and cognitive performance in normal controls and the influence of elective statin use after conversion to mild cognitive impairment: results in a clinical trial cohort.

BACKGROUND: We reported a significant 67% reduction in the hazard risk of incident Alzheimer's disease (AD) with elective statin use in the AD Anti-inflammatory Prevention Trial (ADAPT), without a reduction in risk of incident mild cognitive impairment (MCI). OBJECTIVE: To assess if cholesterol levels are associated with cognitive performance and determine if statin use alters cognitive performance after onset of MCI. DESIGN: Fractionated cholesterol levels, neurological and cognitive status were evaluated annually. Comparisons of non-LLA (lipid-lowering agent) users or statin-LLA users were performed blind to the ADAPT medication randomization. Pearson's correlations were validated using a time-dependent linear mixed model. RESULTS: The MMSE performance significantly declined over time in non-LLA users, and, after adjusting for this, a significant positive correlation between MMSE and HDL was identified (p = 0.0002). A negative correlation between total and LDL cholesterol, and immediate and delayed recall of the Rivermead paragraph was significant (total cholesterol, p < 0.003; LDL, p < 0.02). Pilot data suggest a positive signal on delayed recall of both the Hopkins word list and Rivermead paragraph with deterioration in the non-LLA users and improvement in the statin users after conversion to MCI. CONCLUSION: Cholesterol levels may be associated with differential performance on the MMSE and measures of learning or memory. The trend for improved delayed recall in statin users with MCI compared to non-LLA users with MCI may have contributed to the reduced hazards risk of incident AD without reducing the risk of MCI.

Incidental Lewy body disease: clinical comparison to a control cohort.

Limited clinical information has been published on cases pathologically diagnosed with incidental Lewy body disease (ILBD). Standardized, longitudinal movement and cognitive data was collected on a cohort of subjects enrolled in the Sun Health Research Institute Brain and Body Donation Program. Of 277 autopsied subjects who had antemortem clinical evaluations within the previous 3 years, 76 did not have Parkinson's disease, a related disorder, or dementia of which 15 (20%) had ILBD. Minor extrapyramidal signs were common in subjects with and without ILBD. Cognitive testing revealed an abnormality in the ILBD group in the Trails B test only. ILBD cases had olfactory dysfunction; however, sample size was very small. This preliminary report revealed ILBD cases have movement and cognitive findings that for the most part were not out of proportion to similarly assessed and age-similar cases without Lewy bodies. Larger sample size is needed to have the power to better assess group differences.

Correlation of clinical features with argyrophilic grains at autopsy.

Argyrophilic grains (AGs) are a pathologic feature found in association with neurodegenerative disease. Some have suggested that these features may occur as a distinctive condition. We reviewed 80 subjects from our tissue bank with pathologically confirmed AGs and identified their clinical features. We compared these subjects' features to the features of subjects with matched clinical diagnoses but without AGs. Subjects with AGs represented 21.7% of the entire autopsy sample from 1999 to 2005 (80 out of 367). Of Alzheimer disease (AD) subjects, 43 out of 233 had AGs (18.4% of AD subjects); 11 out of 42 Parkinson disease with dementia subjects had AGs (26.1% of Parkinson disease with dementia subjects); 2 out of 9 dementia with Lewy bodies subjects had AGs (22.2% of dementia with Lewy bodies subjects); 4 out of 15 mild cognitive impairment subjects had AGs (26.7% of mild cognitive impairment subjects); and 20 out of 68 cognitively normal subjects had AGs (29.4% of cognitively normal). Subjects with AGs tended to be older but only significantly so in AD. Many comorbid non-neurologic health conditions were seen in cases of AGs without any single predilection emerging. AGs occur in approximately 22% of the entire autopsy cohort and are likely associated with advanced age. No distinctive antemortem clinical features were over represented in the AG cases. AGs can occur with or without neurodegenerative conditions and can occur in the absence of significant cognitive decline. AGs are not clearly associated with any single comorbid health condition.

Parkinson disease with dementia: comparing patients with and without Alzheimer pathology.

Subjects with Parkinson disease (PD) frequently develop dementia with greater than one-third meeting neuropathologic diagnostic criteria for Alzheimer disease (AD). The objective is to identify clinical and neuropathologic differences between Parkinson disease with dementia (PDD) subjects, with and without coexistent AD pathology. Neuropathologic examination was available on subjects diagnosed by clinicopathologic criteria with PDD-AD (N=23) and PDD+AD (N=28). A small subset of subjects with PDD-AD and PDD+AD had received at least 1 standardized neuropsychologic assessment. PDD+AD subjects were significantly older at age of PD onset and death, progressed to onset of dementia in less time, and had a shorter duration of PD symptoms before the onset of dementia. Education, responsiveness of L-dopa and dopaminergic medications, presence of cognitive fluctuations and hallucinations, and mean Mini-Mental State Examination, Global Deterioration Scale, Functional Assessment Staging, and Unified Parkinson Disease Rating Scale scores did not differ significantly between the 2 groups. The PDD+AD group had significantly greater total plaques, neuritic plaques, total tangles, and Braak stages compared with PDD-AD. This study suggests that it is difficult to distinguish PDD+AD and PDD-AD on the basis of movement, clinical, and neuropsychologic assessment. PDD-AD and PDD+AD have similar degrees of dementia and approximately half of PDD subjects have enough AD pathology to attain a neuropathologic diagnosis of AD. PDD can develop in the absence of significant Alzheimer pathology.

Longitudinal modeling of age-related memory decline and the APOE epsilon4 effect.

BACKGROUND: The APOE epsilon4 allele is associated with the risk of late-onset Alzheimer's disease. The age at which memory decline diverges among persons who are homozygous for the APOE epsilon4 allele, those who are heterozygous for the allele, and noncarriers is unknown. METHODS: Using local advertisements, we recruited cognitively normal subjects between the ages of 21 and 97 years, who were grouped according to their APOE epsilon4 status. We then followed the subjects with longitudinal neuropsychological testing. Anyone in whom mild cognitive impairment or dementia developed during follow-up was excluded. We compared the rates of decline in predetermined cognitive measures between carriers and noncarriers of the APOE epsilon4 allele, using a mixed model for longitudinal change with age. RESULTS: We analyzed 815 subjects: 317 APOE epsilon4 carriers (79 who were homozygous for the APOE epsilon4 allele and 238 who were heterozygous) and 498 noncarriers. Carriers, as compared with noncarriers, were generally younger (mean age, 58.0 vs. 61.4 years; P<0.001) and were followed for a longer period (5.3 vs. 4.7 years, P=0.01), with an equivalent duration of formal education (15.4 years) and proportion of women (69%). Longitudinal decline in memory in carriers began before the age of 60 years and showed greater acceleration than in noncarriers (P=0.03), with a possible allele-dose effect (P=0.008). We observed similar although weaker effects on measures of visuospatial awareness and general mental status. CONCLUSIONS: Age-related memory decline in APOE epsilon4 carriers diverges from that of noncarriers before the age of 60 years, despite ongoing normal clinical status.

Unified staging system for Lewy body disorders: correlation with nigrostriatal degeneration, cognitive impairment and motor dysfunction.

The two current major staging systems in use for Lewy body disorders fail to classify up to 50% of subjects. Both systems do not allow for large numbers of subjects who have Lewy-type alpha-synucleinopathy (LTS) confined to the olfactory bulb or who pass through a limbic-predominant pathway that at least initially bypasses the brainstem. The results of the current study, based on examination of a standard set of ten brain regions from 417 subjects stained immunohistochemically for alpha-synuclein, suggest a new staging system that, in this study, allows for the classification of all subjects with Lewy body disorders. The autopsied subjects included elderly subjects with Parkinson's disease, dementia with Lewy bodies, incidental Lewy body disease and Alzheimer's disease with Lewy bodies, as well as comparison groups without Lewy bodies. All subjects were classifiable into one of the following stages: I. Olfactory Bulb Only; IIa Brainstem Predominant; IIb Limbic Predominant; III Brainstem and Limbic; IV Neocortical. Progression of subjects through these stages was accompanied by a generally stepwise worsening in terms of striatal tyrosine hydroxylase concentration, substantia nigra pigmented neuron loss score, Mini Mental State Examination score and score on the Unified Parkinson's Disease Rating Scale Part 3. Additionally, there were significant correlations between these measures and LTS density scores. It is suggested that the proposed staging system would improve on its predecessors by allowing classification of a much greater proportion of cases.

Amyloid beta peptides in human plasma and tissues and their significance for Alzheimer's disease.

BACKGROUND: We evaluated the amounts of amyloid beta (Abeta)) peptides in the central nervous system (CNS) and in reservoirs outside the CNS and their potential impact on Abeta plasma levels and Alzheimer's disease (AD) pathology. METHODS: Amyloid beta levels were measured in (1) the plasma of AD and nondemented (ND) controls in a longitudinal study, (2) the plasma of a cohort of AD patients receiving a cholinesterase inhibitor, and (3) the skeletal muscle, liver, aorta, platelets, leptomeningeal arteries, and in gray and white matter of AD and ND control subjects. RESULTS: Plasma Abeta levels fluctuated over time and among individuals, suggesting continuous contributions from brain and peripheral tissues and associations with reactive circulating proteins. Arteries with atherosclerosis had larger amounts of Abeta40 than disease-free vessels. Inactivated platelets contained more Abeta peptides than activated ones. Substantially more Abeta was present in liver samples from ND patients. Overall, AD brain and skeletal muscle contained increased levels of Abeta. CONCLUSIONS: Efforts to use plasma levels of Abeta peptides as AD biomarkers or disease-staging scales have failed. Peripheral tissues might contribute to both the circulating amyloid pool and AD pathology within the brain and its vasculature. The wide spread of plasma Abeta values is also due in part to the ability of Abeta to bind to a variety of plasma and membrane proteins. Sources outside the CNS must be accounted for because pharmacologic interventions to reduce cerebral amyloid are assessed by monitoring Abeta plasma levels. Furthermore, the long-range impact of Abeta immunotherapy on peripheral Abeta sources should also be considered.

Melatonin fails to improve sleep or agitation in double-blind randomized placebo-controlled trial of institutionalized patients with Alzheimer disease.

OBJECTIVES: Patients with Alzheimer dementia often display both agitated behavior and poor sleep. Given that the disease is often associated with low endogenous levels of melatonin, exogenous melatonin administration may lead to improvements in sleep and agitation. DESIGN: Randomized, placebo-controlled study. SETTING: Nursing homes in San Diego, CA, metropolitan area. PARTICIPANTS: Subjects were patients with probable Alzheimer disease. INTERVENTION: Melatonin (8.5 mg immediate release and 1.5 mg sustained release) (N = 24) or placebo (N = 17) administered at 10:00 P.M. for 10 consecutive nights. The protocol consisted of baseline (3 days), treatment (10 days), and posttreatment (5 days) phases. MEASUREMENTS: Sleep was measured continuously using actigraphy. Agitation was rated using both the Agitated Behavior Rating Scale and the Cohen-Mansfield Agitation Inventory. Treatment effects were examined both across the 24-hr day and separately by nursing shift. RESULTS: There were no significant effects of melatonin, compared with placebo, on sleep, circadian rhythms, or agitation. CONCLUSION: : This study failed to find a beneficial effect of exogenous melatonin, consistent with a number of other studies. The lack of efficacy may be related to the absence of a true treatment effect or to the superphysiologic dose of melatonin used.

Olfactory bulb alpha-synucleinopathy has high specificity and sensitivity for Lewy body disorders.

Involvement of the olfactory bulb by Lewy-type alpha-synucleinopathy (LTS) is known to occur at an early stage of Parkinson's disease (PD) and Lewy body disorders and is therefore of potential usefulness diagnostically. An accurate estimate of the specificity and sensitivity of this change has not previously been available. We performed immunohistochemical alpha-synuclein staining of the olfactory bulb in 328 deceased individuals. All cases had received an initial neuropathological examination that included alpha-synuclein immunohistochemical staining on sections from brainstem, limbic and neocortical regions, but excluded olfactory bulb. These cases had been classified based on their clinical characteristics and brain regional distribution and density of LTS, as PD, dementia with Lewy bodies (DLB), Alzheimer's disease with LTS (ADLS), Alzheimer's disease without LTS (ADNLS), incidental Lewy body disease (ILBD) and elderly control subjects. The numbers of cases found to be positive and negative, respectively, for olfactory bulb LTS were: PD 55/3; DLB 34/1; ADLS 37/5; ADNLS 19/84; ILBD 14/7; elderly control subjects 5/64. The sensitivities and specificities were, respectively: 95 and 91% for PD versus elderly control; 97 and 91% for DLB versus elderly control; 88 and 91% for ADLS versus elderly control; 88 and 81% for ADLS versus ADNLS; 67 and 91% for ILBD versus elderly control. Olfactory bulb synucleinopathy density scores correlated significantly with synucleinopathy scores in all other brain regions (Spearman R values between 0.46 and 0.78) as well as with scores on the Mini-Mental State Examination and Part 3 of the Unified Parkinson's Disease Rating Scale (Spearman R -0.27, 0.35, respectively). It is concluded that olfactory bulb LTS accurately predicts the presence of LTS in other brain regions. It is suggested that olfactory bulb biopsy be considered to confirm the diagnosis in PD subjects being assessed for surgical therapy.

Administration and scoring variance on the ADAS-Cog.

The Alzheimer's Disease Assessment Scale - Cognitive (ADAS-Cog) is the most commonly used primary outcome instrument in clinical trials for treatments of dementia. Variations in forms, administration procedures and scoring rules, along with rater turnover and intra-rater drift may decrease the reliability of the instrument. A survey of possible variations in the ADAS-Cog was administered to 26 volunteer raters at a clinical trials meeting. Results indicate notable protocol variations in the forms used, administration procedures, and scoring rules. Since change over time is used to determine treatment effect in clinical trials, standardizing the instrument's ambiguities and addressing common problems will greatly increase the instrument's reliability and thereby enhance its sensitivity to treatment effects.

Comment on administration and scoring of the Neuropsychiatric Inventory in clinical trials.

BACKGROUND: The Neuropsychiatric Inventory (NPI) is commonly used in dementia trials to quantify and qualitate changes in psychiatric symptoms. METHODS: A questionnaire was administered to clinical trial raters to assess whether they were being trained to administer and score the NPI differently between clinical trial protocols. RESULTS: Responses to the survey indicated that there are differences between clinical trials protocols in how the instrument is administered and scored. DISCUSSION: Clarification of administration and scoring rules are provided, including the behavioral sampling period, whether premorbid characteristics are considered, and what behaviors are considered in rating frequency, severity, and caregiver distress.

Reduced risk of incident AD with elective statin use in a clinical trial cohort.

Statins have been reported to reduce the risk and be of benefit in the treatment of Alzheimer's disease (AD). Individuals enrolling in the randomized controlled trial testing two anti-inflammatory agents for primary prevention of AD (Alzheimer's Disease Anti-inflammatory Prevention Trial; ADAPT) were allowed the elective use of statins. Our objective was to assess whether statin use is associated with reduced risk of incident AD among ADAPT participants. In primary ADAPT study , participants were assessed annually for cholesterol levels and cognitive status. If impairment in cognition was noted, a dementia evaluation was performed. Onset of mild cognitive impairment (MCI) or AD was taken as the date of this evaluation. Time-to-onset was analyzed in six-month intervals following enrollment. Without knowledge of primary treatment assignment in ADAPT, participants were grouped by their self-reported use of lipid-lowering agents (LLA). In the current ancillary ADAPT study we found that elective statin use was associated with significantly reduced risk of incident AD after adjustment for age, gender, education and Apolipoprotein E (ApoE) genotype. The findings were similar when comparing all LLA use (statin and non-statin LLA) to non-LLA use. Cholesterol levels were lower among statin users compared with non-LLA users, but the MMSE scores were equivalent. The data suggest that statin therapy may be of benefit in reducing the risk of AD.

Hippocampal volume change in the Alzheimer Disease Cholesterol-Lowering Treatment trial.

Numerous clinical studies suggest a link between elevated cholesterol and increased risk of Alzheimer disease (AD), and the preponderance of data suggests that statin therapy may reduce the risk of AD later in life. The first clinical investigation of statin therapy in patients with AD, the AD Cholesterol-Lowering Treatment (ADCLT) trial, found that atorvastatin 80 mg/day was associated with improvements relative to placebo on some, but not all, cognitive measures after 6 months and 1 year of therapy. We report here findings from a pilot ADCLT substudy showing a nonsignificant reduction in total hippocampal volume with 1 year of atorvastatin therapy compared with placebo, driven by a highly significant reduction in right hippocampal volume with atorvastatin therapy.

The Sun Health Research Institute Brain Donation Program: description and experience, 1987-2007.

The Brain Donation Program at Sun Health Research Institute has been in continual operation since 1987, with over 1000 brains banked. The population studied primarily resides in the retirement communities of northwest metropolitan Phoenix, Arizona. The Institute is affiliated with Sun Health, a nonprofit community-owned and operated health care provider. Subjects are enrolled prospectively to allow standardized clinical assessments during life. Funding comes primarily from competitive grants. The Program has made short postmortem brain retrieval a priority, with a 2.75-h median postmortem interval for the entire collection. This maximizes the utility of the resource for molecular studies; frozen tissue from approximately 82% of all cases is suitable for RNA studies. Studies performed in-house have shown that, even with very short postmortem intervals, increasing delays in brain retrieval adversely affect RNA integrity and that cerebrospinal fluid pH increases with postmortem interval but does not predict tissue viability.