Mild Dementia Of The Alzheimer Type Research Articles

Comparing intra‐individual variability on executive functioning tasks in individuals with Mild Cognitive Impairment and Dementia of the Alzheimer Type: Results from the ARMADA Study

AbstractBackgroundCognitive decline is most often assessed mean group differences on static measures of cognitive abilities (MacDonald et al., 2009). Another, perhaps more dynamic, method to understanding cognitive functioning is to evaluate variability in performance within an individual, termed intraindividual variability (IIV), which has been associated with reduction in gray matter and less efficient cognitive processing. Using results from a multi‐site, longitudinal ARMADA study that validated NIH Toolbox across the cognitive aging spectrum, we investigated whether IIV in reaction time processing can differentiate between older adults with normal cognition, mild cognitive impairment (MCI), or dementia of the Alzheimer type (DAT), as well as the relative magnitude of differences between groups.MethodAs part of the Advancing Reliable Measurement in Alzheimer’s Disease and cognitive Aging study (ARMADA; Weintraub et al 2020), participants completed the NIH Toolbox Cognition Battery, including two measures of executive functioning, Dimensional Change Card Sort and Flanker Inhibitory Control, which include granular reaction time data in milliseconds. We analyzed standard deviation and mean absolute deviation of item‐level data of all trials, correct trials only, and incorrect trials only for three groups: normal controls, those with amnestic MCI, and those with mild DAT.ResultWe observe large effect sizes of reaction time by clinical group, with the mild DAT group demonstrating mean standard error across trials of approximately .5 seconds throughout, compared with .25 seconds for MCI and .10 seconds for the control group (Figure 1). This translates to an approximate 5‐fold increase in processing speed in the most severe clinical group. Examining time trends, we see that while the NC and MCI group were faster as the test progressed; there is no similar learning effect for the mild DAT group. Similar effect sizes were observed for the Flanker test.ConclusionThis study represents one of the first studies to examine clinical performance using process data from two executive functioning measures on the NIH Toolbox across the cognitive aging spectrum. Future work will explore more definitions of IIV to determine which measure will maximally differentiate between established clinical groups and examine longitudinal differences.

Clinical Manifestations.

Cognitive decline is most often assessed mean group differences on static measures of cognitive abilities (MacDonald et al., 2009). Another, perhaps more dynamic, method to understanding cognitive functioning is to evaluate variability in performance within an individual, termed intraindividual variability (IIV), which has been associated with reduction in gray matter and less efficient cognitive processing. Using results from a multi-site, longitudinal ARMADA study that validated NIH Toolbox across the cognitive aging spectrum, we investigated whether IIV in reaction time processing can differentiate between older adults with normal cognition, mild cognitive impairment (MCI), or dementia of the Alzheimer type (DAT), as well as the relative magnitude of differences between groups. As part of the Advancing Reliable Measurement in Alzheimer's Disease and cognitive Aging study (ARMADA; Weintraub et al 2020), participants completed the NIH Toolbox Cognition Battery, including two measures of executive functioning, Dimensional Change Card Sort and Flanker Inhibitory Control, which include granular reaction time data in milliseconds. We analyzed standard deviation and mean absolute deviation of item-level data of all trials, correct trials only, and incorrect trials only for three groups: normal controls, those with amnestic MCI, and those with mild DAT. We observe large effect sizes of reaction time by clinical group, with the mild DAT group demonstrating mean standard error across trials of approximately .5 seconds throughout, compared with .25 seconds for MCI and .10 seconds for the control group (Figure 1). This translates to an approximate 5-fold increase in processing speed in the most severe clinical group. Examining time trends, we see that while the NC and MCI group were faster as the test progressed; there is no similar learning effect for the mild DAT group. Similar effect sizes were observed for the Flanker test. This study represents one of the first studies to examine clinical performance using process data from two executive functioning measures on the NIH Toolbox across the cognitive aging spectrum. Future work will explore more definitions of IIV to determine which measure will maximally differentiate between established clinical groups and examine longitudinal differences.

The Paradox in Positive and Negative Aspects of Emotional Functioning Among Older Adults with Early Stages of Cognitive Impairment.

Introduction: Emotional functioning in older adults is influenced by normal aging and cognitive impairment, likely heterogeneous across positive versus negative aspects of emotional functioning. Little is known about positive emotional experiences at the early stages of cognitive impairment. Methods: We assessed different aspects of emotional functioning among 448 participants aged 65+ (Normal Control (NC) = 276, Mild Cognitive Impairment (MCI) = 103, and mild dementia of the Alzheimer type (mild DAT) = 69) and tested moderators. Results: Compared to NC, older adults with MCI and mild DAT have maintained many positive aspects of emotional functioning, despite higher levels of negative affect, sadness, and loneliness. Among the oldest-old, the mild DAT group experienced higher fear and lower self-efficacy. Discussion: Older adults at early stages of cognitive impairment can experience positive aspects of emotional functioning, such as positive affect, purpose, and life satisfaction, all of which are important buildable psychological resources for coping.

Application of the Semantic Fluency Test in the Screening of Mandarin-Chinese-Speaking Older Adults with Mild Dementia of the Alzheimer Type.

Semantic fluency tests have been widely used as a screening test for dementia of Alzheimer type. However, few studies have explored the application of semantic fluency tests in Mandarin Chinese speakers. This study aimed to explore the feasibility of using different semantic fluency test categories to distinguish between older adults without cognitive impairments and those with dementia of Alzheimer type in Taiwan. A total of 58 healthy older adults and 54 individuals with dementia of Alzheimer type were recruited. Semantic categories of "animals", "fruits", "vegetables", "birds", "means of transportations" and "musical instruments" were administered to participants. The scores from two groups of participants for each category were analyzed. Significant differences in the test scores of each category between two groups of participants were found. The results also revealed that the variables related to whether the participant had dementia, gender, age, and years of schooling significantly influenced the semantic fluency scores for each category. Among all the demographic characteristic of participants, the diagnosis of dementia was the most determining factor. Furthermore, this study proposed optimal cutoff points and calculated the AUC for various test durations (i.e., 30 s, 45 s and 60 s) and semantic categories in the semantic fluency test, which may serve as a reference that would help clinical personnel distinguish between older adults without cognitive impairments and those with dementia of Alzheimer type in Taiwan.

NEURONORMA Cognitive Battery Associations with Cerebrospinal Fluid Amyloid-β and Tau Levels in the Continuum of Alzheimer's Disease.

Neuropsychological assessments are essential to define the cognitive profile and contribute to the diagnosis of Alzheimer's disease (AD). The progress in knowledge about the pathophysiological process of the disease has allowed conceptualizing AD through biomarkers as a biological continuum that encompasses different clinical stages. To explore the association between cerebrospinal fluid (CSF) biomarkers of AD and cognition using the NEURONORMA battery, in a sample of cognitively unimpaired (CU), mild cognitive impaired (MCI), and mild dementia of the Alzheimer type (DAT) subjects, and to characterize the cognitive profiles in MCI subjects classified by A/T/N system. 42 CU, 35 MCI, and 35 mild DAT were assessed using the NEURONORMA battery. Core AD biomarkers [amyloid-β42 (Aβ42) peptide, total tau (t-tau), and phosphorylated tau 181 (p-tau181)] proteins were measured in CSF. Correlation coefficients, multivariate regression, and effect sizes were calculated. We explored the age- and education-adjusted cognitive profiles by A/T/N variants within the MCI group. Cognitive outcomes were directly associated with CSF Aβ42 and inversely with CSF tau measures. We found differences in both biomarkers and cognitive outcomes comparing all pairs except for CSF measures between cognitively impaired groups. The highest effect size was in memory tasks and biomarkers ratios. Lower performances were in memory and executive domains in MCI subjects with AD pathology (A+T+N±) compared to those with normal levels of AD biomarkers (A- T- N). This study provides further evidence of the validity of Spanish NEURONORMA cognitive battery to characterize cognitive impairment in the AD pathological continuum.

Social Cognition in Patients with Amnestic Mild Cognitive Impairment and Mild Dementia of the Alzheimer Type.

Social cognition (SC) is a core criterion for neurocognitive disorders. However, findings in patients with amnestic mild cognitive impairment (aMCI) and dementia of the Alzheimer type (DAT) are inconsistent. We report assessments of emotion recognition (ER), affective and cognitive theory of mind (ToM) in young (YC) and older controls (OC) compared to aMCI and DAT. 28 aMCI, 30 DAT, 30 YC, and 29 OC received tests of SC and a comprehensive neuropsychological assessment. Analysis of covariance was used to determine group differences. Multiple regression models were applied to identify predictors for each SC task. In controls, OC performed worse in ER and both ToM tasks compared to YC except for one subtest. No significant differences were found between OC and patients concerning ER and affective ToM. In cognitive ToM, differences between OC and patients depended on content and cognitive load with significant impairment in DAT compared to OC. A cognitive composite score predicted SC in OC, but not in patients. Associations of SC with single cognitive domains were found in all groups with language and complex attention as best predictors. Not all variance of SC performance was explained by variance in cognitive domains. Lower performance on SC tasks in OC versus YC was confirmed, although not all tasks were equally affected. With progressive cognitive impairment, cognitive ToM is more impaired than ER or affective ToM. SC seems to be at least partly independent of other cognitive domains, justifying its inclusion in batteries for dementia diagnostic.

The Effect of Reminiscence Therapy With Internet-Based Videos on Cognitive Status and Apathy of Older People With Mild Dementia.

This study was carried out to assess the effects of reminiscence therapy that was supported with internet-based videos on the cognitive condition and apathy levels of older people with mild dementia living in nursing homes. This randomized controlled experimental study was conducted between May 15, 2016, and August 25, 2016, in two nursing homes in Adana, Turkey. A total of 32 people participated in this study, 16 individuals were in the intervention group and 16 individuals were in the control group. The data were collected using a Personal Information Form, the Standardized Mini-Mental State Examination (SMMSE) test, and the Apathy Rating Scale (ARS) Self-assessment Form. The individuals in the intervention group received group reminiscence therapy involving internet-based videos for 60 minutes once a week for 3 months. During this period, 25 to 30 minutes of unstructured interviews were carried out with individuals in the control group. The data were analyzed using descriptive statistics, Student t test, the Mann-Whitney U test, and Wilcoxon signed rank test. In this study, a significant difference was found between experimental and control groups' posttest mean scores on the SMMSE test and ARS ( P < .01). The experimental group's SMMSE test and ARS posttest mean scores were higher than those of the control group ( P < .01). This study found that group reminiscence therapy using internet-based videos improved the cognitive functions and apathy levels of older people with mild dementia of the Alzheimer type. It is recommended that group reminiscence therapy studies with Internet-based videos be conducted in care institutions that are responsible for managing older people with mild dementia of the Alzheimer type.

Cerebrospinal Fluid Proteins Predict Longitudinal Hippocampal Degeneration in Early-stage Dementia of the Alzheimer Type

Biomarkers are needed to improve the sensitivity and accuracy of diagnosis, and also prognosis, in individuals with early Alzheimer disease (AD). Measures of brain structure and disease-related proteins in the cerebrospinal fluid (CSF) have been proposed as biomarkers, yet relatively little is known about the relationships between such measures. The present study was conducted to assess the relationship between CSF Aβ and tau protein levels and longitudinal measures of hippocampal structure in individuals with and without very mild dementia of the Alzheimer type. A single CSF sample and longitudinal magnetic resonance scans were collected. The CSF samples were assayed for tau, phosphorylated tau181 (p-tau181), Aβ1-42, and Aβ1-40 using an enzyme-linked immunosorbent assay. Large-deformation diffeomorphic metric mapping was used to generate hippocampal surfaces, and a composite hippocampal surface (previously constructed from 86 healthy participants) was used as a structural reference. Thirteen participants with very mild AD (Clinical Dementia Rating, CDR 0.5) and 11 cognitively normal participants (CDR 0). None. Initial and rate-of-change measures of total hippocampal volume and displacement of the hippocampal surface within zones overlying the CA1, subiculum, and CA2-4+DG cellular subfields, and their correlations with initial CSF measures. Lower CSF Αβ1-42 levels and higher tau/Αβ1-42 and p-tau181/Αβ1-42 ratios were strongly correlated with decreases in hippocampal volume and measures of progressive inward deformations of the CA1 subfield in participants with early AD, but not in cognitively normal participants. Despite the small sample size, we found that Αβ1-42 related and tau-related CSF measures were associated with hippocampal degeneration in individuals with clinically diagnosed early AD and may reflect an association with a common underlying disease mechanism.

The effect of response modality on immediate serial recall in dementia of the Alzheimer type.

Contrary to traditional models of verbal short-term memory (STM), psycholinguistic accounts assume that temporary retention of verbal materials is an intrinsic property of word processing. Therefore, memory performance will depend on the nature of the STM tasks, which vary according to the linguistic representations they engage. The aim of this study was to explore the effect of response modality on verbal STM performance in individuals with dementia of the Alzheimer Type (DAT), and its relationship with the patients' word-processing deficits. Twenty individuals with mild DAT and 20 controls were tested on an immediate serial recall (ISR) task using the same items across two response modalities (oral and picture pointing) and completed a detailed language assessment. When scoring of ISR performance was based on item memory regardless of item order, a response modality effect was found for all participants, indicating that they recalled more items with picture pointing than with oral response. However, this effect was less marked in patients than in controls, resulting in an interaction. Interestingly, when recall of both item and order was considered, results indicated similar performance between response modalities in controls, whereas performance was worse for pointing than for oral response in patients. Picture-naming performance was also reduced in patients relative to controls. However, in the word-to-picture matching task, a similar pattern of responses was found between groups for incorrectly named pictures of the same items. The finding of a response modality effect in item memory for all participants is compatible with the assumption that semantic influences are greater in picture pointing than in oral response, as predicted by psycholinguistic models. Furthermore, patients' performance was modulated by their word-processing deficits, showing a reduced advantage relative to controls. Overall, the response modality effect observed in this study for item memory suggests that verbal STM performance is intrinsically linked with word processing capacities in both healthy controls and individuals with mild DAT, supporting psycholinguistic models of STM.

Quantization and analysis of hippocampal morphometric changes due to dementia of Alzheimer type using metric distances based on large deformation diffeomorphic metric mapping

Abstract The metric distance obtained from the large deformation diffeomorphic metric mapping (LDDMM) algorithm is used to quantize changes in morphometry of brain structures due to neuropsychiatric diseases. For illustrative purposes we consider changes in hippocampal morphometry (shape and size) due to very mild dementia of the Alzheimer type (DAT). LDDMM, which was previously used to calculate dense one-to-one correspondence vector fields between hippocampal shapes, measures the morphometric differences with respect to a template hippocampus by assigning metric distances on the space of anatomical images thereby allowing for direct comparison of morphometric differences. We characterize what information the metric distances provide in terms of size and shape given the hippocampal, brain and intracranial volumes. We demonstrate that metric distance is a measure of morphometry (i.e., shape and size) but mostly a measure of shape, while volume is mostly a measure of size. Moreover, we show how metric distances can be used in cross-sectional, longitudinal analysis, as well as left–right asymmetry comparisons, and provide how the metric distances can serve as a discriminative tool using logistic regression. Thus, we show that metric distances with respect to a template computed via LDDMM can be a powerful tool in detecting differences in shape.

Donepezil Treatment and Changes in Hippocampal Structure in Very Mild Alzheimer Disease

To compare longitudinal changes in the hippocampal structure in subjects with very mild dementia of the Alzheimer type (DAT) treated with donepezil hydrochloride, untreated subjects with very mild DAT, and controls without dementia. MPRAGE sequences were collected approximately 2 years apart on two 1.5-T magnetic resonance imaging systems, yielding 2 cohorts. Large-deformation high-dimensional brain mapping was used to compute deformation of hippocampal subfields. A dementia clinic at Washington University School of Medicine. Subjects came from 2 sources: 18 untreated subjects with DAT and 26 controls were drawn from a previous longitudinal study; 18 treated subjects with DAT were studied prospectively, and 44 controls were drawn from a longitudinal study from the same period. Intervention Patients were prescribed donepezil by their physician. Hippocampal volume loss and surface deformation. There was no significant cohort effect at baseline; therefore, the 2 groups of control subjects were combined. The potential confounding effect of cohort/scanner was dealt with by including it as a covariate in statistical tests. There was no significant group effect in the rate of change of hippocampal volume or subfield deformation. Further exploration showed that compared with the untreated subjects with DAT, the treated subjects with DAT did not differ in the rate of change in any of the hippocampal measures. They also did not differ from the controls, while the untreated subjects with DAT differed from the controls in the rates of change of hippocampal volume and CA1 and subiculum subfield deformations. Treatment with donepezil did not alter the progression of hippocampal deformation in subjects with DAT in this study. Small sample size may have contributed to this outcome.

Pittsburgh Compound B Imaging and Prediction of Progression From Cognitive Normality to Symptomatic Alzheimer Disease

To determine whether preclinical Alzheimer disease (AD), as detected by the amyloid-imaging agent Pittsburgh Compound B (PiB) in cognitively normal older adults, is associated with risk of symptomatic AD. A longitudinal cohort study of cognitively normal older adults assessed with positron emission tomography (PET) to determine the mean cortical binding potential for PiB and followed up with annual clinical and cognitive assessments for progression to very mild dementia of the Alzheimer type (DAT). The Alzheimer's Disease Research Center, Washington University, St Louis, Missouri. One hundred fifty-nine participants with a mean age of 71.5 years with a Clinical Dementia Rating (CDR) of 0 on a PET PiB scan at baseline. Progression from CDR 0 to CDR 0.5 status (very mild dementia). Twenty-three participants progressed to CDR 0.5 at follow-up assessment (range, 1-5 assessments after PET PiB). Of these, 9 also were diagnosed with DAT. Higher mean cortical binding potential values for PiB (hazard ratio, 4.85; 95% confidence interval, 1.22-19.01; P = .02) and age (hazard ratio, 1.14; 95% confidence interval, 1.02-1.28; P = .03) predicted progression to CDR 0.5 DAT. The CDR 0.5 DAT group showed decline in 3 cognitive domains (episodic memory, semantic memory, and visuospatial performance) and had volume loss in the parahippocampal gyrus (includes entorhinal cortex) compared with individuals who remained at CDR 0. Preclinical AD as detected by PET PiB is not benign, as it is associated with progression to symptomatic AD.

Absence of Pittsburgh Compound B Detection of Cerebral Amyloid β in a Patient With Clinical, Cognitive, and Cerebrospinal Fluid Markers of Alzheimer Disease

To date, there have been no reports of individuals who have been characterized longitudinally using clinical and cognitive measures and who transitioned from cognitive normality to early symptomatic Alzheimer disease (AD) during a period when both cerebrospinal fluid (CSF) markers and Pittsburgh Compound B (PiB) amyloid imaging were obtained. To determine the temporal relationships of clinical, cognitive, CSF, and PiB amyloid imaging markers of AD. Case report. Alzheimer disease research center. Longitudinally assessed 85-year-old man in a memory and aging study who was cognitively normal at his initial and next 3 annual assessments. Serial clinical and psychometric assessments over 6 years in addition to PiB imaging with positron emission tomography (PET) and CSF biomarker assays before autopsy. Decline in measures of episodic memory and, to a lesser degree, working memory began at about age 88 years. PiB PET amyloid imaging was negative at age 88(1/2) years, but at age 89(1/2) years there was reduced amyloid beta 42 and elevated levels of tau in the CSF. Beginning at age 89 years, very mild cognitive and functional decline reported by his collateral source resulted in a diagnosis of very mild dementia of the Alzheimer type. After death at age 91 years, the autopsy revealed foci of frequent neocortical diffuse amyloid beta plaques sufficient to fulfill Khachaturian neuropathologic criteria for definite AD, but other neuropathologic criteria for AD were not met because only sparse neuritic plaques and neurofibrillary tangles were present. Postmortem biochemical analysis of the cerebral tissue confirmed that PiB PET binding was below the level needed for in vivo detection. Clinical, cognitive, and CSF markers consistent with AD may precede detection of cerebral amyloid beta using amyloid imaging agents such as PiB that primarily label fibrillar amyloid beta plaques.

CSF biomarkers of Alzheimer disease in HIV-associated neurologic disease

HIV-associated neurologic disorders (HAND) continue to develop in many patients with HIV. CSF amyloid measurements in HAND have been reported to be similar to those in dementia of the Alzheimer type (DAT). Confirmatory evaluation of this finding in carefully evaluated subjects is needed. CSF specimens were obtained from subjects clinically categorized with normal cognition from the general population, HIV+ subjects with normal cognition, HIV+ subjects with impaired cognition, or presumed HIV- subjects with mild DAT. CSF measurements of beta-amyloid((1-42)) (Abeta42), beta-amyloid((1-40)) (Abeta40), total tau (t-tau), and phosphorylated tau (p-tau181) were performed. CSF Abeta42 measured in 49 HAND subjects had a median level of 501 pg/mL, which was lower than that of 50 controls of similar age who had median of 686 pg/mL (p < 0.0001) or 21 HIV+ subjects without cognitive impairment who had median of 716 pg/mL (p < 0.003). HAND subjects had similar CSF Abeta42 to 68 subjects with mild DAT. There was no difference of CSF Abeta40 between the groups. Tau and p-tau181 was elevated in DAT, but slightly lower than control in both HIV+ groups. beta-Amyloid((1-42)) (Abeta42) measurements in CSF of cognitively impaired patients with HIV are similar to those in patients with mild dementia of the Alzheimer type (DAT). Normal or slightly depressed CSF tau and p-tau181 measurements distinguish these patients with HIV-associated neurologic disorders (HAND) from patients with DAT. Further evaluation of amyloid metabolism in patients with HIV cognitive disorder is needed to understand the implications of depressed CSF Abeta42 in the setting of HAND.

Emotional Recognition from Face, Voice, and Music in Dementia of the Alzheimer Type

Persons with dementia of the Alzheimer type (DAT) are impaired in recognizing emotions from face and voice. Yet clinical practitioners use these mediums to communicate with DAT patients. Music is also used in clinical practice, but little is known about emotional processing from music in DAT. This study aims to assess emotional recognition in mild DAT. Seven patients with DAT and 16 healthy elderly adults were given three tasks of emotional recognition for face, prosody, and music. DAT participants were only impaired in the emotional recognition from the face. These preliminary results suggest that dynamic auditory emotions are preserved in DAT.

Cerebrospinal Fluid Biomarkers and Rate of Cognitive Decline in Very Mild Dementia of the Alzheimer Type

Cerebrospinal fluid (CSF) levels of Abeta peptide 1-42 (Abeta 42), tau, and phosphorylated tau (ptau) are potential biomarkers of Alzheimer disease. To determine whether Abeta 42, tau, and ptau predict the rate of cognitive change in individuals with very mild dementia of the Alzheimer type (DAT). Retrospective analysis of CSF biomarkers and clinical data. An academic Alzheimer disease research center. Research volunteers in a longitudinal study of aging and cognition. Participants (n = 49) had a clinical diagnosis of very mild DAT with a Clinical Dementia Rating (CDR) of 0.5 at the time of lumbar puncture. All the participants had at least 1 follow-up assessment (mean [SD] follow-up, 3.5 [1.8] years). Baseline CSF levels of Abeta 42, Abeta 40, tau, and ptau at threonine 181 (ptau181) and the rate of dementia progression as measured using the CDR sum of boxes (CDR-SB) score and psychometric performance. The rate of dementia progression was significantly more rapid in individuals with lower baseline CSF Abeta 42 levels, higher tau or ptau181 levels, or high tau: Abeta 42 ratios. For example, the annual change in the CDR-SB score was 1.1 for the lowest 2 tertiles of Abeta 42 values and 0.3 for the highest tertile of Abeta 42 values. In individuals with very mild DAT, lower CSF Abeta 42 levels, high tau or ptau181 levels, or high tau:Abeta 42 ratios quantitatively predict more rapid progression of cognitive deficits and dementia. Biomarkers of CSF may be useful prognostically and to identify individuals who are more likely to progress for participation in therapeutic clinical trials.

Decreased cerebrospinal fluid Aβ42 correlates with brain atrophy in cognitively normal elderly

For therapies for Alzheimer's disease (AD) to have the greatest impact, it will likely be necessary to treat individuals in the "preclinical" (presymptomatic) stage. Fluid and neuroimaging measures are being explored as possible biomarkers of AD pathology that could aid in identifying individuals in this stage to target them for clinical trials and to direct and monitor therapy. The objective of this study was to determine whether cerebrospinal fluid (CSF) biomarkers for AD suggest the presence of brain damage in the preclinical stage of AD. We investigated the relation between structural neuroimaging measures (whole-brain volume) and levels of CSF amyloid-beta (Abeta)(40), Abeta(42), tau, and phosphorylated tau(181) (ptau(181)), and plasma Abeta(40) and Abeta(42) in well-characterized research subjects with very mild and mild dementia of the Alzheimer type (n = 29) and age-matched, cognitively normal control subjects (n = 69). Levels of CSF tau and ptau(181), but not Abeta(42), correlated inversely with whole-brain volume in very mild and mild dementia of the Alzheimer type, whereas levels of CSF Abeta(42), but not tau or ptau(181), were positively correlated with whole-brain volume in nondemented control subjects. Reduction in CSF Abeta(42), likely reflecting Abeta aggregation in the brain, is associated with brain atrophy in the preclinical phase of AD. This suggests that there is toxicity associated with Abeta aggregation before the onset of clinically detectable disease. Increases in CSF tau (and ptau(181)) are later events that correlate with further structural damage and occur with clinical onset and progression.

IC-P2-150: Comparing rates of change versus cross-sectional hippocampal measure in early DAT

Background: In cross-sectional studies comparing subjects with and without very mild dementia of the Alzheimer type (DAT), we showed that deformities of hippocampal surface shape and volume could discriminate groups. While this suggests that irregularities of hippocampal structure are a feature of early AD, they could represent an early form of neurodegeneration or a long-standing “anatomic” vulnerability to disease. In this study, we compared the volume and shape of the hippocampus over time in very mildly demented and nondemented subjects, and determined whether the rate of changes in structural measures would improve the discrimination of subject groups based on cross-sectional (baseline) measures. Methods: MR scans were collected from 54 CDR 0.5 subjects and 69 CDR 0 subjects on multiple occasions (Table 1). Large-deformation high-dimensional brain mapping was applied to all scans to generate hippocampal surfaces in each subject scan. An average hippocampal surface constructed from 86 healthy subjects from a previous study was used as a reference to compute displacements from this reference for all surfaces. Mean displacements for hippocampal surface zones corresponding to the CA1, subiculum and remainder subfields were computed for each subject as shape measures. Mixed models with baseline CDR status as fixed factor and between-scan interval as random factor were used to test for group differences in rates of change in the hippocampal variables. Gender was used as a covariate. Results: At baseline, CDR 0.5 subjects had smaller volumes and more inwardly deformed hippocampal surfaces as compared with CDR 0 subjects. In particular, the surface zone associated with the CA1 hippocampal subfield deformed inwardly at a faster rate in the CDR 0.5 subjects than in the CDR 0 subjects. However, the effect size of the longitudinal comparison was smaller than the effect size of the cross-sectional comparison at baseline. See Table 2. Conclusions: These results suggest that while very mild DAT subjects show a more rapid rate of hippocampal volume loss and shape deformation than nondemented subjects, the degree of hippocampal deformation at the onset of dementia is already substantial and is as good or better than measures of changes in structure for group discrimination. P01-AG026276,P01-AG03991, P50-AG05681,R01-MH60883, R01-MH56584,P41-RR15241.

The Power of Personality in Discriminating Between Healthy Aging and Early-Stage Alzheimer's Disease

This study examined differences in personality in the earliest stages of dementia of the Alzheimer type (DAT) relative to healthy aging, and the power of personality in discriminating healthy aging from early-stage DAT. Four groups of participants (middle-aged controls, older controls, persons with very mild DAT, and persons with mild DAT) and their families were administered Costa and McCrae's NEO Five-Factor Inventory. On the basis of both self-report and informant report, there was an increase in neuroticism and a decrease in conscientiousness in persons with very mild DAT relative to healthy individuals without it, and in persons with mild DAT relative to those with very mild DAT. Moreover, informant reports of neuroticism and conscientiousness capture substantial unique variance in discriminating healthy aging and very mild DAT, above and beyond standard neuropsychological tests. Discussion focuses on the importance of personality traits as a noncognitive indicator of early-stage DAT.

Prospective memory and apolipoprotein e in healthy aging and early stage Alzheimer's disease.

The present study examined whether prospective memory performance discriminates healthy aging from very mild dementia of the Alzheimer type (DAT) and individuals at risk for DAT because of the presence of the apolipoprotein E (ApoE) epsilon4 allele. Four groups (young subjects, young-old control subjects, old-old control subjects, and subjects with very mild DAT) engaged in an event-based prospective memory task wherein they responded to a specific word embedded in a general knowledge test. Results indicated that prospective memory performance was clearly impaired in the very mild DAT group relative to the healthy older control groups. Moreover, prospective memory performance appears to capture unique variance in discriminating these 2 groups above and beyond standard retrospective memory tests. However, prospective memory was not affected by ApoE status in the young-old control group and, contrary to predictions, the epsilon4+ old-old control subjects showed better performance than did the epsilon4- subjects. In contrast to the healthy individuals, in the very mild DAT group, epsilon4+ subjects showed deficits in performance relative to the epsilon4- subjects. Discussion focuses on prospective memory as a cognitive indicator of early stage DAT.