Mild DAT Research Articles

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.

ARMADA: Assessing reliable measurement in Alzheimer's disease and cognitive aging project methods.

Early detection of cognitive decline in older adults is a public health priority. Advancing Reliable Measurement in Alzheimer's Disease and Cognitive Aging (ARMADA), a multisite study, is validating cognition, emotion, motor, and sensory modules of the National Institutes of Health Toolbox for Assessment of Neurological and Behavioral Function (NIHTB) in the aging spectrum from cognitively normal to dementia of the Alzheimer's type (DAT). Participants 65 to 85 years old, in demographic groups racially proportional to the general US population, are recruited in one of three groups to validate the NIHTB: cognitively normal, amnestic mild cognitive impairment (aMCI), or mild DAT. Additional special emphasis cohorts include (1) Blacks in the three clinical groups; (2) Spanish-speakers in the three clinical groups; (3) cognitively normal, population-proportional, over age 85. Longitudinal study will determine whether NIHTB can predict cognitive decline and is associated with Alzheimer's disease biomarkers. Here, we detail the methods for the ARMADA study.

Sentence comprehension in patients with dementia of the Alzheimer's type.

Sentence comprehension is diminished in patients with dementia of the Alzheimer’s type (DAT). However, the underlying reason for such deficits is still not entirely clear. The Syntactic Deficit Hypothesis attributes sentence comprehension deficits in DAT patients to the impairment in syntactic ability, whereas the Processing Resource Deficit Hypothesis proposes that sentence comprehension deficits are the result of working memory deficiency. This study investigated the deficits in sentence comprehension in Chinese-speaking DAT patients with different degrees of severity using sentence-picture matching tasks. The study revealed a significant effect of syntactic complexity in patients and healthy controls, but the effect was stronger in patients than in healthy controls. When working memory demand was minimized, the effect of syntactic complexity was only significant in patients with moderate DAT, but not in healthy controls or those with mild DAT. The findings suggest that in patients with mild DAT, working memory decline was the major source of sentence comprehension difficulty and in patients with moderate DAT, working memory decline and syntactic impairment jointly contributed to the impairments in sentence comprehension. The source of sentence comprehension deficits varied with degree of dementia severity.

Keep Up the Pace: Declines in Simple Repetitive Timing Differentiate Healthy Aging from the Earliest Stages of Alzheimer's Disease

The current study examined whether healthy older adults (OA) and individuals at the earliest stages of dementia of the Alzheimer's type (DAT) differ from younger adults (YA) and from each other on a simple, extended continuous tapping task using intervals (500 ms, 1000 ms, and 1500 ms) thought to differentially engage attentional control systems. OA groups sped up their tapping at the slowest target rate compared to the YA; this pattern was magnified in the early stage DAT groups. Performance variability appeared especially sensitive to DAT-related changes, as reliable differences between healthy OA and very mild DAT individuals emerged for multiple tap rates. These differences are proposed to result from breakdowns in attentional control that disrupt error-correction processes and the ability to resolve discrepancies between internally-generated temporal expectancies and the external temporal demands of the repetitive timing task.

Screening and treatment for Alzheimer's disease: Predicting population‐level outcomes

Advances in screening and treatment are needed to mitigate increasing prevalence of dementia due to Alzheimer's disease (DAT). Current proposals to revise Alzheimer's disease (AD) diagnostic criteria incorporate diagnostic biomarkers. Such revisions would allow identification of persons with AD pathology before the onset of dementia. The population-level impact of screening for preclinical AD and treating with a disease-modifying agent is important when evaluating new biomarkers and medications. A published computer simulation model assigned AD-related event times, such that delays in disease progression due to therapy effectiveness can be estimated for a preclinical AD cohort. Attributes such as screening sensitivity/specificity, treatment efficacy, age at first screening, and rescreening intervals were varied. Outcomes included incident mild cognitive impairment (MCI-AD), incident DAT, and number of patients recommended for treatment. One-time screening at age 65 years, 50% efficacy, and literature-based proxy persistence rates yielded 12.4% incidence of MCI-AD and 0.9% decrease in DAT incidence from base case of no screening/treatment. Modest reductions in incident MCI-AD and DAT were observed with more sensitive testing. Reducing specificity yielded greater reductions in MCI-AD and DAT cases, albeit by treating more patients. Probabilistic sensitivity analysis predicted that for a cohort of patients aged 65 years, the number that needed to be treated to avoid one AD case was 11.6 (range: 5.7-104). The reduction in MCI-AD and DAT depends on initial screening age, screening frequency, and specificity. When considering population-level impact of screening-treatment, the effect of these parameters on incidence would need to be weighed against the number of individuals screened and treated.

Diagnostic Utility of Cerebral White Matter Integrity in Early Alzheimer's Disease

ABSTRACTWe compared white matter integrity with brain atrophy in healthy controls and participants with very mild dementia (Clinical Dementia Rating 0 vs. 0.5) from the Brain Aging Project, a longitudinal study of aging and memory at the University of Kansas Medical Center. Structural magnetic resonance imaging and diffusion tensor imaging (DTI) including fractional anisotropy and mean diffusivity were performed on 27 patients with very mild dementia (Clinical Dementia Rating = 0.5) of the Alzheimer's type (DAT), and 32 cognitively normal subjects. Patient groups were compared across 6 volumetric measures and 14 DTI regions of interest. Very mildly demented patients showed expected disease-related patterns of brain atrophy with reductions in whole-brain and hippocampal volumes most prominent. DTI indices of white matter integrity were mixed. Right parahippocampus showed significant but small disease-related reductions in fractional anisotropy. Right parahippocampus and left internal capsule showed greater mean diffusivity in early DAT compared with controls. A series of discriminant analyses demonstrated that gray matter atrophy was a significantly better predictor of dementia status than were DTI indices. Brain atrophy was most strongly related to very mild DAT. Modest disease-related white matter anomalies were present in temporal cortex, and deep white matter had limited discriminatory diagnostic power, probably because of the very mild stage of disease in these participants.

The utility of placing recollection in opposition to familiarity in early discrimination of healthy aging and very mild dementia of the Alzheimer's type.

This study explored the ability to control familiarity-based information in a memory exclusion paradigm in healthy young, older adults, and early stage DAT individuals. We compared the predictive power of memory exclusion performance to standard psychometric performance in discriminating between aging and the earliest stage of DAT and between APOe4-present and APOe4-absent genotype in healthy control individuals. Participants responded "yes" to words that were previously semantically encoded, and "no" to words that were previously read aloud and to new words. The number of targets and distractors on the read "distractor" list was manipulated to investigate the degree to which aging and DAT influence the ability to recollect in the face of distractor familiarity due to repetition. Memory exclusion performance was better for healthy older adults than very mild DAT individuals and better for healthy control individuals with APOe4 allele than those without APOe4 allele even after controlling for standard psychometric performance. Discussion focuses on the importance of attentional control systems in memory retrieval and the utility of the opposition paradigm for discriminating healthy versus pathological aging.

The utility of intraindividual variability in selective attention tasks as an early marker for Alzheimer’s disease.

This study explored differences in intraindividual variability in 3 attention tasks across a large sample of healthy older adults and individuals with very mild dementia of the Alzheimer's type (DAT). Three groups of participants (healthy young adults, healthy older adults, very mild DAT) were administered 3 experimental measures of attentional selection and switching (Stroop, Simon, task switching). The results indicated that a measure of intraindividual variability, coefficient of variation (CoV; SD/M), increased across age and early stage DAT. The CoV in Stroop discriminated the performance of epsilon4 carriers from noncarriers in healthy older controls and the CoV in task switching was correlated with cerebrospinal fluid (CSF) biomarkers predictive of DAT.

FDG-PET changes in brain glucose metabolism from normal cognition to pathologically verified Alzheimer’s disease

We report the first clinicopathological series of longitudinal FDG-PET scans in post-mortem (PM) verified cognitively normal elderly (NL) followed to the onset of Alzheimer's-type dementia (DAT), and in patients with mild DAT with progressive cognitive deterioration. Four NL subjects and three patients with mild DAT received longitudinal clinical, neuropsychological and dynamic FDG-PET examinations with arterial input functions. NL subjects were followed for 13 +/- 5 years, received FDG-PET examinations over 7 +/- 2 years, and autopsy 6 +/- 3 years after the last FDG-PET. Two NL declined to mild cognitive impairment (MCI), and two developed probable DAT before death. DAT patients were followed for 9 +/- 3 years, received FDG-PET examinations over 3 +/- 2 years, and autopsy 7 +/- 1 years after the last FDG-PET. Two DAT patients progressed to moderate-to-severe dementia and one developed vascular dementia. The two NL subjects who declined to DAT received a PM diagnosis of definite AD. Their FDG-PET scans indicated a progression of deficits in the cerebral metabolic rate for glucose (CMRglc) from the hippocampus to the parietotemporal and posterior cingulate cortices. One DAT patient showed AD with diffuse Lewy body disease (LBD) at PM, and her last in vivo PET was indicative of possible LBD for the presence of occipital as well as parietotemporal hypometabolism. Progressive CMRglc reductions on FDG-PET occur years in advance of clinical DAT symptoms in patients with pathologically verified disease. The FDG-PET profiles in life were consistent with the PM diagnosis.

P4-228: Family-supervised physical activity programs for persons with mild DAT: Impact and process

Because of their unique insights and perspectives into the needs and motivations of their older relatives and also because they often are asked to implement home–based health–related programs, family caregivers of persons with dementia can serve as significant collaborators with health professionals in program development, implementation, and evaluation. In an attempt to provide exercise options for community–dwelling persons with mild levels of dementia of the Alzheimer's type (DAT), individualized home–based exercise programs supervised by family members were developed, implemented, and evaluated. This poster describes the contributions of family caregivers to the refinement of individualized physical activity programs developed for persons with very mild or mild DAT and the impact of the programs on participants' physical functioning. Thirty persons with very mild or mild DAT (CDR 0.5 or 1) and their family exercise supervisors (N=60) participated in the three–month physical activity program. Family members provided information on which the individualized programs were based, received intensive training, and maintained telephone contact with the research team throughout the duration of the program. As they supervised the exercises, family members exercised along with their relative and afterwards recorded information on each session. Measures of physical ability (i.e., balance, flexibility, strength, and endurance) were obtained pre– and post–intervention. In–depth interviews and focus groups with family exercise supervisors provided qualitative data on factors influencing adherence and on the process of exercise participation. Participants who completed the three–month program demonstrated significant improvements in physical functioning. Family exercise supervisors reported their general reactions to the program, barriers to exercise that they encountered and ways they dealt with those problems, their reactions to the training sessions and monitoring process, the modifications or innovations that they made to the program on their own, their perceptions of the impact of the program on their relative and themselves, and their plans for future exercise. Family caregivers proved to be significant resources in the development, implementation, evaluation, and further refinement of successful home–based exercise programs.

IC-P-054: Relationship between in vivo amyloid imaging with 11C-PIB and CSF Aβ42

Abundant evidence supports a central role for amyloid–β (Aβ) and its conversion from soluble to insoluble forms (e.g., fibrils or oligomers) in the pathogenesis of Alzheimer's disease (AD). Potential disease–modifying therapies targeting Aβ and its metabolism are currently being developed and will ultimately provide the definitive test of this hypothesis. In order for therapies to have the greatest clinical impact, it will be necessary to identify individuals with AD pathology prior to marked cognitive symptoms and neuronal cell loss (i.e., ‘preclinical’ or very early stage DAT). We recently investigated the relationship between the in vivo amyloid load (via PET imaging of the amyloid–binding compound, 11C–PIB) and various CSF measures in a small (n=24) research cohort (age 48–83 years) that included both cognitively normal individuals and those diagnosed with very mild or mild DAT (Fagan et al., 2006, Ann. Neurol.). We observed a striking inverse relation between mean cortical amyloid load and CSF Aβ42 (but not other CSF markers); those with positive PIB–binding had low CSF Aβ42 levels and those with negative PIB–binding had high CSF Aβ42 levels, with no overlap between the two groups. Importantly, this pattern was observed in a subset of subjects who were cognitively normal, suggesting the presence of amyloid pathology in the absence of cognitive symptoms (“preclinical AD”). These findings suggest that brain amyloid deposition results in low CSF Aβ42, and that amyloid imaging and CSF Aβ42 may potentially be useful as antecedent biomarkers of (preclinical) AD. We have since expanded our cohort size and will provide an update of our findings, including the consistency of this pattern in this larger sample, the degree to which it is maintained in individuals exhibiting a relatively low level of brain amyloid, and whether analyses of regional PIB binding offer additional discriminatory power. These additional analyses will provide important information regarding the potential utility of these measures as diagnostic and/or antecedent biomarkers of AD and may also offer insights into possible mechanism(s) of amyloid deposition in the AD brain.

Do functional disability is a good predictor index for Alzheimer's disease?

Materials and methods 29 mild DAT patients were included in this study. The mean of age and educational level was 73.2 and 9.4 years respectively, though the mean of mental state as measured by MMSE was 23.7/30. All the patients had an established diagnosis of DAT according to the criteria of the DSM-IV and the NINCDS-ADRDA, as well as based on neurological, neuropsychological and neuroimaging data. We administered the Disability Assessment for Dementia Scale (DAD) (Gauthier and Gilinas, 1999) which is a caregiverbased interview comprised of a 40-item questionnaire to evaluate basic and instrumental ADLs in dementia.

Normative estimates of cross-sectional and longitudinal brain volume decline in aging and AD

To test the hypotheses 1) that whole-brain volume decline begins in early adulthood, 2) that cross-sectional and longitudinal atrophy estimates agree in older, nondemented individuals, and 3) that longitudinal atrophy accelerates in the earliest stages of Alzheimer disease (AD). High-resolution, high-contrast structural MRIs were obtained from 370 adults (age 18 to 97). Participants over 65 (n = 192) were characterized using the Clinical Dementia Rating (CDR) as either nondemented (CDR 0, n = 94) or with very mild to mild dementia of the Alzheimer type (DAT, CDR 0.5 and 1, n = 98). Of these older participants, 79 belonged to a longitudinal cohort and were imaged again a mean 1.8 years after baseline. Estimates of gray matter (nGM), white matter (nWM), and whole-brain volume (nWBV) normalized for head sizes were generated based on atlas registration and image segmentation. Hierarchical regression of nWBV estimates from nondemented individuals across the adult lifespan revealed a strong linear, moderate quadratic pattern of decline beginning in early adulthood, with later onset of nWM than nGM loss. Whole-brain volume differences were detected by age 30. The cross-sectional atrophy model overlapped with the rates measured longitudinally in older, nondemented individuals (mean decline of -0.45% per year). In those individuals with very mild DAT, atrophy rate more than doubled (-0.98% per year). Nondemented individuals exhibit a slow rate of whole-brain atrophy from early in adulthood with white-matter loss beginning in middle age; in older adults, the onset of dementia of the Alzheimer type is associated with a markedly accelerated atrophy rate.

Word fluency skills in dementia of the Alzheimer's type for common and goal‐directed categories

Background: Categorisation abilities, as measured by word fluency, have been observed to deteriorate in dementia of the Alzheimer's type (DAT). Specifically, patients with early dementia have been observed to produce fewer examples than their healthy age‐matched cohorts. As disease severity increases, accuracy of responses decreases. This decrease appears to be related to increased deterioration in semantic memory. Thus, exemplar generation is a sensitive indicator of early effects of dementia. Individuals' responses on word fluency have been analysed in a variety of ways and reveal unique quantitative and qualitative profiles for adults with DAT. Furthermore, type of category may also affect performance of adults with DAT. Two types of categories that have been examined are common and goal‐directed categories.Aim: The purpose of the investigation was to study the categorisation skills of adults with dementia as the result of Alzheimer's disease. Specifically, the generation of goal‐directed and common category exemplars by adults with mild and moderate severity DAT and normal elderly adults was examined. One concern of the study was participants' sensitivity to graded structure, examined through analysis of mean typicality ratings for responses. Another focus was identification and frequency of usage of particular response strategies. Total number of category examples produced and accuracy of these responses were also examined.Methods & Procedures: A total of 30 adults, comprising 20 individuals meeting the NINCSD‐ADRDA criteria for DAT and 10 neurologically intact elderly adults, participated. Dementia severity was determined using the Global Deterioration Scale and the Dementia Rating Scale resulting in 10 mildly impaired and 10 moderately impaired DAT participants. Four common and four goal‐directed categories were presented to each participant. Common categories were four of ten categories for which Rosch (1975) established typicality norms with young adults; goal‐directed categories were four of sixteen for which typicality norms were developed with normal middle‐aged adults (Hough, 1988). Each participant was asked to generate as many exemplars as possible for each category. No preset time limit was established for the amount of time to respond to each category.Outcomes & Results: The NBD participants produced significantly more exemplars for both category types than either DAT groups. However, the moderate DAT group was significantly less accurate than the mild DAT and NBD groups. The NBD group produced significantly more exemplars and had significantly lower mean typicality ratings for the common than the goal‐directed categories; both DAT groups showed no differences between category types for these variables. Both DAT groups used fewer response strategies overall, regardless of category type, and utilised a significantly smaller percentage of semantic and subordinate association strategies than the NBD participants.Conclusions: DAT may, to some extent, adversely affect sensitivity to the general process of category construction, regardless of category type. This pervasive deficit is apparent even in milder stages of the disease process and supports the hypothesis that as severity of DAT increases, there is an accompanying increase in the deterioration of semantic memory. This greater deterioration appears to result in increased problems with creation and ordering of ideas, one of the primary bases for exemplar generation.

Visual event-related potential in mild dementia of the Alzheimer's type.

Visual event-related potentials (ERP) and behavioral measures were recorded during a geometrical-figure discrimination task to examine sensory processing in 10 patients with mild dementia of the Alzheimer's type (DAT) and 10 age-matched controls. No difference existed between the groups in P1, N1, and P2 potentials, which reflects the early stage of sensory processing, as well as in NA potential, which reflects pattern recognition. The patients showed reduced amplitude of P3 potential, retarded reaction time, and increased behavioral errors compared to controls. These findings suggest that the patients with mild DAT were intact in early sensory processing including pattern recognition but were selectively compromised in higher-level processing, including integration of information and memory matching, which may influence behavioral deviation.

Semantic, phonological, and hybrid veridical and false memories in healthy older adults and in individuals with dementia of the Alzheimer type.

Five groups of participants (young, healthy old, healthy old-old, very mild dementia of the Alzheimer type [DAT], and mild DAT) studied 12-item lists of words that converged on a critical nonpresented word (cold) semantically (chill, frost, warm, ice), phonologically (code, told, fold, old), or in a hybrid list of both (chill, told, warm, old). The results indicate that (a) veridical recall decreased with age and dementia; (b) recall of the nonpresented items increased with age and remained fairly stable across dementia; and (c) false recall varied by list type, with hybrid lists producing superadditive effects. For hybrid lists, individuals with DAT were 3 times more likely to recall the critical nonpresented word than a studied word. When false memory was considered as a proportion of veridical memory, there was an increase in relative false memory as a function of age and dementia. Results are discussed in terms of age- and dementia-related changes in attention and memory.

Dysgraphia in mild dementia of Alzheimer's type

We assessed writing abilities in a cohort of 31 patients with a diagnosis of DAT (in two subgroups, with minimal [MMSE 24–28] and mild [MMSE 16–23] levels of dementia), and 10 matched controls. Central aspects of writing were assessed by both written and oral spelling to dictation of 72 single words varying in frequency (high or low) and predictability of sound-to-spelling correspondences (predictable, unpredictable and irregular). All subjects achieved better scores on high, as compared to low, frequency words. The performance of both patient groups was significantly affected by degree of predictability, and was equivalent in the written and oral spelling conditions. Phonologically acceptable alternative spellings (e.g. `wade' → WAID) constituted the majority of errors. More peripheral processes in writing were assessed by copying and cross-case transcription of single letters. Subjects were more successful at copying within case than transcribing across case. Performance was also better—substantially so for the mild DAT group—when the target response in either task was an upper- rather than a lower-case letter. There was considerable heterogeneity in performance on the spelling and the letter tasks. Some patients (even in the more affected DAT group) were unimpaired on both tasks, suggesting that dysgraphia is not a constant feature in early DAT. When writing deficits do become apparent, in the earliest stages of the disease the pattern is most likely to be one of mild surface dysgraphia, a form of central dysgraphia; impairments in more peripheral aspects of writing tend to emerge once the disease has progressed beyond the minimal stage. ©1997 Elsevier Science Ltd. All rights reserved.

Lexical Priming by Pictures and Words in Normal Aging and in Dementia of the Alzheimer's Type

Alzheimer's disease causes a progressive loss of semantic memory, one manifestation of which is a progressive language deficit. In order to delineate the relationship between cognitive processing deficits and language disturbance, word–word and picture–word lexical-decision priming tasks were administered to patients with mild dementia of the Alzheimer's type (DAT) (n = 6), very mild DATs (n = 7), and older normals (n = 23). The mild DATs differed from the other two groups in both tasks. When pictures were used as primes, significant identity priming was seen in the normals and very mild DATs, but not in the mild DATs. The mild DATs showed an aberrant pattern—responses significantly slower with picture primes than with nonsense primes in all three picture–word conditions. This may reflect residual inhibitory activity within a damaged associational network. In the word–word paradigm, the mild DAT subjects demonstrated significant priming both when the prime and target were identical (identity priming, e.g.,dog–dog) and when they were semantically related (semantic priming, e.g.,cat–dog). The other two groups showed no significant priming. These data reinforce other studies which have found that DAT subjects show a supranormal amount of word–word lexical-decision priming. This “hyperpriming” may occur due to partially degraded internal representations which benefit from priming more than intact representations (a cognitive crutch). Both paradigms thus exposed information-processing deficits which distinguished mild DATs from the other two groups. DAT-induced changes in selective attention are probably contributing to these results.

Confrontational and generative naming in very mild DAT vs. very severe CHI

Confrontational and generative naming in very mild DAT vs. very severe CHI

Attention and Driving Skills in Aging and Alzheimer's Disease

The number of older drivers with dementia is rising with the aging of the adult population. A public health issue is growing because of concerns about the motor vehicle accident risk posed by drivers with dementia of the Alzheimer's type (DAT) and other progressive, degenerative dementias. However, little is known about the specific perceptual/cognitive deficits contributing to impaired driving in DAT. The present paper proposes, on both theoretical and empirical grounds, that attentional skills in relation to driving should be examined in older adults with and without DAT. Such investigations should focus on normal older adults and those in the mild, early stages of dementia because the latter are the most likely among the dementia population to be still driving. Evidence is presented indicating (1) that motor vehicle accident rates are related to performance on information-processing measures of different components of attention; (2) that this relationship is greatest for measures of the switching of selective attention and less for that of divided and sustained attention (vigilance); and (3) that many of these same attentional functions, and particularly the switching of visual selective attention, are impaired in the early stages of DAT and thus may contribute to increased accident risk. Further studies of cognitive and driving performance in older drivers are necessary to establish that the attentional impairments found in mild DAT contribute to increased accident risk. Implications of these findings for driver assessment, education, and training are discussed.