Probable AD Patients Research Articles

Approximate quantification in young, healthy older adults’, and Alzheimer patients

Forty young adults, 40 healthy older adults, and 39 probable AD patients were asked to estimate small (e.g., 25) and large (e.g., 60) collections of dots in a choice condition and in two no-choice conditions. Participants could choose between benchmark and anchoring strategies on each collection of dots in the choice condition and were required to use either benchmark or anchoring on all configurations in the no-choice conditions (one per strategy). The benchmark strategy involves visual estimation processes whereas the anchoring strategy involves both enumeration and estimation processes. Results showed that strategy use was influenced by collection, participant, and strategy characteristics. Age-related and dementia-related differences were found in both strategy use and strategy execution. The findings have implications for our understanding of aging effects in approximate quantification, strategic variations in Alzheimer’s patients, and sources of cognitive decline during early stages of Alzheimer’s disease.

Event‐related delta oscillatory responses of Alzheimer patients

Alzheimer type of dementia (AD) is the most common neuropsychiatric morbidity in elderly individuals. Event-related oscillations (ERO) provide an useful tool for detecting subtle abnormalities of cognitive processes with high temporal resolution. In the present report, event-related oscillations of patients with AD were analyzed by using a visual oddball paradigm. A total of 22 mild probable AD subjects according to NINCDS-ADRDA criteria and 20 age-, gender-, and education-matched healthy control subjects were compared. AD group consisted from 11 untreated patients and 11 patients treated with cholinesterase inhibitor. Oscillatory responses were recorded from 13 scalp electrodes. Significant differences in delta frequency range were seen between the groups by using repeated measures of anova analysis [F(9.120) = 2.228; P = 0.022]. Post-hoc analyses using Wilcoxon test showed that at mid- and left central regions, (Cz, C3) peak amplitudes of delta responses of healthy subjects were significantly higher than either group. Also cholinesterase inhibitors did not have effect on delta oscillatory responses. Our findings imply that the delta oscillatory responses at central locations are highly instable in mild probable AD patients regardless of treatment when compared to the healthy aged controls. This study supports the importance of oscillatory event-related potentials for investigating AD brain dynamics.

Depth of word processing in Alzheimer patients and normal controls: a magnetoencephalographic (MEG) study.

Effects related to depth of verbal information processing were investigated in probable Alzheimer's disease patients (AD) and age matched controls. During word encoding sessions 10 patients and 10 controls had either to decide whether the letter "s" appeared in visually presented words (alphabetical decision, shallow encoding), or whether the meaning of each presented word was animate or inanimate (lexical decision, deep encoding). These encoding sessions were followed by test sessions during which all previously encoded words were presented again together with the same number of new words. The task was then to discriminate between repeated and new words. Magnetic field changes related to brain activity were recorded with a whole cortex MEG.5 probable AD patients showed recognition performances above chance level related to both depths of information processing. Those patients and 5 age matched controls were then further analysed. Recognition performance was poorer in probable AD patients compared to controls for both levels of processing. However, in both groups deep encoding led to a higher recognition performance than shallow encoding. We therefore conclude that the performance reduction in the patient group was independent of depth of processing. Reaction times related to false alarms differed between patients and controls after deep encoding which perhaps could already be used for supporting an early diagnosis. The analysis of the physiological data revealed significant differences between correctly recognised repetitions and correctly classified new words (old/new-effect) in the control group which were missing in the patient group after deep encoding. The lack of such an effect in the patient group is interpreted as being due to the respective neuropathology related to probable AD. The present results demonstrate that magnetic field recordings represent a useful tool to physiologically distinguish between probable AD and age matched controls.

ApoE isoforms and measures of anxiety in probable AD patients and Apoe−/− mice

Increased anxiety may occur in up to 70% of AD patients during the course of their illness. Here we show that human apoE isoforms, which differ in AD risk, have differential effects on measures of anxiety in adult Apoe −/− male mice expressing human apoE3 or apoE4 in their brains and male probable AD (PRAD) patients. Compared with wild-type mice, Apoe −/− mice without human apoE or with apoE4, but not apoE3, showed increased measures of anxiety. These behavioral alterations were associated with reduced microtubule-associated protein 2-positive neuronal dendrites in the central nucleus of the amygdala. Consistent with the mouse data, male and female PRAD patients with ɛ4/ɛ4 showed higher anxiety scores than those with ɛ3/ɛ3. We conclude that human apoE isoforms have differential effects on measures of anxiety.

P1-089 Longitudinal analyses of the Alzheimer's disease assessment scale in a large cohort of probable AD patients

P1-089 Longitudinal analyses of the Alzheimer's disease assessment scale in a large cohort of probable AD patients

Alzheimer’s disease disrupts arithmetic fact retrieval processes but not arithmetic strategy selection

Three groups of healthy younger adults, healthy older adults, and probable AD patients, performed an addition/number comparison task. They compared 128 couples of additions and numbers (e.g., 4 + 9 15) and had to identify the largest item for each problem by pressing one of two buttons located under each item. Manipulations of problem characteristics (i.e., problem difficulty and splits between correct sums and proposed numbers) enabled us to examine strategy selection and specific arithmetic fact retrieval processes. Results showed that arithmetic facts retrieval processes, which were spared with aging, were impaired in AD patients. However, AD patients were able to switch between strategies across trials according to problem characteristics as well as healthy older adults, and less systematically than healthy younger adults. We discuss implications of these findings for further understanding AD-related differences in arithmetic in particular, and problem solving in general.

The effect of APOE epsilon4 allele on cerebral glucose metabolism in AD is a function of age at onset.

Although the APOE epsilon4 allele is a well-known risk factor for developing AD, the impact of the epsilon4 allele on clinical manifestations in patients with AD is still controversial. One possible reason for this controversy is that previous studies did not consider the effect of patient age at symptom onset. To investigate the possible impact of patient age at onset of AD on the effect of APOE genotype on regional cerebral glucose metabolism (rCMRglc). The authors compared rCMRglc between probable AD patients (based on criteria of the National Institute of Neurologic Disease and Stroke/AD and Related Disorders Association) with APOE epsilon4/4 and APOE epsilon3/3 alleles in early-onset (< or =65 years old) and late-onset (>65 years old) groups. In each group, the patients with APOE epsilon4/4 and APOE epsilon3/3 alleles were comparable for age at onset, age at examination, sex, disease duration, education level, and severity of dementia. In the early-onset group, the patients with the APOE epsilon4/4 genotype showed a significant decrease of rCMRglc in the medial temporal lobe and a significant increase of rCMRglc in the inferior parietal and posterior temporal cortices as compared with those patients with the APOE epsilon3/3 genotype. In the late-onset group, there were no significant differences in the rCMRglc pattern between the patients with APOE epsilon4/4 and APOE epsilon3/3 alleles. The current findings indicate that the impact of the APOE epsilon4 genotype on cerebral glucose metabolism of patients with AD may be a function of age at symptom onset.

Apolipoprotein E epsilon 4 and the pattern of regional brain atrophy in Alzheimer's disease.

Although the APOE epsilon 4 allele increases the risk of developing AD, the effects of the epsilon 4 allele on brain atrophy in clinical AD patients are controversial. To investigate a possible relationship between the genetic variants of APOE and brain atrophy in patients with AD. Using MRI-based volumetry techniques, the authors compared the volumes of the hippocampal formation, amygdaloid complex, and whole brain in probable AD patients (based on criteria of the National Institute for Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association) with different APOE alleles. One group (n = 46) had the epsilon 3/3 allele, one group (n = 46) had the epsilon 3/4 allele, and one group (n = 46) had the epsilon 4/4 allele. The three groups were matched for age, sex, disease duration, education level, and severity of dementia represented by their score of the Mini-Mental State Examination. A possible difference in pattern of cognitive deficits with dose of the APOE epsilon 4 allele was also examined. The normalized hippocampal volume was correlated with the number of APOE epsilon 4 alleles (r = -0.285, p = 0.0007). The amygdalar volume was also correlated with the number of APOE epsilon 4 alleles (r = -0.178, p = 0.037). The number of APOE epsilon 4 alleles was positively correlated with the whole-brain volume (r = 0.185, p = 0.030). It was also correlated with Wechsler Adult Intelligence Scale-Revised performance IQ (r = 0.203, p = 0.017) and with Wechsler Memory Scale-Revised attention/concentration score (r = 0.191, p = 0.025). Different patterns of regional brain atrophy were found among patients of different APOE genotypes. The effect of APOE epsilon 4 allele on the brains of AD patients may have regional specificity.

Research evaluation and diagnosis of probable Alzheimer's disease over the last two decades: I.

To describe the experience of a research clinic diagnosing AD during the last two decades, with special emphasis on patients who meet the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria for probable AD, their patterns of clinical presentation, and neuropathologic outcomes. Probable AD has a heterogeneous clinical presentation, and can occur in the context of complicating factors. There are few reports, and none with this large of a sample, about the pattern of presentation, the nature of comorbidities, and the sensitivity and specificity of diagnosis. The AD Research Center of Pittsburgh examined 1139 patients with probable AD between April 1983 and February 2000. Of these 1139 probable AD patients, 29 (2.5%) had slow progression, 27 (2%) had rapid progression, 70 (6%) had an atypical presentation, and 85 (7%) had coexistent cerebrovascular disease. Confluent periventricular white matter lesions were found in 348 (30.5%) patients with probable AD. The overall sensitivity for the diagnosis of AD was 97% and the specificity 80%. However, the accuracy for the diagnosis of AD varied over the years: from 1983 to 1989, the sensitivity was 94% and specificity 52%, and from 1990 to 2000, the sensitivity was 98% and specificity 88%. Although the diagnosis of probable AD has been used to indicate the presence of a homogeneous clinical entity, these patients can vary in presentation, onset, or clinical course. This finding is of particular importance for the understanding of the pathophysiologic basis of the disease, and for the better identification of responders to dementia treatments. Although the sensitivity for the diagnosis of AD remained above 90% over the last two decades, the specificity increased, reflecting progressive improvement in the diagnosis of other dementing disorders.

Regional metabolic patterns in mild cognitive impairment and Alzheimer's disease: A 1H MRS study.

Mild cognitive impairment (MCI) is a recently described transitional clinical state between normal aging and AD. Assuming that amnestic MCI patients had pathologic changes corresponding to an early phase and probable AD patients to a later phase of the disease progression, the authors could approximate the temporal course of proton MR spectroscopic (1H MRS) alterations in AD with a cross-sectional sampling scheme. The authors compared 1H MRS findings in the superior temporal lobe, posterior cingulate gyri, and medial occipital lobe in 21 patients with MCI, 21 patients with probable AD, and 63 elderly controls. These areas are known to be involved at different neurofibrillary pathologic stages of AD. The N-acetylaspartate (NAA)/creatine (Cr) ratios were significantly lower in AD patients compared to both MCI and normal control subjects in the left superior temporal and the posterior cingulate volumes of interest (VOI) and there were no between-group differences in the medial occipital VOI. Myoinositol (MI)/Cr ratios measured from the posterior cingulate VOI were significantly higher in both MCI and AD patients than controls. The choline (Cho)/Cr ratios measured from the posterior cingulate VOI were higher in AD patients compared to both MCI and control subjects. These findings suggest that the initial 1H MRS change in the pathologic progression of AD is an increase in MI/Cr. A decrease in NAA/Cr and an increase in Cho/Cr develop later in the disease course.

APOE and lipid profiles in probable and possible AD patients versus controls in Bogotá (Colombia)

APOE and lipid profiles in probable and possible AD patients versus controls in Bogotá (Colombia)

Memory and MRI-based hippocampal volumes in aging and AD.

To demonstrate structural-functional relationships between MRI-based volumetric measurements of medial temporal lobe structures and cognitive function. Previous work has documented the ability of MRI-based measurements of the hippocampus to discriminate between age-matched control subjects and patients with very mild AD. Relatively less is known about the correlation between medial temporal lobe structures and cognitive functions. We evaluated structural-functional relationships among the hippocampal formation, parahippocampal gyrus, and amygdala, and measures of memory, language, and general cognitive performance in 220 probable AD patients and normal control subjects. Standardized instruments of memory and general cognitive function were used to assess subjects enrolled in a longitudinal study of aging and dementia. The volume of the hippocampal formation predicted performance on most acquisition and recall measures across the spectrum of normal aging and AD. If the groups were segregated, most of the expected associations between medial temporal lobe structures and memory measures were observed in the AD patients. MRI-based hippocampal volumetry accurately depicts the structural-functional relationships between memory loss and hippocampal damage across the spectrum from normal aging to dementia.

Association between apolipoprotein E polymorphism and Alzheimer's disease in Koreans

We analyzed the aplolipoprotein E (APOE) genotypes of 110 probable AD patients and 226 cognitively normal controls in Koreans. The APOE ε4 allele was more prevalent in both early- and late-onset AD patients (P<0.01) than in controls. The odds for the APOE ε4-heterozygous subjects were 2.7 (95% CI=1.6–4.5), and those for the APOE ε4-homozygous subjects were 17.4 (95% CI=2.0–147.3). But the odds were not uniform across age groups, and were higher in women than in men. Although the APOE ε2 allele frequency did not differ by diagnosis, the patients carrying an APOE ε2 allele showed delayed age-at-onset ( P=0.02). In conclusion, the APOE ε4 allele increased the risk for AD in dose-dependent manner, and the APOE ε4-conferred AD risk was age- and sex-dependent in Koreans.

Elevated CSF prostaglandin E2 levels in patients with probable AD.

To determine CSF eicosanoid concentrations and brain cyclo-oxygenase activity in AD patients and age-matched control subjects. Nonsteroidal anti-inflammatory drugs may benefit AD patients by inhibiting cyclo-oxygenases and thereby reducing prostaglandin (PG) production or oxidant stress in the CNS. CSF eicosanoid and F2-isoprostane (IsoP) levels were determined in seven probable AD patients and seven age-matched control subjects. Cyclo-oxygenase activity was determined in microsomes prepared from the hippocampus of 10 definite AD patients and 8 age-matched control subjects. All measurements were made using gas chromatography/mass spectrometry. CSF concentrations of prostaglandin (PG) E2 were increased fivefold (p < 0.01) and 6-keto-PGF1alpha was decreased fourfold (p < 0.01) in probable AD patients. There was no change in total CSF eicosanoid concentration in probable AD patients. CSF F2-IsoP, a quantitative marker of lipid peroxidation in vivo, was increased in probable AD patients (p < 0.05). Cyclo-oxygenase activity in the hippocampus from definite AD patients was not different from age-matched control subjects. These data suggest that cyclo-oxygenase activity may not contribute significantly to CNS oxidative damage in AD. Increased CSF PGE2 concentration in probable AD patients suggest that cyclo-oxygenase inhibitors may benefit AD patients by limiting PG production.

CSF beta-amyloid, cognition, and APOE genotype in Alzheimer's disease.

We examined the relationship between CSF amyloid beta peptide (A beta) concentration and AD severity in 31 probable AD patients and explored whether APOE genotype modifies this relationship. A beta deposition in AD brains has been correlated with disease severity and with APOE-epsilon4 allele frequency. Few studies have examined the effects of APOE genotype on the relationship between CSF A beta and disease severity in an antemortem sample. Patients carried the clinical diagnosis of probable AD and did not have serious medical illness, current or past diagnosis of mood disorder, schizophrenia or alcoholism, or current psychotic features. The Mini-Mental State Examination (MMSE) was administered to the patient within 3 months of CSF collection. CSF was analyzed for A beta1-40 and A beta1-42 by sandwich ELISAs, and APOE genotype was determined by PCR run from blood. Correlations were performed between MMSE score and A beta1-40 and A beta1-42 concentrations while controlling for potential confounding variables. CSF measures of A beta1-40 and A beta1-42 concentrations were correlated with each other (r = 0.56, df = 28, p < 0.01). CSF A beta1-40 and A beta1-42 concentrations were positively correlated with MMSE score. The negative association between CSF A beta measures and disease severity remained significant after controlling for age (A beta1-40 and MMSE score: r = 0.46, df = 28, p = 0.01; A beta1-42 and MMSE score: r = 0.35, df = 28, p = 0.05). Among the APOE-epsilon3/3 homozygotes there was a significant positive correlation only between A beta1-42 and MMSE score (A beta1-42, r = 0.94, p = 0.02; A beta1-40, r = 0.79, p = 0.11). We hypothesize that an increased deposition of A beta in plaques results in decreased CSF A beta concentration. The stronger relationship between MMSE score and CSF A beta, specifically in APOE-epsilon3/3 homozygotes, suggests that patients with APOE-epsilon3/3 genotype may have different pathogenic mechanisms than the other genotypes for A beta deposition or clearance.

Alzheimer's disease: patterns of cognitive impairment at different levels of disease severity

The aim of this study was to establish the presence and the consistency of different cognitive profiles in AD patients taking into consideration the severity of mental impairment. Therefore we stratified 679 neuropsychological observations on 119 probable AD patients followed longitudinally on the basis of overall degree of cognitive impairment. To compare performance on tests with different score ranges we transformed raw test scores into coefficients; to summarize our results in terms of language versus visuo-spatial performance we computed indices of prevalent impairment of performance (IPIP) by subtracting the coefficients for constructional praxis from coefficients for language-related tests. Finally, we converted these indices into z-scores for each level of mental decline to identify patients with generalized, language (L) or visuo-spatial (V) prevalent impairment. The latter, 30% of the sample, can be detected at all stages of dementia. There was a higher percentage of males among language impaired patients ( P<0.05). Approximately half of patients with L/V prevalent impairment continued to show such a focality when followed longitudinally. The groups did not differ in the annual rate of cognitive decline.

Use of temporal context information in Azheimer's disease

Current theories of memory and memory dysfunction emphasize the importance of the use of contextual information in the storage and retrieval of specific episodes. Patients with lesions primarily in the diencephalon perform poorly on a measure of temporal recency, while those with temporal lobe amnesia are significantly better. The present study evaluated the ability of Probable AD patients to utilize information about temporal recency in the context of a recognition memory task. The performance of the AD patients was significantly impaired and resembled that of patients with Korsakoff's syndrome. The pattern of performance suggested that they were able to recognize which stimuli had been previously presented, but were unable to recall the correct temporal context. Further, there were no significant correlations between measures of temporal recency and those of frontal lobe function. These data suggest that AD patients, like other groups of patients with severe memory defects, are impaired at the use of context information in their attempts to remember recent events.

The cognitive efficiency profile: Description and validation in patients with Alzheimer's disease

AbstractThe rigorous diagnosis of dementia, especially in the early stages, requires clinical observation and neuropsychological tests. This article shows how a short strategy‐oriented neuropsychological battery, the Cognitive Efficiency Profile (CEP), can contribute to the early diagnosis of Alheimer's disease.The CEP was given to 56 subjects who had been independently diagnosed as being cognitively unimpaired (N = 16), as having probable AD with mild dementia (N = 32) or as having “borderline” deterioration (N = 8). One‐year follow‐up showed that all the latter patients developed unequivocal dementia. There was a clear‐cut separation in the test results between the controls and the probable AD cases when the scores were corrected for age and education. There was some overlap between the borderline cases and the probable AD patients but, in all cases, the corrected scores fell below those of normal controls.The usefulness of the CEP rests on the fact that it assesses the efficiency or the failure of strategies applied to a number of abilities related to cognitive efficiency. Coupled with clinical data, a good or a poor performance on the CEP strongly corroborates the diagnosis of normal cognitive functioning or of dementia in the elderly.