ABSTRACT
The reason for differences in rate of cognitive decline in AD is unknown. The interleukin-1 alpha (IL-1 alpha) -889 *2 allele is associated with increased risk for AD. Surprisingly, in a sample of 114 patients followed for an average of 3.8 years, individuals homozygous for the IL-1 alpha -889 *1 allele declined significantly more rapidly on the Mini-Mental State Examination than did others. There was no difference in rate of decline between patients with and without the APOE epsilon 4 allele. These results support the hypothesis that inflammation is important in the clinical course of AD.
Subject(s)
Alzheimer Disease/genetics , Cognition Disorders/genetics , Interleukin-1/genetics , Adult , Aged , Aged, 80 and over , Alleles , Alzheimer Disease/immunology , Cognition Disorders/immunology , Disease Progression , Female , Genotype , Humans , Male , Polymorphism, GeneticABSTRACT
The authors recorded event-related brain potentials (ERPs) to picture primes and word targets (picture-name verification task) in patients with Alzheimer's disease (AD) and in elderly and young participants. N400 was more negative to words that did not match pictures than to words that did match pictures in all groups: In the young, this effect was significant at all scalp sites; in the elderly, it was only at central-parietal sites; and in AD patients, it was limited to right central-parietal sites. Among AD patients pretested with a confrontation-naming task to identify pictures they could not name, neither the N400 priming effect nor its scalp distribution was affected by ability to name pictures correctly. This ERP evidence of spared knowledge of these items was complemented by 80% performance accuracy. Thus, although the name of an item may be inaccessible in confrontation naming, N400 shows that knowledge is intact enough to prime cortical responses.
Subject(s)
Alzheimer Disease/diagnosis , Alzheimer Disease/physiopathology , Brain/physiopathology , Cognition Disorders/diagnosis , Evoked Potentials/physiology , Adult , Aged , Aged, 80 and over , Cognition Disorders/epidemiology , Electroencephalography , Electrooculography , Female , Humans , Male , Severity of Illness Index , Time FactorsABSTRACT
This study examined the relationships between regional cortical and hippocampal brain volumes and components of remote memory (recall, recognition, sequencing, and photo naming of presidential candidates) in 13 individuals with Alzheimer's disease (AD). Recognition and sequencing of remote memory for public figures were associated with regional cortical volumes. Specifically, lower recognition and sequencing scores were associated with smaller parietal-occipital cortical volumes; poorer sequencing was also associated with smaller prefrontal cortical volumes. By contrast, poorer anterograde but not remote memory scores were correlated with smaller hippocampal volumes. Within the constraints of the brain regions measured, these findings highlight the importance of the posterior cortical areas for selective remote memory processes and provide support for the dissociation between cortically mediated remote memory and hippocampally mediated anterograde memory.
Subject(s)
Alzheimer Disease/pathology , Alzheimer Disease/psychology , Cerebral Cortex/pathology , Limbic System/pathology , Memory/physiology , Aged , Aged, 80 and over , Female , Humans , Male , Middle AgedABSTRACT
In a 24-patient case series from retrospective chart review, the authors examined the use of gabapentin for the treatment of aggressive and agitated behaviors in nursing home patients with a DSM-IV diagnosis of dementia. On Clinical Global Rating Scale scores, 17 of 22 patients were much or greatly improved; 4 were minimally improved; and only 1 remained unchanged. Two of the 24 patients discontinued use of the medication because of excessive sedation. No other significant side effects were noted in treatment lasting up to 2 years.
Subject(s)
Acetates/therapeutic use , Amines , Antimanic Agents/therapeutic use , Cyclohexanecarboxylic Acids , Dementia/complications , Dementia/drug therapy , Social Behavior Disorders/etiology , gamma-Aminobutyric Acid , Acetates/administration & dosage , Aged , Aged, 80 and over , Aggression/drug effects , Antimanic Agents/administration & dosage , California , Dementia/psychology , Dose-Response Relationship, Drug , Gabapentin , Humans , Inpatients/statistics & numerical data , Male , Medical Records , Middle Aged , Nursing Homes , Retrospective Studies , Treatment OutcomeABSTRACT
Content and contextual memory for remote public figures and events was assessed with a modified version of the Presidents Test in patients with Alzheimer's disease (AD) or Parkinson's disease (PD). Contributions of executive functioning, semantic memory, and explicit anterograde memory to remote memory abilities were also examined. The AD group had temporally extensive deficits in content and contextual remote memory not accountable for by dementia severity. The PD group did not differ from the control group in remote memory, despite anterograde memory impairment. These results support the position that different component processes characterize remote memory, various mnemonic and nonmnemonic cognitive processes contribute to remote memory performance, and anterograde and remote memory processes are dissociable and differentially disrupted by neurodegenerative disease.
Subject(s)
Alzheimer Disease/psychology , Cognition , Memory , Parkinson Disease/psychology , Aged , Analysis of Variance , Case-Control Studies , Female , Humans , Male , Memory Disorders , Middle Aged , Neuropsychological Tests , Semantics , Severity of Illness IndexABSTRACT
OBJECTIVE: Comparative study of CSF levels of tau and AD7C-neuronal thread protein (NTP) in patients with AD and control subjects. BACKGROUND: AD is characterized by neurofibrillary tangles composed of the abnormally hyperphosphorylated microtubule-associated protein tau. AD7C-NTP is a proposed AD marker expressed at early stages of neurofibrillary degeneration. METHODS: Enzyme-linked immunosorbent assays specific for tau and AD7C-NTP. CSF samples were obtained from 35 demented patients (25 with antemortem clinical diagnosis of probable AD, 5 with neuropathologic diagnosis of definite AD, 5 with Lewy body pathology), 29 nondemented patients with PD, and 16 elderly healthy control subjects. Receiver operating characteristics (ROC) and multivariate discriminant analysis for AD versus controls. Correlational analysis of CSF tau and AD7C-NTP and of each marker with Mini-Mental State Examination (MMSE) scores was performed. RESULTS: Levels of both tau and AD7C-NTP were significantly elevated in the AD patients compared with control subjects. ROC analysis showed that CSF tau distinguished between patients with AD and nondemented control subjects with 63% sensitivity and 89% specificity, AD7C-NTP with 70% sensitivity and 87% specificity. Combined evaluation of both markers with discriminant analysis raised the specificity to 93% at a 63% sensitivity level. Both markers positively correlated with each other within the AD group, but not among control subjects. CSF levels of AD7C-NTP, but not of tau, showed a small but significant inverse correlation (r = -0.43) with MMSE scores of AD patients. CONCLUSIONS: CSF levels of tau and AD7C-NTP may be useful biomarkers for AD.
Subject(s)
Alzheimer Disease/cerebrospinal fluid , Alzheimer Disease/diagnosis , Nerve Tissue Proteins/cerebrospinal fluid , tau Proteins/cerebrospinal fluid , Aged , Biomarkers/cerebrospinal fluid , Discriminant Analysis , Enzyme-Linked Immunosorbent Assay , Female , Humans , Male , Middle Aged , Multivariate Analysis , Neuropsychological Tests , Parkinson Disease/cerebrospinal fluid , Predictive Value of Tests , ROC Curve , Sensitivity and SpecificityABSTRACT
This study examined the relationships between regional brain volumes and semantic, phonological, and nonverbal fluency in 32 participants with Alzheimer's disease (AD). Object but not animal semantic fluency correlated with frontal and temporal gray matter volumes. Phonological fluency was not significantly associated with any brain volume examined. Nonverbal fluency was selectively associated with bilateral frontal gray matter volumes. Hippocampal volumes, although markedly reduced in these patients, were not related to any of the fluency measures. Results lend evidence to the importance of the frontal lobes in the directed generation of nonverbal and verbal exemplars by AD patients. Furthermore, both left- and right-hemisphere regions contribute to the generation of verbal and nonverbal exemplars.
Subject(s)
Alzheimer Disease/pathology , Brain/pathology , Nonverbal Communication/physiology , Verbal Behavior/physiology , Adult , Aged , Aged, 80 and over , Frontal Lobe/pathology , Functional Laterality , Hippocampus/pathology , Humans , Magnetic Resonance Imaging , Middle Aged , Phonetics , Semantics , Speech/physiologyABSTRACT
BACKGROUND: alpha2 Macroglobulin is a panproteinase inhibitor that is found immunohistochemically in neuritic plaques, a requisite neuropathologic feature of AD. Recently, a pentanucleotide deletion near the 5' end of the "bait region" of the alpha2 macroglobulin (A2M) gene was reported to be associated with AD in a large cohort of sibpairs, in which the mutation conferred a similar odds ratio with AD as the APOE-epsilon4 allele for carriers of at least one copy of the A2M gene (Mantel-Haenszel odds ratio, 3.56). METHODS: We studied three independent association samples of AD patients (n = 309) with an age range of 50 to 94 years and representative controls (n = 281) to characterize the allele frequency of the pentanucleotide deletion in this cohort. We detected the mutation near the 5' splice site of exon 18 using standard PCR and restriction fragment length polymorphism methods. The results were adjusted for age, gender, education, and APOE polymorphism. RESULTS: We found that the A2M gene polymorphism conferred an increased risk for AD, with an estimated Mantel-Haenszel ratio of 1.5 (95% CI 1.1 to 2.2; p = 0.025). There was no age- or gender-dependent increase in A2M gene allele frequencies in AD patients compared with controls. The combined sample showed the expected association between AD and APOE-epsilon 4. In one of our three samples there was an interaction between the A2M and APOE-epsilon4 genes, but the other two samples showed no interaction between the two risk factors. CONCLUSIONS: Our data support an association between the A2M gene and AD. This association is less pronounced, however, in our cohort than in the previously reported sample of sibpairs.
Subject(s)
Alzheimer Disease/epidemiology , Alzheimer Disease/genetics , alpha-Macroglobulins/genetics , Aged , Aged, 80 and over , Apolipoproteins E/genetics , Exons , Female , Gene Deletion , Genetic Predisposition to Disease , Genotype , Humans , Male , Middle Aged , Odds Ratio , Polymorphism, Genetic , Risk FactorsABSTRACT
The Clock Drawing Test (CDT) is widely used in the assessment of dementia and is known to be sensitive to the detection of deficits in neurodegenerative disorders such as Alzheimer's disease (AD). CDT performance is dependent not only on visuospatial and constructional abilities, but also on conceptual and executive functioning; therefore, it is likely to be mediated by multiple brain regions. The purpose of the present study was to identify component cognitive processes and regional cortical volumes that contribute to CDT performance in AD. In 29 patients with probable AD, CDT performance was significantly related to right-, but not left-hemisphere, regional gray matter volume. Specifically, CDT score correlated significantly with the right anterior and posterior superior temporal lobe volumes. CDT scores showed significant relationships with tests of semantic knowledge, executive function, and visuoconstruction, and receptive language. These results suggest that in AD patients, CDT performance is attributable to impairment in multiple cognitive domains but is related specifically to regional volume loss of right temporal cortex.
Subject(s)
Alzheimer Disease , Brain/abnormalities , Cognition Disorders/diagnosis , Neuropsychological Tests , Psychomotor Disorders/diagnosis , Adult , Aged , Aged, 80 and over , Cognition Disorders/complications , Female , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Psychomotor Disorders/complications , Severity of Illness IndexABSTRACT
Patients with Alzheimer's disease (AD) and healthy control participants performed 2 conceptual repetition priming tasks, word-associate production and category-exemplar production. Both tasks had identical study-phases of reading target words aloud, had the most common responses as target items, and required production of a single response. Patients with AD showed normal priming on word-associate production but impaired priming on category-exemplar production. This dissociation in AD suggests that conceptual priming is not a unitary form of memory but rather is mediated by separable memory systems.
Subject(s)
Alzheimer Disease/psychology , Association Learning , Cognition , Memory , Aged , Analysis of Variance , Case-Control Studies , Cues , Female , Humans , Male , Mental Recall , Word Association TestsABSTRACT
The pattern of deterioration in patients with Alzheimer's disease is highly variable within a given population. With recent speculation that the apolipoprotein E allele may influence rate of decline and claims that certain drugs may slow the course of the disease, there is a compelling need for sound statistical methodology to address these questions. Current statistical methods for describing decline do not adequately take into account between-patient variability and possible floor and/or ceiling effects in the scale measuring decline, and they fail to allow for uncertainty in disease onset. In this paper, the authors analyze longitudinal Mini-Mental State Examination scores from two groups of Alzheimer's disease subjects from Palo Alto, California, and Minneapolis, Minnesota, in 1981-1993 and 1986-1988, respectively. A Bayesian hierarchical model is introduced as an elegant means of simultaneously overcoming all of the difficulties referred to above.
Subject(s)
Alzheimer Disease/epidemiology , Models, Statistical , Bayes Theorem , California/epidemiology , Disease Progression , Humans , Longitudinal Studies , Minnesota/epidemiology , Patient SelectionABSTRACT
Four experiments examined a distinction between kinds of repetition priming which involve either the identification of the form or meaning of a stimulus or the production of a response on the basis of a cue. Patients with Alzheimer's disease had intact priming on picture-naming and category-exemplar identification tasks and impaired priming on word-stem completion and category-exemplar production tasks. Division of study-phase attention in healthy participants reduced priming on word-stem completion and category-exemplar production tasks but not on picture-naming and category-exemplar identification tasks. The parallel dissociations in normal and abnormal memory cannot be explained by implicit-explicit or perceptual-conceptual distinctions but are explained by an identification-production distinction. There may be separable cognitive and neural bases for implicit modulation of identification and production forms of knowledge.
Subject(s)
Alzheimer Disease/psychology , Attention , Cues , Memory , Adult , Aged , Aged, 80 and over , Case-Control Studies , Female , Humans , Male , Mental Recall , Middle Aged , Pattern Recognition, Visual , Word Association TestsABSTRACT
'Stages', as used in clinical practice and research, are defined, their value described, and criteria are proposed for their evaluation. The specific interest is in staging Alzheimer's disease (AD). Two staging systems, one based on the Global Deterioration Scale (GDS) and one based on the Mini-Mental State Exam (MMSE), are compared in terms of these criteria, as an illustration of the process involved. We propose that there is not one unique staging system, that different staging criteria might be appropriate to different research or clinical needs, depending on which part of the temporal course of the disease is of primary interest, and on whether the focus is on cognitive, functional, neurological, behavioral, economic, or other issues. GDS staging seems a better choice for the later stages of AD when the focus is on functional change. MMSE staging seems a better choice for tracking the earlier stages of AD when the focus is on cognitive change.
Subject(s)
Alzheimer Disease/diagnosis , Cognition Disorders/diagnosis , Aged , Alzheimer Disease/pathology , Female , Follow-Up Studies , Health Status , Humans , Male , Neuropsychological Tests , Surveys and QuestionnairesABSTRACT
Picture-naming priming was examined across different study-test transformations to explore the nature of memory representations of objects supporting implicit memory processes in patients with Alzheimer's disease (AD). Although severely impaired in explicit memory for pictures and words, AD patients demonstrated normal priming across perceptual transformations in picture orientation (Experiment 1) and picture size (Experiment 2) and across symbolic transformations from words to pictures (Experiment 3). In addition, the priming across alterations in picture size was invariant. This demonstrates that AD patients have preserved implicit memory for high-level, abstract representations of objects.
Subject(s)
Alzheimer Disease/physiopathology , Memory Disorders/physiopathology , Pattern Recognition, Visual/physiology , Transfer, Psychology/physiology , Verbal Behavior/physiology , Aged , Aged, 80 and over , Alzheimer Disease/complications , Analysis of Variance , Anomia/physiopathology , Concept Formation/physiology , Cues , Female , Humans , Male , Memory Disorders/etiology , Middle Aged , Orientation/physiology , Reaction Time , Reading , Size Perception/physiology , VocabularyABSTRACT
Neuroimaging and lesion studies have demonstrated that hippocampal volume correlates with memory performance, but material-specific lateralization of this structure-function relationship has been inconsistent. This MRI study examined the relative contributions of left and right temporal lobe volumes to verbal and nonverbal recognition memory in a group of 20 Alzheimer's disease (AD) patients. There was a significant relationship between extent of right hippocampal and right temporal gray matter tissue volume deficit and performance on the face recognition subtest of the Warrington Recognition Memory Test. The face recognition test correlated with right hemisphere volume but not to left, indicating a material-specific relationship between brain structure and function in this patient group. Right temporal horn volume did not account for a significant proportion of variance in face recognition memory. Although word recognition was not significantly correlated with either left or right hippocampal volume in the total group, there was a strong correlation between left hippocampal volume and word recognition memory in the female AD patients. Thus, face recognition shows a material specific relationship with select lateralized hippocampal and temporal cortical volumes in AD patients, regardless of gender, whereas the verbal recognition-left-hippocampal volume relationship may be mediated by gender.
Subject(s)
Alzheimer Disease/pathology , Alzheimer Disease/psychology , Memory/physiology , Adult , Aged , Female , Humans , Magnetic Resonance Imaging , Male , Middle AgedABSTRACT
OBJECTIVE: To examine whether each of the 5 Mattis Dementia Rating Scale (DRS) scores related to magnetic resonance imaging-derived volumes of specific cortical or limbic brain regions in patients with Alzheimer disease (AD). DESIGN: Relations between DRS measures and regional brain volume measures were tested with bivariate and multivariate regression analyses. SETTING: The Aging Clinical Research Center of the Stanford (Calif) University Department of Psychiatry and Behavioral Science and the Geriatric Psychiatry Rehabilitation Unit of the Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif. PATIENTS AND OTHER PARTICIPANTS: Fifty patients with possible or probable AD. Magnetic resonance imaging data from 136 healthy control participants, age 20 to 84 years, were used to correct brain volumes for normal variation arising from intracranial volume and age. MAIN OUTCOME MEASURES: The DRS scores and volumes of regional cortical gray matter and of the hippocampus. RESULTS: Memory scores of the patients with AD were selectively related to hippocampal volumes. Attention and construction scores were related to several anterior brain volume measures, with attention showing a significantly greater association to right than left hemisphere measures. Initiation/perseveration scores were not significantly correlated with any measure of regional gray matter volume, but performance was related to prefrontal sulcal widening, with a greater association with the left than right sulcal volume. CONCLUSIONS: Certain DRS subtests are predictably correlated with selective regional brain volumes in AD. The specific relation between memory and hippocampal volumes and the nonsignificant relations between memory and regional cortical volumes suggest a dissociation between cortical and hippocampal contributions to explicit memory performance.
Subject(s)
Alzheimer Disease/pathology , Alzheimer Disease/psychology , Cerebral Cortex/pathology , Cognition , Hippocampus/pathology , Magnetic Resonance Imaging , Mental Status Schedule , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Regression AnalysisABSTRACT
The alpha 1-antichymotrypsin (ACT) A allele was recently associated with Alzheimer's disease (AD), and the ACT AA genotype was reported to be more frequent in AD subjects with the apolipoprotein E (APOE) epsilon4 allele. We examined ACT and APOE genotypes in a sample of 160 subjects with probable AD and in 102 elderly control subjects. ACT A allele frequencies were similar in AD subjects (0.503) and elderly controls (0.519). In addition, we found no evidence that in AD the AA genotype is more frequent in subjects with the APOE epsilon4 allele than in those without it. Our results do not support an association between the ACT A allele and AD.
Subject(s)
Alleles , Alzheimer Disease/genetics , alpha 1-Antichymotrypsin/genetics , Adult , Aged , Apolipoprotein E4 , Apolipoproteins E/genetics , Female , Gene Frequency , Genotype , Heterozygote , Humans , Male , Middle Aged , Reference ValuesABSTRACT
OBJECTIVE: The relationship between number of apolipoprotein E epsilon 4 (APOE epsilon 4) alleles and the rate of cognitive decline in patients with Alzheimer's disease was examined. METHOD: Rate of decline in score on the Mini-Mental State was measured during the active phase of the decline curve between Mini-Mental State scores of 23 and 0. To characterize onset, the authors also estimated for each subject the age at which the Mini-Mental State score fell below 23 and obtained a retrospective report of age at onset from the caregiver. The number of APOE epsilon 4 alleles carried by each subject was determined from genomic DNA samples. The study included 86 subjects with probable Alzheimer's disease who had had at least two cognitive evaluations (a mean of 5.6 evaluations per subject over an average period of 3.6 years). RESULTS: The results did not support an association between APOE epsilon 4 dosage and rate of cognitive decline. Age at onset and age at which the Mini-Mental State score fell below 23 were also not related to APOE epsilon 4 dosage. The APOE allele frequencies were similar to those in other studies of subjects with Alzheimer's disease, showing an enrichment of the epsilon 4 allele. CONCLUSIONS: Although the APOE epsilon 4 allele is a risk factor for Alzheimer's disease, there is no support of a strong association between APOE epsilon 4 dosage and rate of cognitive decline. The epsilon 4 allele did not predict age at onset. Methodological inconsistencies may account for discrepancies between these results and previous findings.
Subject(s)
Alzheimer Disease/diagnosis , Alzheimer Disease/genetics , Apolipoproteins E/genetics , Cognition Disorders/diagnosis , Age of Onset , Aged , Alleles , Alzheimer Disease/psychology , Apolipoprotein E4 , Cognition Disorders/genetics , Cognition Disorders/psychology , Disease Progression , Female , Gene Dosage , Humans , Male , Middle Aged , Psychiatric Status Rating Scales/statistics & numerical data , Risk FactorsABSTRACT
Automatic and effortful processes were investigated using event-related brain potentials (ERPs) recorded from moderately impaired subjects with probable Alzheimer's Disease (AD), normal elderly, and normal young controls. The effects of effortful attention on ERPs to loud noises and the effects of stimulus intrusiveness on effortfully elicited ERPs were studied. First, ERPs to task relevant and irrelevant startling noises were compared. Second, ERPs to startling noises and moderate tones were compared when both were targets. The effects of age (young vs. elderly controls) and effects of dementing disease (AD subjects vs. elderly controls) were also assessed. Effortful attention augmented noise-elicited P300 amplitude in elderly subjects, but not in young. Intrusiveness augmented task-relevant P300 amplitude in young subjects, but not in elderly. Neither variable affected P300 amplitude in AD subjects. Thus, effects of age and disease depended on how P300 was elicited: when effortfully elicited, P300 amplitude was affected by disease but not age; when automatically elicited, P300 amplitude was affected by age but not disease. N1 effects differed from P300 effects.