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Biology, Immunohistochemistry, Confocal Microscopy, Down Syndrome, Antibodies, and 15 moreHumans, Cerebral Cortex, Female, Animals, Frontal Cortex, Clinical Sciences, Aged, Fluorescent Antibody Technique, Cognitive impairment, Adult, ACTA, Biological markers, Alzheimer Disease, General Population, and Age of Onset
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Page 1. Aging Neuropsychology and Cognition 1382-5585/00/0701-305$16.00 2001, Vol. 8, No. 2, pp. 120±136 © Swets & Zeitlinger Dependence on Visual Feedback During Motor Skill Learning in... more
Page 1. Aging Neuropsychology and Cognition 1382-5585/00/0701-305$16.00 2001, Vol. 8, No. 2, pp. 120±136 © Swets & Zeitlinger Dependence on Visual Feedback During Motor Skill Learning in Alzheimer's Disease Malcolm ...
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Psychology, Neuropsychology, Dementia, Language, Cultural Diversity, and 15 moreMedicine, Learning, Memory, Humans, Female, Male, Ethnic Groups, Aged, Middle Aged, Ethnic Group, Memory Disorders, Memory Testing, Neuropsychological Tests, Psychology and Cognitive Sciences, and Medical and Health Sciences
Background: Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of... more
Background: Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease.Methods: We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants, adjusting for sex, age, vendor (for clinical labs), and the first four ...
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IntroductionLate-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly1, and risk is partially driven by genetics2. Many of the loci responsible for this genetic risk were identified by... more
IntroductionLate-onset Alzheimer’s disease (LOAD, onset age > 60 years) is the most prevalent dementia in the elderly1, and risk is partially driven by genetics2. Many of the loci responsible for this genetic risk were identified by genome-wide association studies (GWAS)3–8. To identify additional LOAD risk loci, the we performed the largest GWAS to date (89,769 individuals), analyzing both common and rare variants. We confirm 20 previous LOAD risk loci and identify four new genome-wide loci (IQCK, ACE, ADAM10, and ADAMTS1). Pathway analysis of these data implicates the immune system and lipid metabolism, and for the first time tau binding proteins and APP metabolism. These findings show that genetic variants affecting APP and Aβ processing are not only associated with early-onset autosomal dominant AD but also with LOAD. Analysis of AD risk genes and pathways show enrichment for rare variants (P = 1.32 × 10−7) indicating that additional rare variants remain to be identified.
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Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of... more
Mutations in known causal Alzheimer disease (AD) genes account for only 1% to 3% of patients and almost all are dominantly inherited. Recessive inheritance of complex phenotypes can be linked to long (>1-megabase [Mb]) runs of homozygosity (ROHs) detectable by single-nucleotide polymorphism (SNP) arrays. To evaluate the association between ROHs and AD in an African American population known to have a risk for AD up to 3 times higher than white individuals. Case-control study of a large African American data set previously genotyped on different genome-wide SNP arrays conducted from December 2013 to January 2015. Global and locus-based ROH measurements were analyzed using raw or imputed genotype data. We studied the raw genotypes from 2 case-control subsets grouped based on SNP array:…
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Psychology, Positron Emission Tomography, Medicine, Linear models, Fitness, and 15 moreHumans, Glucose, Glucose Metabolism, Cerebral Cortex, Female, Male, Apolipoprotein E, Clinical Sciences, Physical Fitness, Aged, Middle Aged, Oxygen Consumption, Neurosciences, Psychiatric Status Rating Scales, and Neuropsychological Tests
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Genetics, Molecular Biology, Biology, Risk, Progressive Supranuclear Palsy, and 14 moreMedicine, Biological Sciences, Humans, Haplotypes, Human Molecular Genetics, Aged, Middle Aged, Genotype, Frontotemporal Dementia, Genetic variation, Alzheimer Disease, Tau protein, Tau proteins, and Medical and Health Sciences
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The UC Irvine Institute for Memory Impairments and Neurological Disorders, UCI MIND, is nationally recognized for its expertise in the area of Alzheimer’s disease and related neurological disorders. Director, Frank LaFerla, Ph.D. will... more
The UC Irvine Institute for Memory Impairments and Neurological Disorders, UCI MIND, is nationally recognized for its expertise in the area of Alzheimer’s disease and related neurological disorders. Director, Frank LaFerla, Ph.D. will speak about dementia and provide updates on areas such as diagnosis, treatment, and the current state of research. A major portion of the program reserved for YOUR questions and answers.
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Psychology and Dementia
Publisher Summary This chapter discusses motor and procedural memory in Alzheimer's disease (AD). The chapter outlines the importance of studying motor memory and also compares memory for motor skills and discrete movements. The... more
Publisher Summary This chapter discusses motor and procedural memory in Alzheimer's disease (AD). The chapter outlines the importance of studying motor memory and also compares memory for motor skills and discrete movements. The chapter suggests how knowledge about motor memory may be used in the management, care, and rehabilitation of AD patients, and identifies areas for further research. . Numerous studies examining memory for verbal, visual, and spatial information have shown that AD patients perform at a level far below that of normal older adults. The handful of studies performed to date clearly show that AD patients can learn motor- or movement-based information and some rather complex perceptual-motor skills such as the rotary pursuit. In addition, memory for motor information, which by its very nature requires the subject's active participation, may be relatively spared in this impaired population. AD patients may be able to use the relatively preserved procedural memory system which governs motor learning to partially compensate for losses in other cognitive abilities
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Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. To... more
Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results ...
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Chemistry, Biology, Immunohistochemistry, Confocal Microscopy, Medicine, and 15 moreNeurodegenerative Diseases, Alpha Synuclein, Caspases, Humans, Female, Male, Clinical Sciences, Inclusion Bodies, Aged, Middle Aged, ACTA, Frontotemporal Dementia, Neurodegenerative Disease, Brc, and Dementia With Lewy Bodies
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We present a Two-Stage Machine Learning (ML) model as a data mining method to develop practice guidelines and apply it to the problem of dementia staging. Dementia staging in clinical settings is at present complex and highly subjective... more
We present a Two-Stage Machine Learning (ML) model as a data mining method to develop practice guidelines and apply it to the problem of dementia staging. Dementia staging in clinical settings is at present complex and highly subjective because of the ambiguities and the complicated nature of existing guidelines. Our model abstracts the two-stage process used by physicians to arrive at the global Clinical Dementia Rating Scale (CDRS) score. The model incorporates learning intermediate concepts (CDRS category scores) in the first stage that then become the feature space for the second stage (global CDRS score). The sample consisted of 678 patients evaluated in the Alzheimer's Disease Research Center at the University of California, Irvine. The demographic variables, functional and cognitive test results used by physicians for the task of dementia severity staging were used as input to the machine learning algorithms. Decision tree learners and rule inducers (C4.5, Cart, C4.5 rul...
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Engineering, Psychology, Computer Science, Algorithms, Artificial Intelligence, and 13 moreMachine Learning, Data Mining, Medicine, Problem Solving, Humans, Computer Simulation, Artificial Intelligence in Medicine, Decision Tree, University of Southern California, Alzheimer Disease, Logistic Models, Classification Accuracy, and Feature Space
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This work focused on re ning the Cognitive Abilities Screening Instrument (CASI) by selecting a clinically signi cant subset of tests, and generating simple and useful models for dementia screening in a cross cultural populace. This is a... more
This work focused on re ning the Cognitive Abilities Screening Instrument (CASI) by selecting a clinically signi cant subset of tests, and generating simple and useful models for dementia screening in a cross cultural populace. This is a retrospective study of 57 mild-to-moderately demented patients of African-American, Caucasian, Chinese, Hispanic, and Vietnamese origin and an equal number of age matched controls from a cross cultural pool. We used a Knowledge Discovery from Databases (KDD) approach. Decision tree learners (C4.5, CART), rule inducers (C4.5Rules, FOCL) and a reference classi er (Naive Bayes) were the machine learning algorithms used for model building. This study identi ed a clinically useful subset of CASI, consisting of only twenty Mini Mental State Examination (MMSE) attributes|CASI-MMSE-M, saving test time and cost, while maintaining or improving dementia screening accuracy. Also, the machine learning algorithms (in particular C4.5 and CART) gave stable clinical...
We are applying Knowledge Discovery and Data Mining (KDD) methods in conjunction with Electronic Medical Records (EMRs) of normally aging and demented subjects to automate the screening and differential diagnosis of Alzheimer's... more
We are applying Knowledge Discovery and Data Mining (KDD) methods in conjunction with Electronic Medical Records (EMRs) of normally aging and demented subjects to automate the screening and differential diagnosis of Alzheimer's Disease (AD), Vascular Dementia (VD) and other causes. Having successfully developed dementia screening tools with KDD methods, this report describes the extension of these techniques to the harder task of differential diagnosis. We show that the domain of neuropsychologic test performance helps diagnose AD, but not VD, and that additional domains are needed for accurate diagnosis. An additional benefit of KDD methods applied to EMRs includes detecting subtle data entry errors.
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Objectives: Individuals aged 90 or older (oldest-old), the fastest growing segment of the population, are at increased risk of developing cognitive impairment compared with younger old. Neuropsychological evaluation of the oldest-old is... more
Objectives: Individuals aged 90 or older (oldest-old), the fastest growing segment of the population, are at increased risk of developing cognitive impairment compared with younger old. Neuropsychological evaluation of the oldest-old is important yet challenging in part because of the scarcity of test norms for this group. We provide neuropsychological test norms for cognitively intact oldest-old. Methods: Test norms were derived from 403 cognitively intact participants of The 90+ Study, an ongoing study of aging and dementia in the oldest-old. Cognitive status of intact oldest-old was determined at baseline using cross-sectional approach. Individuals with cognitive impairment no dementia or dementia (according to DSM-IV criteria) were excluded. Participants ranged in age from 90 to 102 years (mean=94). The neuropsychological battery included 11 tests (Mini-Mental Status Examination, Modified Mini-Mental State Examination, Boston Naming Test – Short Form, Letter Fluency Test, Animal...
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Two groups of EMR children were given a series of free recall tasks. One group was trained to use a strategy designed to induce deeper level semantic encoding and a “no training” control group received standard free recall instructions.... more
Two groups of EMR children were given a series of free recall tasks. One group was trained to use a strategy designed to induce deeper level semantic encoding and a “no training” control group received standard free recall instructions. Subjects received either related or unrelated lists during training and related or unrelated lists during two posttests (immediately following and one week after training). Semantic strategy usage was retained at posttesting and also generalized to word lists unlike those used during training.
We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated... more
We identified rare coding variants associated with Alzheimer's disease in a three-stage case-control study of 85,133 subjects. In stage 1, we genotyped 34,174 samples using a whole-exome microarray. In stage 2, we tested associated variants (P…
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Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. We conducted a transethnic genome-wide association study... more
Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P < 5 × 10(-8)) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the APOE ɛ4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10(-6)) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10(-6)). Our findings highlight...
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Previous research has revealed similarities in the neuropathology, clinical presentation, and risk factors between persons with Alzheimer disease from the general population (GP-AD) and those with Down syndrome (DS-AD). Less is known,... more
Previous research has revealed similarities in the neuropathology, clinical presentation, and risk factors between persons with Alzheimer disease from the general population (GP-AD) and those with Down syndrome (DS-AD). Less is known, however, about the extent of similarities and differences in the cognitive profiles of these 2 populations. Fifty-one moderate to severely demented GP-AD and 59 DS-AD individuals participated in this study which compared the cognitive profiles of these 2 populations on the Severe Impairment Battery (SIB), controlling for sex as well as level of functional ability using a modified version of the Bristol Activities of Daily Living Scale. Overall, the neuropsychological profiles of the higher-functioning individuals within the DS-AD and advanced GP-AD groups, as represented by mean difference scores on the SIB as a whole and across the 9 separate cognitive domains, were very similar to one another after adjusting for sex and functional impairment. To our ...
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Two experiments examined the coding and retention of psychomotor information in patients with mild to moderate dementia of the Alzheimer-type (DAT), healthy elderly controls, and young adults. Experiment 1 compared recall accuracy for... more
Two experiments examined the coding and retention of psychomotor information in patients with mild to moderate dementia of the Alzheimer-type (DAT), healthy elderly controls, and young adults. Experiment 1 compared recall accuracy for preselected (subject-defined) and constrained (experimenter-defined) movements under three different retention conditions. Not surprisingly, the DAT patients showed significantly larger reproduction errors than did the controls. In all three groups, however, preselected movements were recalled more accurately than constrained movements. This preselection advantage was replicated in Experiment 2 using a new group of DAT patients with recall being performed under both same- and switch-limb conditions. While the results suggested that DAT patients suffer from both an encoding deficiency and a rapid loss of information from short-term memory, they also indicate that patients are capable of coding meaningful aspects of motor movements. Most importantly, the...
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Gerontology, Memory, Humans, Female, Male, and 4 moreAged, Adult, Alzheimer Disease, and Psychomotor Performance
Contrast sensitivity has been shown to be affected in Alzheimer's disease (Ad). We investigated low contrast acuity and contrast sensitivity using clinical test charts in this patient population. Additionally, we tested patients with... more
Contrast sensitivity has been shown to be affected in Alzheimer's disease (Ad). We investigated low contrast acuity and contrast sensitivity using clinical test charts in this patient population. Additionally, we tested patients with vascular dementia (vd) and mixed dementia (md), (Alzheimer' with vascular dementia). Contrast sensitivity was assessed using the Vistech VCTS 6500 test chart. Low contrast acuity was measured using the Regan charts at four contrast levels (96%, 50%, 25% and 11%). The patient population consisted of 19 Ad patients, 9 vd patients and 10 md patients. Reduction in acuity was found with contrast level in all cases. Regression lines were fit to the data and statistical analysis was performed. We did not find a statistically significant difference between the Ad and vd or md groups. We did, however, find a difference between the vd and md groups. We did find reduction in contrast sensitivity at all spatial frequencies when compared to the elderly norma...
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Memory for unfamiliar faces has received little attention in the effort to identify neuropsychological measures that could differentiate mild cognitive impairment (MCI) from normal aging and/or predict conversion from MCI to dementia. We... more
Memory for unfamiliar faces has received little attention in the effort to identify neuropsychological measures that could differentiate mild cognitive impairment (MCI) from normal aging and/or predict conversion from MCI to dementia. We used the Wechsler Memory Scale-III Faces test to investigate facial memory in normal aging (n = 58), MCI (n = 74), and mild Alzheimer's disease (n = 22). After adjustment for age, gender, and years of education, MCI patients demonstrated significantly poorer memory for unfamiliar faces than their healthy peers. Lower scores were also associated with worsening cognition and functional abilities but not an increased risk of dementia.
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The current study investigated the utility of the Dementia Severity Rating Scale (DSRS) total score to identify individuals at the earliest stage of impairment (ie, mild cognitive impairment/MCI). In addition, the authors sought to... more
The current study investigated the utility of the Dementia Severity Rating Scale (DSRS) total score to identify individuals at the earliest stage of impairment (ie, mild cognitive impairment/MCI). In addition, the authors sought to investigate how well the measure correlates with an expanded battery of cognitive tests and other measures of functional abilities. Of the 320 participants included in this study, 85 were normal controls, 96 had single-domain or multiple-domain amnestic MCI, and 139 had possible or probable Alzheimer disease (AD). Each participant underwent a thorough cognitive, neurological, and physical examination. Results from this study indicated that the DSRS total scores differed significantly between the 3 groups (P<0.001) and accurately identified 81% of the control group, 60% of the MCI group, and 78% of the AD group in a post hoc discriminant analysis. When combined with a brief cognitive measure (ie, Consortium to Establish a Registry for Alzheimer's Di...
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43 VERBAL AND MOTOR MEMORY IN ALZHEIMER&#x27;S DISEASE: RELEASE FROM PROACTIVE INHIBITION Joseph Harris, 1 Malcolm Dick, 2 Veronica Sandoval, 3 Daniel Gallegos, Sean Lozano, 3 Sergio Rangel, 3 and Mary-Louise Kean1... more
43 VERBAL AND MOTOR MEMORY IN ALZHEIMER&#x27;S DISEASE: RELEASE FROM PROACTIVE INHIBITION Joseph Harris, 1 Malcolm Dick, 2 Veronica Sandoval, 3 Daniel Gallegos, Sean Lozano, 3 Sergio Rangel, 3 and Mary-Louise Kean1 &#x27;Psychology Program, Institute of ...
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Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset... more
Recently, a rare variant in the amyloid precursor protein gene (APP) was described in a population from Iceland. This variant, in which alanine is replaced by threonine at position 673 (A673T), appears to protect against late-onset Alzheimer disease (AD). We evaluated the frequency of this variant in AD cases and cognitively normal controls to determine whether this variant will significantly contribute to risk assessment in individuals in the United States. To determine the frequency of the APP A673T variant in a large group of elderly cognitively normal controls and AD cases from the United States and in 2 case-control cohorts from Sweden. Case-control association analysis of variant APP A673T in US and Swedish white individuals comparing AD cases with cognitively intact elderly controls. Participants were ascertained at multiple university-associated medical centers and clinics across the United States and Sweden by study-specific sampling methods. They were from case-control stu...
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Recent reports that complement proteins comprising the classical pathway are associated with senile plaques suggest that activation of the classical complement cascade in Alzheimer&amp;amp;#39;s disease tissue results in bystander... more
Recent reports that complement proteins comprising the classical pathway are associated with senile plaques suggest that activation of the classical complement cascade in Alzheimer&amp;amp;#39;s disease tissue results in bystander cell lysis and may contribute to AD neuropathology. Analysis of cerebrospinal fluid may prove to be a useful means of detecting changes in immunological activity in the brain. We use an enzyme-linked immunosorbent assay to measure levels of C1q, a subunit of the classical complement cascade, in the CSF of patients clinically diagnosed with possible or probable AD. Significantly lower levels of C1q were detected in the CSF of the Alzheimer group as compared to control CSF [AD: mu = 268 ng/ml, SD = 84; non-AD: mu = 340 ng/ml, SD = 76; F(1, 44) = 5.84, p = 0.02]. Diminished performance on global measures of mental status such as the Mini-Mental State Exam (R = 0.45; p = 0.0072) and Blessed&amp;amp;#39;s Information, Memory, and Concentration test (R = 0.42; p = 0.0138) showed high correlations with decreased C1q levels. More specific measures of cognitive function, such as word recall (R = 0.42; p = 0.012), word recognition (R = 0.52; p = 0.0017) and delayed recall (R = 0.45; p = 0.0062) memory tasks also correlated strongly with decreased C1q levels.
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Neurobiology, Cerebrospinal Fluid, Humans, Female, Male, and 13 moreRegression Analysis, Clinical Sciences, Aged, Middle Aged, Adult, Complement, Neurobiology of Aging, Alzheimer Disease, Neurosciences, Enzyme Linked Immunosorbent Assay, Cognition disorders, Neurologic Examination, and Neuropsychological Tests
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ABSTRACT
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Two groups of 11-to 12-year-old educable mentally retarded children, equated on the basis of a free recall pretest, were given a series of lists for free recall. Approximately half the subjects were trained in the use of a strategy... more
Two groups of 11-to 12-year-old educable mentally retarded children, equated on the basis of a free recall pretest, were given a series of lists for free recall. Approximately half the subjects were trained in the use of a strategy designed to induce deeper level semantic encoding ...
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The purpose of the present research was to examine the nature of the encoding problem in patients with dementia of the Alzheimer type (DAT) using a nonstrategic memory task, namely the recall of action events or subject-performed tasks... more
The purpose of the present research was to examine the nature of the encoding problem in patients with dementia of the Alzheimer type (DAT) using a nonstrategic memory task, namely the recall of action events or subject-performed tasks (SPTs). The first experiment investigated the retention of SPTs and the verbal descriptions of action events in patients with mild-to-moderate DAT, young, and old adults. While the healthy older adults showed significantly higher recall for SPTs than for verbal descriptions, the DAT patients failed to exhibit this effect. A follow-up study replicated this same pattern using SPTs and tasks performed by the experimenter. As the multimodal and contextually rich encoding environment present in SPTs had no effect on the patients&#39; retention, this suggests that manipulations designed to enhance encoding in this population will be unsuccessful. The relevance of the results to (1) memory compensation in the aged, and (2) the development of mnemonic training programs for the elderly are discussed.
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ABSTRACT