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John C Morris

Publications and source records attributed to John C Morris.

At least 19 recordsLinked to original sources
PubMed2012

Clinical and biomarker changes in dominantly inherited Alzheimer's disease.

BACKGROUND: The order and magnitude of pathologic processes in Alzheimer's disease are not well understood, partly because the disease develops over many years. Autosomal dominant Alzheimer's disease has a predictable age at onset and provides an opportunity to determine the sequence and magnitude of pathologic changes that culminate in symptomatic disease. METHODS: In this prospective, longitudinal study, we analyzed data from 128 participants who underwent baseline clinical and cognitive assessments, brain imaging, and cerebrospinal fluid (CSF) and blood tests. We used the participant's age at baseline assessment and the parent's age at the onset of symptoms of Alzheimer's disease to calculate the estimated years from expected symptom onset (age of the participant minus parent's age at symptom onset). We conducted cross-sectional analyses of baseline data in relation to estimated years from expected symptom onset in order to determine the relative order and magnitude of pathophysiological changes. RESULTS: Concentrations of amyloid-beta (Aβ)(42) in the CSF appeared to decline 25 years before expected symptom onset. Aβ deposition, as measured by positron-emission tomography with the use of Pittsburgh compound B, was detected 15 years before expected symptom onset. Increased concentrations of tau protein in the CSF and an increase in brain atrophy were detected 15 years before expected symptom onset. Cerebral hypometabolism and impaired episodic memory were observed 10 years before expected symptom onset. Global cognitive impairment, as measured by the Mini-Mental State Examination and the Clinical Dementia Rating scale, was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset. CONCLUSIONS: We found that autosomal dominant Alzheimer's disease was associated with a series of pathophysiological changes over decades in CSF biochemical markers of Alzheimer's disease, brain amyloid deposition, and brain metabolism as well as progressive cognitive impairment. Our results require confirmation with the use of longitudinal data and may not apply to patients with sporadic Alzheimer's disease. (Funded by the National Institute on Aging and others; DIAN ClinicalTrials.gov number, NCT00869817.).

Age of Onset↗
PubMed2011

Common variants at ABCA7, MS4A6A/MS4A4E, EPHA1, CD33 and CD2AP are associated with Alzheimer's disease.

We sought to identify new susceptibility loci for Alzheimer's disease through a staged association study (GERAD+) and by testing suggestive loci reported by the Alzheimer's Disease Genetic Consortium (ADGC) in a companion paper. We undertook a combined analysis of four genome-wide association datasets (stage 1) and identified ten newly associated variants with P ≤ 1 × 10(-5). We tested these variants for association in an independent sample (stage 2). Three SNPs at two loci replicated and showed evidence for association in a further sample (stage 3). Meta-analyses of all data provided compelling evidence that ABCA7 (rs3764650, meta P = 4.5 × 10(-17); including ADGC data, meta P = 5.0 × 10(-21)) and the MS4A gene cluster (rs610932, meta P = 1.8 × 10(-14); including ADGC data, meta P = 1.2 × 10(-16)) are new Alzheimer's disease susceptibility loci. We also found independent evidence for association for three loci reported by the ADGC, which, when combined, showed genome-wide significance: CD2AP (GERAD+, P = 8.0 × 10(-4); including ADGC data, meta P = 8.6 × 10(-9)), CD33 (GERAD+, P = 2.2 × 10(-4); including ADGC data, meta P = 1.6 × 10(-9)) and EPHA1 (GERAD+, P = 3.4 × 10(-4); including ADGC data, meta P = 6.0 × 10(-10)).

ATP-Binding Cassette Transporters↗
PubMed2007

Education and Alzheimer disease without dementia: support for the cognitive reserve hypothesis.

BACKGROUND: Individuals with no cognitive impairment during life but with neuropathologic Alzheimer disease (AD) may represent cases of presymptomatic, or unrecognized early symptomatic, AD. The cognitive reserve hypothesis suggests that at a particular level of AD pathology, highly educated individuals are less likely to manifest clinical symptoms of dementia vs less-educated individuals. OBJECTIVE: To investigate whether education can help explain a clinical diagnosis of no dementia within 1 year of death among individuals with neuropathologic diagnoses of AD. METHODS: Samples of participants (age 65+ years at last clinical assessment) meeting each of three neuropathologic criteria for AD were constructed using data from the National Alzheimer's Coordinating Center Minimum and Neuropathology Data Sets. Generalized linear mixed models (using the logit link function) were used in each sample to examine whether years of education was associated with dementia within 1 year of death, adjusting for other relevant variables. RESULTS: Twelve percent of individuals meeting Khachaturian (122/1,009), 19% meeting low, intermediate, or high likelihood for National Institute on Aging/Reagan Institute (320/1,704), and 14% meeting possible, probable, or definite Consortium to Establish a Registry for Alzheimer's Disease (265/1,835) neuropathologic criteria for AD were nondemented at their final clinical assessment. Persons with more education were less likely to have a dementia diagnosis in each sample. CONCLUSIONS: Regardless of the neuropathologic criteria used, education is predictive of dementia status among individuals with neuropathologic Alzheimer disease. These results support the theory that individuals with greater cognitive reserve, as reflected in years of education, are better able to cope with AD brain pathology without observable deficits in cognition.

Aged↗
PubMed2007

Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults.

OBJECTIVES: To investigate the ability of cerebrospinal fluid (CSF) and plasma measures to discriminate early-stage Alzheimer disease (AD) (defined by clinical criteria and presence/absence of brain amyloid) from nondemented aging and to assess whether these biomarkers can predict future dementia in cognitively normal individuals. DESIGN: Evaluation of CSF beta-amyloid(40) (Abeta(40)), Abeta(42), tau, phosphorylated tau(181), and plasma Abeta(40) and Abeta(42) and longitudinal clinical follow-up (from 1 to 8 years). SETTING: Longitudinal studies of healthy aging and dementia through an AD research center. PARTICIPANTS: Community-dwelling volunteers (n = 139) aged 60 to 91 years and clinically judged as cognitively normal (Clinical Dementia Rating [CDR], 0) or having very mild (CDR, 0.5) or mild (CDR, 1) AD dementia. RESULTS: Individuals with very mild or mild AD have reduced mean levels of CSF Abeta(42) and increased levels of CSF tau and phosphorylated tau(181). Cerebrospinal fluid Abeta(42) level completely corresponds with the presence or absence of brain amyloid (imaged with Pittsburgh Compound B) in demented and nondemented individuals. The CSF tau/Abeta(42) ratio (adjusted hazard ratio, 5.21; 95% confidence interval, 1.58-17.22) and phosphorylated tau(181)/Abeta(42) ratio (adjusted hazard ratio, 4.39; 95% confidence interval, 1.62-11.86) predict conversion from a CDR of 0 to a CDR greater than 0. CONCLUSIONS: The very mildest symptomatic stage of AD exhibits the same CSF biomarker phenotype as more advanced AD. In addition, levels of CSF Abeta(42), when combined with amyloid imaging, augment clinical methods for identifying in individuals with brain amyloid deposits whether dementia is present or not. Importantly, CSF tau/Abeta(42) ratios show strong promise as antecedent (preclinical) biomarkers that predict future dementia in cognitively normal older adults.

Aged↗
PubMed2006

Retroviral vectors encoding a reverse transcription-activated transgene efficiently limit expression of the gene to target cells.

Recombinant retroviral vectors are indispensable tools for the study of gene function and for therapeutic gene transfer owing to their ability to transfer and stably express foreign genes in target cells. A limitation of these vectors, however, is the difficulty in generating stable vector producer cell (VPC) lines when the vectors encode cytotoxic proteins. We developed a series of Moloney murine leukemia virus-based vectors encoding a reverse transcription-activated transgene. These vectors preclude gene expression in the producer cells, yet allow lines for transgene expression in target cells. The vectors were generated by cloning the gene of interest in reverse orientation either just upstream of the viral 3' long terminal repeat (LTR) or in the U3 region of the 3'LTR. An exogenous promoter was inserted, also in reverse orientation, at the R-U5 border of the viral 5'LTR. Upon transduction of target cells, the inserted promoter is copied to the 3'LTR during reverse transcription of the vector genomic RNA, where it then drives transgene expression. We tested this system using a green fluorescent protein (GFP) gene and the SV40 promoter. Reverse transcription-activated retroviral vectors may allow for the generation of stable retroviral VPC lines encoding cytotoxic or inhibitory genes.

Cell Line↗
PubMed2006

Survival and mortality differences between dementia with Lewy bodies vs Alzheimer disease.

OBJECTIVE: To determine whether dementia with Lewy bodies (DLB) progresses more rapidly than Alzheimer disease (AD). METHODS: We compared 315 participants (63 with DLB and 252 with AD) enrolled in a prospective longitudinal study of memory and aging with annual clinical and cognitive assessments and followed until death. The main outcome measure was dementia progression to institutionalization and death. Neuropathologic examinations were performed on all participants in this study. Subject classification (DLB vs AD) was based on neuropathology. RESULTS: Patients with DLB had an increased risk of mortality vs patients with AD (hazard ratio [HR] 1.88, 95% CI: 1.4 to 2.5). The median survival time for DLB was 78.0 years and for AD was 84.6 years (chi(2) = 19.9, p < 0.001) with significant modification effects due to gender (HR 1.51, 95% CI: 1.0 to 2.3) and the presence of at least 1 APOE epsilon4 allele (HR 1.50, 95% CI: 1.0 to 2.2). Survival after dementia onset was also different between DLB and AD (7.3 vs 8.5 years; chi(2) = 5.4, p < 0.02). DLB cases had similar risks of institutionalization and survival in long-term care facilities to AD cases. Self-reports of depression and the presence of extrapyramidal signs were important covariates. The rate of cognitive decline as measured by psychometric performance and clinical staging methods did not differ between DLB and AD. CONCLUSIONS: Dementia with Lewy bodies (DLB) increases the risk of mortality compared with Alzheimer disease (AD), but the two groups did not differ in rate of cognitive decline. The greater risk for noncognitive disease progression for DLB compared with AD suggests clinically meaningful differences for the two disorders.

Aged↗
PubMed2006

Validity and reliability of the AD8 informant interview in dementia.

OBJECTIVE: To establish the validity, reliability, and discriminative properties of the AD8, a brief informant interview to detect dementia, in a clinic sample. METHODS: We evaluated 255 patient-informant dyads. We compared the number of endorsed AD8 items with an independently derived Clinical Dementia Rating (CDR) and with performance on neuropsychological tests. Construct and concurrent validity, test-retest, interrater and intermodal reliability, and internal consistency of the AD8 were determined. Receiver operator characteristic curves were used to assess the discriminative properties of the AD8. RESULTS: Concurrent validity was strong with AD8 scores correlating with the CDR (r = 0.75, 95% CI 0.63 to 0.88). Construct validity testing showed strong correlation between AD8 scores, CDR domains, and performance on neuropsychological tests. The Cronbach alpha of the AD8 was 0.84 (95% CI 0.80 to 0.87), suggesting excellent internal consistency. The AD8 demonstrated good intrarater reliability and stability (weighted kappa = 0.67, 95% CI 0.59 to 0.75). Both in-person and phone administration showed equal reliability (weighted kappa = 0.65, 95% CI 0.57 to 0.73). Interrater reliability was very good (Intraclass correlation coefficient = 0.80, 95% CI 0.55 to 0.92). The area under the curve was 0.92 (95% CI 0.88 to 0.95), suggesting excellent discrimination between nondemented individuals and those with cognitive impairment regardless of etiology. CONCLUSION: The AD8 is a brief, sensitive measure that validly and reliably differentiates between nondemented and demented individuals. It can be used as a general screening device to detect cognitive change regardless of etiology and with different types of informants.

Adult↗
PubMed2006

Clinical phenotype of Parkinson disease dementia.

OBJECTIVE: To determine which clinical features best characterize Parkinson disease dementia (PDD), compared with Alzheimer disease (AD) and dementia with Lewy bodies (DLB), and to determine the pathologic basis for PDD. METHODS: We examined 103 participants enrolled in a longitudinal study (nondemented control = 10, PD = 42, DLB = 20, AD = 31) who were followed to autopsy using standardized protocols. We characterized the features of PDD using published criteria for AD and DLB as a framework. Statistical analysis was performed using chi(2) and Fisher exact tests, Kaplan-Meier curves, and logistic regression models. RESULTS: The sample's mean age was 74.0 years (range 53 to 91 years), and individuals were followed for a mean of 3.4 visits (range 1 to 12 visits). During longitudinal follow-up, 83% of subjects with PD developed dementia, defined as a Clinical Dementia Rating score of >or=0.5. Features that distinguished PDD from AD included cognitive fluctuations (p = 0.001), visual (p < 0.001) and auditory (p = 0.006) hallucinations, depression (p = 0.003), and sleep disturbance (p = 0.003). These PDD features were identical to those observed for DLB. The pathologic substrates for PDD included DLB (38%), AD (32%), and nigral LB alone (24%). Clinical predictors of PDD were visual hallucinations (odds ratio [OR] 21.3; 95% CI: 1.5 to 309.6) and male gender (OR 9.6; 95% CI: 1.3 to 71.4). CONCLUSIONS: Parkinson disease dementia (PDD) shares identical clinical features with dementia with Lewy bodies (DLB); both entities can be distinguished from Alzheimer disease. The presence of PDD/DLB features at any time during the course of PD is highly predictive of dementia and the presence of LB at autopsy; in particular, male gender and visual hallucinations in PD predict dementia.

Aged↗
PubMed2006

MicroCT for high-resolution imaging of ectopic pheochromocytoma tumors in the liver of nude mice.

Successful outcomes for patients with cancer often depend on the early detection of tumor and the prompt initiation of active therapy. Despite major advances in the treatment of many cancers, early-stage lesions often go undetected due to the suboptimal resolution of current anatomical and functional imaging modalities. This limitation also applies to preclinical animal tumor models that are crucial for the evaluation and development of new therapeutic approaches to cancer. We report a new mouse model of metastatic pheochromocytoma, generated using tail vein injection of the mouse pheochromocytoma cell (MPC) line that reproducibly generated multiple liver tumors in the animals. Furthermore, we show that in vivo microCT imaging enhanced using a hepatobiliary-specific contrast agent, glyceryl-2-oleyl-1,3-di-7-(3-amino-2,4,6-triiodophenyl)-heptanoate (DHOG), detected tumors as small as 0.35 mm as early as 4 weeks after the injection of the tumor cells. This model may be useful for in vivo studies of tumor biology and for development of new strategies to treat metastatic pheochromocytoma.

Adrenal Gland Neoplasms↗
PubMed2006

Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain.

In this article, we have characterized and compared gene expression profiles from laser capture microdissected neurons in six functionally and anatomically distinct regions from clinically and histopathologically normal aged human brains. These regions, which are also known to be differentially vulnerable to the histopathological and metabolic features of Alzheimer's disease (AD), include the entorhinal cortex and hippocampus (limbic and paralimbic areas vulnerable to early neurofibrillary tangle pathology in AD), posterior cingulate cortex (a paralimbic area vulnerable to early metabolic abnormalities in AD), temporal and prefrontal cortex (unimodal and heteromodal sensory association areas vulnerable to early neuritic plaque pathology in AD), and primary visual cortex (a primary sensory area relatively spared in early AD). These neuronal profiles will provide valuable reference information for future studies of the brain, in normal aging, AD and other neurological and psychiatric disorders.

Aged↗
PubMed2006

Longitudinal course and neuropathologic outcomes in original vs revised MCI and in pre-MCI.

OBJECTIVES: To compare the natural history of individuals classified with mild cognitive impairment (MCI) in accordance with original criteria to the natural history of individuals classified with revised MCI criteria. METHODS: The authors compared the rates of progression in 32 individuals with amnestic MCI and in 90 people with MCI according to revised criteria that allow nonamnestic deficits with progression in 276 individuals who were too minimally impaired (pre-MCI) to meet either MCI criteria. All individuals in this study were determined clinically to be very mildly cognitively impaired with a Clinical Dementia Rating (CDR) of 0.5. RESULTS: Rates of progression for the two MCI groups were similar with a decline of almost 0.50 SD per year on a psychometric composite. Decline was less (0.23 SD) in the pre-MCI group. Median survival time to CDR 1 (mild dementia) was comparable for the original (95% CI: 3.79 to 4.07 years) and revised (95% CI: 3.29 to 5.40) criteria MCI groups but approximately twice as long in the pre-MCI group (95% CI: 6.72 to 8.93). All cases from the amnestic MCI criteria group with neuropathologic diagnoses met criteria for Alzheimer disease as did more than 90% in the other two groups. CONCLUSIONS: Mild cognitive impairment as originally and currently defined is usually early stage Alzheimer disease, which can begin with a cognitive deficit other than memory. It is possible to identify Alzheimer disease at an even earlier stage than mild cognitive impairment by focusing on intraindividual change rather than comparison with group norms.

Aged↗
PubMed2006

DAPK1 variants are associated with Alzheimer's disease and allele-specific expression.

Genetic factors play an important role in the etiology of late-onset Alzheimer's disease (LOAD). We tested gene-centric single nucleotide polymorphisms (SNPs) on chromosome 9 and identified two SNPs in the death-associated protein kinase, DAPK1, that show significant association with LOAD. SNP rs4878104 was significantly associated with LOAD in our discovery case-control sample set (WU) and replicated in each of two initial validation case-control sample sets (P<0.05, UK1, SD). The risk-allele frequency of this SNP showed a similar direction in three other case-control sample sets. A meta-analysis of the six sample sets combined, totaling 2012 cases and 2336 controls, showed an allelic P-value of 0.0016 and an odds ratio (OR) of 0.87 (95%CI: 0.79-0.95). Minor allele homozygotes had a consistently lower risk than major allele homozygotes in the discovery and initial two replication sample sets, which remained significant in the meta-analysis of all six sample sets (OR=0.7, 95%CI: 0.58-0.85), whereas the risk for heterozygous subjects was not significantly different from that of major allele homozygotes. A second SNP, rs4877365, which is in high linkage disequilibrium with rs4878104 (r2=0.64), was also significantly associated with LOAD (meta P=0.0017 in the initial three sample sets). Furthermore, DAPK1 transcripts show differential allelic gene expression, and both rs4878104 and rs4877365 were significantly associated with DAPK1 allele-specific expression (P=0.015 to <0.0001). These data suggest that genetic variation in DAPK1 modulates susceptibility to LOAD.

Alleles↗
PubMed2006

Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fluid in vivo.

Certain disease states are characterized by disturbances in production, accumulation or clearance of protein. In Alzheimer disease, accumulation of amyloid-beta (Abeta) in the brain and disease-causing mutations in amyloid precursor protein or in enzymes that produce Abeta indicate dysregulation of production or clearance of Abeta. Whether dysregulation of Abeta synthesis or clearance causes the most common form of Alzheimer disease (sporadic, >99% of cases), however, is not known. Here, we describe a method to determine the production and clearance rates of proteins within the human central nervous system (CNS). We report the first measurements of the fractional production and clearance rates of Abeta in vivo in the human CNS to be 7.6% per hour and 8.3% per hour, respectively. This method may be used to search for novel biomarkers of disease, to assess underlying differences in protein metabolism that contribute to disease and to evaluate treatments in terms of their pharmacodynamic effects on proposed disease-causing pathways.

Amino Acid Sequence↗
PubMed2006

Measuring and estimating diagnostic accuracy when there are three ordinal diagnostic groups.

This article studies the problem of measuring and estimating the diagnostic accuracy when there are three ordinal diagnostic groups. We use a receiver operating characteristic (ROC) surface to describe the probabilities of correct classifications into three diagnostic groups based on various sets of diagnostic thresholds of a test and propose to use the entire and the partial volume under the surface to measure the diagnostic accuracy. Mathematical properties and probabilistic interpretations of the proposed measure of diagnostic accuracy are discussed. Under the assumption of normal distributions of the diagnostic test from three diagnostic groups, we present the maximum likelihood estimate to the volume under the ROC surface and give the asymptotic variance to the estimate. We further propose several asymptotic confidence interval estimates to the volume under the ROC surface. The performance of these confidence interval estimates is evaluated in terms of attaining the nominal coverage probability based on a simulation study. In addition, we develop a method of sample size determination to achieve an adequate accuracy of the confidence interval estimate. Finally, we demonstrate the proposed methodology by applying it to the clinical diagnosis of early stage Alzheimer's disease based on the neuropsychological database of the Washington University Alzheimer's Disease Research Center.

Alzheimer Disease↗
PubMed2006

Older adult drivers with cognitive impairment.

As the number of drivers with cognitive impairment increases, family physicians are more likely to become involved in decisions about cessation of driving privileges in older patients. Physicians who care for cognitively impaired older adults should routinely ask about driving status. In patients who continue to drive, physicians should assess pertinent cognitive domains, determine the severity and etiology of the dementia, and screen for risky driving behaviors. Cognitive impairment detected by office-based tests may indicate that the patient is at risk of a motor vehicle crash. Referral for performance-based road testing may further clarify risk and assist in making driving recommendations. Physicians should assist families in the difficult process of driving cessation, including providing information about Web sites and other resources and clarifying the appropriate state regulations. Some states require reporting of specific medical conditions to their departments of motor vehicles.

Adult↗