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1.  Four-Year Outcome of Mild Cognitive Impairment: The Contribution of Executive Dysfunction 
Neuropsychology  2012;27(1):95-106.
Objective
The contribution of executive cognition (EC) to the prediction of incident dementia remains unclear. This prospective study examined the predictive value of EC for subsequent cognitive decline in persons with mild cognitive impairment (MCI) over a 4-year period.
Methods
141 persons with MCI (amnestic and non-amnestic, single- and multiple-domain) received a baseline and two biennial follow-up assessments. Eighteen tests, assessing six different aspects of EC, were administered at baseline and at 2-year follow-up, together with screening cognitive and daily functioning measures. Longitudinal logistic regression models and generalized estimating equations (GEE) were used to examine whether EC could predict progression to a Clinical Dementia Rating Scale (CDR) score of 1 or more over the 4-year period, first at the univariate level and then in the context of demographic and clinical characteristics, daily functioning measures and other neurocognitive factors.
Results
Over the 4-year period, 56% of MCI patients remained stable, 35% progressed to CDR≥1, and 8% reverted to normal (CDR=0). Amnestic MCI subtypes were not associated with higher rates of progression to dementia, whereas subtypes with multiple impairments were so associated. Eight out of the 18 EC measures, including all three measures assessing inhibition of prepotent responses, predicted MCI outcome at the univariate level. However, the multivariate GEE model indicated that age, daily functioning, and overall cognitive functioning best predicted progression to dementia.
Conclusion
Measures of EC (i.e., inhibitory control) are associated with MCI outcome. However, age and global measures of cognitive and functional impairment are better predictors of incident dementia.
doi:10.1037/a0030481
PMCID: PMC3933818  PMID: 23106114
mild cognitive impairment; predictors; executive cognition; dementia
2.  Evaluation of Excess Significance Bias in Animal Studies of Neurological Diseases 
PLoS Biology  2013;11(7):e1001609.
The evaluation of 160 meta-analyses of animal studies on potential treatments for neurological disorders reveals that the number of statistically significant results was too large to be true, suggesting biases.
Animal studies generate valuable hypotheses that lead to the conduct of preventive or therapeutic clinical trials. We assessed whether there is evidence for excess statistical significance in results of animal studies on neurological disorders, suggesting biases. We used data from meta-analyses of interventions deposited in Collaborative Approach to Meta-Analysis and Review of Animal Data in Experimental Studies (CAMARADES). The number of observed studies with statistically significant results (O) was compared with the expected number (E), based on the statistical power of each study under different assumptions for the plausible effect size. We assessed 4,445 datasets synthesized in 160 meta-analyses on Alzheimer disease (n = 2), experimental autoimmune encephalomyelitis (n = 34), focal ischemia (n = 16), intracerebral hemorrhage (n = 61), Parkinson disease (n = 45), and spinal cord injury (n = 2). 112 meta-analyses (70%) found nominally (p≤0.05) statistically significant summary fixed effects. Assuming the effect size in the most precise study to be a plausible effect, 919 out of 4,445 nominally significant results were expected versus 1,719 observed (p<10−9). Excess significance was present across all neurological disorders, in all subgroups defined by methodological characteristics, and also according to alternative plausible effects. Asymmetry tests also showed evidence of small-study effects in 74 (46%) meta-analyses. Significantly effective interventions with more than 500 animals, and no hints of bias were seen in eight (5%) meta-analyses. Overall, there are too many animal studies with statistically significant results in the literature of neurological disorders. This observation suggests strong biases, with selective analysis and outcome reporting biases being plausible explanations, and provides novel evidence on how these biases might influence the whole research domain of neurological animal literature.
Author Summary
Studies have shown that the results of animal biomedical experiments fail to translate into human clinical trials; this could be attributed either to real differences in the underlying biology between humans and animals, to shortcomings in the experimental design, or to bias in the reporting of results from the animal studies. We use a statistical technique to evaluate whether the number of published animal studies with “positive” (statistically significant) results is too large to be true. We assess 4,445 animal studies for 160 candidate treatments of neurological disorders, and observe that 1,719 of them have a “positive” result, whereas only 919 studies would a priori be expected to have such a result. According to our methodology, only eight of the 160 evaluated treatments should have been subsequently tested in humans. In summary, we judge that there are too many animal studies with “positive” results in the neurological disorder literature, and we discuss the reasons and potential remedies for this phenomenon.
doi:10.1371/journal.pbio.1001609
PMCID: PMC3712913  PMID: 23874156
3.  The Fate of the 0.5s: Predictors of 2-Year Outcome in Mild Cognitive Impairment 
Impairments in executive cognition (EC) may be predictive of incident dementia in patients with mild cognitive impairment (MCI). The present study examined whether specific EC tests could predict which MCI individuals progress from a Dementia Rating Scale (CDR) score of 0.5 to a score ≥1 over a 2-year period. Eighteen clinical and experimental EC measures were administered at baseline to 104 MCI patients (amnestic and non-amnestic, single- and multiple-domain) recruited from clinical and research settings. Demographic characteristics, screening cognitive measures and measures of everyday functioning at baseline were also considered as potential predictors. Over the two-year period, 18% of the MCI individuals progressed to CDR≥1, 73.1% remained stable (CDR=0.5), and 4.5% reverted to normal (CDR=0). Multiple-domain MCI participants had higher rates of progression to dementia than single-domain, but amnestic and non-amnestic MCIs had similar rates of conversion. Only three EC measures were predictive of subsequent cognitive and functional decline at the univariate level, but they failed to independently predict progression to dementia after adjusting for demographic, other cognitive characteristics, and measures of everyday functioning. Decline over 2 years was best predicted by informant ratings of subtle functional impairments and lower baseline scores on memory, category fluency and constructional praxis.
doi:10.1017/S1355617710001621
PMCID: PMC3078700  PMID: 21205413
Mild cognitive impairment; dementia; predictors of decline; executive cognition; Clinical Dementia Rating scale; MCI outcome
4.  Episodic Memory in Dementia: Characteristics of New Learning that Differentiate Alzheimer's, Huntington's, and Parkinson's Diseases 
Differences in the memory characteristics of patients with Alzheimer's disease (AD), Huntington's disease (HD), and Parkinson's disease (PD) were investigated with tests that assess learning and retention of words, line-drawn objects, and locations. Large groups of AD, HD, and PD patients were administered the Hopkins Verbal Learning Test-Revised (HVLT-R) and the Hopkins Board (HB). Eight learning and memory measures were subjected to discriminant function analysis. A 91% classification accuracy was achieved for the separation of cortical and subcortical dementias and 79% accuracy for the discrimination of the three groups. The delayed recall of items was the best discriminator. Receiver-operating curve analysis indicated up to 90% sensitivity and 90% specificity in differentiating the three diseases using the discriminant scores. Individual learning and memory measures of the HVLT-R and the HB provided very high sensitivity and specificity in distinguishing cortical versus subcortical dementias and modest accuracy in separating the two subcortical diseases.
doi:10.1093/arclin/acq038
PMCID: PMC2904670  PMID: 20530592
Episodic memory; Alzheimer's disease; Huntington's disease; Parkinson's disease
5.  Everyday functioning in mild cognitive impairment and its relationship with executive cognition 
Objective
Elderly persons with mild cognitive impairment (MCI) are at increased risk of dementia and functional impairments. The present study investigated the contribution of three domains of executive cognition to everyday functioning among persons with MCI.
Methods
124 MCI patients and 68 cognitively normal elderly participants were administered a cognitive screening battery. These tests were used to divide patients into four subgroups (amnestic single domain, amnestic multiple domain, non-amnestic single domain, and non-amnestic multiple domain). Subjects were then administered 18 executive function tests that assess planning/problem-solving, working memory, and judgment. Performance of everyday activities and everyday cognition was rated with two informant-reported measures.
Results
All MCI subtypes had more difficulties in everyday activities than cognitively normal elderly participants. Multiple domain MCI patients had more functional impairments than single domain MCI patients. Contrary to our expectations, only one executive function component, working memory, contributed significantly to functional status after controlling for demographic, health-related and other cognitive factors.
Conclusions
Functional abilities are compromised in all MCI subtypes. Working memory may be associated with functional impairments, but general cognitive measures account for more unique variance.
doi:10.1002/gps.2325
PMCID: PMC2987652  PMID: 19650160
everyday functioning; executive cognition; working memory; mild cognitive impairment
6.  SELECTIVITY OF EXECUTIVE FUNCTION DEFICITS IN MILD COGNITIVE IMPAIRMENT 
Neuropsychology  2009;23(5):607-618.
Impairment in executive cognition (EC) is now recognized as relatively common among older persons with mild cognitive impairment (MCI), and may be predictive of the development of dementia. However, both MCI and executive functioning are broad and heterogeneous constructs. The present study sought to determine whether impairments in specific domains of EC are associated with specific subtypes of MCI. 124 MCI patients were divided into four subgroups (amnestic versus nonamnestic, and single- versus multiple-domain) based on their performance of widely-used neuropsychological screening tests. These patients and 68 normal elderly were administered 18 clinical and experimental tests of executive function. Principal components analysis suggested two highly reliable EC components, planning/problem-solving and working memory, and a less reliable third component, judgment. Planning/problem-solving and working memory, but not judgment, were impaired among the MCI patients. This was true even among those with Apure amnestic@ MCI, the least impaired group overall. Multiple-domain MCI patients had more severe impairments in planning/problem-solving and working memory than single-domain patients, leading to the supposition that they, not pure amnestic MCIs, are at highest risk of imminent dementia.
doi:10.1037/a0015851
PMCID: PMC2769993  PMID: 19702414
executive function; mild cognitive impairment; dementia; principal components analysis; flexibility; working memory; planning

Results 1-6 (6)