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1.  Statistical Approaches to Assess the Effects of Disease on Neurocognitive Function Over Time 
Introduction
Assessment of the effects of disease on neurocognitive outcomes in children over time presents several challenges. These challenges are particularly pronounced when conducting studies in low-income countries, where standardization and validation is required for tests developed originally in high-income countries. We present a statistical methodology to assess multiple neurocognitive outcomes over time. We address the standardization and adjustment for age in neurocognitive testing, present a statistical methodology for development of a global neurocognitive score, and assess changes in individual and global neurocognitive scores over time in a cohort of children with cerebral malaria.
Methods
Ugandan children with cerebral malaria (CM, N = 44), uncomplicated malaria (UM, N = 54) and community controls (N = 89) were assessed by cognitive tests of working memory, executive attention and tactile learning at 0, 3, 6 and 24 months after recruitment. Tests were previously developed and validated for the local area. Test scores were adjusted for age, and a global score was developed based on the controls that combined the assessments of impairment in each neurocognitive domain. Global normalized Z-scores were computed for each of the three study groups. Model-based tests compare the Z-scores between groups.
Results
We found that continuous Z-scores gave more powerful conclusions than previous analyses of the dataset. For example, at all four time points, children with CM had significantly lower global Z-scores than controls and children with UM. Our methods also provide more detailed descriptions of longitudinal trends. For example, the Z-scores of children with CM improved from initial testing to 3 months, but remained at approximately the same level below those of controls or children with UM from 3 to 24 months. Our methods for combining scores are more powerful than tests of individual cognitive domains, as testing of the individual domains revealed differences at only some but not all time points.
doi:10.4172/2155-6180.S7-016
PMCID: PMC4221235  PMID: 25383237
Neurocognitive; Development; Malaria; Normalization; Longitudinal data analysis; Cumulative; Global score
2.  Healthcare Resource Use among Heart Failure Patients in a Randomized Pilot Study of a Cognitive Training Intervention 
Objectives
To compare healthcare resource use of patients with heart failure (HF) randomized to the cognitive training intervention and to the health education active control intervention in a randomized controlled pilot study.
Background
Cognitive training interventions may be efficacious and improve patients’ memory and abilities to perform instrumental activities of daily living and self-care behaviors that may, in turn, lower healthcare resource use, but the influence of these interventions on healthcare resource use is unknown.
Methods
Thirty-four HF patients were randomized to the computerized plasticity-based cognitive training intervention called Brain Fitness and to the health education active control intervention and completed the study. The primary outcome variable for the study was memory (recall and delayed recall). The secondary purpose of the study that is the focus of this paper was to compare healthcare resource use between the two groups using the third-party payer perspective. Data were collected at baseline and at 8 and 12 weeks after baseline. Healthcare resources were priced at Medicare payment levels for services and average wholesale price for medications.
Results
Average costs of visits, procedures, and medications were similar between groups. Average costs of hospitalizations and tests, and therefore total costs, were half as much in the Brain Fitness group as compared to the active control group, but this difference was not significantly different from zero (p = .24).
Conclusions
Larger randomized controlled trials are needed that include analyses of program costs and costs associated with medical and non-medical services in order to fully evaluate efficacy of this intervention.
doi:10.1016/j.hrtlng.2013.05.001
PMCID: PMC3781586  PMID: 23809197
cognition; healthcare resource use; heart failure; memory; cost
3.  A Randomized Trial of Adenotonsillectomy for Childhood Sleep Apnea 
The New England journal of medicine  2013;368(25):2366-2376.
BACKGROUND
Adenotonsillectomy is commonly performed in children with the obstructive sleep apnea syndrome, yet its usefulness in reducing symptoms and improving cognition, behavior, quality of life, and polysomnographic findings has not been rigorously evaluated. We hypothesized that, in children with the obstructive sleep apnea syndrome without prolonged oxyhemoglobin desaturation, early adenotonsillectomy, as compared with watchful waiting with supportive care, would result in improved outcomes.
METHODS
We randomly assigned 464 children, 5 to 9 years of age, with the obstructive sleep apnea syndrome to early adenotonsillectomy or a strategy of watchful waiting. Polysomnographic, cognitive, behavioral, and health outcomes were assessed at baseline and at 7 months.
RESULTS
The average baseline value for the primary outcome, the attention and executive-function score on the Developmental Neuropsychological Assessment (with scores ranging from 50 to 150 and higher scores indicating better functioning), was close to the population mean of 100, and the change from baseline to follow-up did not differ significantly according to study group (mean [±SD] improvement, 7.1±13.9 in the early-adenotonsillectomy group and 5.1±13.4 in the watchful-waiting group; P = 0.16). In contrast, there were significantly greater improvements in behavioral, quality-of-life, and polysomnographic findings and significantly greater reduction in symptoms in the early-adenotonsillectomy group than in the watchful-waiting group. Normalization of polysomnographic findings was observed in a larger proportion of children in the early-adenotonsillectomy group than in the watchful-waiting group (79% vs. 46%).
CONCLUSIONS
As compared with a strategy of watchful waiting, surgical treatment for the obstructive sleep apnea syndrome in school-age children did not significantly improve attention or executive function as measured by neuropsychological testing but did reduce symptoms and improve secondary outcomes of behavior, quality of life, and polysomnographic findings, thus providing evidence of beneficial effects of early adenotonsillectomy. (Funded by the National Institutes of Health; CHAT ClinicalTrials.gov number, NCT00560859.)
doi:10.1056/NEJMoa1215881
PMCID: PMC3756808  PMID: 23692173
4.  Neuropsychiatric Symptoms and Executive Functioning in Patients with Mild Cognitive Impairment: Relationship to Caregiver Burden 
Background
Caregivers of patients with mild cognitive impairment (MCI) need similar levels of support services as Alzheimer’s disease (AD) caregivers, but it is unclear if this translates to increased caregiver burden.
Methods
135 participants and their caregivers (40 MCI, 55 AD and 40 normal controls, NC) completed questionnaires, and the patients were administered neuropsychological tests.
Results
The MCI caregivers reported significantly more overall caregiving burden than the NC, but less than the AD. They showed similar levels of emotional, physical and social burden as the AD caregivers. Among the MCI caregivers, the neuropsychiatric symptoms and executive functioning of the patients were related to a greater burden, and the caregivers with a greater burden reported lower life satisfaction and social support, and a greater need for support services.
Conclusion
These results indicate that MCI caregivers are at increased risk for caregiver stress, and they require enhanced assistance and/or education in caring for their loved ones.
doi:10.1159/000339955
PMCID: PMC3698846  PMID: 23128102
Mild cognitive impairment; Caregiver burden; Neuropsychology; Neuropsychiatric symptoms
5.  Assessing Mild Cognitive Impairment with Amyloid and Dopamine Terminal Molecular Imaging 
We evaluated positron emission tomography (PET)-based classification of neurodegenerative pathology in mild cognitive impairment (MCI).
Methods
A cross-sectional and prospective evaluation of a cohort of 27 MCI subjects drawn from a university-based Cognitive Disorders clinic. We compared expert clinical consensus classification of MCI at entry, and possible dementia at follow-up, with molecular imaging-based classification employing [11C]DTBZ-PET measurement of striatal dopamine terminal integrity and [11C]PiB-PET measurement of cerebral amyloid burden.
Results
Eleven subjects were initially classified clinically as amnestic MCI, 7 as multidomain MCI, and 9 as nonamnestic MCI. At mean follow-up of 3 years, 18 subjects converted to dementia. PET imaging evidence of significant cerebral amyloid deposition and/or nigrostriatal denervation were strong predictors of conversion to dementia. There was only moderate concordance between expert clinical classifications and PET-based classifications of dementia subtypes.
Conclusions
Combined PET molecular imaging of cerebral amyloid burden and striatal dopamine terminal integrity may be useful identifying subjects at high risk for progression to dementia and in defining neurochemically differentiated subsets of MCI subjects.
doi:10.2967/jnumed.112.112599
PMCID: PMC3790329  PMID: 23572495
Dementia; Alzheimer disease; Lewy Body dementia; Frontotemporal dementia
6.  The Prevalence of Cognitive Impairment in Older Adults with Heart Failure 
BACKGROUND
Our understanding of the prevalence of cognitive impairment (CI) in older adults with heart failure (HF) in a nationally-representative sample is limited.
OBJECTIVES
We used a national probability sample to determine the prevalence of CI in older adults with HF.
DESIGN
Cross-sectional analysis of the 2004 wave of the nationally representative Health and Retirement Study linked to 2002–04 Medicare administrative claims
SETTING
United States, community-dwelling
PARTICIPANTS
6,189 respondents ≥ 67 years old.
MEASUREMENTS
An algorithm was developed using a combination of self- and proxy-report of a heart problem and the presence of ≥ 1 Medicare claim in administrative files using standard HF diagnostic codes. On the basis of the algorithm, 3 categories were created to characterize the likelihood of a HF diagnosis: 1) High or Moderate Probability of HF; 2) Low Probability of HF; and 3) Not a HF case. Cognitive function was assessed using a screening measure of cognitive function or by proxy rating. Age-adjusted prevalence estimates of CI were calculated for the high-moderate probability HF group, the low probability HF group, and the non-HF cases.
RESULTS
The prevalence of CI consistent with dementia in older adults with HF was 15%; while the prevalence of mild CI was 24%. The odds of dementiain those with HF was significantly increased, even after adjustment for age, education level, net worth and prior stroke (OR: 1.52; 95% CI: 1.14 – 2.02).
CONCLUSION
CI is common in older adults with HF and is independently associated with an increased risk for dementia. A cognitive assessment should be routinely incorporated into HF-focused models of care.
doi:10.1111/j.1532-5415.2012.04097.x
PMCID: PMC3445700  PMID: 22882000
Heart failure; aged; cognitive impairment; Medicare claims data
7.  Fall Risk-Relevant Functional Mobility Outcomes in Dementia Following Dyadic Tai Chi Exercise 
Whether persons with dementia benefit from fall prevention exercise is unclear. Applying the Positive Emotion-Motivated Tai Chi protocol, preliminary findings concerning adherence and effects of a dyadic Tai Chi exercise program on persons with Alzheimer’s disease (AD) are reported. Using pre/ posttest design, 22 community-dwelling AD-caregiver dyads participated in the program. Fall-risk-relevant functional mobility was measured using Unipedal Stance Time (UST) and Timed Up and Go (TUG) tests. Results showed that 19/22 (86.4%) AD patients completed the 16-week program and final assessment; 16/19 dyads (84.2%) completed the prescribed home program as reported by caregivers. UST adjusted mean improved from 4.0 to 5.1 (Week 4, p < .05) and 5.6 (Week 16, p < .05); TUG improved from 13.2 to 11.6 (Week 4, p < .05) and 11.6 (Week 16, p > .05) post intervention. Retaining dementia patients in an exercise intervention remains challenging. The dyadic Tai Chi approach appears to succeed in keeping AD-caregiver dyads exercising and safe.
doi:10.1177/0193945912443319
PMCID: PMC3468653  PMID: 22517441
dementia; Tai Chi; exercise; positive emotional motivators; fall risks
8.  Impact of Chronic Hypercortisolemia on Affective Processing 
Neuropharmacology  2011;62(1):217-225.
Cushing syndrome (CS) is the classic condition of cortisol dysregulation, and cortisol dysregulation is the prototypic finding in Major Depressive Disorder (MDD). We hypothesized that subjects with active CS would show dysfunction in frontal and limbic structures relevant to affective networks, and also manifest poorer facial affect identification accuracy, a finding reported in MDD.Twenty-one patients with confirmed CS (20 ACTH-dependent and 1 ACTH-independent) were compared to 21 healthy controlsubjects. Identification of affective facial expressions (Facial Emotion Perception Test) was conducted in a 3 Tesla GE fMRI scanner using BOLD fMRI signal. The impact of disease (illness duration, current hormone elevation and degree of disruption of circadian rhythm), performance, and comorbid conditions secondary to hypercortisolemia were evaluated.CS patients made more errors in categorizing facial expressions and had less activation in left anterior superior temporal gyrus, a region important in emotion processing. CS patients showed higher activation in frontal, medial, and subcortical regions relative to controls. Two regions of elevated activation in CS, left middle frontal and lateral posterior/pulvinar areas, were positively correlated with accuracy in emotion identification in the CS group, reflecting compensatory recruitment. In addition, within the CSgroup, greater activation in left dorsal anterior cingulatewas related to greater severity of hormone dysregulation. In conclusion, cortisol dysregulation in CS patients is associated with problems in accuracy of affective discrimination and altered activation of brain structures relevant to emotion perception, processing and regulation, similar to the performance decrements and brain regions shown to be dysfunctional in MDD.
doi:10.1016/j.neuropharm.2011.07.006
PMCID: PMC3196277  PMID: 21787793
HPA; cortisol; ACTH; emotion; affect; fMRI; Cushings
9.  Nurse Enhanced Memory Intervention in Heart Failure: The MEMOIR Study 
Journal of cardiac failure  2011;17(10):832-843.
Background
Many patients with heart failure (HF) have cognitive deficits, including memory loss.
Objectives
To evaluate the efficacy of a cognitive training intervention on memory (primary outcome), working memory, psychomotor speed, executive function, and performance of cognitive activities and instrumental activities of daily living (IADLs).
Methods
Forty patients with HF were randomly assigned to the computerized plasticity-based cognitive training intervention called Brain Fitness and to the health education active control intervention. Advanced practice nurses made weekly home visits to assess symptoms and monitor intervention adherence. Patients completed demographic and clinical data (baseline), neuropsychological tests (baseline, 8, and 12 weeks), and measures of cognitive and IADLs performance (baseline and 12 weeks)and satisfaction (12 weeks).
Results
Linear mixed models analyses indicated a significant group by time interaction for delayed recall memory (p = .032) and a significant time effect for total (list learning) (p < .001) and delayed (p = .015) recall memory, psychomotor speed (p = .029), and performance of IADLs (p = .006). Intervention adherence and patient satisfaction were high.
Conclusions
To our knowledge, this was thefirst test of Brain Fitness in HF. Although it was a preliminary study with limitations, results support the need for a largerrandomized, controlled trialto determine whether the memory loss of HF is amenable to plasticity-based interventions.
doi:10.1016/j.cardfail.2011.06.650
PMCID: PMC3227743  PMID: 21962422
heart failure; cognitive deficits; memory loss; cognitive training
10.  Incidence of Dementia and Cognitive Impairment Not Dementia in the United States 
Annals of neurology  2011;70(3):418-426.
Objective
Estimates of incident dementia, and cognitive impairment, not dementia (CIND) (or the related mild cognitive impairment (MCI)) are important for public health and clinical care policy. In this paper, we report US national incidence rates for dementia and CIND.
Methods
Participants in the Aging, Demographic and Memory Study (ADAMS) were evaluated for cognitive impairment using a comprehensive in-home assessment. A total of 456 individuals age 72 and older, who were not demented at baseline were followed longitudinally from August 2001 to December 2009. An expert consensus panel assigned a diagnosis of normal cognition, CIND, or dementia and its subtypes. Using a population-weighted sample, we estimated the incidence of dementia, Alzheimer’s disease (AD), vascular dementia (VaD), and CIND by age. We also estimated the incidence of progression from CIND to dementia.
Results
The incidence of dementia was 33.3 (s.e. = 4.2) per 1000 person-years and 22.9 (s.e. =2.9) per 1000 person-years for AD. The incidence of CIND was 60.4 (s.e.= 7.2) cases per 1000 person-years. An estimated 120.3 (s.e.=16.9) individuals per 1000 person-years progressed from CIND to dementia. Over a 5.9 year period, about 3.4 million individuals aged 72 and older in the US developed incident dementia; of which approximately 2.3 million developed AD and about 637,000 developed VaD. Over this same period, almost 4.8 million individuals developed incident CIND.
Interpretation
The incidence of CIND is greater than the incidence of dementia, and those with CIND are at high risk of progressing to dementia, making CIND a potentially valuable target for treatments aimed at slowing cognitive decline.
doi:10.1002/ana.22362
PMCID: PMC3139807  PMID: 21425187
11.  The Impact of Depression on Dual Tasking Among Patients With High Fall Risk 
Depression predicts fall risk among older adults, and this relationship may be partially explained by depression-associated executive dysfunction, relevant to navigating demanding environments. This pilot study examined timed stepping accuracy under simple and complex dual-task conditions, using an instrumented walkway based on the Trail Making Test. Participants were balance-impaired older adults, either with (n = 8; major depressive disorder [MDD]) or without (n = 8; nondepressed [ND]) MDD. After accounting for comfortable gait speed and age, the MDD group was significantly slower than the ND group on the walkway with the highest cognitive demand and demonstrated greater dual-task cost, both of which were correlated with performance on traditional measures of executive functioning. No group differences were observed on the walkway with the least cognitive demand. Balance-impaired older adults with MDD demonstrate increased stepping accuracy time under cognitively demanding conditions, reflecting executive dysfunction and an additional contribution to increased fall risk.
doi:10.1177/0891988711409408
PMCID: PMC3417319  PMID: 21705740
late life depression; dual task; gait
12.  Auditory Memory Decrements, Without Dissimulation, among Patients with Major Depressive Disorder 
Questions have been raised about whether poor performance on memory tasks by individuals with major depressive disorder (MDD) might be the result of poor or variable effort or disease-related disruption of neural circuits supporting memory functions. The present study examined performance on a measure of task engagement and on an auditory memory task among 45 patients with MDD (M age = 47.82, SD = 19.55) relative to 32 healthy controls (HC; M age = 51.03, SD = 22.09). One-hundred percent of HC and MDD volunteers performed above the threshold for adequate effort on a formal measure of task engagement. The MDD subjects performed significantly more poorly than the HC subjects on an auditory learning and memory test. The present results suggest that auditory memory difficulties do occur among those with MDD and that decrements in performance in this group may be related to factors other than lack of effort.
doi:10.1093/arclin/acr041
PMCID: PMC3201698  PMID: 21593060
Depression; Malingering/symptom validity testing; Learning and memory
13.  Assessment of mild dementia with amyloid and dopamine terminal positron emission tomography 
Brain  2011;134(6):1647-1657.
We assessed the relationship between consensus clinical diagnostic classification and neurochemical positron emission tomography imaging of striatal vesicular monoamine transporters and cerebrocortical deposition of aβ-amyloid in mild dementia. Seventy-five subjects with mild dementia (Mini-Mental State Examination score ≥ 18) underwent a conventional clinical evaluation followed by 11C-dihydrotetrabenazine positron emission tomography imaging of striatal vesicular monoamine transporters and 11C-Pittsburgh compound-B positron emission tomography imaging of cerebrocortical aβ-amyloid deposition. Clinical classifications were assigned by consensus of an experienced clinician panel. Neuroimaging classifications were assigned as Alzheimer’s disease, frontotemporal dementia or dementia with Lewy bodies on the basis of the combined 11C-dihydrotetrabenazine and 11C-Pittsburgh compound-B results. Thirty-six subjects were classified clinically as having Alzheimer’s disease, 25 as having frontotemporal dementia and 14 as having dementia with Lewy bodies. Forty-seven subjects were classified by positron emission tomography neuroimaging as having Alzheimer’s disease, 15 as having dementia with Lewy bodies and 13 as having frontotemporal dementia. There was only moderate agreement between clinical consensus and neuroimaging classifications across all dementia subtypes, with discordant classifications in ∼35% of subjects (Cohen’s κ = 0.39). Discordant classifications were least frequent in clinical consensus Alzheimer’s disease (17%), followed by dementia with Lewy bodies (29%) and were most common in frontotemporal dementia (64%). Accurate clinical classification of mild neurodegenerative dementia is challenging. Though additional post-mortem correlations are required, positron emission tomography imaging likely distinguishes subgroups corresponding to neurochemically defined pathologies. Use of these positron emission tomography imaging methods may augment clinical classifications and allow selection of more uniform subject groups in disease-modifying therapeutic trials and other prospective research involving subjects in the early stages of dementia.
doi:10.1093/brain/awr089
PMCID: PMC3102241  PMID: 21555336
Alzheimer’s disease; Lewy body dementia; frontotemporal dementia; amyloid; dopamine; diagnosis
14.  Common variants in MS4A4/MS4A6E, CD2uAP, CD33, and EPHA1 are associated with late-onset Alzheimer’s disease 
Naj, Adam C | Jun, Gyungah | Beecham, Gary W | Wang, Li-San | Vardarajan, Badri Narayan | Buros, Jacqueline | Gallins, Paul J | Buxbaum, Joseph D | Jarvik, Gail P | Crane, Paul K | Larson, Eric B | Bird, Thomas D | Boeve, Bradley F | Graff-Radford, Neill R | De Jager, Philip L | Evans, Denis | Schneider, Julie A | Carrasquillo, Minerva M | Ertekin-Taner, Nilufer | Younkin, Steven G | Cruchaga, Carlos | Kauwe, John SK | Nowotny, Petra | Kramer, Patricia | Hardy, John | Huentelman, Matthew J | Myers, Amanda J | Barmada, Michael M | Demirci, F. Yesim | Baldwin, Clinton T | Green, Robert C | Rogaeva, Ekaterina | St George-Hyslop, Peter | Arnold, Steven E | Barber, Robert | Beach, Thomas | Bigio, Eileen H | Bowen, James D | Boxer, Adam | Burke, James R | Cairns, Nigel J | Carlson, Chris S | Carney, Regina M | Carroll, Steven L | Chui, Helena C | Clark, David G | Corneveaux, Jason | Cotman, Carl W | Cummings, Jeffrey L | DeCarli, Charles | DeKosky, Steven T | Diaz-Arrastia, Ramon | Dick, Malcolm | Dickson, Dennis W | Ellis, William G | Faber, Kelley M | Fallon, Kenneth B | Farlow, Martin R | Ferris, Steven | Frosch, Matthew P | Galasko, Douglas R | Ganguli, Mary | Gearing, Marla | Geschwind, Daniel H | Ghetti, Bernardino | Gilbert, John R | Gilman, Sid | Giordani, Bruno | Glass, Jonathan D | Growdon, John H | Hamilton, Ronald L | Harrell, Lindy E | Head, Elizabeth | Honig, Lawrence S | Hulette, Christine M | Hyman, Bradley T | Jicha, Gregory A | Jin, Lee-Way | Johnson, Nancy | Karlawish, Jason | Karydas, Anna | Kaye, Jeffrey A | Kim, Ronald | Koo, Edward H | Kowall, Neil W | Lah, James J | Levey, Allan I | Lieberman, Andrew P | Lopez, Oscar L | Mack, Wendy J | Marson, Daniel C | Martiniuk, Frank | Mash, Deborah C | Masliah, Eliezer | McCormick, Wayne C | McCurry, Susan M | McDavid, Andrew N | McKee, Ann C | Mesulam, Marsel | Miller, Bruce L | Miller, Carol A | Miller, Joshua W | Parisi, Joseph E | Perl, Daniel P | Peskind, Elaine | Petersen, Ronald C | Poon, Wayne W | Quinn, Joseph F | Rajbhandary, Ruchita A | Raskind, Murray | Reisberg, Barry | Ringman, John M | Roberson, Erik D | Rosenberg, Roger N | Sano, Mary | Schneider, Lon S | Seeley, William | Shelanski, Michael L | Slifer, Michael A | Smith, Charles D | Sonnen, Joshua A | Spina, Salvatore | Stern, Robert A | Tanzi, Rudolph E | Trojanowski, John Q | Troncoso, Juan C | Deerlin, Vivianna M Van | Vinters, Harry V | Vonsattel, Jean Paul | Weintraub, Sandra | Welsh-Bohmer, Kathleen A | Williamson, Jennifer | Woltjer, Randall L | Cantwell, Laura B | Dombroski, Beth A | Beekly, Duane | Lunetta, Kathryn L | Martin, Eden R | Kamboh, M. Ilyas | Saykin, Andrew J | Reiman, Eric M | Bennett, David A | Morris, John C | Montine, Thomas J | Goate, Alison M | Blacker, Deborah | Tsuang, Debby W | Hakonarson, Hakon | Kukull, Walter A | Foroud, Tatiana M | Haines, Jonathan L | Mayeux, Richard | Pericak-Vance, Margaret A | Farrer, Lindsay A | Schellenberg, Gerard D
Nature genetics  2011;43(5):436-441.
The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study (GWAS) of late-onset Alzheimer disease (LOAD) using a 3 stage design consisting of a discovery stage (Stage 1) and two replication stages (Stages 2 and 3). Both joint and meta-analysis analysis approaches were used. We obtained genome-wide significant results at MS4A4A [rs4938933; Stages 1+2, meta-analysis (PM) = 1.7 × 10−9, joint analysis (PJ) = 1.7 × 10−9; Stages 1–3, PM = 8.2 × 10−12], CD2AP (rs9349407; Stages 1–3, PM = 8.6 × 10−9), EPHA1 (rs11767557; Stages 1–3 PM = 6.0 × 10−10), and CD33 (rs3865444; Stages 1–3, PM = 1.6 × 10−9). We confirmed that CR1 (rs6701713; PM = 4.6×10−10, PJ = 5.2×10−11), CLU (rs1532278; PM = 8.3 × 10−8, PJ = 1.9×10−8), BIN1 (rs7561528; PM = 4.0×10−14; PJ = 5.2×10−14), and PICALM (rs561655; PM = 7.0 × 10−11, PJ = 1.0×10−10) but not EXOC3L2 are LOAD risk loci1–3.
doi:10.1038/ng.801
PMCID: PMC3090745  PMID: 21460841
15.  Comparable Results of FDG-PET CMRglc and DTBZ-PET K1 in Evaluation of Early Dementia and Mild Cognitive Impairment 
Archives of neurology  2010;67(4):440-446.
Objective
To compare assessment of regional cerebral metabolic changes with DTBZ-PET measurement of regional cerebral blood flow (K1) and FDG-PET measurement of regional cerebral glucose uptake (CMRglc) in a clinically representative sample of mild dementia and mild cognitive impairment (MCI) subjects. We hypothesized that DTBZ-PET K1 and FDG-PET CMRglc provide equivalent information.
Design, Setting, Participants
DTBZ-PET K1 measurement of regional cerebral blood flow and FDG-PET CMRglc measurement of regional cerebral glucose uptake was performed in 50 subjects with either mild dementia (MMSE ≥ 18) or MCI drawn from a university based Cognitive Disorders Clinic. Results were compared with 80 normal control subjects.
Main Outcome Measures
DTBZ-PET regional K1 measurements and FDG-PET CMRglc measurements were compared with standard correlation analysis. The overall patterns of DTBZ-PET K1 deficits and FDG-PET CMRglc deficits were assessed with stereotaxic surface projections (SSP) of parametric images.
Results
DTBZ-PET regional K1 measurements and FDG-PET CMRglc measurements were highly correlated, both within and between subjects. SSP maps of deficits in DTBZ-PET regional K1 measurements and FDG-PET CMRglcs were markedly similar. DTBZ-PET K1 SSP maps exhibited a mild decrease in sensitivity relative to FDG-PET CMRglc maps.
Conclusion
DTBZ-PET K1 and FDG-PET CMRglc provide comparable information in assessment of regional cerebral metabolic deficits in mild dementia and MCI. K1 measures can assess regional cerebral metabolism deficits accurately in mild dementia and MCI. K1 assessments of regional cerebral metabolic deficits can be combined with tracer binding results to improve of utility of PET imaging in mild dementia and MCI.
doi:10.1001/archneurol.2010.34
PMCID: PMC3141210  PMID: 20385910
16.  Caregiver support service needs for patients with mild cognitive impairment and Alzheimer’s disease 
Little is known about the service needs for persons caring for individuals with Mild Cognitive Impairment (MCI). In this study, the level of support service need for caregivers of individuals diagnosed with Alzheimer’s Disease (AD; N=55) and MCI (N=25) was compared to normal controls (NC; N=44). Study partners (i.e., caregivers) completed questionnaires about their service needs and participants’ neurobehavioral symptoms, functional abilities, and frailty. Total, social, and mental health service needs were significantly different among the three groups (p<.0001), with MCI and AD caregivers reporting more need for services as compared to the NC group. There was no significant difference between MCI and AD groups for total and social service need. In the MCI group, caregiver’s service need was related to neurobehavioral symptoms and frailty, whereas service need among the AD caregivers was related to functional disability and frailty. Caregivers of individuals with MCI are already experiencing a need for increased services comparable to that of individuals caring for AD patients, though the pattern of patient-related factors is different between the two patient groups. These findings suggest possible areas of intervention that could be considered at the earliest stages of memory loss.
doi:10.1097/WAD.0b013e3181aba90d
PMCID: PMC2877755  PMID: 19571729
mild cognitive impairment; Alzheimer’s disease; service need; support services; caregiver
17.  Immediate neuropsychological and behavioral benefits of computerized cognitive rehabilitation in Ugandan pediatric cerebral malaria survivors 
Objective
Our earlier studies on Ugandan children surviving cerebral malaria showed cognitive deficits mainly in attention and memory. We now present the first study in sub-Saharan Africa to investigate the feasibility and potential benefits of computerized cognitive rehabilitation training on neuropsychological and behavioural functioning of children surviving cerebral malaria.
Methods
A randomized trial in which 65 children admitted 45 months earlier with cerebral malaria were recruited at Mulago Hospital, Kampala, Uganda. For eight weeks, 32 of the children received weekly training sessions using Captain’s Log cognitive training software and the other 33 were assigned to a non treatment condition. Pre- and post-intervention assessments were completed using CogState, a computerized neuropsychological battery, measuring Visuomotor Processing Speed, Working Memory, Learning, Attention and Psychomotor Speed and the Child Behavior Checklist measuring Internalising Problems, Externalising Problems and Total Problems.
Results
Pre-intervention scores were similar between both groups. Treatment effects were observed on Visual Spatial Processing Speed (group effect (standard error) 0.14 (0.03); p< 0.001); on a Working Memory and Learning task (0.08 (0.02); p< 0.001), Psychomotor Speed (0.14 (0.07); p= 0.04) and on Internalising Problems (−3.80 (1.56); p= 0.02) after controlling for age, sex, school grade, quality of the home environment and weight for age z scores. Similar treatment effects were observed when no adjustments for the above covariates were made.
Conclusions
Computerized cognitive training long after the cerebral malaria episode has immediate benefit on some neuropsychological and behavioral functions in African children. The long-term benefit of this intervention needs to be investigated.
doi:10.1097/DBP.0b013e3181b0f01b
PMCID: PMC2747354  PMID: 19668094
cognitive rehabilitation; Neuropsychology; behaviour; cerebral malaria; African children
18.  Reliability of the Luganda version of the Child Behaviour Checklist in measuring behavioural problems after cerebral malaria 
Background
No measure of childhood behaviour has been validated in Uganda despite the documented risks to behaviour. Cerebral malaria in children poses a great risk to their behaviour, however behavioural outcomes after cerebral malaria have not been described in children. This study examined the reliability of the Luganda version of the Child Behaviour Checklist (CBCL) and described the behavioural outcomes of cerebral malaria in Ugandan children.
Methods
The CBCL was administered to parents of 64 children aged 7 to 16 years participating in a trial to improve cognitive functioning after cerebral malaria. These children were assigned to the treatment or control group. The CBCL parent ratings were completed for the children at baseline and nine weeks later. The CBCL was translated into Luganda, a local language, prior to its use. Baseline scores were used to calculate internal consistency using Cronbach Alpha. Correlations between the first and second scores of the control group were used to determine test-retest reliability. Multicultural norms for the CBCL were used to identify children with behavioural problems of clinical significance.
Results
The test-retest reliability and internal consistency of the Internalising scales were 0.64 and 0.66 respectively; 0.74 and 0.78 for the Externalising scale and 0.67 and 0.83 for Total Problems. Withdrawn/Depressed (15.6%), Thought Problems (12.5%), Aggressive Behaviour (9.4%) and Oppositional Defiant Behaviour (9.4%) were the commonly reported problems.
Conclusion
The Luganda version of the CBCL is a fairly reliable measure of behavioural problems in Ugandan children. Depressive and thought problems are likely behavioural outcomes of cerebral malaria in children. Further work in children with psychiatric diagnoses is required to test its validity in a clinical setting.
doi:10.1186/1753-2000-3-38
PMCID: PMC2799377  PMID: 19995426
19.  Neuropsychological and Behavioral Functioning in Children with and without Obstructive Sleep Apnea Referred for Tonsillectomy 
Adenotonsillectomy (AT) is among the most common pediatric surgical procedures and is performed as often for obstructive sleep apnea (OSA) as for recurrent tonsillitis. This study compared behavioral, cognitive, and sleep measures in 27 healthy control children recruited from a university hospital-based pediatric general surgery clinic with 40 children who had OSA (AT/OSA+) and 27 children who did not have OSA (AT/OSA−) scheduled for AT. Parental ratings of behavior, sleep problems, and snoring, along with specific cognitive measures (i.e., short term attention, visuospatial problem solving, memory, arithmetic) reflected greater difficulties for AT children compared with controls. Differences between the AT/OSA− and control groups were larger and more consistent across test measures than were those between the AT/OSA+ and control groups. The fact that worse outcomes were not clearly demonstrated for the AT/OSA+ group compared with the other groups was not expected based on existing literature. This counterintuitive finding may reflect a combination of factors, including age, daytime sleepiness, features of sleep-disordered breathing too subtle to show on standard polysomnography, and academic or environmental factors not collected in this study. These results underscore the importance of applying more sophisticated methodologies to better understand the salient pathophysiology of childhood sleep-disordered breathing.
doi:10.1017/S1355617708080776
PMCID: PMC2561942  PMID: 18577286
Polysomnography; Neuropsychology; Sleep-Disordered Breathing; Adenotonsillectomy; Tonsillitis; Snoring
20.  DSM-IV DIAGNOSES AND OBSTRUCTIVE SLEEP APNEA IN CHILDREN BEFORE AND 1 YEAR AFTER ADENOTONSILLECTOMY 
Objectives
Obstructive sleep apnea, a common indication for adenotonsillectomy in children, has been linked to behavioral morbidity. We assessed psychiatric diagnoses in children before and after adenotonsillectomy and examined whether baseline sleep apnea predicted improvement after surgery.
Method
Subjects of this prospective cohort study were children aged 5.0–12.9 years-old who had been scheduled for adenotonsillectomy (n = 79), or care for unrelated surgical conditions (n=27, among whom 13 had surgery after baseline assessment). Prior to intervention and one year later, subjects underwent structured diagnostic interviews and polysomnography. The main outcome measure was frequency of DSM-IV attention and disruptive behavior disorder diagnoses (A&DBDs) at baseline and follow-up.
Results
At baseline, A&DBDs were diagnosed in 36.7% of adenotonsillectomy subjects and 11.1% of controls (p<.05); attention-deficit/hyperactivity disorder was found in 27.8% and 7.4%, respectively (p<.05). One year later, group differences were non-significant, A&DBDs were diagnosed in only 23.1% (p<.01), and 50% of subjects with baseline attention-deficit/hyperactivity disorders no longer met diagnostic criteria. Obstructive sleep apnea on polysomnography at baseline did not predict concurrent psychiatric morbidity or later improvement.
Conclusions
Attention and disruptive behavior disorders, diagnosed by DSM-IV criteria, were more common before clinically-indicated adenotonsillectomy than one year later. Surgery may be associated with reduced morbidity even among subjects lacking polysomnographic evidence of obstructive sleep apnea.
doi:10.1097/chi.0b013e31814b8eb2
PMCID: PMC2408827  PMID: 18049292
sleep apnea; obstructive; sleep disorders; child behavior disorders; attention deficit disorder with hyperactivity; adenotonsillectomy
21.  Preliminary effects of pagoclone, a partial GABAA agonist, on neuropsychological performance 
Pagoclone is a novel cyclopyrrolone that acts as a partial GABAA receptor agonist. Preclinical studies suggest that pagoclone may have clinical utility as an anxiolytic agent, as well as a reduced incidence of side-effects. The present study was conducted to determine whether pagoclone would affect healthy individuals’ performances on neuropsychological measures as a function of dose within the projected therapeutic range. Twelve healthy adult subjects were randomly assigned to dosage groups in a 3-way crossover study. Participants were administered neuropsychological measures six hours following dosing on Day 1 and Day 6 of administration of the drug. Dose effects were noted on measures of alertness, learning, and memory and movement time. Significant effects were also noted on measures of alertness, learning and memory, information processing and psychomotor speed. Overall, the results of this small, preliminary study do not support a finding of behavioral toxicity for these doses of pagoclone. Rather, a pattern was found of transient and mild negative effects on learning and memory scores at the highest dose administered, though these changes were small and no longer evident by the sixth day of use.
PMCID: PMC2515892  PMID: 18728798
pagoclone; cyclopyrrolone; neuropsychological; memory; generalized anxiety disorder
22.  SLEEP-DISORDERED BREATHING, BEHAVIOR, AND COGNITION IN CHILDREN BEFORE AND AFTER ADENOTONSILLECTOMY 
Pediatrics  2006;117(4):e769-e778.
Objectives: Most children with sleep-disordered breathing (SDB) have mild to moderate forms, for which neurobehavioral complications are believed to be the most important adverse outcomes. To improve understanding of this morbidity, its long-term response to adenotonsillectomy, and its relationship to polysomnographic measures, we studied a series of children before and after clinically-indicated adenotonsillectomy or unrelated surgical care.
Methods: We recorded sleep and assessed behavioral, cognitive, and psychiatric morbidity in 105 children 5.0 to 12.9 years old: 78 were scheduled for clinically-indicated adenotonsillectomy, usually for suspected SDB, and 27 for unrelated surgical care. One year later, we repeated all assessments in 100 of these children.
Results: Adenotonsillectomy subjects, in comparison to controls, were more hyperactive on well-validated parent rating scales (p<0.001), inattentive on cognitive testing (p=0.003), sleepy on Multiple Sleep Latency Tests (p=0.002), and likely to have DSM-IV-defined Attention-Deficit/Hyperactivity Disorder as judged by a child psychiatrist (p=0.03). In contrast, one year later, the two groups showed no significant differences in the same measures. Adenotonsillectomy subjects had improved substantially (p≤0.01) in all measures and control subjects in none. However, polysomnographic assessment of baseline SDB and its subsequent amelioration did not clearly predict either baseline neurobehavioral morbidity or improvement in any area other than sleepiness.
Conclusions: Children scheduled for adenotonsillectomy often have mild to moderate SDB and significant neurobehavioral morbidity -- including hyperactivity, inattention, Attention-Deficit/Hyperactivity Disorder, and excessive daytime sleepiness -- all of which tend to improve by one year after surgery. However, the lack of better correspondence between SDB measures and neurobehavioral outcomes suggests the need for better measures or improved understanding of underlying causal mechanisms.
doi:10.1542/peds.2005-1837
PMCID: PMC1434467  PMID: 16585288
polysomnography; sleep apnea, obstructive; tonsillectomy; child; attention deficit disorder with hyperactivity
23.  SUBJECTIVE SLEEPINESS AND POLYSOMNOGRAPHIC CORRELATES IN CHILDREN SCHEDULED FOR ADENOTONSILLECTOMY VS. OTHER SURGICAL CARE 
Sleep  2006;29(4):495-503.
Study Objectives: To compare a validated subjective measure of childhood sleepiness to an objective determination, assess the frequency of problematic sleepiness among children with suspected sleep-disordered breathing (SDB), and examine what standard or investigational polysomnographic measures of SDB predict subjective sleepiness.
Design: Prospective, cross-sectional
Setting: University-based sleep disorders laboratory
Participants: Washtenaw County Adenotonsillectomy Cohort
Intervention: Polysomnography followed by Multiple Sleep Latency Tests in 103 children 5-12 years old: 77 were scheduled for clinically-indicated adenotonsillectomy, usually for suspected SDB, and 26 for unrelated surgical care. Parents completed the previously-validated, 4-item Pediatric Sleep Questionnaire–Sleepiness Subscale (PSQ-SS).
Results: Thirty-three (43%) of the adenotonsillectomy children had high PSQ-SS scores, in comparison to only 3 (12%) of the controls (p=0.004). The PSQ-SS scores correlated inversely with mean sleep latencies on the Multiple Sleep Latency Tests (rho=−0.23, p=0.006). The obstructive apnea index, apnea/hypopnea index, and respiratory disturbance index (which included respiratory event-related arousals identified by esophageal pressure monitoring) each correlated similarly with PSQ-SS scores, as did investigational quantification of esophageal pressures and respiratory cycle-related EEG changes (each rho≈0.30, p<0.02). A stepwise regression identified sigma-frequency respiratory cycle-related EEG changes as the strongest independent predictor of subjective sleepiness among all subjects, and particularly those without obstructive sleep apnea.
Conclusions: Sleepiness is a frequent problem among children with suspected SDB. Subjective sleepiness (PSQ-SS) reflects Multiple Sleep Latency Test results to a limited extent, as in adults. Standard polysomnographic measures of SDB predict subjective sleepiness, but respiratory cycle-related EEG changes may offer additional clinical utility.
PMCID: PMC1463996  PMID: 16676783
polysomnography; sleep apnea, obstructive; tonsillectomy; child; sleepiness; Multiple Sleep Latency Test; Pediatric Sleep Questionnaire

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