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issn:1421-98.4
1.  Cerebrospinal Fluid Biomarkers and Proximity to Diagnosis in Preclinical Familial Alzheimer's Disease 
Background/Aims:
Biological markers of utility in tracking Alzheimer's disease (AD) during the presymptomatic prodromal phase are important for prevention studies. Changes in cerebrospinal fluid (CSF) levels of 42-amino-acid β-amyloid (Aβ42), total tau protein (t-tau) and phosphorylated tau at residue 181 (p-tau181) during this state are incompletely characterized.
Methods
We measured CSF markers in 13 carriers of familial AD (FAD) mutations that are fully penetrant for causing AD (PSEN1 and APP) and in 5 non-mutation-carrying family members.
Results
Even among the entirely presymptomatic mutation carriers (n = 9), Aβ42 was diminished (388.7 vs. 618.4 pg/ml, p = 0.004), and t-tau (138.5 vs. 50.5 pg/ml, p = 0.002) and p-tau181 (71.7 vs. 24.6 pg/ml, p = 0.003) were elevated. There was a negative correlation between Aβ42 levels and age relative to the family-specific age of dementia diagnosis.
Conclusions
Our data are consistent with a decline in CSF Aβ42 levels occurring at least 20 years prior to clinical dementia in FAD.
doi:10.1159/000335729
PMCID: PMC3696356  PMID: 22343824
Cerebrospinal fluid; Biomarkers; Familial Alzheimer's disease, presymptomatic; PSEN1 gene; APP gene; tau protein; β-Amyloid, 42-amino-acid form
2.  Prevalence of Sleep Disturbances in Mild Cognitive Impairment and Dementing Disorders: A Multicenter Italian Clinical Cross-Sectional Study on 431 Patients 
Background/Aims:
Sleep disturbances are common in the elderly and in persons with cognitive decline. The aim of this study was to describe frequency and characteristics of insomnia, excessive daytime sleepiness, sleep-disordered breathing, REM behavior disorder and restless legs syndrome in a large cohort of persons with mild cognitive impairment or dementia.
Methods
431 consecutive patients were enrolled in 10 Italian neurological centers: 204 had Alzheimer's disease, 138 mild cognitive impairment, 43 vascular dementia, 25 frontotemporal dementia and 21 Lewy body dementia or Parkinson's disease dementia. Sleep disorders were investigated with a battery of standardized questions and questionnaires.
Results
Over 60% of persons had one or more sleep disturbances almost invariably associated one to another without any evident and specific pattern of co-occurrence. Persons with Alzheimer's disease and those with mild cognitive impairment had the same frequency of any sleep disorder. Sleep-disordered breathing was more frequent in vascular dementia. REM behavior disorder was more represented in Lewy body or Parkinson's disease dementia.
Conclusion
A careful clinical evaluation of sleep disorders should be performed routinely in the clinical setting of persons with cognitive decline. Instrumental supports should be used only in selected patients.
doi:10.1159/000335363
PMCID: PMC3696366  PMID: 22415141
Sleep disorders; Excessive daytime sleepiness; Mild cognitive impairment; Alzheimer's disease; Frontotemporal dementia; Lewy body dementia; Parkinson's disease dementia; Vascular dementia
3.  The Diagnostic Value of Controlled Oral Word Association Test-FAS and Category Fluency in Single-Domain Amnestic Mild Cognitive Impairment 
Background
Recent studies have shown that decreases in both letter fluency and category fluency may be present in addition to memory impairment in single-domain amnestic mild cognitive impairment (aMCI). However, the clinical utility of these fluency measures is unclear. The aim of this study was to determine what, if any, diagnostic value letter and category fluency provide in differentiating single-domain aMCI from normal cognition.
Methods
Data from 66 individuals [33 cognitively normal (CN) and 33 aMCI] between the ages of 66 and 87 years participating in the Florida Alzheimer's Disease Research Center were compared on the Controlled Oral Word Association Test (COWAT)-FAS and Category Fluency test, both in terms of raw and scaled scores.
Results
Participants were matched on age, education and sex. Two-tailed independent sample t-tests found statistically significant differences between the CN and aMCI groups for both raw and scaled scores of COWAT-FAS and Category Fluency (p < 0.001). Logistic regression analyses found that COWAT-FAS and Category Fluency did not significantly improve diagnostic accuracy when combined with the Hopkins Verbal Learning Test-Revised delayed recall.
Conclusion
Although decreased COWAT-FAS and Category Fluency performance may be present in single-domain aMCI, these tests do not improve the ability of the Hopkins Verbal Learning Test-Revised delayed recall to differentiate aMCI from CN individuals.
doi:10.1159/000334525
PMCID: PMC3250647  PMID: 22156335
Prodromal Alzheimer's disease; Alzheimer's disease; Dementia; Neuropsychology; Mild cognitive impairment; Verbal fluency
4.  Estrogen Receptor-Beta Variants Are Associated with Increased Risk of Alzheimer's Disease in Women with Down Syndrome 
Background/Aims
Genetic variants that affect estrogen activity may influence the risk of Alzheimer's disease (AD). We examined the relation of polymorphisms in the gene for the estrogen receptor-beta (ESR2) to the risk of AD in women with Down syndrome.
Methods
Two hundred and forty-nine women with Down syndrome, 31–70 years of age and nondemented at baseline, were followed at 14- to 18-month intervals for 4 years. Women were genotyped for 13 single-nucleotide polymorphisms (SNPs) in the ESR2 gene, and their association with AD incidence was examined.
Results
Among postmenopausal women, we found a 2-fold increase in the risk of AD for women carrying 1 or 2 copies of the minor allele at 3 SNPs in introns seven (rs17766755) and six (rs4365213 and rs12435857) and 1 SNP in intron eight (rs4986938) of ESR2.
Conclusion
These findings support a role for estrogen and its major brain receptors in modulating susceptibility to AD in women.
doi:10.1159/000334522
PMCID: PMC3250648  PMID: 22156442
Estrogen; Estrogen receptor-beta; Down syndrome; Alzheimer's disease
5.  Association of Cognitive Function and Risk for Elder Abuse in a Community-Dwelling Population 
Aim
This study aimed to examine the cross-sectional association between cognitive function and elder abuse.
Methods
The Chicago Health and Aging Project (CHAP) is a population-based study conducted in a geographically defined community (n = 8,932). We identified 238 CHAP participants who had elder abuse reported to a social services agency. Cognitive function was assessed using the Mini-Mental State Examination (MMSE), the Symbol Digit Modalities Test (perceptual speed), and both immediate and delayed recall of the East Boston Memory Test (episodic memory). An index of global cognitive function scores was derived by averaging the z-scores of all tests. Logistic regression models were used to assess the association of cognitive function domains and risk of elder abuse.
Results
After adjusting for confounders, lowest tertiles of global cognition (odd's ratio, OR 4.18, 95% confidence interval, 95% CI 2.44–7.15), MMSE (OR 2.97, 95% CI 1.93–4.57), episodic memory (OR 2.27, 95% CI 1.49–3.43) and perceptual speed (OR 2.37, 95% CI 1.51–3.73) were associated with increased risk of elder abuse. The lowest levels of global cognitive function were associated with an increased risk of physical abuse (OR 3.56, 95% CI 1.08–11.67), emotional abuse (OR 3.02, 95% CI 1.41–6.44), caregiver neglect (OR 6.24, 95% CI 2.68–14.54), and financial exploitation (OR 3.71, 95% CI 1.88–7.32).
Conclusion
Lower levels of global cognitive function, MMSE, episodic memory and perceptual speed are associated with an increased risk of elder abuse.
doi:10.1159/000334047
PMCID: PMC3237103  PMID: 22095098
Elder abuse; Cognitive function; Mini-Mental State Examination
6.  Propositional Density and Apolipoprotein E Genotype among Persons at Risk for Familial Alzheimer's Disease 
Background/Aims
A relationship between decreased propositional density (p-density) in young adulthood and future risk for Alzheimer's disease (AD) has been postulated, but multiple interpretations of the nature of this relationship are possible. This study explored the relationship between familial AD (FAD) mutation status, apolipoprotein E (APOE) genotype, and p-density.
Methods
Thirty-five non-demented persons at risk for FAD mutations were recruited. Subjects wrote brief biographical essays from which p-density, the ratio of the number of unique ideas to the number of words in the text, was calculated. Mixed-effects regression models were used to examine the relationship of p-density and FAD mutation status and APOE genotype.
Results
FAD mutation status was not significantly associated with p-density. However, results from both models indicated that the presence of the APOE ∊4 allele was significantly associated with p-density (p < 0.0001), with APOE ∊4 carriers having lower p-density than non-carriers.
Conclusions
Our results are consistent with an influence of APOE status on p-density in young adulthood that is independent of the AD risk per se and suggest the previous finding of increased risk for the development of AD in persons with decreased p-density may be related to APOE genotype.
doi:10.1159/000333023
PMCID: PMC3542946  PMID: 22134129
Presenilin 1; Amyloid precursor protein; Early-onset Alzheimer's disease; Preclinical dementia; Alzheimer's disease; Linguistic ability
7.  Impact of SORL1 Single Nucleotide Polymorphisms on Alzheimer's Disease Cerebrospinal Fluid Markers 
Background
Recently, genetic variants of the neuronal sortilin-related receptor with A-type repeats (SORL1, also called LR11 or sorLA) have emerged as risk factors for the development of Alzheimer's disease (AD).
Methods
In this study, SORL1 gene polymorphisms, which have been shown to be related to AD, were analyzed for associations with cerebrospinal fluid (CSF) amyloid beta1–42 (Aβ1–42), phosphorylated tau181, and total tau levels in a non-Hispanic Caucasian sample, which encompassed 100 cognitively healthy elderly individuals, 166 patients with mild cognitive impairment, and 87 patients with probable AD. The data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database (www.loni.ucla.edu/ADNI). Moreover, the impact of gene-gene interactions between SORL1 single nucleotide polymorphisms (SNPs) and the apolipoprotein E (APOE) ∊4 allele, the major genetic risk factor for sporadic AD, on Aβ1–42 concentrations was investigated.
Results
Significant associations between CSF Aβ1–42 levels and the SORL1 SNPs 23 (rs3824968) and 24 (rs2282649) were detected in the AD group. The latter association became marginally statistically insignificant after Bonferroni correction for multiple comparisons. Carriers of the SORL1 SNP24 T allele and the SNP23 A allele both had lower CSF Aβ1–42 concentrations than non-carriers of these alleles. The analysis of the impact of interactions between APOE ∊4 allele and SORL1 SNPs on CSF Aβ1–42 levels unraveled significant influences of APOE.
Conclusions
Our findings provide further support for the notion that SORL1 genetic variants are related to AD pathology, probably by regulating the amyloid cascade.
doi:10.1159/000332017
PMCID: PMC3696367  PMID: 21997402
Dementia; Mild cognitive impairment; Healthy aging; Amyloid cascade; Association
8.  Cortical and Hippocampal Atrophy in Patients with Autosomal Dominant Familial Alzheimer's Disease 
Background
Both familial and sporadic Alzheimer's disease (AD) result in progressive cortical and subcortical atrophy. Familial autosomal dominant AD (FAD) allows us to study AD brain changes presymptomatically.
Methods
33 subjects at risk for FAD (25 for PSEN1 and 8 for APP mutations; 22 mutation carriers and 11 controls) and 3 demented PSEN1 mutation carriers underwent T1-weighted MPRAGE 1.5T MRI. Using the hippocampal radial distance and cortical pattern matching techniques, we investigated the effects of carrier status and dementia diagnosis on cortical and hippocampal atrophy. All analyses were corrected for age and relative age (years to median age of disease onset in the family).
Results
The dementia cases had pronounced cortical atrophy in the lateral and medial parietal, posterior cingulate and frontal cortices and hippocampal atrophy bilaterally relative to both nondemented carriers and controls. Nondemented carriers did not show significant cortical thinning or hippocampal atrophy relative to controls.
Conclusions
FAD is associated with thinning of the posterior association and frontal cortices and hippocampal atrophy. Larger sample sizes may be necessary to reliably identify cortical atrophy in presymptomatic carriers.
doi:10.1159/000330471
PMCID: PMC3222115  PMID: 21952501
Familial Alzheimer's disease; Familial autosomal dominant Alzheimer's disease; Presenilin; Amyloid precursor protein; Hippocampal atrophy; Cortical atrophy; Mutation carriers
9.  A Blood-Based Algorithm for the Detection of Alzheimer's Disease 
Background
We previously created a serum-based algorithm that yielded excellent diagnostic accuracy in Alzheimer's disease. The current project was designed to refine that algorithm by reducing the number of serum proteins and by including clinical labs. The link between the biomarker risk score and neuropsychological performance was also examined.
Methods
Serum-protein multiplex biomarker data from 197 patients diagnosed with Alzheimer's disease and 203 cognitively normal controls from the Texas Alzheimer's Research Consortium were analyzed. The 30 markers identified as the most important from our initial analyses and clinical labs were utilized to create the algorithm.
Results
The 30-protein risk score yielded a sensitivity, specificity, and AUC of 0.88, 0.82, and 0.91, respectively. When combined with demographic data and clinical labs, the algorithm yielded a sensitivity, specificity, and AUC of 0.89, 0.85, and 0.94, respectively. In linear regression models, the biomarker risk score was most strongly related to neuropsychological tests of language and memory.
Conclusions
Our previously published diagnostic algorithm can be restricted to only 30 serum proteins and still retain excellent diagnostic accuracy. Additionally, the revised biomarker risk score is significantly related to neuropsychological test performance.
doi:10.1159/000330750
PMCID: PMC3169374  PMID: 21865746
Algorithm, blood-based; Alzheimer's disease; Diagnosis
10.  Type 2 Diabetes and Late-Onset Alzheimer's Disease 
Background/Aims
To confirm in a cohort recruited in 1999–2001 our finding in a cohort recruited in 1992–1994 relating type 2 diabetes (T2D) to late-onset Alzheimer's disease (LOAD).
Methods
Participants were 1,488 persons aged 65 years and older without dementia at baseline from New York City. T2D was ascertained by self-report. Dementia and LOAD were ascertained by standard research procedures. Proportional hazard regression was used for analyses relating T2D and LOAD.
Results
The prevalence of T2D was 17%. There were 161 cases of dementia and 149 cases of LOAD. T2D was related to dementia (hazard ratio = 1.7; 95% confidence interval = 1.4–2.9) and LOAD (1.6; 1.0–2.6) after adjustment for age, sex, education, ethnic group and apolipoprotein E ∊4. This association was weaker when only AD – excluding cases of mixed dementia – was considered (hazard ratio = 1.3; 95% confidence interval = 0.8–2.2).
Conclusion
T2D is associated with LOAD. Cerebrovascular disease may be an important mediator.
doi:10.1159/000324134
PMCID: PMC3142096  PMID: 21757907
Type 2 diabetes; Alzheimer's disease
11.  Instrumental Activities of Daily Living Impairment Is Associated with Increased Amyloid Burden 
Background/Aims
Instrumental activities of daily living (IADL) impairment in Alzheimer's disease has been associated with global amyloid deposition in postmortem studies. We sought to determine whether IADL impairment is associated with increased cortical Pittsburgh Compound B (PiB) retention.
Methods
Fifty-five subjects (19 normal older controls, NC, and 36 with mild cognitive impairment, MCI) underwent clinical assessments and dynamic PiB positron emission tomography imaging.
Results
A linear multiple regression model showed that greater IADL impairment was associated with greater global PiB retention in all subjects (R2 = 0.40; unstandardized partial regression coefficient, β = 5.8; p = 0.0002) and in MCI subjects only (R2 = 0.28; β = 6.1; p = 0.003), but not in NC subjects only.
Conclusion
These results suggest that daily functional impairment is related to greater amyloid burden in MCI.
doi:10.1159/000329543
PMCID: PMC3150869  PMID: 21778725
Alzheimer's disease; Amyloid; Instrumental activities of daily living; Mild cognitive impairment; Pittsburgh compound B; Positron emission tomography
12.  Visual Rating versus Volumetry to Detect Frontotemporal Dementia 
Background/Aims
Automated, volumetrically defined atrophy in the left anterior cingulate (LAC) and anterior temporal regions (LAT) on MRI can be used to distinguish most patients with frontotemporal dementia (FTD) from controls. FTD and Alzheimer's disease (AD) can differ in the degree of anterior temporal atrophy. We explored whether clinicians can visually detect this atrophy pattern and whether they can use it to classify the 2 groups of dementia patients with the same accuracy.
Methods
Four neurologists rated atrophy in the LAC and LAT regions on MRI slices from 21 FTD, 21 controls, and 14 AD participants. Inter-rater reliability and diagnostic accuracy were assessed.
Results
All 4 raters agreed on the presence of clinically significant atrophy, and their atrophy scoring correlated with the volumes, but without translation into high inter-rater diagnostic agreement.
Conclusions
Volumetric analyses are difficult to translate into routine clinical practice.
doi:10.1159/000328415
PMCID: PMC3202946  PMID: 21625137
Alzheimer's disease; Frontotemporal dementia; Magnetic resonance imaging; Visual rating
13.  Current Serum Lipoprotein Levels and fMRI Response to Working Memory in Midlife 
Aims
Given that high cholesterol levels at midlife are a risk factor for future cognitive decline, the goal of the current study was to determine if cholesterol-related alterations in the cerebrovascular response to cognition could be detected at midlife.
Methods
Forty adults, aged 40–60 years, performed a 2-Back working memory task during fMRI. The associations between serum total cholesterol, HDL-cholesterol, and total cholesterol/HDL-cholesterol concentrations to task-related activation intensity were modeled using multivariate multiple regression (two-tailed p < 0.02).
Results
Higher levels of total cholesterol/HDL-cholesterol related to reduced working memory-related activation intensity in the left inferior parietal lobe, right superior frontal gyrus, and right middle frontal gyrus.
Conclusion
These data provide preliminary support for a deleterious effect of elevated total cholesterol/HDL-cholesterol ratio on cerebrovascular support for cognition in midlife.
doi:10.1159/000324713
PMCID: PMC3085033  PMID: 21494033
Brain imaging; Cholesterol; Cognition; Cognitive impairment; Vascular causes; Working memory
14.  Minimal Atrophy of the Entorhinal Cortex and Hippocampus: Progression of Cognitive Impairment 
Background
In Alzheimer's disease, neurodegenerative atrophy progresses from the entorhinal cortex (ERC) to the hippocampus (HP), limbic system and neocortex. The significance of very mild atrophy of the ERC and HP on MRI scans among elderly subjects is unknown.
Methods
A validated visual rating system on coronal MRI scans was used to identify no atrophy of the HP or ERC (HP0; ERC0), or minimal atrophy of the HP or ERC (HPma; ERCma), among 414 participants. Subjects fell into the following groups: (1) ERC0/HP0, (2) ERCma/HP0, (3) ERC0/HPma, and (4) ERCma/HPma. HP volume was independently measured using volumetric methods.
Results
In comparison to ERC0/HP0 subjects, those with ERC0/HPma had impairment on 1 memory test, ERCma/HP0 subjects had impairment on 2 memory tests and the Mini Mental State Examination (MMSE), while ERCma/HPma subjects had impairment on 3 memory tests, the MMSE and Clinical Dementia Rating. Progression rates of cognitive and functional impairment were significantly greater among subjects with ERCma.
Conclusion
Minimal atrophy of the ERC results in greater impairment than minimal atrophy of the HP, and the combination is additive when measured by cognitive and functional tests. Rates of progression to greater impairment were higher among ERCma subjects.
doi:10.1159/000324711
PMCID: PMC3085034  PMID: 21494034
Alzheimer disease; Brain MRI; Cognitive and functional impairment; Dementia; Entorhinal and hippocampal atrophy; Progression; Visual rating
15.  Clock Drawing in the Montreal Cognitive Assessment: Recommendations for Dementia Assessment 
Background
Clock drawing is part of the Montreal Cognitive Assessment (MoCA) test but may have administration and scoring limitations. We assessed (1) the reliability of the MoCA clock criteria relative to a published error scoring approach, (2) whether command-only administration could distinguish dementia from cognitively intact individuals and (3) the value of adding a clock copy condition to the MoCA.
Methods
Three novice raters and clocks from dementia and control participants were used to assess the 3 aims.
Results
MoCA interrater and intrarater reliability were low (i.e. intraclass correlation coefficient = 0.12–0.31) and required repeat training. Clocks drawn to command classified dementia at chance. Inclusion of a copy condition demonstrated expected dementia subgroup patterns.
Conclusion
Reliable clock scoring with MoCA criteria requires practice. Supplementing a clock copy to the standard MoCA test (takes <1 min) will improve dementia assessment.
doi:10.1159/000324639
PMCID: PMC3065510  PMID: 21389719
Montreal Cognitive Assessment scoring, rater reliability; Parkinson disease with dementia; Alzheimer disease; Vascular dementia; Cognition
16.  Sleep Disturbance in Dementia with Lewy Bodies and Alzheimer's Disease: A Multicenter Analysis 
Background/Aims
Evidence suggests that patients with dementia with Lewy bodies (DLB) may have more nocturnal sleep disturbance than patients with Alzheimer's disease (AD). We sought to confirm such observations using a large, prospectively collected, standardized, multicenter-derived database, i.e. the National Alzheimer's Coordinating Center Uniform Data Set.
Methods
Nocturnal sleep disturbance (NSD) data, as characterized by the Neuropsychiatric Inventory Questionnaire (NPI-Q), were derived from 4,531 patients collected between September 2005 and November 2008 from 32 National Institute on Aging participating AD centers. Patient and informant characteristics were compared between those with and without NSD by dementia diagnosis (DLB and probable AD). Finally, a logistic regression model was created to quantify the association between NSD status and diagnosis while adjusting for these patient/informant characteristics, as well as center.
Results
NSD was more frequent in clinically diagnosed DLB relative to clinically diagnosed AD (odds ratio = 2.93, 95% confidence interval = 2.22–3.86). These results were independent from the gender of the patient or informant, whether the informant lived with the patient, and other patient characteristics, such as dementia severity, depressive symptoms, and NPI-Q-derived measures of hallucinations, delusions, agitation and apathy. In AD, but not DLB, patients, NSD was associated with more advanced disease. Comorbidity of NSD with hallucinations, agitation and apathy was higher in DLB than in AD. There was also evidence that the percentage of DLB cases with NSD showed wide variation across centers.
Conclusion
As defined by the NPI-Q, endorsement of the nocturnal behavior item by informants is more likely in patients with DLB when compared to AD, even after the adjustment of key patient/informant characteristics.
doi:10.1159/000326238
PMCID: PMC3085031  PMID: 21474933
Dementia with Lewy bodies; Alzheimer's disease; Sleep; Neuropsychiatric Inventory Questionnaire
17.  Longitudinal Changes in Cognition in Parkinson's Disease with and without Dementia 
Background
The longitudinal cognitive course in Parkinson's disease (PD) with and without dementia remains undefined. We compared cross-sectional models of cognition in PD (both with and without dementia), Alzheimer's disease (AD), and nondemented aging and followed the participants over time.
Method
Previously validated models of cognitive performance in AD and nondemented aging were extended to individuals with PD (with dementia, n = 71; without dementia, n = 47). Confirmatory factor analysis and piecewise regression were used to compare the longitudinal course of participants with PD with 191 cognitively healthy subjects and 115 individuals with autopsy-confirmed AD.
Results
A factor analytic model with one general factor and three specific factors (verbal memory, visuospatial memory, working memory) fit demented and nondemented PD. Longitudinal change indicated that individuals with PD with dementia declined significantly more rapidly on visuospatial and verbal memory tasks than AD alone. Cognitive declines across all factors in AD and PD dementia accelerated several years prior to clinical dementia diagnosis.
Conclusion
Both specific and global cognitive changes are witnessed in PD and AD. Longitudinal profiles of cognitive decline in PD and AD differed. PD with or without dementia has a core feature of longitudinal decline in visuospatial abilities.
doi:10.1159/000323570
PMCID: PMC3047760  PMID: 21242691
Alzheimer's disease; Parkinson's disease with dementia; Parkinson's disease/parkinsonism; Longitudinal cognitive course; Confirmatory factor analysis
18.  A Method to Combine Cognitive and Neurophysiological Assessments of the Elderly 
Background
The development of better treatments for brain diseases of the elderly will necessitate more sensitive and efficient means of repeatedly assessing an individual's neurocognitive status.
Aim
To illustrate the development of an assessment combining episodic memory and working memory tasks with simultaneous electroencephalography and evoked potential (EP) brain function measures.
Methods
Data from matched groups of elderly subjects with mildly impaired episodic verbal memory on neuropsychological tests and those with no objective signs of impairment were used for scale development. An exploratory multivariate divergence analysis selected task performance and neurophysiological variables that best recognized impairment. Discriminant validity was then initially assessed on separate impaired and unimpaired groups.
Results
Decreased response accuracy and parietal late positive component EP amplitude in the episodic memory task best characterized impaired subjects. Sensitivity in recognizing impairment in the validation analysis was 89% with 79% specificity (area under the curve = 0.94). Retest reliability was 0.89 for the unimpaired and 0.74 for the impaired validation groups.
Conclusion
These promising initial results suggest that with further refinement and testing, an assessment combining cognitive task performance with simultaneous neurofunctional measures could eventually provide an important benefit for clinicians and researchers.
doi:10.1159/000322108
PMCID: PMC3019365  PMID: 21109739
Mild cognitive impairment; Neuropsychology; Neurophysiology; Neurocognitive; Electroencephalography; Evoked potential; Episodic memory; Working memory
19.  Serum Brain-Derived Neurotrophic Factor Levels Are Specifically Associated with Memory Performance among Alzheimer's Disease Cases 
Aims
Our purpose was to study the link between serum brain-derived neurotrophic factor (BDNF) levels and neuropsychological functioning through the Texas Alzheimer's Research Consortium cohort.
Methods
A total of 399 participants [probable Alzheimer's disease (AD) n = 198, controls n = 201] were available for analysis. The BDNF levels were assayed via multiplex immunoassay. Regression analyses were utilized to examine the relation between BDNF levels and neuropsychological functioning.
Results
There were no significant mean differences in BDNF levels between cases and controls. In the AD group, the BDNF levels were significantly negatively associated with the scores on immediate [B = −0.07 (0.02), t = −3.55, p = 0.001] and delayed [B = −0.05 (0.02), t = −2.79, p = 0.01] verbal memory and immediate [B = −0.12 (0.05), t = −2.70, p = 0.01] visual memory. No other neuropsychological variables were significantly related to the BDNF levels. The BDNF levels were not significantly related to the neuropsychological test scores in the control group.
Conclusions
Increased serum BDNF levels were associated with poorer visual and verbal memory, but only among AD cases. The current findings point toward an upregulation of serum BDNF as one possible mechanism linked to memory disturbances in AD though it does not appear to be linked to disease severity.
doi:10.1159/000321980
PMCID: PMC3019366  PMID: 21135555
Alzheimer's disease; Biomarkers; Brain-derived neurotrophic factor; Cognition; Neuropsychology; Aging
20.  Probable Early-Onset Alzheimer's Disease in an Apolipoprotein E2 Homozygote 
Objective
To describe a case of early-onset Alzheimer's disease (AD) in an apolipoprotein (Apo) ∊2/∊2 homozygote.
Background
Apo ∊2/∊2 is the rarest of the ApoE genotypes, representing only 1.4% of the population. Cognitive decline in ApoE ∊2 homozygotes has rarely been reported. Case Report/Methods: We report a 58-year-old Apo ∊2/∊2 female who meets clinical criteria for probable AD as confirmed by neuropsychological testing, positron emission/computed tomography scan, CSF analysis and genetic screening for known mutations.
Results
The clinical course is typical of AD, with progressive cognitive and functional decline.
Conclusion
Clinically confirmed early-onset AD is atypical in ApoE2 homozygotes but can occur.
doi:10.1159/000320589
PMCID: PMC2992638  PMID: 20975270
Alzheimer's disease; Apolipoprotein E2; Homozygote; Positron emission tomography scan; Neuropsychological assessment; Cerebrospinal fluid analysis
21.  Subtle Deficits in Instrumental Activities of Daily Living in Subtypes of Mild Cognitive Impairment 
Background/Aims
Greater cognitive and functional deficits in mild cognitive impairment (MCI) are associated with higher rates of dementia. We explored the relationship between these factors by comparing instrumental activities of daily living (IADLs) among cognitive subtypes of MCI and examining associations between IADL and neuropsychological indices.
Methods
We analyzed data from 1,108 MCI and 3,036 normal control subjects included in the National Alzheimer's Coordinating Center Uniform Data Set who were assessed with the Functional Activities Questionnaire (FAQ).
Results
IADL deficits were greater in amnestic than nonamnestic MCI, but within these subgroups, did not differ between those with single or multiple domains of cognitive impairment. FAQ indices correlated significantly with memory and processing speed/executive function.
Conclusions
IADL deficits are present in both amnestic MCI and nonamnestic MCI but are not related to the number of impaired cognitive domains. These cross-sectional findings support previous longitudinal reports suggesting that cognitive and functional impairments in MCI may be independently associated with dementia risk.
doi:10.1159/000313540
PMCID: PMC2948658  PMID: 20798539
Mild cognitive impairment; Functional impairment; Activities of daily living; Memory performance; Executive function
22.  Thyroid Hormones Are Associated with Poorer Cognition in Mild Cognitive Impairment 
Background
Alterations in interrelated endocrine axes may be related to the pathogenesis of mild cognitive impairment (MCI) and dementia.
Methods
Salivary cortisol before and after a 0.5-mg dexamethasone test, and serum levels of thyroid-stimulating hormone, total thyroxine (T4), free T4, total triiodothyronine (TT3), estradiol, testosterone and insulin-like growth factor 1 were measured in 43 MCI cases and 26 healthy controls. All participants underwent a comprehensive neuropsychological test battery covering the cognitive domains of speed/attention, memory, visuospatial functions, language and executive functions.
Results
The MCI group did not differ in basal levels of endocrine markers compared to controls. Among those with MCI, TT3 levels were inversely associated with cognitive performance across all domains. After stratifying MCI cases according to TT3 levels, those with relatively high TT3 levels showed impairment in memory as well as in visuospatial and executive functions. Those with TT3 levels at or below the lower boundary of the normal range performed comparably to healthy controls. Other endocrine markers were not related to cognitive performance.
Conclusions
Among those with MCI, TT3 was associated with a neuropsychological profile typical of prodromal Alzheimer's disease. While the mechanisms remain unclear, optimal levels of thyroid hormone under a compromising condition such as MCI and related neuropathology need reconsideration.
doi:10.1159/000319746
PMCID: PMC2948659  PMID: 20798541
Mild cognitive impairment; Neuropsychology; Cortisol; Thyroid hormones; Insulin-like growth factor 1; Sex steroids
23.  Predictive Utility of Type and Duration of Symptoms at Initial Presentation in Patients with Mild Cognitive Impairment 
Background/Aims
To assess (1) the duration and symptoms present in participants with mild cognitive impairment (MCI) and (2) the impact of these variables on predicting conversion to Alzheimer's disease (AD).
Methods
Participants with MCI (n = 148) were assessed and followed systematically.
Results
Decline in memory was reported as the first symptom in 118 of the cases. Converters had more symptoms (e.g. language decline, depression), and the combination of decline in memory and in performance of high-order social/cognitive activities as well as disorientation more often than nonconverters (p = 0.036). In an age-stratified Cox model, predictors of conversion to AD were shorter time since onset of memory decline and lower baseline MMSE score.
Conclusions
Recent onset of memory decline with older age, decreased MMSE score, change in performance and disorientation indicate a greater likelihood of short-term conversion to AD.
Copyright © 2010 S. Karger AG, Basel
doi:10.1159/000320137
PMCID: PMC2948660  PMID: 20847554
Age at onset; Alzheimer's disease; Behavioral symptoms; Mild cognitive impairment; Neuropsychological assessment
24.  Baseline Predictors of Clinical Progression among Patients with Dysexecutive Mild Cognitive Impairment 
Background/Aims
There are few studies that evaluate the clinical outcomes of individuals with non-amnestic mild cognitive impairment (MCI). The purpose of this study was to evaluate baseline predictors of clinical progression after 2 years for patients with dysexecutive MCI (dMCI), a single-domain non-amnestic MCI subgroup.
Methods
We evaluated clinical progression in a sample of 31 older adults with dMCI. Clinical progression was defined as a worsening on the Clinical Dementia Rating sum of boxes at the 2-year visit, whereas patients were classified as stable if the score did not worsen over 2 years. We compared baseline brain MRI, neuropsychological tests, and health risk factors.
Results
Twelve individuals with dMCI progressed clinically, and 19 individuals remained stable over 2 years. Compared to the stable dMCI patients, the dMCI patients who progressed showed brain atrophy in the bilateral insula and left lateral temporal lobe on MRI. dMCI patients who progressed were also older, had lower baseline performance on category fluency and a spatial location task, and reported fewer dysexecutive symptoms. Health risk factors, except hypertension, did not differ between groups.
Conclusion
The results suggest that dMCI patients who progress relatively quickly over 2 years may have unique clinical and brain MRI features.
doi:10.1159/000318836
PMCID: PMC2975734  PMID: 20938178
Executive function; Non-amnestic mild cognitive impairment; Dysexecutive mild cognitive impairment
25.  An MRI-Based Semiquantitative Index for the Evaluation of Brain Atrophy and Lesions in Alzheimer's Disease, Mild Cognitive Impairment and Normal Aging 
Background
This study investigates how T1-weighted MRI can be used to evaluate brain anatomical changes. We investigated these changes in Alzheimer's disease (AD) and normal aging.
Methods
A semiquantitative brain atrophy and lesion index (BALI) was constructed by adapting existing visual rating scales and validated in 3 datasets.
Results
The T1- and T2-weighted-imaging-based scores were highly correlated. They were both closely associated with age and with cognitive test scores.
Conclusion
The T1-based BALI helps describe brain structural variability in AD, mild cognitive impairment and normal aging.
doi:10.1159/000319537
PMCID: PMC2969164  PMID: 20733305
Aging; Alzheimer's disease; Brain lesions; Brain atrophy; Mild cognitive impairment

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