Alzheimer Disease: Harrell LE

Marson DC, Sawrie SM, Snyder S, McInturff B, Stalvey T, Boothe A, Aldridge T, Chatterjee A, Harrell LE. · Department of Neurology, University of Alabama at Birmingham School of Medicine, 625 19th St S, 1216 Jefferson Tower, Birmingham, AL 35233-7340, USA. · Arch Neurol. · Pubmed #10867786 links to  free full text

Abstract: OBJECTIVE: To investigate financial capacity in patients with Alzheimer disease (AD) using a new theoretical model and prototype psychometric instrument. DESIGN: Cross-sectional comparisons of older control subjects (n=23) and patients with mild (n=30) and moderate AD (n=20). MAIN OUTCOME MEASURES: Financial capacity was measured using the Financial Capacity Instrument, a prototype psychometric instrument that tests financial capacity using 14 tasks of financial ability comprising 6 clinically relevant domains of financial activity: basic monetary skills, financial conceptual knowledge, cash transactions, checkbook management, bank statement management, and financial judgment. RESULTS: The Financial Capacity Instrument tasks and domains showed adequate to excellent internal, interrater, and test-retest reliabilities. At the task level, patients with mild AD performed equivalently with controls on simple tasks such as counting coins/currency and conducting a 1-item grocery purchase, but significantly below controls on more complex tasks such as using a checkbook/register and understanding and using a bank statement. At the domain level, patients with mild AD performed significantly below controls on all domains except basic monetary skills. Patients with moderate AD performed significantly below controls and patients with mild AD on all tasks and domains. Regarding capacity status outcomes (capable, marginally capable, incapable) on domains, patients with mild AD had high proportions of marginally capable or incapable outcomes (range, 47%-87%), particularly on difficult domains like bank statement management (domain 5) and financial judgment (domain 6), but variability in individual outcomes. Patients with moderate AD had almost exclusively incapable outcomes across the 6 domains (range, 90%-100%). CONCLUSIONS: Financial capacity is already significantly impaired in mild AD. Patients with mild AD demonstrate deficits in more complex financial abilities and impairment in most financial activities. Patients with moderate AD demonstrate severe impairment of all financial abilities and activities. The Financial Capacity Instrument has promise as an instrument for assessing domain-level financial activities and task-specific financial abilities in patients with dementia. Arch Neurol. 2000.

Marson DC, Martin RC, Wadley V, Griffith HR, Snyder S, Goode PS, Kinney FC, Nicholas AP, Steele T, Anderson B, Zamrini E, Raman R, Bartolucci A, Harrell LE. · Department of Neurology, SC 650, University of Alabama at Birmingham, Birmingham, AL 35294, USA. · J Am Geriatr Soc. · Pubmed #19453308 No free full text.

Abstract: OBJECTIVES: To investigate financial capacity in patients with mild cognitive impairment (MCI) and Alzheimer's disease (AD) using a clinician interview approach. DESIGN: Cross-sectional. SETTING: Tertiary care medical center. PARTICIPANTS: Healthy older adults (n=75) and patients with amnestic MCI (n=58), mild AD (n=97), and moderate AD (n=31). MEASUREMENTS: The investigators and five study physicians developed a conceptually based, semistructured clinical interview for evaluating seven core financial domains and overall financial capacity (Semi-Structured Clinical Interview for Financial Capacity; SCIFC). For each participant, a physician made capacity judgments (capable, marginally capable, or incapable) for each financial domain and for overall capacity. RESULTS: Study physicians made more than 11,000 capacity judgments across the study sample (N=261). Very good interrater agreement was obtained for the SCIFC judgments. Increasing proportions of marginal and incapable judgment ratings were associated with increasing disease severity across the four study groups. For overall financial capacity, 95% of physician judgments for older controls were rated as capable, compared with 82% for patients with MCI, 26% for patients with mild AD, and 4% for patients with moderate AD. CONCLUSION: Physicians and other clinicians can reliably evaluate financial capacity in cognitively impaired older adults using a relatively brief, semistructured clinical interview. Patients with MCI have mild impairment in financial capacity, those with mild AD have emerging global impairment, and those with moderate AD have advanced global impairment. Patients with MCI and their families should proactively engage in financial and legal planning, given these patients' risk of developing AD and accelerated loss of financial abilities.

Sherod MG, Griffith HR, Copeland J, Belue K, Krzywanski S, Zamrini EY, Harrell LE, Clark DG, Brockington JC, Powers RE, Marson DC. · Department of Neurology, University of Alabama at Birmingham, 35294-0017, USA. · J Int Neuropsychol Soc. · Pubmed #19203439 No free full text.

Abstract: Financial capacity is a complex instrumental activity of daily living critical to independent functioning of older adults and sensitive to impairment in patients with amnestic mild cognitive impairment (MCI) and Alzheimer's disease (AD). However, little is known about the neurocognitive basis of financial impairment in dementia. We developed cognitive models of financial capacity in cognitively healthy older adults (n = 85) and patients with MCI (n = 113) and mild AD (n = 43). All participants were administered the Financial Capacity Instrument (FCI) and a neuropsychological test battery. Univariate correlation and multiple regression procedures were used to develop cognitive models of overall FCI performance across groups. The control model (R2 = .38) comprised (in order of entry) written arithmetic skills, delayed story recall, and simple visuomotor sequencing. The MCI model (R2 = .69) comprised written arithmetic skills, visuomotor sequencing and set alternation, and race. The AD model (R2 = .65) comprised written arithmetic skills, simple visuomotor sequencing, and immediate story recall. Written arithmetic skills (WRAT-3 Arithmetic) was the primary predictor across models, accounting for 27% (control model), 46% (AD model), and 55% (MCI model) of variance. Executive function and verbal memory were secondary model predictors. The results offer insight into the cognitive basis of financial capacity across the dementia spectrum of cognitive aging, MCI, and AD.

Okonkwo OC, Griffith HR, Copeland JN, Belue K, Lanza S, Zamrini EY, Harrell LE, Brockington JC, Clark D, Raman R, Marson DC. · Department of Psychology, SC 650K, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA. · Neurology. · Pubmed #18981368 No free full text.

Abstract: OBJECTIVE: To investigate longitudinal change in the medical decision-making capacity (MDC) of patients with amnestic mild cognitive impairment (MCI) under different consent standards. METHODS: Eighty-eight healthy older controls and 116 patients with MCI were administered the Capacity to Consent to Treatment Instrument at baseline and at 1 to 3 (mean = 1.7) annual follow-up visits thereafter. Covariate-adjusted random coefficient regressions were used to examine differences in MDC trajectories across MCI and control participants, as well as to investigate the impact of conversion to Alzheimer disease on MCI patients' MDC trajectories. RESULTS: At baseline, MCI patients performed significantly below controls only on the three clinically relevant standards of appreciation, reasoning, and understanding. Compared with controls, MCI patients experienced significant declines over time on understanding but not on any other consent standard. Conversion affected both the elevation (a decrease in performance) and slope (acceleration in subsequent rate of decline) of MCI patients' MDC trajectories on understanding. A trend emerged for conversion to be associated with a performance decrease on reasoning in the MCI group. CONCLUSIONS: Medical decision-making capacity (MDC) decline in mild cognitive impairment (MCI) is a relatively slow but detectable process. Over a 3-year period, patients with amnestic MCI show progressive decline in the ability to understand consent information. This decline accelerates after conversion to Alzheimer disease (AD), reflecting increasing vulnerability to decisional impairment. Clinicians and researchers working with MCI patients should give particular attention to the informed consent process when conversion to AD is suspected or confirmed.

Baye TM, Perry RT, Wiener HW, Chen Z, Harrell LE, Go RC. · Section on Statistical Genetics, Department of Biostatistics, University of Alabama at Birmingham, Birmingham, AL 35294, USA. · Dis Markers. · Pubmed #18688078 No free full text.

Abstract: The objective of this research was to develop a procedure to identify candidate genes under linkage peaks confirmed in a follow-up of candidate regions of interests (CRIs) identified in our original genome scan in the NIMH Alzheimer's diseases (AD) Initiative families (Blacker et al. [1]). There were six CRIs identified that met the threshold of multipoint lod score (MLS) of >or= 2.0 from the original scan. The most significant peak (MLS = 7.7) was at 19q13, which was attributed to APOE. The remaining CRIs with 'suggestive' evidence for linkage were identified at 9q22, 6q27, 14q22, 11q25, and 3p26. We have followed up and narrowed the 9q22 CRI signal using simple tandem repeat (STR) markers (Perry et al. [2]). In this confirmatory project, we have followed up the 6q27, 14q22, 11q25, and 3p26 CRIs with a total of 24 additional flanking STRs, reducing the mean interval marker distance (MID) in each CRI, and substantially increase in the information content (IC). The linkage signals at 6q27, 14q22 and 11q25 remain 'suggestive', indicating that these CRIs are promising and worthy of detailed fine mapping and assessment of candidate genes associated with AD. We have developed a bioinformatics approach for identifying candidate genes in these confirmed regions based on the Gene Ontology terms that are annotated and enriched among the systematic meta-analyzed genes, confirmed by at least three case-control samples, and cataloged in the "AlzGene database" as potential Alzheimer disease susceptibility genes (http://www.alzgene.org).

Okonkwo OC, Wadley VG, Griffith HR, Belue K, Lanza S, Zamrini EY, Harrell LE, Brockington JC, Clark D, Raman R, Marson DC. · Department of Psychology, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA. · Am J Geriatr Psychiatry. · Pubmed #18669943 No free full text.

Abstract: OBJECTIVE: Self and informant reports of functional abilities are weighted heavily in diagnostic decision making regarding mild cognitive impairment (MCI). However, it is unclear whether patients with MCI are fully aware and provide reliable estimates of their functional status. In this study, the authors used three different approaches to examine accuracy of self-report of financial abilities among patients with MCI. DESIGN: Cross-sectional, case-comparison group study. SETTING: University medical center. PARTICIPANTS: Seventy-four patients with MCI and their informants, and 73 cognitively healthy older adults and their informants. MEASUREMENTS: The authors compared MCI patients' report of their financial abilities with their performance on an objective measure of financial capacity. The authors also compared informant reports of patients' abilities with patients' objective test performance, and informant reports with patients' self-report. RESULTS: The authors found that the discrepancy between self-report and objective performance was higher among MCI patients compared with the cognitively healthy older adults on the financial domains of Checkbook Management, Bank Statement Management, and Bill Payment, and on overall financial capacity. The authors also found that MCI patients with poorer global cognition overestimated their financial abilities whereas those with higher depressive symptoms underestimated their financial abilities. Overall, MCI patients were better at estimating their financial abilities than their informants. CONCLUSIONS: Patients with MCI are not fully aware of deficits in their financial abilities. Both cognitive impairment and depression impact MCI patients' self-reported functioning. In addition, MCI informants misestimate patients' financial abilities. This raises concerns about the widespread use of informant report as the gold standard against which to evaluate patient self-report of functioning.

Okonkwo OC, Griffith HR, Belue K, Lanza S, Zamrini EY, Harrell LE, Brockington JC, Clark D, Raman R, Marson DC. · Department of Psychology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0017, USA. · J Int Neuropsychol Soc. · Pubmed #18282327 No free full text.

Abstract: This study investigated cognitive predictors of medical decision-making capacity (MDC) in patients with amnestic mild cognitive impairment (MCI). A total of 56 healthy controls, 60 patients with MCI, and 31 patients with mild Alzheimer's disease (AD) were administered the Capacity to Consent to Treatment Instrument (CCTI) and a neuropsychological test battery. The CCTI assesses MDC across four established treatment consent standards--S1 (expressing choice), S3 (appreciation), S4 (reasoning), and S5 (understanding)--and one experimental standard [S2] (reasonable choice). Scores on neuropsychological measures were correlated with scores on each CCTI standard. Significant bivariate correlates were subsequently entered into stepwise regression analyses to identity group-specific multivariable predictors of MDC across CCTI standards. Different multivariable cognitive models emerged across groups and consent standards. For the MCI group, measures of short-term verbal memory were key predictors of MDC for each of the three clinically relevant standards (S3, S4, and S5). Secondary predictors were measures of executive function. In contrast, in the mild AD group, measures tapping executive function and processing speed were primary predictors of S3, S4, and S5. MDC in patients with MCI is supported primarily by short-term verbal memory. The findings demonstrate the impact of amnestic deficits on MDC in patients with MCI.

Okonkwo O, Griffith HR, Belue K, Lanza S, Zamrini EY, Harrell LE, Brockington JC, Clark D, Raman R, Marson DC. · Department of Neurology, JT 1216, University of Alabama at Birmingham, Birmingham, AL 35233-7340, USA. · Neurology. · Pubmed #17923615 No free full text.

Abstract: OBJECTIVES: To empirically assess the capacity of patients with amnestic mild cognitive impairment (MCI) to consent to medical treatment under different consent standards (Ss). METHODS: Participants were 56 healthy controls, 60 patients with MCI, and 31 patients with mild Alzheimer disease (AD). Each participant was administered the Capacity to Consent to Treatment Instrument (CCTI) and a comprehensive neuropsychological battery. Group differences in performance on the CCTI and neuropsychological variables were examined. In addition, the capacity status (capable, marginally capable, or incapable) of each MCI participant on each CCTI standard was examined using cut scores derived from control performance. RESULTS: Patients with MCI performed comparably to controls on minimal consent standards requiring merely expressing a treatment choice (S1) or making the reasonable treatment choice [S2], but significantly below controls on the three clinically relevant standards of appreciation (S3), reasoning (S4), and understanding (S5). In turn, the MCI group performed significantly better than the mild AD group on [S2], S4, and S5. Regarding capacity status, patients with MCI showed a progressive pattern of capacity compromise (marginally capable and incapable outcomes) related to stringency of consent standard. CONCLUSIONS: Patients with amnestic mild cognitive impairment (MCI) demonstrate significant impairments on clinically relevant abilities associated with capacity to consent to treatment. In obtaining informed consent, clinicians and researchers working with patients with MCI must consider the likelihood that many of these patients may have impairments in consent capacity related to their amnestic disorder and related cognitive impairments.

Chen Z, Simmons MS, Perry RT, Wiener HW, Harrell LE, Go RC. · Department of Epidemiology, University of Alabama at Birmingham School of Public Health, Birmingham, Alabama 35294, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #17918233 No free full text.

Abstract: Brain-derived neurotrophic factor (BDNF)/tyrosine receptor kinase (TRK) signaling pathway activates a wide range of downstream intracellular cascades, regulating neuronal development and plasticity, long-term potentiation, and apoptosis. The NTRK family encodes the receptors TRKA, TRKB, and TRKC, to which the neurotrophins, nerve growth factor (NGF), BDNF and neurotrophin-3 (NT-3) bind, respectively, with high affinity. Signaling through these receptors appears to be compromised in Alzheimer's disease (AD). This study is the most comprehensive investigation of genetic variants of NTRK2, and the first to show significant association between NTRK2 with AD. Fourteen single nucleotide polymorphisms (SNPs), located in 8 of 18 linkage disequilibrium (LD) blocks, were genotyped in 203 families with at least two AD affected siblings with mean age of onset (MAO) of 70.9 +/- 7.4 years and one unaffected sibling from the NIMH-ADGJ dataset. Family based association testing found no single SNP association, however, significant associations were found for two and three locus haplotypes (P = 0.012, P = 0.009, respectively) containing SNPs rsl624327, rsl443445, and rs378645. These SNPs are located in areas of the gene containing sequences that could be involved in alternative splicing and/or regulation of NTRK2. Our results suggest that NTRK2 may be a genetic susceptibility gene contributing to AD pathology.

Li J, Cowden LG, King JD, Briles DA, Schroeder HW, Stevens AB, Perry RT, Chen Z, Simmons MS, Wiener HW, Tiwari HK, Harrell LE, Go RC. · Department of Epidemiology and International Health, School of Public Health, University of Alabama at Birmingham, Birmingham, Alabama, USA. · Psychosom Med. · Pubmed #17634568 links to  free full text

Abstract: OBJECTIVE: To assess the effects of psychological stress on the antibody response to tetanus vaccine adjusting for cytokine gene polymorphisms and other nongenetic factors in caregivers of patients with Alzheimer's disease (AD). METHODS: A family-based follow-up study was conducted in 119 spouses and offspring of community-dwelling patients with AD. Psychological stress was measured by the Perceived Stress Scale (PSS) and the Center for Epidemiologic Studies Depression (CES-D) scale at baseline and 1 month after the vaccination. Nutritional status, health behaviors, comorbidity, and stress-buffering factors were assessed by self-administered questionnaires, 10 single nucleotide polymorphisms (SNP) from six selected cytokines genotyped, and anti-tetanus toxoid immunoglobulin G (IgG) concentrations tested using enzyme-linked immunosorbent assays. The effects of stress and other potential confounders were assessed by mixed models that account for familial correlations. RESULTS: The baseline PSS score, the baseline CES-D score, the interleukin-10-1082 A>G SNP GG genotype, and the baseline anti-tetanus IgG were inversely associated with antibody fold increase. CONCLUSION: Both psychological stress and cytokine gene polymorphisms affected antibody fold increase. The study provided additional support for the detrimental effects of psychological stress on the antibody response to tetanus vaccine.

Wiener HW, Perry RT, Chen Z, Harrell LE, Go RC. · Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL 35294-0022, USA. · Genes Brain Behav. · Pubmed #17376152 No free full text.

Abstract: Genes involved in cellular mechanisms to repair oxidative damage are strong candidates as etiologic factors for Alzheimer's disease (AD). One important enzyme involved in this mechanism is superoxide dismutase 2 (SOD2). The gene for this enzyme lies within a single haplotype block at 6q25.3, a region showing evidence for linkage to AD in a genome scan. We genotyped four single nucleotide polymorphisms (SNPs) in SOD2 in families of the National Institute of Mental Health-AD Genetics Initiative (ADGI): rs2758346 in the 5' untranslated region (UTR), rs4880 in exon 2, rs2855116 in intron 3 and rs5746136 in the 3'UTR. Under a dominant model, family-based association tests showed significant evidence for association of AD with the first three loci in a candidate gene set of families with individuals having age of onset of at least 50 years and two affected and one unaffected sibling, and in a late-onset subset of families (families with all affected individuals having age of onset of at least 65 years) from the full ADGI sample. The alleles transmitted more frequently to cases than expected under the null hypothesis were T, C, G, and G. Global tests of the transmission of haplotypes indicate that the first two loci have the most consistent association with risk of AD. Because of the high linkage disequilibrium in this small (14 kb) gene, and the presence of 100 SNPs in this gene, 26 of which may have functional significance, additional genotyping and sequencing are needed to identify the functionally relevant SNP. We discuss the importance of our findings and the relevance of SOD2 to AD risk.

Griffith HR, den Hollander JA, Stewart CC, Evanochko WT, Buchthal SD, Harrell LE, Zamrini EY, Brockington JC, Marson DC. · Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA. · NMR Biomed. · Pubmed #17295394 No free full text.

Abstract: in vivo (1)H MRS reveals reduced N-acetylaspartate (NAA) and elevated myo-inositol (mI) in patients with mild Alzheimer's disease (AD) and patients with amnestic mild cognitive impairment (MCI). We are unaware of studies that have documented abnormal scyllo-inositol (sI) levels in patients with AD or patients with MCI, although a previous MRS study in older adults has indicated that sI is a peak of interest to measure in AD. Fifteen patients with mild AD, 26 patients with amnestic MCI, and 19 healthy older adults were recruited to this study. All underwent (1)H MRS of the posterior cingulate gyrus of the brain using a 3 T MRI scanner. Increases in the sI/creatine (Cr) ratio were observed in patients with mild AD (P < 0.05). The mI/Cr ratio was raised in patients with mild AD (P < 0.01) and MCI (P < 0.05). Reduced NAA/Cr was detected in patients with mild AD (P < 0.05). The sI/Cr ratio correlated negatively (r = -0.60, P < 0.05) with a measure of clock drawing in patients with mild AD, indicating that impaired cognitive ability in AD is associated with higher concentrations of sI/Cr. In vivo measurement of sI/Cr in the posterior cingulate gyrus of patients with mild AD revealed increases compared with cognitively healthy older adults. Further research on the mechanisms of sI increase in AD is needed. Future studies on the longitudinal course of sI/Cr in MCI and AD appear warranted.

Perry RT, Gearhart DA, Wiener HW, Harrell LE, Barton JC, Kutlar A, Kutlar F, Ozcan O, Go RC, Hill WD. · Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL 35294-0022, USA. · Neurobiol Aging. · Pubmed #17157413 links to  free full text

Abstract: From a normal human brain phage display library screen we identified the gamma (A)-globin chain of fetal hemoglobin (Hb F) as a protein that bound strongly to A beta1-42. We showed the oxidized form of adult Hb (metHb A) binds with greater affinity to A beta1-42 than metHb F. MetHb is more toxic than oxyhemoglobin because it loses its heme group more readily. Free Hb and heme readily damage vascular endothelial cells similar to Alzheimer's disease (AD) vascular pathology. The XmnI polymorphism (C-->T) at -158 of the gamma (G)-globin promoter region can contribute to increased Hb F expression. Using family-based association testing, we found a significant protective association of this polymorphism in the NIMH sibling dataset (n=489) in families, with at least two affected and one unaffected sibling (p=0.006), with an age of onset >50 years (p=0.010) and >65 years (p=0.013), and families not homozygous for the APOE4 allele (p=0.041). We hypothesize that Hb F may be less toxic than adult Hb in its interaction with A beta and may protect against the development of AD.

Perry RT, Wiener H, Harrell LE, Blacker D, Tanzi RE, Bertram L, Bassett SS, Go RC. · Department of Epidemiology and International Health, University of Alabama at Birmingham, Birmingham, Alabama 35294-0022, USA. · Am J Med Genet B Neuropsychiatr Genet. · Pubmed #17034007 No free full text.

Abstract: Other than the APOE peak at 19q13, the 9q22 region was identified in our original genomic scan as the candidate region with the highest multipoint lod score (MLS) in the subset of late onset Alzheimer's Disease (AD) families (MLS = 2.9 at 101 cM) from the NIMH Genetics Initiative sample. We have now genotyped an additional 12 short tandem repeats (STR) in this region. Multipoint analysis shows the region remains significant with an increase in the peak MLS from 2.9 to 3.8 at 95 cM near marker D9S1815, and the 1 LOD interval narrows from 21.5 to 11 cM. HLOD scores also provide evidence for significant linkage (4.5 with an alpha = 31%) with a further narrowing of the region to 6.6 cM (92.2-98.8 cM). Single nucleotide polymorphisms (SNPs) in the Ubiquilin1 gene (UBQLN1), located at 83.3 cM, have been reported to be significantly associated to AD, accounting for a substantial portion of the original linkage signal [Bertram et al., 2005]. Our analyses of the higher resolution genotype data generated here provide further support for the existence of a least one additional locus on chromosome 9q22. In an effort to pinpoint this putative AD susceptibility gene, we have begun to analyze SNPs in other candidate genes in and around this narrowed region to test for additional associations to AD.

Huthwaite JS, Martin RC, Griffith HR, Anderson B, Harrell LE, Marson DC. · Department of Neurology, University of Alabama at Birmingham, Birmingham, AL 35233-7340, USA. · Behav Sci Law. · Pubmed #16883623 No free full text.

Abstract: This is a report of a two-year longitudinal study comparing healthy older adult subjects (n = 15) and mild Alzheimer's disease (AD) patients (n = 20) using an objective performance measure of medical decision-making capacity (MDC). Capacity to consent to medical treatment was measured using the Capacity to Consent to Treatment Instrument (CCTI). The CCTI is a psychometric measure that tests MDC using a series of four core capacity standards: S1 (evidencing/communicating choice), S3 (appreciating consequences), S4 (providing rational reasons), and S5 (understanding treatment situation), and one experimental standard [S2] (making the reasonable treatment choice). For each standard, mild AD patients were assigned one of three capacity outcomes (capable, marginally capable, or incapable) based on cut-off scores derived from control group performance.At baseline, mild AD patients performed equivalently with controls on simple standards of evidencing a choice (S1) and making the reasonable choice ([S2]), but significantly below controls on complex standards of appreciation, reasoning, and understanding (S3, S4, and S5) (p < 0.02). Control performance was stable over time on all capacity standards. At one-year follow-up, the mild AD group did not show significant decline from baseline on any capacity standard. However, at two-year follow-up the mild AD group showed significant declines from baseline on the three complex standards (S3, S4, and S5) (p < 0.02), and a trend on one of the simple standards (S1). Over the two-year period, the proportion of marginally capable and incapable outcomes in the AD group increased substantially for four of the five standards (S1, S3, S4, and S5). Performance on [S2] remained stable over time in the AD group.We conclude that mild AD patients have impaired MDC at baseline, and demonstrate significant additional decline on complex consent abilities of appreciation, reasoning, and understanding over a two-year period. AD patients also show emerging impairment on the simple consent ability of evidencing choice at two-year follow-up. Capacity outcome data reflect similar declines over time for these four consent standards. The findings suggest the value of early assessment and regular monitoring at two-year intervals of MDC in patients with mild AD.

Griffith HR, Netson KL, Harrell LE, Zamrini EY, Brockington JC, Marson DC. · Department of Neurology, University of Alabama at Birmingham, 1216 Jefferson Tower, 625 19th Street South, Birmingham, AL, USA. · J Int Neuropsychol Soc. · Pubmed #16573850 No free full text.

Abstract: Amnestic mild cognitive impairment (MCI) has been defined as a precursor to Alzheimer's disease (AD), although it is sometimes difficult to identify which persons with MCI will eventually convert to AD. We sought to predict MCI conversion to AD over a two-year follow-up period using baseline demographic and neuropsychological test data from 49 MCI patients. Using a stepwise discriminant function analysis with Dementia Rating Scale (DRS) Initiation/Perseveration and Wechsler Memory Scale, third edition (WMS-III) Visual Reproduction Percent Retention scores, we correctly classified 85.7% of the sample as either AD converters or MCI nonconverters, with 76.9% sensitivity and 88.9% specificity. Adding race, the presence of vascular risk factors, or cholinesterase inhibitor use to the analysis did not greatly change the classification rates obtained with neuropsychological test data. Examining neuropsychological test cutoff scores revealed that DRS Initiation/Perseveration scores below 37 and Visual Reproduction Percent Retention scores below 26% correctly identified AD converters with 76.9% sensitivity and 91.7% specificity. These results demonstrate that commonly administered neuropsychological tests identify persons with MCI at baseline who are at risk for conversion to AD within 1-2 years. Such methods could aid in identifying MCI patients who might benefit from early treatment, in providing prognostic information to patients, and identifying potential clinical trial participants.

Harrell LE, Parsons DS, Kolasa K. · Department of Neurology, VA Medical Center, University of Alabama at Birmingham, 975 Sparks Ctr, 1720 7th Avenue South, Birmingham, AL 35294, USA. · Exp Neurol. · Pubmed #15899255 No free full text.

Abstract: In rat, injection of the specific cholinotoxin, 192 IgG-saporin, into the medial septum results not only in a selective cholinergic denervation of hippocampus, but in an ingrowth of peripheral sympathetic fibers, originating from the superior cervical ganglion, into the hippocampus. A similar process, in which peripheral noradrenergic axons invade hippocampus, may also occur in Alzheimer's disease. Since apoptotic cell death has been demonstrated in the selective neuronal loss found in Alzheimer's disease, the aim of this study was to measure apoptotic protein expression and DNA fragmentation in hippocampal sympathetic ingrowth and cholinergic denervation. Western blot, TdT-mediated dUTP nick end labeling, and oligo ligation techniques were used. Choline acetyltransferase activity and norepinephrine concentrations were also measured. As seen in our previous results, an increase in apoptotic markers was induced by cholinergic denervation alone (medial septum lesion + ganglionectomy), while hippocampal sympathetic ingrowth (medial septum + sham ganglionectomy) reduced or normalized apoptotic effects to control group levels. A decrease in choline acetyltransferase activity was also found in the dorsal hippocampus of hippocampal sympathetic ingrowth and cholinergic denervation groups. An increase in norepinephrine concentration was found in hippocampal sympathetic ingrowth but not in cholinergic denervation group. Results of this study suggest that cholinergic denervation is responsible for most of the proapoptotic responses, while hippocampal sympathetic ingrowth produces a protective effect in the process of programmed cell death in rat dorsal hippocampus. This effect may be a secondary to an altered relationship between norepinephrine-acetylcholine.

Liu H, Harrell LE, Shenvi S, Hagen T, Liu RM. · Department of Environmental Health Sciences, School of Public Health, University of Alabama at Birmingham (UAB), Birmingham, AL 35294-0022, USA. · J Neurosci Res. · Pubmed #15693022 No free full text.

Abstract: The mechanism underlying Alzheimer's disease (AD), an age-related neurodegenerative disease, is still an area of significant controversy. Oxidative damage of macromolecules has been suggested to play an important role in the development of AD; however, the underlying mechanism is still unclear. In this study, we showed that the concentration of glutathione (GSH), the most abundant intracellular free thiol and an important antioxidant, was decreased in red blood cells from male AD patients compared with age- and gender-matched controls. However, there was no difference in blood GSH concentration between the female patients and female controls. The decrease in GSH content in red blood cells from male AD patients was associated with reduced activities of glutamate cysteine ligase and glutathione synthase, the two enzymes involved in de novo GSH synthesis, with no change in the amount of oxidized glutathione or the activity of glutathione reductase, suggesting that a decreased de novo GSH synthetic capacity is responsible for the decline in GSH content in AD. These results showed for the first time that GSH metabolism was regulated differently in male and female AD patients.

Zamrini E, Parrish JA, Parsons D, Harrell LE. · Veteran's Administration Hospital, Alzheimer's Disease Center, Birmingham, AL, USA. · South Med J. · Pubmed #14746413 No free full text.

Abstract: BACKGROUND: Little is known about co-medical illnesses in black and white patients with probable Alzheimer's disease (AD). METHODS: To address this question, we used two methods. In the first (Group I), black and white probable AD patients were matched on age at presentation to the clinic, age of onset of AD, duration of illness, and Mini-Mental State Examination scores; then, a variety of co-medical illnesses were compared between blacks and whites. In Group II, whites were randomly matched to blacks on the variables listed above. RESULTS: In Group I, blacks were found to have a higher rate of hypertension than whites, whereas whites had a higher incidence of atrial fibrillation and cancer than blacks. In Group II, age at presentation to the clinic was found to be shorter for men than for women; duration of illness was shorter for black men than for white men, white women, and black women; and Mini-Mental State Examination scores were lower in blacks than whites. As in Group I, blacks were found to have a higher rate of hypertension, whereas whites had higher rates of atrial fibrillation, cancer, coronary artery disease, high cholesterol, and gastrointestinal disease. CONCLUSION: In both groups, black patients with probable AD had a higher rate of hypertension than white patients with probable AD, and whites had higher rates of atrial fibrillation and cancer. This finding suggests that these comorbid illnesses in black and white patients with probable AD is not due to a statistical Type II error, but rather to differences in these groups.

Wadley VG, Harrell LE, Marson DC. · Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama 35233, USA. · J Am Geriatr Soc. · Pubmed #14687393 No free full text.

Abstract: OBJECTIVES: To evaluate the consistency, stability, and accuracy of reports by patients with Alzheimer's disease (AD) and their caregivers regarding the patients' premorbid and current financial abilities. DESIGN: Consistency of reports was assessed within patient/caregiver dyads and within control/control informant dyads. Stability of reports over a 1-month interval was assessed for each group: patients with AD, caregivers, controls, and control informants. Accuracy of each group's reports was evaluated in reference to patients' and controls' performance on a direct psychometric measure of financial capacity. SETTING: University medical center. PARTICIPANTS: Twenty patients with AD and 20 family caregivers; 23 controls and 23 family informants. MEASUREMENTS: The Prior Financial Capacity Form (PFCF) and the Current Financial Capacity Form (CFCF) were used. Parallel versions assessed self-report (patients, controls) and informant report (caregivers, control informants) at two visits 1 month apart. Patients with AD and controls were also administered the Financial Capacity Instrument (FCI), a direct assessment of the same abilities reported on the PFCF and CFCF. RESULTS: Patients with AD reported that they had more-intact current abilities than their caregivers reported. Patients with AD and their caregivers showed lower levels of stability over time on the PFCF and CFCF than did controls and their informants. Half of the patients with AD overestimated their current abilities relative to their FCI performance, whereas caregivers demonstrated both underestimation and overestimation errors. Controls and informants evidenced high levels of consistency, stability, and accuracy in PFCF and CFCF ratings. CONCLUSION: Patients with AD overestimate their financial abilities in comparison with the reports of their family caregivers. Both patients and caregivers' reports of patients' financial abilities showed limited stability and validity. The reliability and accuracy of self- and informant reports of financial abilities may be compromised in the context of dementia and caregiving, underscoring the need for direct assessment methods to augment self- and informant report in assessing functional decline in dementia.

Blacker D, Bertram L, Saunders AJ, Moscarillo TJ, Albert MS, Wiener H, Perry RT, Collins JS, Harrell LE, Go RC, Mahoney A, Beaty T, Fallin MD, Avramopoulos D, Chase GA, Folstein MF, McInnis MG, Bassett SS, Doheny KJ, Pugh EW, Tanzi RE, Anonymous00039. · Massachusetts General Hospital, Charlestown, MA, USA. · Hum Mol Genet. · Pubmed #12490529 links to  free full text

Abstract: Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (epsilon 4) in the gene encoding apolipoprotein E (APOE ) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9 cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) >/=1.9 and/or multipoint lod score (MLS) >/=2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.

Perry RT, Collins JS, Harrell LE, Acton RT, Go RC. · Department of Epidemiology and International Health, University of Alabama at Birmingham, 35294, USA. · Am J Med Genet. · Pubmed #11378846 No free full text.

Abstract: Alzheimer disease (AD) is an emotionally devastating and exceptionally costly disease. Apolipoprotein E (APOE) is a major risk factor gene for AD regardless of age of onset or family history. However, this association may not be as strong or consistent in ethnic groups such as African Americans, raising the possibility of other modifier gene(s). In a group of African American AD patients, a significantly increased risk of AD was associated with two E4 alleles (OR = 5.6; 95% CI = 1.5-21.0) or one E4 allele (OR = 2.5; 95% CI = 1.3-5.0) when compared to E3/E3 genotype, and there was a significant lowering of age of onset for affecteds with E4/E4 genotype as compared to one E2 allele (P = 0.02) or all others (P = 0.03). We also found a significant increase in age of onset with the -308 #2 (A) allele of TNF when compared to AD cases with no #2 allele. A significant increase in age was also demonstrated with the #2 allele (99 base pairs) of the microsatellite TNFa, located approximately 10.5 kb upstream of TNF. When these two alleles were combined with the TNF -238G (#1) allele to give a haplotype, the significant increase in age was still demonstrated. Polymorphisms in the APOE promoter and six other candidate genes did not appear to demonstrate any significant association with our African American AD patients. Our results confirm the established association of APOE4 to AD observed in several ethnic groups, including African Americans. In addition, TNF appears to have some modifying effect in AD, primarily on age of onset, or it could be in linkage disequilibrium with a modifier locus nearby.

Collins JS, Perry RT, Watson B, Harrell LE, Acton RT, Blacker D, Albert MS, Tanzi RE, Bassett SS, McInnis MG, Campbell RD, Go RC. · Department of Epidemiology and International Health, University of Alabama at Birmingham, Birmingham, Alabama 35294-0022, USA. · Am J Med Genet. · Pubmed #11121190 No free full text.

Abstract: Tumor necrosis factor (TNF), a proinflammatory cytokine, may be involved in the pathogenesis of Alzheimer disease (AD) based on observations that senile plaques have been found to upregulate proinflammatory cytokines. Additionally, nonsteroidal anti-inflammatory drugs have been found to delay and prevent the onset of AD. A collaborative genome-wide scan for AD genes in 266 late-onset families implicated a 20 centimorgan region at chromosome 6p21.3 that includes the TNF gene. Three TNF polymorphisms, a -308 TNF promoter polymorphism, whose TNF2 allele is associated with autoimmune inflammatory diseases and strong transcriptional activity, the -238 TNF promoter polymorphism, and the microsatellite TNFa, whose 2 allele is associated with a high TNF secretion, were typed in 145 families consisting of 562 affected and unaffected siblings. These polymorphisms formed a haplotype, 2-1-2, respectively, that was significantly associated with AD (P = 0.005) using the sibling disequilibrium test. Singly, the TNFa2 allele was also significantly associated (P = 0.04) with AD in these 145 families. This TNF association with AD lends further support for an inflammatory process in the pathogenesis of AD. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:823-830, 2000.

Kolasa K, Harrell LE. · Alzheimer's Disease Center, Department of Neurology, VA Medical Center, 975 Sparks Center, University of Alabama at Birmingham, AL 35294-0017, USA. · Neuroscience. · Pubmed #11113303 No free full text.

Abstract: Following cholinergic denervation of the hippocampus by medial septal lesions, an unusual neuronal reorganization occurs in which peripheral adrenergic fibers arising from superior cervical ganglia grow into the hippocampus (hippocampal sympathetic ingrowth). Recent studies suggest that a similar process, in which sympathetic noradrenergic axons invade the hippocampus, can occur in Alzheimer's disease patients. In the last few years, the occurrence of apoptotic cell death has been studied in Alzheimer's disease patients and in animal models of this disorder. Several studies suggest that the hippocampus is an important area to be considered for apoptotic cell death. In our studies in the rat hippocampus, we have measured the expression of inducers and blockers of apoptosis in membrane, cytosolic and mitochondrial fractions, and the activity of caspases. The level of cytosolic Fas was increased in cholinergic denervation compared to control and hippocampal sympathetic ingrowth groups. The membrane Fas ligand expression was significantly increased in hippocampal sympathetic ingrowth and in cholinergic denervation compared to the control group. The level of caspase-3 (CPP32) was increased in the cholinergic denervation group compared to control and hippocampal sympathetic ingrowth groups. The cytosolic expression of bcl-x was increased in hippocampal sympathetic ingrowth compared to control and cholinergic denervation. The cytosolic activity of caspase-3 appeared to be significantly decreased in hippocampal sympathetic ingrowth and increased in cholinergic denervation groups compared to control and cholinergic denervation/hippocampal sympathetic ingrowth, respectively.From the present results, we suggest that cholinergic denervation may be responsible for pro-apoptotic responses, while hippocampal sympathetic ingrowth may protect neurons from apoptosis in rat dorsal hippocampus.

Harrell LE, Marson D, Chatterjee A, Parrish JA. · Alzheimer's Disease Center and Department of Neurology, VA Medical Center, Birmingham, Alabama, USA. · Alzheimer Dis Assoc Disord. · Pubmed #10994658 No free full text.

Abstract: The bedside and office assessment of cognitive abilities in moderately to severely impaired patients with Alzheimer disease could be enhanced by a well-standardized instrument. The authors' group has developed such an instrument (i.e., Severe Mini-Mental State Examination; SMMSE) to assess this population. Based on the Folstein Mini-Mental State Examination (MMSE), the SMMSE, which totals 30 points, was designed to briefly assess cognitive domains relatively preserved in moderate to severe Alzheimer disease. One hundred eighty-two patients with possible or probable Alzheimer disease were administered both the MMSE and SMMSE. Performances on the SMMSE and MMSE were found to correlate significantly only when MMSE fell below 9 points (p < 0.0001). However, as performance on the MMSE approached floor levels, patients continued to score at half maximal levels on the SMMSE. Functional staging with the Clinical Dementia Rating Scale and the Global Deterioration Scale also were found to significantly correlate with performance on the SMMSE (p < 0.001). Test-retest performance on both the SMMSE and MMSE was relatively stable over a period of 5 months. Inter-rater reliability of the SMMSE was excellent. These results suggest that the SMMSE has both construct and criterion validity for assessing severely impaired Alzheimer disease patients. Our results also suggest that the SMMSE may be a useful instrument for assessing severely impaired patients at the bedside and in the office.