Medical decision-making capacity in mild cognitive impairment: a 3-year longitudinal study.

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.

Cognitive models of medical decision-making capacity in patients with mild cognitive impairment.

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.

Medical decision-making capacity in patients with mild cognitive impairment.

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.

A polymorphism in SOD2 is associated with development of Alzheimer's disease.

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.

Hippocampal sympathetic ingrowth occurs following 192-IgG-Saporin administration.

Electrolytic lesions of the medial septal region leads to an unusual neuronal reorganization in which peripheral sympathetic fibers, originating from the superior cervical ganglia, grow into the cholinergically denervated areas of the hippocampus. Since these lesions disrupt cells and fibers of passage which are non-cholinergic, there has been a debate whether Hippocampal Sympathetic Ingrowth is due only to cholinergic denervation of the hippocampus. Using the intraseptal administration of 192-IgG-Saporin, a specific cholinergic neurotoxin, we have found that hippocampal sympathetic ingrowth occurs in the cholinergically denervated hippocampus at 4, 8 and 12 weeks post Saporin injection. These results clearly suggest that hippocampal sympathetic ingrowth is due to the specific loss of the cholinergic projection from the medial septum.

The utility of urgent colonoscopy in the evaluation of acute lower gastrointestinal tract bleeding: a 2-year experience from a single center.

OBJECTIVE: Urgent colonoscopy is often recommended to evaluate acute rectal bleeding. However, it may not identify a source because of blood in the lumen or inadequate preparation. Our aim was to determine the utility of urgent colonoscopy as the initial test for acute rectal bleeding. METHODS: This was a retrospective chart review of all patients discharged in 1997 and 1998 with an International Classification of Diseases, 9th Revision, code for hematochezia or rectal bleeding. RESULTS: We identified 514 charts but excluded 424 because of inaccurate coding. In the 90 with confirmed acute rectal bleeding, colonoscopy was the initial test in 39; age, sex, and race distributions were similar to those who did not have colonoscopy. A definite source of bleeding was seen at colonoscopy in only three patients, a probable source in 26, and no source in 10. Therapeutic intervention in four patients with a definite or probable source was successful in three. The commonest reasons for not performing urgent colonoscopy were bleeding from presumed hemorrhoids or bleeding that was clinically insignificant. Spontaneous resolution of bleeding and length of hospital stay were not affected by urgent colonoscopy. Five patients had surgery for unrelated reasons. In-hospital mortality was 2% and was unrelated to bleeding. CONCLUSION: Urgent colonoscopy as the initial investigation in acute lower GI tract bleeding probably does not alter the outcome in most cases. Identification of a definite bleeding source leading to successful therapeutic intervention is rare. Spontaneous resolution is frequent, length of hospital stay is similar, and clinical outcome is excellent regardless of whether or not urgent colonoscopy is performed.

Investigation of association of 13 polymorphisms in eight genes in southeastern African American Alzheimer disease patients as compared to age-matched controls.

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.

Apoptotic protein expression and activation of caspases is changed following cholinergic denervation and hippocampal sympathetic ingrowth in rat hippocampus.

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.

Association of a haplotype for tumor necrosis factor in siblings with late-onset Alzheimer disease: the NIMH Alzheimer Disease Genetics Initiative.

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.

The Severe Mini-Mental State Examination: a new neuropsychologic instrument for the bedside assessment of severely impaired patients with Alzheimer disease.

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.

Consistency of physicians' legal standard and personal judgments of competency in patients with Alzheimer's disease.

OBJECTIVES: To investigate the consistency of physician judgments of treatment consent capacity (competency) for patients with Alzheimer's disease (AD) when specific legal standards (LS) for competency are used, and to identify the LS most clinically relevant to experienced physicians. DESIGN: Control and AD patient participants were videotaped being administered a measure of capacity to consent to medical treatment. Study physicians viewed videotapes of these assessments individually and made competency judgments for each participant under different LS followed by their own personal judgment of competency. SETTING: A university medical center. PARTICIPANTS: Participants were 10 older controls and 21 patients with AD (10 with mild and 11 with moderate AD). Five physicians with experience assessing the competency of AD patients were recruited from the geriatric psychiatry, geriatric medicine, and neurology services of a university medical center. MEASUREMENTS: The 31 participants were videotaped performing on a measure of treatment consent capacity (Capacity to Consent to Treatment Instrument) (CCTI). The CCTI consists of two clinical vignettes (A-neoplasm and B-cardiac) that test competency under five LS. Vignette A and B assessments were videotaped separately for each participant (total videotapes for sample = 62). Each study physician viewed each videotaped vignette individually, made judgments under each of the LS (competent or incompetent), and then made his/her own personal competency judgment. Physicians were blinded to participant diagnosis. Within participant group, consistency of physician judgments was evaluated across LS and personal judgments using percentage agreement and kappa. Agreement between personal and LS judgments for the AD group was evaluated for each physician using logistic regression. RESULTS: As expected, physicians as a group generally demonstrated very high percentage agreement in their LS and personal competency judgments for the control group. For the AD group, mean percentage judgment agreement among physicians ranged from a high of 84% (LS1) (evidencing a treatment choice) to a low of 67% (LS3) (appreciating consequences of treatment choice). Mean percentage agreement for personal competency judgments was 76%. For the AD sample, kappa analyses for physicians as a group demonstrated significant agreement not attributable to chance for LS5 (understanding treatment situation/choices) (k = 0.57, P = .001), LS4 (providing rational reasons for treatment choice) (k = 0.39, P = .04), and also for personal judgments (k = 0.48, P = .009). Analysis of LS judgment agreement within physician indicated that physicians applied the LS as discrete standards. Within-physician and for the AD sample, personal competency judgments were associated significantly with judgments on LS5 (P = .001), LS4 (P = .004), and LS3 (P < .04). CONCLUSIONS: Experienced physicians demonstrated significant agreement assessing competency in AD patients when judgments were based upon specific legal standards. Personal competency judgments of physicians showed a substantially higher level of agreement than found in a previous study, where specific LS were not used. These results suggest that consistency of physician competency judgments can be enhanced if they are guided by knowledge of specific LS. Physicians' personal competency judgments were most closely associated with comprehension and reasoning LS, the most conservative and clinically appropriate standards for deciding competency.

Cognitive models of physicians' legal standard and personal judgments of competency in patients with Alzheimer's disease.

OBJECTIVES: To investigate measures of patient cognitive abilities as predictors of physician judgments of medical treatment consent capacity (competency) in patients with Alzheimer's disease (AD). DESIGN: Predictor models of legal standards (LS) and personal competency judgments were developed for each study physician using independent neuropsychological test measures and logistic regression analyses. SETTING: A university medical center. PARTICIPANTS: Five physicians with experience assessing the competency of AD patients were recruited to make competency judgments of videotaped vignettes from 10 older controls and 21 patients with AD (10 with mild and 11 with moderate dementia). MEASUREMENTS: The 31 patient and control videotapes of performance on a measure of treatment consent capacity (Capacity to Consent to Treatment Instrument) (CCTI) were rated by the five physicians. The CCTI consists of two clinical vignettes (A-neoplasm and B-cardiac) that test competency under five LS. Each study physician viewed each vignette videotape individually, made judgments of competent or incompetent under each of the LS, and then made his/her own personal competency judgment. Physicians were blinded to participant diagnosis and neuropsychological test performance. Stepwise logistic regression was conducted to identify cognitive predictors of each physician's LS and personal competency judgments for Vignette A using the full sample (n = 31). Classification logistic regression analysis was used to determine how well these cognitive predictor models classified each physician's competency judgments for Vignette A. These classification models were then cross-validated using physician's Vignette B judgments. RESULTS: Cognitive predictor models for Vignette A competency judgments differed across individual physicians, and were related to difficulty of LS and to incompetency outcome rates across LS for AD patients. Measures of semantic knowledge and receptive language predicted judgments under less difficult LS of evidencing a treatment choice (LS1) and making the reasonable treatment choice (LS2). Measures of semantic knowledge, short-term verbal recall, and simple reasoning ability predicted judgments under more difficult and clinically relevant LS of appreciating consequences of a treatment choice (LS3), providing rational reasons for a treatment choice (LS4), and understanding the treatment situation and choices (LSS). Cognitive models for physicians' personal competency judgments were virtually identical to their respective models for LS5 judgments. For AD patients, shortterm memory predictors were associated with high incompetency outcome rates (over 70%), a simple reasoning measure was associated with moderately high incompetency outcome rates (60-70%), and a semantic knowledge measure was associated with lower incompetency outcome rates (30-60%). Overall, single predictor models were relatively robust, correctly classifying an average of 83% of physician judgments for Vignette A and 80% of judgments for Vignette B. CONCLUSIONS: Multiple cognitive functions predicted physicians' LS and personal competency judgments. Declines in semantic knowledge, short-term verbal recall, and simple reasoning ability predicted physicians' judgments on the three most difficult and clinically most relevant LS (LS3-LS5), as well as their personal competency judgments. Our findings suggest that clinical assessment of competency should include evaluation of semantic knowledge, verbal recall, and simple reasoning abilities.

Effect of phospholipase C and protein kinase C following cholinergic denervation and hippocampal sympathetic ingrowth in rat hippocampus.

Following cholinergic denervation of the hippocampus by medial septal lesions, an unusual neuronal reorganization occurs in which peripheral adrenergic fibers arising from the superior cervical ganglia grow into the hippocampus (hippocampal sympathetic ingrowth). We have reported previously that cholinergic denervation and hippocampal sympathetic ingrowth differentially affected cholinergically stimulated phosphoinositide hydrolysis, concentration and affinity of muscarinic receptors, Go-protein level and protein kinase C activity. To complete these studies, we determined whether cholinergic denervation and hippocampal sympathetic ingrowth influenced phospholipase C and protein kinase C expression in dorsal hippocampal membranes and cytosol. Using immunoblotting methods, the results showed that the 100,000 mol. wt subunit of phospholipase Cbeta was increased in the membrane fraction in the hippocampal sympathetic ingrowth group by 45% compared to controls and the 150,000 mol.wt subunit was increased by 75% and 59% compared to controls and cholinergic denervation, respectively. For protein kinase C detection, immunoblots were prepared using antibodies selective for "classical" protein kinase C members (alpha, beta, gamma) and for the "novel" protein kinase C subfamily members (delta, θ). Membrane protein kinase Cbeta was decreased in hippocampal sympathetic ingrowth by 35% compared to controls and by 41% compared to cytosolic hippocampal sympathetic ingrowth. Membrane protein kinase Cbeta was decreased in cholinergic denervation by 28% compared to controls. When compared to membranes from controls and the cholinergic denervation group, and to cytosolic fractions from the hippocampal sympathetic ingrowth groups, respectively, the following membrane protein kinase isoforms were found to be decreased by hippocampal sympathetic ingrowth: gamma by 55%, 40% and 57%; delta by 91.5%, 70% and 120%; theta; by 95%, 100% and 86%.In conclusion, our results may indicate the connection between the previously reported differential influence of hippocampal sympathetic ingrowth and cholinergic denervation on cholinergically stimulated phosphoinositol hydrolysis. The "normalization" of phosphoinositol hydrolysis found in hippocampal sympathetic ingrowth may be due to the increase in phospholipase Cbeta expression in hippocampal sympathetic ingrowth membrane fractions. Since the activation of protein kinase C is known to block phosphoinositol hydrolysis, hippocampal sympathetic ingrowth "normalization" of phosphoinositol hydrolysis may result from a reduction in protein kinase expression in hippocampal sympathetic ingrowth membranes.

Assessing financial capacity in patients with Alzheimer disease: A conceptual model and prototype instrument.

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.

Densitometric analysis of Galphao protein subunit levels from postmortem Alzheimer disease hippocampal and prefrontal cortical membranes.

An immunoblotting method using prefrontal cortical and hippocampal membranes from control and Alzheimer disease postmortem brains was employed to detect three subtypes of Galphao protein. In the membranes from control subjects, the density of Galphao1 in hippocampus and cortex was the highest, whereas the density of Galphao2 was the lowest and that of Galphao3 was intermediate. In the Alzheimer disease membranes from hippocampus, the density of total Galphao and all three subtype forms was not changed significantly when compared with control values. There were statistically significant alterations in Galphao in cortical membranes from Alzheimer disease when compared with controls. The density of Galphao1 was decreased by approximately 85%, density of Galphao3 was decreased by approximately 95%, and total Galphao density was decreased by approximately 84% of control value. However, Galphao2 density was decreased by approximately 44% but was found not to be statistically different from controls.

Effects of pertussis toxin and galpha-protein-specific antibodies on phosphoinositide hydrolysis in rat brain membranes after cholinergic denervation and hippocampal sympathetic ingrowth.

Cholinergic denervation of the hippocampal formation, via medial septal lesions, induces peripheral noradrenergic fibers, originating from the superior cervical ganglion, to grow into the hippocampus. We have previously reported that cholinergic denervation and hippocampal sympathetic ingrowth differentially affect guanosine-5'-O-(3-thiotriphosphate)- as well as guanosine-5'-O-(3-thiotriphosphate) + carbachol-stimulated polyphosphoinositide hydrolysis, suggesting an alteration in G proteins and/or the entire receptor complex. To examine the type of G protein which may be involved in these effects, rat dorsal hippocampal membranes were preincubated with pertussis toxin in the presence of guanosine-5'-O-(3-thiotriphosphate) and guanosine-5'-O-(3-thiotriphosphate) + carbachol. Pertussis toxin reduced guanosine-5'-O-(3-thiotriphosphate) in all groups, while guanosine-5'-O-(3-thiotriphosphate) + carbachol-stimulated phosphoinositide hydrolysis was reduced in controls and animals without sympathetic ingrowth but not in animals with hippocampal sympathetic ingrowth. This suggests that pertussis toxin-sensitive G proteins may be involved in the mediation of phosphoinositide hydrolysis. To confirm this hypothesis, membranes were preincubated with antibodies to Galphao and Gq/11. The Go antibody significantly decreased guanosine-5'-O-(3-thiotriphosphate) in all groups, while guanosine-5'-O-(3-thiotriphosphate) +carbachol-stimulated phosphoinositide hydrolysis was reduced only in hippocampal sympathetic ingrowth. Impairment of guanosine-5'-O-(3-thiotriphosphate) and carbachol-stimulated phosphoinositide hydrolysis was also decreased in all groups when preincubated with Gq/11 antibody. To determine whether hippocampal sympathetic ingrowth or cholinergic denervation altered the concentration of various G proteins, immunoblotting methodology was utilized. Gq/11 concentrations were found to be equivalent among groups. The density of Go1, Go2, and Go3 isoforms was significantly increased in the cholinergic denervation, while in the hippocampal sympathetic ingrowth only group Go3 was significantly increased. When assessed as total Go protein, density was increased significantly only in the cholinergic denervation group. Overall, these results suggest that hippocampal sympathetic ingrowth and cholinergic denervation induce alterations in phosphoinositide hydrolysis through both the Gq/11 and the Go proteins and that the coupling between muscarinic receptor and G protein is the possible site which affects changes in phosphoinositide turnover. Our results also suggest that cholinergic denervation and hippocampal sympathetic ingrowth may mediate phosphoinositide hydrolysis through an effect on different isoforms of the same G protein.

Error behaviors associated with loss of competency in Alzheimer's disease.

OBJECTIVE: To investigate qualitative behavioral changes associated with declining medical decision-making capacity (competency) in patients with AD. BACKGROUND: Qualitative measures can yield clinical information about functional changes in neurologic disease not available through quantitative measures. METHODS: Normal older controls (n = 21) and patients with mild and moderate probable AD (n = 72) were compared using a standardized competency measure and neuropsychological measures. A system of 16 qualitative error scores representing conceptual domains of language, executive dysfunction, affective dysfunction, and compensatory responses was used to analyze errors produced on the competency measure. Patterns of errors were examined across groups. Relationships between error behaviors and competency performance were determined, and neurocognitive correlates of specific error behaviors were identified. RESULTS: AD patients demonstrated more miscomprehension, factual confusion, intrusions, incoherent responses, nonresponsive answers, loss of task, and delegation than controls. Errors in the executive domain (loss of task, nonresponsive answer, and loss of detachment) were key predictors of declining competency performance by AD patients. Neuropsychological analyses in the AD group generally confirmed the conceptual domain assignments of the qualitative scores. CONCLUSIONS: Loss of task, nonresponsive answers, and loss of detachment were key behavioral changes associated with declining competency of AD patients and with neurocognitive measures of executive dysfunction. These findings support the growing linkage between executive dysfunction and competency loss.

A method for assessing clinically relevant individual cognitive change in older adult populations.

The evaluation of individual cognitive change has relied heavily upon the raw change score, defined simply as the difference between follow-up and baseline scores. However, raw changes scores are susceptible to the confounding effects of both regression-to-the-mean and practice effect. The clinical relevance of raw change scores for the older adult is also obscured by normal, age-related cognitive change. The present study illustrates the use of a standardized regression-based (SRB) methodology to generate an alternative to the raw change score; the SRB change score. SRB change scores provide a standardized alternative to the raw change score, allowing the clinician to evaluate the magnitude of change on one or more variables along a common metric that controls for practice effect, regression-to-the-mean, and normal cognitive decline. Case data illustrate how SRB change scores can identify clinically relevant cognitive change in the individual older adult patient.

Polymorphic tetranucleotide repeat site within intron 7 of the beta-amyloid precursor protein gene and its lack of association with Alzheimer's disease.

Mutations found in the beta-amyloid precursor protein (APP) gene in a small subset of patients with Alzheimer's disease (AD) are associated with the development of the disease. Several lines of evidence indicate that specific isoforms of APP generated by alternative splicing of the primary transcript may contribute to the etiology of AD. One of the isoforms, APP695, lacks the Kunitz protease inhibitor (KPI) domain and is produced predominantly in neurons by skipping exon 7 of the APP gene. Previous studies imply that the controlling elements for exon 7 skipping exist in the flanking sequences of the exon. Therefore, we have sequenced the human intron 7 of the APP gene and found a polymorphic tetranucleotide (ATTT)n repeat site within the intron 7. In 183 genetically unrelated subjects (97 AD patients and 86 controls), we found four alleles by polymerase chain reaction (PCR) amplification of the repeat site. Although no particular alleles are associated with AD, this newly identified polymorphic site may be useful in other genetic analyses since preliminary evidence suggests allele frequency differences between African Americans and Caucasians.

Cholinergic activity and amyloid precursor protein metabolism.

With more than 4 million Alzheimer's victims nationwide, there is intense research to elucidate the relationship among the hallmarks of the disease, amyloid plaques, neurofibrillary tangles, and degeneration of the basal forebrain cholinergic neurons. There has been much debate about which of these is the primary lesion, and which develops secondarily. The correlation between plaques and tangles and dementia is not absolute, but a consistent feature of Alzheimer's disease is loss of cortical and hippocampal cholinergic function as a result of basal forebrain compromise. Additionally, factors associated with the cholinergic system have been shown to influence the processing and metabolism of the amyloid precursor, a protein that contains the amyloidogenic sequence found in plaques. In this paper, the relationship between cholinergic compromise and amyloid deposition, as well as the cholinergic system-associated factors which appear to participate in amyloid precursor protein processing, are discussed.