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Technology is a force which drives itself. Organizations must adopt to emerging technology or risk being obsolete. Leveraging technology to create value involves more then circumferentially managing technology. To create value, leaders must encourage staff to transmute technology. The principles and practices of quantum leadership provide for this possibility. This chapter will irradiate why simply managing technology does not offer organizations the maximum value from technology. The reader will be introduced to the four core features of quantum leadership: duality, superposition, entanglement, and observation. With this groundwork, the principles and practices of this leadership perspective will be discussed in context of transmuting technology into unique organizational value. Which lens one uses to see which possibility becomes reality are exclusively in the eyes of the viewer. Using information systems technology, artificial intelligence (AI), and 5G technology as the exemplars, readers can decide whether to accept, reject, or suspend judgement on using quantum leadership as the perspective to transmute technology into valuable organizational gold.

It is possible that disturbances of systems modulating reward may contribute to a vulnerability to develop an eating disorder.This hypothesis was tested by assessing functional magnetic resonance brain imaging response to a monetary reward task known to activate the anterior ventral striatum (AVS), a region implicated in motivational aspects toward stimuli. To avoid the confounding effects of malnutrition, 10 women who had recovered from bulimia nervosa (BN) were compared with 10 healthy comparison women (CW).For the AVS, CW distinguished positive and negative feedback, whereas recovered BN women had similar responses to both conditions. In addition, these groups had similar patterns of findings for the dorsal caudate.We have previously shown that individuals recovered from anorexia nervosa (AN) also had altered striatal responses and difficulties in differentiating positive and negative feedback. Thus BN and AN individuals may share a difficulty in discriminating the emotional significance of a stimulus.

Several lines of evidence suggest that altered serotonin (5-HT) function persists after recovery from anorexia nervosa (AN) and bulimia nervosa (BN).We compared 11 subjects who recovered (1 year normal weight, regular menstrual cycles, no binging or purging) from restricting-type AN (REC RAN), 7 who recovered from bulimia-type AN (REC BAN), 9 who recovered from BN (REC BN), and 10 healthy control women (CW).Positron emission tomography (PET) imaging with [11C]McN5652 was used to assess the 5-HT transporter (5-HTT). For [11C]McN5652, distribution volume (DV) values were determined using a two-compartment, three-parameter tracer kinetic model, and specific binding was assessed using the binding potential (BP, BP=DVregion of interest/DVcerebellum-1).After correction for multiple comparisons, the four groups showed significant (p0.05) differences for [11C]McN5652 BP values for the dorsal raphe and antero-ventral striatum (AVS). Post-hoc analysis revealed that REC RAN had significantly increased [11C]McN5652 BP compared to REC BAN in these regions.Divergent 5-HTT activity in subtypes of eating disorder subjects may provide important insights as to why these groups have differences in affective regulation and impulse control.

Anorexia nervosa (AN) is an illness characterized by aversion to ingestion of normally palatable foods. We examined whether there is a primary disturbance of taste processing and experience of pleasure using a sucrose/water task in conjunction with functional magnetic resonance imaging (fMRI). To avoid confounding effects of illness, 16 women recovered from restricting-type AN were compared to 16 control women (CW). We used a region of interest-based fMRI approach to test the idea that individuals with AN have differential neural activation in primary and secondary taste cortical regions after sucrose and water administration. Compared to CW, individuals recovered from AN showed a significantly lower neural activation of the insula, including the primary cortical taste region, and ventral and dorsal striatum to both sucrose and water. In addition, insular neural activity correlated with pleasantness ratings for sucrose in CW, but not in AN subjects. Altered taste processing may occur in AN, based on differences in activity in insular-striatal circuits. These data provide the first evidence that individuals with AN process taste stimuli differently than controls, based on differences in neural activation patterns.

Background: Cerebrospinal fluid (CSF) measures of β-amyloid1–42 and tau differ between patients with Alzheimer’s Disease (AD) and elderly normal controls. The effect of time and APOE genotype on these biomarkers continues to be elucidated. Methods: We assessed CSF β-amyloid1–42 and tau in 20 mild-to-moderate AD patients, 11 APOE Ε4+ and 9 APOE Ε4–, over a mean time of 3.8 years (range 1–11.1 years). Results: Over the period measured, CSF β-amyloid1–42 levels were lower in APOE Ε4+ compared to APOE Ε4– patients, and the levels decreased over time. Tau levels were stable over time and did not show an effect of APOE allele. Conclusions: While this is a limited clinical sample, the further decrease in CSF β-amyloid1–42 (i.e., more abnormal) combined with the CSF tau stability over a mean period of almost 4 years suggests that β-amyloid1–42 and tau maintain their potential usefulness as diagnostic biomarkers over time. These findings should be taken into account if CSF β-amyloid1–42 and tau are used as measures of treatment response.

The effect of apolipoprotein E (APOE) genotype on longitudinal cognitive decline in midlife was investigated with attentional scaling. Healthy individuals (mean age 59.6 years) genotyped for APOE were tested at 3 12-month intervals on a cued visual search task. A random effects model revealed significant interaction in effect of precue size on search speed between APOE-epsilon4 gene dose and assessment, with longitudinal increases in noncarriers and heterozygotes but longitudinal decreases in homozygotes. Association of APOE-epsilon4 with cognitive decline in midlife is consistent with an Alzheimer's disease (AD) prodrome, albeit a decade or more before average age of AD diagnosis. However, cognitive decline in midlife associated with a gene modulating neuronal response to insult argues that the concept of an AD prodrome includes factors that allow as well as cause AD.

Sex-related differences in the stress response are well described in the animal literature but in humans are inconsistent and appear to reflect both the method used to stimulate the hypothalamic-pituitary-adrenal (HPA) axis and the age of the subjects. Sex-related differences in reproductive steroid levels further confound efforts to define the specific role of the sex of the individual in stress axis responsivity.The aim of this study was to address this role independent of differences in reproductive steroid levels. We compared HPA axis response to pharmacological (CRH) and physiological (exercise) stressors in two groups of young to middle-aged (18-45 yr) men (n = 10 and 8) and women (n = 12 and 13) undergoing gonadal suppression with leuprolide acetate (monthly im injection of 7.5 mg in men and 3.75 mg in women).Exercise and CRH stimulation tests were performed during induced hypogonadal conditions.The study was conducted at a National Institutes of Health Clinical Center Outpatient Clinic. PATIENT OR OTHER PARTICIPANTS: Male and female normal volunteers participated in the study.The main outcome measures were stimulated ACTH and cortisol levels.Both CRH (1 microg/kg) stimulation and graded treadmill exercise stimulation occurred in the month after the second leuprolide injection to ensure gonadal suppression. Despite the absence of sex differences in estradiol or testosterone at the time of testing, men showed increased stimulated ACTH (repeated-measures ANOVA for CRH, P0.005) and cortisol (repeated-measures ANOVA for exercise, P0.05) compared with women. Among the summary measures, area under the curve (AUC) for cortisol was significantly greater in men than women after exercise. Although the AUC for ACTH was not significantly different across sexes, the initial AUC (0-30 min) was significantly greater in men for both procedures. No significant sex differences were found in a measure of adrenal responsivity, the cortisol to ACTH ratio, for either procedure. Cortisol-binding globulin levels did not differ between men and women and were not correlated with stimulated HPA axis measures. These data confirm earlier reports of sex differences in stimulated HPA axis activity and demonstrate that these differences exist even under induced hypogonadal conditions (i.e. in the absence of characteristic differences in reproductive steroids).

Objective Major Depressive Disorder (MDD) may be a risk factor for subsequent development of irreversible dementia; however, the influence of a premorbid history of MDD on the clinical course of patients diagnosed with probable Alzheimer disease (AD) has not been fully explored. Methods Forty-three AD patients with mild-to-moderate cognitive impairment were screened for a life-long history of MDD with the Clinical Assessment of Depression in Dementia Scale. Twenty-two subjects had a history of MDD before onset of cognitive impairment, but none was suffering from an MDD episode at time of cognitive assessment. Results After controlling for age, education, duration of illness, gender, and medication status, subjects with a history of MDD had significantly lower scores, as a group, on cognitive performance tests, including the Mini-Mental State Exam, WAIS Full-Scale and Verbal Scale I.Q., and the Initiation/Perseveration subscale of the Mattis Dementia Rating Scale. These subjects also developed symptoms of dementia at a significantly earlier age than the subjects who had no premorbid history of MDD. Conclusions Although previous studies have shown that late-onset MDD may increase risk for subsequent dementia, the current results suggest that premorbid MDD is associated with more severe cognitive deficits during the actual course of dementia.

Two groups of non-demented individuals, who differed on genetic risk for Alzheimer's disease (AD) based on their apolipoprotein E (APOE) genotype, were tested on a category fluency task. Twenty varepsilon4 carriers and twenty varepsilon4 non-carriers were tape recorded while saying animal names for ten minutes. Five measures were examined: total names generated; total clusters; mean cluster size; mean within-cluster retrieval time; and mean between-cluster retrieval time. Groups were matched on age and education and scored as normal on a battery of psychometric tests. The varepsilon4 carriers generated significantly fewer names and clusters, and took significantly longer to access clusters, when compared to the varepsilon4 non-carriers. No group differences were found for cluster size or within-cluster retrieval times. We previously reported [Rosen, V. M., Bergeson, J. L., Putnam, K., Harwell, A., Sunderland, T. (2002). Working memory and apolipoprotein E: What's the connection? Neuropsychologia 40, 2226-2233] that the varepsilon4 carriers in the present study scored significantly lower than the varepsilon4 non-carriers on a measure of working memory/attentional capacity [Operation Span Task, see Turner, M. L., Engle, R. W. (1989). Is working memory capacity task dependent? Journal of Memory and Language 28, 127-154]. In the present study, a significant negative relationship found between span performance and between-cluster retrieval times suggested that reduced attentional capacity may have negatively impacted semantic access for the varepsilon4 carriers. Finally, we found significant relationships between a Trail Making Test [Reitan, R. M. (1992). Trail Making Test, manual for administration and scoring. Tucson, AZ: Reitan Neuropsychology Laboratory] "switch" measure (Form B-Form A) and three of the five fluency measures. The findings suggested that the varepsilon4 carrier's reduced attentional capacity may have interfered with their covertly shifting attention among subcategories in the fluency task, resulting in fewer names and clusters generated and longer times to access clusters.

Objective: Recent studies have raised the question as to whether a dysregulation of the neurotransmitter serotonin may contribute to the alterations in mood seen in anorexia nervosa (AN). People with AN tend to be anxious, obsessional, perfectionistic, and harm avoidant. These traits are premorbid and persist after recovery. It has been suggested that increased activity of brain serotonin systems could contribute to this pathologic condition. Dieting in AN, which serves to reduce plasma levels of tryptophan (TRP), may serve to reduce symptoms of dysphoric mood. Method: Fourteen women currently symptomatic with AN (ILL AN), 14 women recovered from AN (REC AN), and 15 healthy control women (CW) underwent acute tryptophan depletion (ATD). Measures of psychological state were self- assessed at baseline and hourly after ATD to determine whether ATD would reduce negative mood. Results: ILL AN and REC AN had significantly higher mean baseline TRP/LNAA (tryptophan/large neutral amino acids) ratios compared with CW. In contrast to placebo, the ATD challenge demonstrated a significantly greater reduction in the TRP/LNAA ratio for ILL AN (� 95%) and REC AN (� 84%) compared with CW (� 70%). Both the ILL AN and REC AN had a significant reduction in anxiety on the ATD day compared with the placebo day. Discussion: These data demonstrate that a dietary-induced reduction of TRP, the precursor of serotonin, is associated with decreased anxiety in people with AN. Restricting dietary intake may represent a mechanism through which individuals with AN modulate a dysphoric mood. # 2003 by Wiley Periodicals, Inc. Int J Eat Disord 33: 257-267, 2003.

Background Individuals who are ill with anorexia (AN) and bulimia nervosa (BN) often have increased cerebrospinal fluid (CSF) volumes and decreased total gray and white matter volumes. It is unclear whether such disturbances persist after recovery from an eating disorder. Methods Magnetic resonance imaging was performed on 40 women who were long-term recovered (>1 year no binging, purging, or restricting behaviors, normal weight, and menstrual cycles, not on medication) from restricting or binge/purging type AN or BN and 31 healthy control women (CW). Voxel-based morphometry (VBM) was used for data analysis. Results Recovered AN and BN subgroups were similar to CW in terms of cerebrospinal fluid (CSF) volume as well as total or regional gray or white matter volume. Conclusions These findings suggest that structural brain abnormalities are reversible in individuals with eating disorders after long-term recovery.

A study was conducted to examine the tolerability and pharmacokinetics of single and multiple oral doses of L-365,260, a novel antagonist for type B cholecystokinin (CCK) receptors and to quantify effects of selective blockade of type B CCK receptors through treatment with L-365,260 on measures of anxiety, hunger, and cognitive performance. Healthy volunteers were given single oral doses of up to 50 mg of L-365,260 and multiple oral doses of up to 25 mg every 6 hours for 10 days. Plasma concentrations of L-365,260 were quantified by means of high-performance liquid chromatography. Anxiety and hunger were assessed by visual analog scale and the Spielberger State Anxiety Index. Cognitive testing was used to evaluate attention level and short-term memory. L-365,260 was rapidly absorbed and a biphasic pattern of elimination was demonstrated with a terminal half-life (t 1/2 ) of 8 to 12 hours. The mean (n = 6) values for peak plasma concentration (C max ) and time to peak concentration (t max ) of L-365,260 were 503 ng/mL and 1.25 hours, respectively, after a single 50-mg oral dose. Accumulation of L-365,260 plasma concentrations was seen after the prescribed multiple-dose regimens. Steady state was achieved after 3 days of oral administration. L-365,260 had an acceptable tolerability profile after oral administration. No changes in measures of anxiety, hunger, or short-term memory were observed at doses of L-365,260 shown to have antagonist activity at the CCK-B receptor.

Individuals with anorexia nervosa (AN) and bulimia nervosa (BN) tend to have disordered thinking and eating behaviours in regards to fat containing foods. This is the first study to investigate neuronal pathways that may contribute to altered fat consumption in eating disordered patients.We used functional magnetic resonance imaging (fMRI) to compare responses to a high-fat cream stimulus, water, and a non-caloric viscous stimulus (CMC) to control for response to viscosity in individuals recovered from AN (N = 15), BN (N = 14) and a healthy control sample (CW, N = 18).An interaction analysis (ANOVAR) comparing the three groups (AN, BN, CW) and the three conditions (cream, CMC, water) revealed significant differences in the left anterior ventral striatum (AVS). A post hoc analysis displayed a higher magnitude of response for the contrast cream/water in BN compared to AN or CW and for the contrast CMC/water in BN compared to AN.BN showed an exaggerated AVS response for the cream/water contrast in comparison to AN or CW. Moreover, BN showed an exaggerated AVS response for the CMC/water contrast in comparison to AN. These findings support the possibility that BN have an altered hedonic and/or motivational drive to consume fats.

Individuals with anorexia nervosa (AN) and bulimia nervosa (BN) have alterations of measures of serotonin (5-HT) and dopamine (DA) function, which persist after long-term recovery and are associated with elevated harm avoidance (HA), a measure of anxiety and behavioral inhibition. Based on theories that 5-HT is an aversive motivational system that may oppose a DA-related appetitive system, we explored interactions of positron emission tomography (PET) radioligand measures that reflect portions of these systems. Twenty-seven individuals recovered (REC) from eating disorders (EDs) (7 AN-BN, 11 AN, 9 BN) and nine control women (CW) were analyzed for correlations between [(11)C]McN5652 and [(11)C]raclopride binding. There was a significant positive correlation between [(11)C]McN5652 binding potential (BP(non displaceable(ND))) and [(11)C]Raclopride BP(ND) for the dorsal caudate, antero-ventral striatum (AVS), middle caudate, and ventral and dorsal putamen. No significant correlations were found in CW. [(11)C]Raclopride BP(ND), but not [(11)C]McN5652 BP(ND), was significantly related to HA in REC EDs. A linear regression analysis showed that the interaction between [(11)C]McN5652 BP(ND) and [(11)C]raclopride BP(ND) in the dorsal putamen significantly predicted HA. This is the first study using PET and the radioligands [(11)C]McN5652 and [(11)C]raclopride to show a direct relationship between 5-HT transporter and striatal DA D2/D3 receptor binding in humans, supporting the possibility that 5-HT and DA interactions contribute to HA behaviors in EDs.

Although the central cholinergic deficits are still considered to be of primary importance in Alzheimer's disease, there is great need for an expansion of the pharmacological approach in this illness beyond the simple cholinergic replacement hypothesis. This report focuses on the concept of “combination chemotherapy” in Alzheimer's disease as the next generation of therapeutic strategies. Based on earlier positive findings in Alzheimer patients with the monoamine oxidase B inhibitor, 1-deprenyl, the authors speculate that a combination of physostigmine, the short-acting cholinesterase inhibitor, and 1-deprenyl might be more beneficial than either agent alone. The authors outline a sample paradigm for such combination studies, report preliminary data on the first 16 Alzheimer subjects to have received an initial combination of physostigmine and deprenyl, and point to other possible “combination chemotherapy” strategies for future study.

Individuals with anorexia nervosa are known to be ascetic and able to sustain self-denial of food as well as most comforts and pleasures in life. Building on previous findings of altered striatal dopamine binding in anorexia nervosa, the authors sought to assess the response of the anterior ventral striatum to reward and loss in this disorder.Striatal responses to a simple monetary reward task were investigated using event-related functional magnetic resonance imaging. To avoid the confounding effects of malnutrition, the authors compared 13 healthy comparison women and 13 women who had recovered from restricting-type anorexia nervosa and had 1 year of normal weight and regular menstrual cycles, without binge eating or purging.Recovered women showed greater hemodynamic activation in the caudate than comparison women. Only the recovered women showed a significant positive relationship between trait anxiety and the percentage change in hemodynamic signal in the caudate during either wins or losses. In contrast, in the anterior ventral striatum, comparison women distinguished positive and negative feedback, whereas recovered women had similar responses to both conditions.Individuals who have recovered from anorexia nervosa may have difficulties in differentiating positive and negative feedback. The exaggerated activation of the caudate, a region involved in linking action to outcome, may constitute an attempt at "strategic" (as opposed to hedonic) means of responding to reward stimuli. The authors hypothesize that individuals with anorexia nervosa have an imbalance in information processing, with impaired ability to identify the emotional significance of a stimulus but increased traffic in neurocircuits concerned with planning and consequences.

Objective: To evaluate neurotransmitter deficiencies and neurotransmitter-based treatments for frontotemporal dementia (FTD). Methods: The authors conducted a systematic review of the literature on the mechanism and treatment of FTD and a meta-analysis of treatment studies of antidepressants for the behavioral symptoms of FTD. Results: Patients with FTD show deficiencies in the serotonin and dopamine neurotransmitter systems, while the acetylcholine system appears relatively intact. Antidepressant treatment significantly improves behavioral symptoms in FTD, but most studies are small and uncontrolled. Serotonergic treatments appear to improve the behavioral but not cognitive symptoms of FTD. Conclusions: Studies of neurotransmitter deficiencies in frontotemporal dementia (FTD) can be helpful in developing treatments. Treatment studies on FTD are scarce, given the prevalence and severity of this illness. Larger, well-controlled treatment studies are required to reach more definitive conclusions about treatment efficacy. Multicenter studies are likely the best way to complete treatment studies in a timely manner.

Despite observations of age-dependent sexual dimorphisms in hypothalamic-pituitary-adrenal (HPA) axis activity, the role of androgens in the regulation of HPA axis activity in men has not been examined. We assessed this role by performing CRH stimulation tests in 10 men (ages 18-45 years) during gonadal suppression with leuprolide acetate and during testosterone addition to leuprolide. CRH-stimulated cortisol levels as well as peak cortisol and greatest cortisol excursion were significantly lower (p

Relationship of a 5-HT transporter functional polymorphism to 5-HT 1A receptor binding in healthy women

Major Depressive Disorder (MDD) may be a risk factor for subsequent development of irreversible dementia; however, the influence of a premorbid history of MDD on the clinical course of patients diagnosed with probable Alzheimer disease (AD) has not been fully explored.Forty-three AD patients with mild-to-moderate cognitive impairment were screened for a life-long history of MDD with the Clinical Assessment of Depression in Dementia Scale. Twenty-two subjects had a history of MDD before onset of cognitive impairment, but none was suffering from an MDD episode at time of cognitive assessment.After controlling for age, education, duration of illness, gender, and medication status, subjects with a history of MDD had significantly lower scores, as a group, on cognitive performance tests, including the Mini-Mental State Exam, WAIS Full-Scale and Verbal Scale I.Q., and the Initiation/Perseveration subscale of the Mattis Dementia Rating Scale. These subjects also developed symptoms of dementia at a significantly earlier age than the subjects who had no premorbid history of MDD.Although previous studies have shown that late-onset MDD may increase risk for subsequent dementia, the current results suggest that premorbid MDD is associated with more severe cognitive deficits during the actual course of dementia.

Patients with minimal cognitive impairment (MCI) or Alzheimer's disease (AD) have smaller hippocampal volumes (HV) and increased rates of HV loss (rHVL). A 6-year study was conducted to assess rHVL in healthy aging subjects (HC) in which four MRI scans, each 2 years apart, were obtained on 26 HC with a mean age of 58.8 years when entering the study. rHVLs were linear and significantly differed among subjects, even those sharing an identical apoliporotein E genotype, ranging from .027 to .191 cc/year (S.D. = .022 cc/year), and were not affected by age or sex. rHVL, but not HV, at time of subject entry, was found to predict performance on the delayed recall measure of the Selective Reminder Task obtained 6 years after subject entry into study. Although the molecular events underlying rHVL are unclear, the significance of rHVL in subjects in their sixth and seventh decades of life for predicting age-related cognitive trajectories and whether changes in rHVLs foreshadow the development of MCI are the subject of ongoing study.

Recent studies show that specific regions of the cortex contribute to modulation of appetitive behaviors. The purpose of this study was to determine whether neural response in these regions changes over time when a taste stimulus is administered repeatedly. Such a paradigm may be useful for determining whether altered habituation contributes to disturbed eating behavior. This study used a programmable syringe pump to compare administration of a 10% sucrose solution to distilled water in 11 healthy female subjects using functional magnetic resonance imaging. The stimuli were presented in either a sequential or pseudorandom order. An a priori 'Region of Interest' (ROI) based analysis method was used, with ROIs defined in the prefrontal cortex, insula, amygdala, and hippocampus. To test habituation, activation during the first half of each block was compared with activation during the second half. For the pseudorandom blocks, subjects showed habituation in almost all ROIs to water, but in none to sucrose. By contrast, for sequential blocks, both stimuli produced habituation in taste-related brain regions. These data suggest that habituation patterns in healthy subjects may depend on frequency and regularity of stimulus administration.

Cerebrospinal fluid (CSF) measures of beta-amyloid(1-42) and tau are linked with the known neuropathology of Alzheimer's disease (AD). Numerous lines of evidence have also suggested that individuals with at least one APOE epsilon4 allele on chromosome 19 are at increased risk of developing AD. We tested these CSF markers in groups of subjects with AD and healthy older control subjects, using the absence or presence of the APOE epsilon4 allele as a predictive variable in the search for possible prognostic biomarkers of AD.We assessed the levels of beta-amyloid(1-42) and total tau in the CSF of 292 subjects (142 control subjects and 150 subjects with mild-to-moderate AD), who were research participants at the National Institute of Mental Health. The group of control subjects was enriched with a high percentage of subjects with a positive family history of AD. All subjects underwent extensive global cognitive testing.When divided according to the absence or presence of the APOE epsilon4 allele, the control subjects with at least one epsilon4 allele had significantly lower CSF beta-amyloid(1-42) but not tau levels than control subjects without an APOE epsilon4 allele (p.01). As expected, the AD patients had lower levels of CSF beta-amyloid(1-42) and higher CSF tau levels than the normal control group (p.01).The association of APOE epsilon4 allele and lower, more AD-like levels of CSF beta-amyloid(1-42) in older control subjects is consistent with previous studies showing possible neuroimaging and cognitive abnormalities with epsilon4 carriers and suggests that CSF beta-amyloid(1-42) decreases might represent an early biomarker of AD. Longitudinal follow-up is of course required to verify whether this biomarker is indeed predictive of clinical conversion to AD.

Publisher Summary This chapter describes the proteomic approaches in drug discovery and development. Proteomics represents the effort to establish the identities, quantities, structures, and biochemical and cellular functions of all proteins in an organism, organ, or organelle and how these properties vary in space, time, or physiological state. The proteome is more complex than the genome, because the inherent biochemical nature of proteins depends on more complicated building blocks. Intracellular localization, proteolytic processing, post-translational modification, and protein-protein interactions add greatly to protein complexity. The chapter provides an overview of the existing technologies, and presents a case study that shows how two-dimensional gel electrophoresis (2DE)-mass spectroscopy (MS) profiling approaches can be applied to one type of issue central to drug discovery and development. From a drug discovery and development perspective, the greatest challenge is translating the information garnered from proteomic initiatives into quantitative, sensitive, and specific assays capable of delivering information about a drug's effect on the target, and if the drug can effectively alter the disease in a clinically beneficial manner. Although proteomics may provide information about new targets, one of the major hurdles in early drug discovery is to demonstrate that the drug has bound specifically to target and produced a biological, meaningful activity both in vitro and in vivo . Despite the existing challenges, proteomic technologies offer powerful tools for difficult scientific questions, and are certainly a path to the future for more efficient drug discovery and development.

Previous studies in animals indicate that reproductive steroids are potent modulators of the hypothalamic-pituitary-adrenal (HPA) axis, a physiologic system that is typically dysregulated in affective disorders, such as major depression. Determination of the role of reproductive steroids in HPA axis regulation in humans is of importance when attempting to understand the pathophysiology of premenstrual syndrome (PMS), a disorder characterized by affective symptoms during the luteal phase of the menstrual cycle. We performed two studies using treadmill exercise stress testing to determine the effect of menstrual cycle phase and diagnosis on the HPA axis in women with PMS and controls and the role of gonadal steroids in HPA axis modulation in control women. The results of these studies indicate that women with PMS fail to show the normal increased HPA axis response to exercise during the luteal phase and that progesterone, not estradiol, produces increased HPA axis response to treadmill stress testing in control women. These data demonstrate that women with PMS, when symptomatic, appear to have an abnormal response to progesterone and, furthermore, do not display the HPA axis abnormalities characteristic of major depression.

ContextAlzheimer disease (AD) is characterized by pathological results at autopsy of amyloid plaques and tau-associated neurofibrillary tangles, but the clinical diagnosis of AD is determined on the basis of medical history, cognitive symptoms, and exclusionary criteria. The search for antemortem biomarkers is intense and has focused on cerebrospinal fluid (CSF) β-amyloid1-42 and tau proteins.ObjectivesTo compare CSF β-amyloid and tau levels in a new population of AD patients and controls. To perform a meta-analysis of studies of CSF β-amyloid and tau levels in AD patients and controls.DesignCross-sectional study of the comparison of baseline CSF β-amyloid1-42 and tau levels in AD patients and controls. Meta-analysis involved 17 studies of CSF β-amyloid and 34 studies of CSF tau.SettingClinical research unit of the National Institute of Mental Health, Bethesda, Md.PatientsThe Geriatric Psychiatry Branch evaluated AD patients as inpatients at the National Institutes of Health Clinical Center between May 1985 and January 2001. A total of 203 patients participated in this study (131 with AD and 72 controls). None had other serious illnesses, and 31 of 131 AD cases had AD confirmed at autopsy. Meta-analysis provided an additional 3133 AD patients and 1481 controls.Main Outcome MeasuresLevels of CSF β-amyloid1-42 were measured by a sandwich enzyme-linked immunoabsorbent assay with a polyclonal capture antibody and a monoclonal detection antibody. Levels of CSF tau were measured with a standard commercial immunoassay.ResultsLevels of CSF β-amyloid1-42 were significantly lower in the AD patients vs controls (mean [SD], 183 [121] pg/mL vs 491 [245] pg/mL; P

The aim of the study was to determine whether the epsilon 4 allele of the apolipoprotein E (ApoE) gene was associated primarily with context-specific memory among individuals at genetic risk for developing Alzheimer's disease. The effect of ApoE status on comprehensive neuropsychological results was examined in 176 healthy adults during baseline cognitive testing in the NIMH Prospective Study of Biomarkers for Older Controls at Risk for Alzheimer's Disease (NIMH Prospective BIOCARD Study). The presence of the epsilon 4 allele was associated with significantly lower total scores on the Logical Memory II subtest of the Wechsler Memory Scale-Revised and percent of information retained after delay. Further analysis indicated the prose recall and retention effect was partially explained by a small subgroup of epsilon 4 homozygotes, suggesting a gradually progressive process that may be presaged with specific cognitive measures. The current results may represent an epsilon 4-associated breakdown between gist-related information and context-bound veridical recall. This relative disconnection may be understood in light of putative epsilon 4-related preclinical accumulation of Alzheimer pathology (tangles and plaques) in the entorhinal cortex (EC) and among frontal networks, as well as the possibility of less-efficient compensatory strategies.

Two robust findings in the Alzheimer's literature are that patients with Alzheimer's disease (AD) show executive function and primacy deficits. The present study examined whether we would find similar deficits when comparing two groups of middle-aged individuals who differed with respect to genetic risk for AD, based on their apolipoprotein E (APOE) genotype. All individuals were screened as normal on a battery of standardized cognitive measures. They were tested on the "Operation span task", which engages the central executive component of working memory [J. Exp. Psychol.: Gen. 128 (1999) 309, J. Exp. Psychol.: Gen. 126 (1997) 211, J. Mem. Language 39 (1998) 418] by dividing attention between processing math operations and remembering words. Individuals were grouped according to APOE genotype ( epsilon 4 carrier versus epsilon 4 non-carrier), matched on age and education, and their Total span and Primacy scores were compared. Despite having no overt symptoms of dementia or deficits on a series of standardized psychometric tests, the epsilon 4 carriers showed divided-attention and primacy deficits on the Operation span task, when compared to the epsilon 4 non-carriers. As a point of comparison, Primacy scores were extracted from the first trial of the "Buschke selective reminding task" [J. Verbal Learn. Verbal Behav. 12 (1973) 543] for these same individuals, and no group differences were found. The Buschke task is a list-learning task that does not require divided attention. These findings suggested that the epsilon 4 carriers were less able to divide their attention, when compared to the epsilon 4 non-carriers. The findings provide the first direct evidence for a relationship between APOE genotype and cognitive performance on measures of divided attention and primacy with non-demented individuals who showed no cognitive impairments on standardized measures.

It has been argued that the role of the hippocampus in memory is time-limited: during a period of memory consolidation, other brain regions such as the neocortex are said to acquire the ability to support memory retention and retrieval on their own. An alternative view is that retention and retrieval of memory for autobiographical episodes depend on the hippocampal complex, regardless of the age of the memory. We examined the participation of the hippocampal complex in a functional magnetic resonance imaging (fMRI) study in which participants were asked to recollect autobiographical events that occurred either within the last 4 years or more than 20 years ago. We found equivalent levels of hippocampal activation in both conditions in all participants (N = 10). In addition, activation in neocortical regions did not differ as a function of the age of the memory, even though most of the recent memories recalled were less than 2 years old and the remote memories more than 35 years old. The results support the notion that the hippocampal complex participates in retention and recovery of even very old autobiographical memories, and place boundary conditions on theories of memory consolidation.

Analysis of CSF is an important component of clinical and research studies involving illnesses such as AD. In fact, longitudinal analysis of CSF may be vital to identify and track potential biological markers in people at risk for developing AD. However, recruiting initial and long-term participation of research subjects in lumbar puncture (LP)-based studies can be challenging, especially because the incidence of post-LP headaches (post-LPHAs) with traditional methods often exceeds 30%.1 Reduction of post-LPHAs through the use of small-diameter spinal needles is well documented,2 presumably due to reduced leakage of CSF from the smaller hole produced when the spinal needle traverses the dura.3-5⇓⇓ There is relatively little experience obtaining large quantities of fluid from small-diameter Whitacre spinal needles compared with the traditional 20-guage, Quincke needles. Therefore, we sought to determine whether research quantities of CSF could be withdrawn using small, atraumatic needles and negative pressure techniques without causing a significant increase in the rate of …

The metamemory (knowledge of the veracity of memories) of moderately impaired Alzheimer's patients was compared to that of aged controls. Despite their profoundly impaired recall of information from both long-term (knowledge) and recent (episodic) memory, Alzheimer's patients were as accurate as controls in assigning confidence ratings related to the probability that their recalls were correct. They were impaired, however, at predicting the likelihood that they would subsequently recognize correct answers (feeling-of-knowing) to knowledge memory questions which they had been unable to recall correctly. Nevertheless, their performance on this task did exceed chance. Thus, the moderately impaired Alzheimer's patient demonstrates intact awareness of the veracity of recall from knowledge and episodic memory but shows impaired feeling-of-knowing for knowledge memory.

Aggleton & Brown rightly point out the shortcomings of the medial temporal lobe hypothesis as an approach to anterograde amnesia. Their broader perspective is a necessary corrective, and one hopes it will be taken very seriously. Although they correctly note the dangers of conflating recognition and recall, they themselves make a similar mistake in discussing familiarity; we suggest an alternative approach. We also discuss implications of their view for an analysis of retrograde amnesia. The notion that there are two routes by which the hippocampus can reactivate neuronal ensembles in the neocortex could help us understand some currently puzzling facts about the dynamics of memory consolidation.