Considering drugs or other exogenous substances as challenge agents is quite common in medical practice, but this strategy is relatively new to biologic psychiatry research in general, and Alzheimer’s research in particular. The scopolamine memory impairment model is much less tested in humans as a screening ground for new agents. Up until now, the focus has usually been whether or not pro-cholinergic agents can, as would be expected, block the anticholinergic effects of scopolamine. This chapter focuses primarily on the scopolamine challenge, but it is by no means the only approach to pharmacologic modelling in Alzheimer’s disease. It continues to expand our understanding of Alzheimer’s disease beyond the previously narrow focus on the cholinergic system. The lack of an adequate animal model in Alzheimer’s disease research makes it important that we develop human models of reversible memory impairment.

How and when the known genetic risk allele, apolipoprotein E-epsilon4 (APOEepsilon4), confers risk to Alzheimer's disease has yet to be determined. We studied older adults and found that APOEepsilon4 carriers had greater neural activation in the medial frontal and parahippocampal gyrus during a memory task (cluster-corrected p < .01). When compared to a group of younger adults, interactive effects of age and APOEepsilon4 were found in the inferior frontal-anterior temporal region, one of the first areas to develop amyloid plaques in patients with Alzheimer's disease, and, in the posterior cingulate, one of the earliest areas to show decreased cerebral metabolism in Alzheimer's disease. Thus, abnormally high activation in fronto-temporal areas are present in both younger and older APOEepsilon4 carriers confronted with a working memory task when compared to non-APOEepsilon4 carriers. This effect, however, appears to diminish with age.

Although it is established that apolipoprotein E (APOE) e4 allele increases the risk of Alzheimer's disease (AD), epidemiological studies indicate that genetic risk decreases late in life. This raises the question of whether the effects of APOE on cognition that are seen in midlife arise from a cognitive phenotype of APOE or from the presence of early AD in some APOE-e4 carriers. The authors addressed this question by comparing the cognitive consequences of variation in the APOE gene between individuals over the age of 80 (old-old) and middle-aged and young-old individuals. A spatially cued discrimination paradigm--previously shown to be sensitive to AD and to APOE genotype--required a speeded categorization of a target letter following cues that were valid, invalid, or neutral in predicting target location. Results revealed greater costs of invalid cues in the APOE-e4 carriers of middle-aged and young-old, but not old-old, groups. The dissipation of the APOE effect in old-old individuals at lower risk of AD suggests that visuospatial attention impairments seen as early as midlife in APOE-e4 carriers may be a preclinical marker of AD.

Macroscopically, Alzheimer's disease (AD) is characterized by global atrophy that is more pronounced, at least, initially, in medial temporal lobe structures and accompanied by ventricular enlargement. Rates of hippocampal atrophy (rHVLs) and ventricular volume gain (rVVGs) have been proposed as possible measures to judge the efficacy of treatments designed to be disease modifying. Our interest has focused on whether and when rHVL and rVVG differ between healthy subjects destined to develop AD and those destined to remain healthy. In prior work, based on 4 MRI scans obtained in a 6 year period, on 26 healthy subjects (mean age = 58.8 years), we found that rHVLs were linear and significantly differed among subjects, even those sharing identical apolipoprotein E (APOE) genotypes and that higher rHVLs were associated with subsequent poorer memory performance. In this study, the same scans were used to investigate rVVGs. rVVGs were also found to be linear with differences observed among subjects independent of APOE genotype. However, in contrast to rHVLs and hippocampal volumes, rVVGs and baseline ventricular volumes correlated with age, but not with memory performance on a selective reminding task. The findings are consistent with selective atrophy of the hippocampus rather than global cortical atrophy as responsible for age-related declines in episodic memory in healthy subjects in their 6th and 7th decades while higher rVVGs may be associated with other age-related cognitive impairments.

Terrorists are attacking scientists who are attempting to alleviate human suffering. We need a concerted public effort to eliminate these acts, particularly the harassment of scientists studying nonhuman primates. This need is highlighted by the attacks upon the home of our friend and colleague, the noted medical scientist, Dr. Edythe London, professor of psychiatry and biobehavioral sciences and of molecular and medical pharmacology at the David Geffen School of Medicine at the University of California Los Angeles (UCLA). Her work exemplifies the unique role of research involving nonhuman primates in enabling the results of research in simple systems (oocytes, cell culture) and lower organisms to be applied to human diseases. The importance of Dr. London’s research was highlighted in a public letter issued on February 8, 2008 from the Director of the National Institutes of Health (NIH), Dr. Elias Zerhouni, who stated, “her work is a prime example of NIH’s efforts … to develop effective treatments for people suffering from addiction—a disease that devastates individuals, families, communities, and costs society more than half a trillion dollars annually in health and crime-related costs and losses in productivity.”Dr. London suffered two attacks upon her home within 4 months that have escalated in their level of threat to her life and work. The first occurred on October 20, 2007, and it involved the flooding of her house with water. A press release from the Animal Liberation Front, a group that has publicized both attacks, noted that water was used for the initial act because “we don’t risk starting brush fires,” a serious public threat in Southern California. Nevertheless, in the second attack on February 5, 2008, a Molotov cocktail firebomb was ignited, setting fire to Dr. London’s home. These crimes mirror other recent attacks on scientists conducting medical research involving animals, only a few of which we will mention here (1Miller G. Animal extremists get personal.Science. 2007; 318: 1856-1858Crossref PubMed Scopus (12) Google Scholar). In June 2006, another incendiary device intended for UCLA neuroscientist, Dr. Lynn Fairbanks, was placed on the doorstep of her 70-year-old neighbor. In June 2007, a third incendiary device was found at the home of another UCLA neuroscientist, Dr. Arthur Rosenbaum, the chief of pediatric ophthalmology at that institution. Dr. Rosenbaum’s wife also received a letter that included death threats and that was accompanied by razor blades and animal hair. Problems also have been escalating at the University of California Santa Cruz (UCSC). Most recently, on February 25, 2008, after a series of other incidents, six people broke into the home of a UCSC faculty member, whose name has not been released, and attacked a member of that faculty person’s family. The Santa Cruz Sentinel, on February 26, implicated a group of six people and a corporation, Stop Huntingdon Animal Cruelty USA. Threatening acts have occurred at other American medical research institutions, including the Oregon Health Sciences University and the University of Utah (1Miller G. Animal extremists get personal.Science. 2007; 318: 1856-1858Crossref PubMed Scopus (12) Google Scholar). The attacks in the United States follow a more vigorous program of terrorism in the United Kingdom aimed at disrupting medical research, particularly research involving nonhuman primates (2Cyranoski D. Animal research: Primates in the frame.Nature. 2006; 444: 812-813Crossref PubMed Scopus (4) Google Scholar).The attacks are horribly misguided. It is impossible to reconcile the willingness of these terrorists to harm humans, particularly people who are working to alleviate human suffering, with their contention that they value life of all kinds. Scientists, like Dr. London, care about the primates that they study. Scientists are partners with other interested groups in the ongoing international effort to improve the principles and practices governing animal research (briefly reviewed at http://www.nabr.org/pdf/orange.pdf). This peaceful and collaborative process is critical to preserve in the face of the recent violence.We need to support our colleagues and to work to preserve the integrity of the mission of alleviating human suffering through biomedical research involving animals. In so doing, we might help to ensure that these attacks upon scientists do not discourage much-needed research by demoralizing scientists or by stimulating institutions to adopt overly burdensome administrative practices (2Cyranoski D. Animal research: Primates in the frame.Nature. 2006; 444: 812-813Crossref PubMed Scopus (4) Google Scholar). The recent events at UCLA make clear that diligently improving the ethical standards for primate research procedures is not, by itself, sufficient to prevent attacks. It is encouraging, for example, that on February 22, 2008, a Los Angeles County Superior Court judge issued a restraining order against the Animal Liberation Brigade, the Animal Liberation Front, and UCLA Primate Freedom Project that created a protective buffer zone around the homes of UCLA research faculty members.These terrorist acts might intimidate people and institutions that would otherwise speak out in support of nonhuman primate research and against terrorism. By failing to take public action, we contribute to the isolation of the scientists involved and the institutions in which they work. Frustration with the absence of a vigorous public response to recent terrorist attacks led Robert Palazzo, president of the Federation of American Societies for Experimental Biology in Bethesda, Maryland to ask “Where’s the noise on this?” (1Miller G. Animal extremists get personal.Science. 2007; 318: 1856-1858Crossref PubMed Scopus (12) Google Scholar). Several organizations, such as the Society for Neuroscience (http://www.sfn.org), the National Association for Biomedical Research (http://www.nabr.org), and the American College of Neuropsychopharmacology (http://www.acnp.org), are helping to educate the public on these issues. There are growing opportunities for animal research advocacy. The failure to publicly address the crimes against its faculty was initially a problem at UCLA, but this institution now is at the vanguard of protecting its scientists and speaking out on behalf of medical research (1Miller G. Animal extremists get personal.Science. 2007; 318: 1856-1858Crossref PubMed Scopus (12) Google Scholar). In addition, the Society for Neuroscience has issued a report on “Best Practices for Protecting Researchers and Research” to assist investigators and institutions targeted by terrorists (http://www.sfn.org/skins/main/pdf/gpa/Best_Practices_for_Protecting.pdf).We seek a more vigorous investigation and prosecution of the criminals committing the crimes against these scientists, their staffs, their families, their neighbors, and the communities in which they live. We are heartened that stronger laws enacted in the United States and the United Kingdom provide enforcement agencies with legal tools needed to bring these offenders to justice (1Miller G. Animal extremists get personal.Science. 2007; 318: 1856-1858Crossref PubMed Scopus (12) Google Scholar). The United Kingdom is ahead of the United States in this regard. As reported in Science, the United Kingdom formed a National Extremism Tactical Coordination Unit in 2004. This unit helped to conduct a 2-year investigation involving more than 700 police, which resulted in raids in the United Kingdom, the Netherlands, and Belgium and the arrest of 30 suspected terrorists. There seem to be signs that the vigorous prosecution of terrorism in the United Kingdom is having a positive effect (3Fighting animal rights terrorism.Nat Neurosci. 2006; 9 (Anonymous): 1195Crossref PubMed Scopus (4) Google Scholar). However, the number of attacks on scientists conducting medical research in animals in the United States is increasing (1Miller G. Animal extremists get personal.Science. 2007; 318: 1856-1858Crossref PubMed Scopus (12) Google Scholar), and we need to mount an equally vigorous campaign in this country to prevent these heinous attacks.Lastly, we wish to laud the dedication and courage shown by Dr. London and those like her that continue to strive to reduce suffering and advance science despite obvious personal cost. As the beneficiaries of progress in medical care, it is also our responsibility to join the struggle to preserve medical research. Terrorists are attacking scientists who are attempting to alleviate human suffering. We need a concerted public effort to eliminate these acts, particularly the harassment of scientists studying nonhuman primates. This need is highlighted by the attacks upon the home of our friend and colleague, the noted medical scientist, Dr. Edythe London, professor of psychiatry and biobehavioral sciences and of molecular and medical pharmacology at the David Geffen School of Medicine at the University of California Los Angeles (UCLA). Her work exemplifies the unique role of research involving nonhuman primates in enabling the results of research in simple systems (oocytes, cell culture) and lower organisms to be applied to human diseases. The importance of Dr. London’s research was highlighted in a public letter issued on February 8, 2008 from the Director of the National Institutes of Health (NIH), Dr. Elias Zerhouni, who stated, “her work is a prime example of NIH’s efforts … to develop effective treatments for people suffering from addiction—a disease that devastates individuals, families, communities, and costs society more than half a trillion dollars annually in health and crime-related costs and losses in productivity.” Dr. London suffered two attacks upon her home within 4 months that have escalated in their level of threat to her life and work. The first occurred on October 20, 2007, and it involved the flooding of her house with water. A press release from the Animal Liberation Front, a group that has publicized both attacks, noted that water was used for the initial act because “we don’t risk starting brush fires,” a serious public threat in Southern California. Nevertheless, in the second attack on February 5, 2008, a Molotov cocktail firebomb was ignited, setting fire to Dr. London’s home. These crimes mirror other recent attacks on scientists conducting medical research involving animals, only a few of which we will mention here (1Miller G. Animal extremists get personal.Science. 2007; 318: 1856-1858Crossref PubMed Scopus (12) Google Scholar). In June 2006, another incendiary device intended for UCLA neuroscientist, Dr. Lynn Fairbanks, was placed on the doorstep of her 70-year-old neighbor. In June 2007, a third incendiary device was found at the home of another UCLA neuroscientist, Dr. Arthur Rosenbaum, the chief of pediatric ophthalmology at that institution. Dr. Rosenbaum’s wife also received a letter that included death threats and that was accompanied by razor blades and animal hair. Problems also have been escalating at the University of California Santa Cruz (UCSC). Most recently, on February 25, 2008, after a series of other incidents, six people broke into the home of a UCSC faculty member, whose name has not been released, and attacked a member of that faculty person’s family. The Santa Cruz Sentinel, on February 26, implicated a group of six people and a corporation, Stop Huntingdon Animal Cruelty USA. Threatening acts have occurred at other American medical research institutions, including the Oregon Health Sciences University and the University of Utah (1Miller G. Animal extremists get personal.Science. 2007; 318: 1856-1858Crossref PubMed Scopus (12) Google Scholar). The attacks in the United States follow a more vigorous program of terrorism in the United Kingdom aimed at disrupting medical research, particularly research involving nonhuman primates (2Cyranoski D. Animal research: Primates in the frame.Nature. 2006; 444: 812-813Crossref PubMed Scopus (4) Google Scholar). The attacks are horribly misguided. It is impossible to reconcile the willingness of these terrorists to harm humans, particularly people who are working to alleviate human suffering, with their contention that they value life of all kinds. Scientists, like Dr. London, care about the primates that they study. Scientists are partners with other interested groups in the ongoing international effort to improve the principles and practices governing animal research (briefly reviewed at http://www.nabr.org/pdf/orange.pdf). This peaceful and collaborative process is critical to preserve in the face of the recent violence. We need to support our colleagues and to work to preserve the integrity of the mission of alleviating human suffering through biomedical research involving animals. In so doing, we might help to ensure that these attacks upon scientists do not discourage much-needed research by demoralizing scientists or by stimulating institutions to adopt overly burdensome administrative practices (2Cyranoski D. Animal research: Primates in the frame.Nature. 2006; 444: 812-813Crossref PubMed Scopus (4) Google Scholar). The recent events at UCLA make clear that diligently improving the ethical standards for primate research procedures is not, by itself, sufficient to prevent attacks. It is encouraging, for example, that on February 22, 2008, a Los Angeles County Superior Court judge issued a restraining order against the Animal Liberation Brigade, the Animal Liberation Front, and UCLA Primate Freedom Project that created a protective buffer zone around the homes of UCLA research faculty members. These terrorist acts might intimidate people and institutions that would otherwise speak out in support of nonhuman primate research and against terrorism. By failing to take public action, we contribute to the isolation of the scientists involved and the institutions in which they work. Frustration with the absence of a vigorous public response to recent terrorist attacks led Robert Palazzo, president of the Federation of American Societies for Experimental Biology in Bethesda, Maryland to ask “Where’s the noise on this?” (1Miller G. Animal extremists get personal.Science. 2007; 318: 1856-1858Crossref PubMed Scopus (12) Google Scholar). Several organizations, such as the Society for Neuroscience (http://www.sfn.org), the National Association for Biomedical Research (http://www.nabr.org), and the American College of Neuropsychopharmacology (http://www.acnp.org), are helping to educate the public on these issues. There are growing opportunities for animal research advocacy. The failure to publicly address the crimes against its faculty was initially a problem at UCLA, but this institution now is at the vanguard of protecting its scientists and speaking out on behalf of medical research (1Miller G. Animal extremists get personal.Science. 2007; 318: 1856-1858Crossref PubMed Scopus (12) Google Scholar). In addition, the Society for Neuroscience has issued a report on “Best Practices for Protecting Researchers and Research” to assist investigators and institutions targeted by terrorists (http://www.sfn.org/skins/main/pdf/gpa/Best_Practices_for_Protecting.pdf). We seek a more vigorous investigation and prosecution of the criminals committing the crimes against these scientists, their staffs, their families, their neighbors, and the communities in which they live. We are heartened that stronger laws enacted in the United States and the United Kingdom provide enforcement agencies with legal tools needed to bring these offenders to justice (1Miller G. Animal extremists get personal.Science. 2007; 318: 1856-1858Crossref PubMed Scopus (12) Google Scholar). The United Kingdom is ahead of the United States in this regard. As reported in Science, the United Kingdom formed a National Extremism Tactical Coordination Unit in 2004. This unit helped to conduct a 2-year investigation involving more than 700 police, which resulted in raids in the United Kingdom, the Netherlands, and Belgium and the arrest of 30 suspected terrorists. There seem to be signs that the vigorous prosecution of terrorism in the United Kingdom is having a positive effect (3Fighting animal rights terrorism.Nat Neurosci. 2006; 9 (Anonymous): 1195Crossref PubMed Scopus (4) Google Scholar). However, the number of attacks on scientists conducting medical research in animals in the United States is increasing (1Miller G. Animal extremists get personal.Science. 2007; 318: 1856-1858Crossref PubMed Scopus (12) Google Scholar), and we need to mount an equally vigorous campaign in this country to prevent these heinous attacks. Lastly, we wish to laud the dedication and courage shown by Dr. London and those like her that continue to strive to reduce suffering and advance science despite obvious personal cost. As the beneficiaries of progress in medical care, it is also our responsibility to join the struggle to preserve medical research. This article was not prepared with support from any funding agency or within the context of any official capacity. The opinions expressed herein are solely the private personal opinions of the authors and do not indicate any official institutional (university, government agencies, private foundations) position. Financial disclosures for the contributing authors are presented online as supplementary material. Supplementary data Download .doc (.05 MB) Help with doc files Supplementary data Download .doc (.05 MB) Help with doc files Supplementary data ErrataBiological PsychiatryVol. 63Issue 10PreviewThe financial and conflict of interest disclosures for two authors were inadvertently misreported in the supplementary document of the article “It Is Time to Take a Stand for Medical Research and Against Terrorism Targeting Medical Scientists” by Krystal et al., which appeared in the April 15, 2008 issue of Biological Psychiatry, Volume 63, Number 8 (Biol Psychiatry 2008;63:725–727). Full-Text PDF

Children of persons with Alzheimer disease (AD), as a group, face an increased risk of developing AD. Many of them, throughout their adult lives, seek input on how to reduce their chances of one day suffering their parent's fate. We examine the state of knowledge with respect to risk and protective factors for AD and recommend a research agenda with special emphasis on AD offspring.

Cognitive changes such as attention, executive operations, and higher–order semantic functioning may precede the development of memory impairment and presage the development of Alzheimer's disease (AD). A pronounced breakdown in semantic dominance networks for ambiguous words (homographs) is associated with early and mild AD (e.g., no expected preference for “monetary” vs. “shoreline–related” word associates for the homograph “bank”). To determine if homograph dominance, in combination with attention and mental switching, is altered in healthy older adults with apolipoprotein E4 alleles (apoE4+) and thus are at increased genetic risk for AD. We developed a novel paradigm that selectively directed the focus of attention between two simultaneously presented homograph associates (“money” & “river”), followed by a rapid switch to reading the actual homograph aloud (“bank”). This paradigm was administered to 86 apoE4–, 52 apoE4+ heterozygotes, and 12 apoE4+ homozygotes without memory impairment on neuropsychological testing. We measured the reaction time (RT) for directed attention and reading responses, and homograph recognition (correct hits & false responses). Inheritance of apoE4 had a significant effect on RT during the directed attention condition, F (2,294) = 5.05, p < .01. Heterozygotes were on average 100 msec faster to respond than the apoE4– subjects. Homozygotes were slowest to respond on both directed attention and homograph reading. While homograph correct hits did not differ between groups, the ϵ4–absent group made more false responses (9.5) as compared with those with genetic risk (7.0), especially for foils unrelated to study homographs, t (141) = 2.5, p < .05. The seeming paradox of “faster” RT in heterozygotes and higher rates of recognition false responses in the overall apoE4+ group is indicative of reduced homograph dominance, while slowing of RT in homozygotes is probably explained by the demands of rapid task switching overriding subtle semantic deficits among those with presumed greater disease burden. Subtle declines in homograph dominance in our apoE4+ subjects indicate that impairment of ambiguous word networks, directed attention, and mental switching precede the cardinal memory impairments of AD.

Functional neural alterations are present in middle-aged to late-aged healthy individuals carrying the epsilon4 allele of the apolipoprotein E (APOEepsilon4) gene, a known risk factor for Alzheimer's disease. Neural activity was measured in young adults with and without the epsilon4 allele (APOEepsilon4+ and APOEepsilon4-) by functional magnetic resonance imaging and magnetoencephalography while performing a visual working memory task on two separate days. Greater activity was observed in frontal areas and cingulate gyri in APOEepsilon4+ participants by both functional magnetic resonance imaging and magnetoencephalography with regional blood oxygenation level-dependent responses correlating with increased theta band power. The findings suggest that the presence of the APOEepsilon4 allele has physiological consequences before aging that may contribute to risk for Alzheimer's disease.

Although clinical manifestations of cognitive dysfunction and impairments of activities of daily living are the current standard measures for the diagnosis of Alzheimer’s disease, biomarkers are receiving increasing attention in research centers as possible early diagnostic measures or as surrogate measures of the ongoing pathology. In preparation for the upcoming development of the Diagnostic and Statistical Manual of Mental Disorders (5th ed; DSM-V) nosology, the American Psychiatric Association has sponsored an effort to reassess the current approaches to diagnosis in dementia in general and Alzheimer’s disease in particular. This article focuses on the potential use of biomarkers in the diagnosis of Alzheimer’s disease, in the monitoring of mild cognitive impairment, and as possible prognostic markers in normal controls at risk for dementia. Most advanced information is available with the biomarkers found in the cerebrospinal fluid, but there are many other potential biomarkers using blood, brain imaging, or a combination. The current biomarker approaches to diagnosis are reviewed along with a special emphasis on near-term recommendations and further research directions. ( J Geriatr Psychiatry Neurol 2006;19:172-179)

There is extensive evidence of an immune–mediated inflammatory component to neurodegeneration in Alzheimer's Disease (AD). A previous trial of oral cyclophosphamide (CY), a potent immunomodulatory drug, in AD patients reported improvement in cognitive function that correlated with the degree of immunomodulation achieved. To evaluate the safety and tolerability of CY, 2 doses of intravenous (IV) pulse CY were administered to patients with mild to moderate AD, in a randomized placebo–controlled trial. 21 subjects with mild to moderate AD were enrolled (mean age 68.7 ± 6.7, range 58 to 82 years). 7 subjects were randomized to CY 0.75 g/m2 once a month for 6 months, 8 subjects were randomized to CY 0.4 g/m2 once a month for 6 months and 6 subjects were randomized to placebo. At the end of 6 months, 5 of the 6 subjects who had been initially randomized to placebo elected to be crossed over to 6 months of active treatment with IV CY. Subjects were monitored primarily for safety measures, but they also had lymphocyte immunophenotyping and cognitive testing prior to treatment, and one month after the last infusion. The adverse effects observed were consistent with the known effects of CY, and were transient. There was no hemorrhagic cystitis, gross hematuria, appreciable hair loss, clinically significant neutropenia or increased infection in the CY–treated subjects. None of the subjects discontinued prematurely. CY induced significant decreases from baseline in CD20 (see Figure 1) and CD27, and significant increases in C3DR, CD3 and CD5. Although this study was not designed to assess cognitive outcome, exploratory analysis of several cognitive outcome measures suggested a favorable effect of CY as compared with placebo. IV pulse CY appears to be safe in patients with mild to moderate AD. Further studies are needed to confirm and extend these preliminary findings.

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 apolipoprotein E-epsilon 4 allele (APOE-epsilon 4) confers greater susceptibility to age-related memory disorders. Abnormalities in the cholinergic system are likely contributors to these disorders with both age and APOE-epsilon 4 genotype modifying behavioral and physiological responses to drugs that alter cholinergic pathway function. Recently, we reported a greater in vivo distribution volume of the F-18 labeled muscarinic-2 (M2) selective agonist, 3-(3-(3-[F-18]Flouropropyl)thio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine ([F-18]FP-TZTP), in aging healthy subjects with an APOE-epsilon 4 allele. To examine the effects of aging and the APOE-epsilon 4 allele on the response of the muscarinic component of cholinergic pathway to pharmacologic augmentation, two [F-18]FP-TZTP PET scans were conducted in 19 subjects varying in age from 22 to 74 years, the first served as baseline for the second scan that was performed while the subjects were either infused with saline (n = 6) or with the acetylcholinesterase inhibitor physostigmine (6 with an APOE-epsilon 4 allele and 7 without an APOE-epsilon 4 allele). Using a multiple regression analysis, both AGE (beta = 0.621 +/- 0.135, B = 0.353 +/- 0.077, t(10) = 4.61, P < 0.001) and APOE-epsilon 4 genotype (beta = 0.742, B = 14.8 +/- 2.69, t(10) = 5.51, P < 0.0003) were found to be significant contributors to subject response to physostigmine. The adjusted R-2 for the model as a whole was 0.786 (F(2,10) = 23.00, P < 0.0002) with both increasing age and the presence of the APOE-epsilon 4 allele modifying the response to physostigmine in the direction of larger decreases in [F-18]FP-TZTP distribution volumes in all brain regions examined. The findings, particularly the absence of an interaction between AGE and APOE-epsilon 4 genotype, contribute to the growing body of evidence that suggests that the APOE-epsilon 4 genotype is likely to contribute to brain structure and function prior to aging.

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.

In 1979, there were 420 members in the newly formed American Association of Geriatric Psychiatry. The focus of the nascent guild was initially clinical, and research was mostly guided by the older traditions of gerontology, neuropsychology, and psychoanalytic theory. Investigative tools and specific nomenclature for geriatric psychiatry were limited. By 1989, the American Board of Psychiatry and Neurology established the Certification of Added Qualifications in Geriatric Psychiatry, and the first specialty board certificates for geriatric psychiatry were awarded to 490 individuals in 1991. Today, there are over 2600 board-certified geriatric psychiatrists, and the intrinsic research tradition is beginning to blossom. In this issue of Biological Psychiatry, we have four examples of that expanding clinical research effort spanning the breadth of the emerging field.

Objective. The purpose of this review is to assess the relationship between mood disorders and development, course, and associated morbidity and mortality of selected medical illnesses, review evidence for treatment, and determine needs in clinical practice and research.Data Sources. Data were culled from the 2002 Depression and Bipolar Support Alliance Conference proceedings and a literature review addressing prevalence, risk factors, diagnosis, and treatment. This review also considered the experience of primary and specialty care providers, policy analysts, and patient advocates. The review and recommendations reflect the expert opinion of the authors.Study Selection/Data Extraction: Reviews of epidemiology and mechanistic studies were included, as were open-label and randomized controlled trials on treatment of depression in patients with medical comorbidities. Data on study design, population, and results were extracted for review of evidence that includes tables of prevalence and pharmacological treatment. The effect of depression and bipolar disorder on selected medical comorbidities was assessed, and recommendations for practice, research, and policy were developed.Conclusions: A growing body of evidence suggests that biological mechanisms underlie a bidirectional link between mood disorders and many medical illnesses. In addition, there is evidence to suggest that mood disorders affect the course of medical illnesses. Further prospective studies are warranted.

Previous literature shows that feature binding processes elicit fronto-hippocampal areas. The time course of this process, however, remains unknown. This is the first study that investigates feature binding using magnetoencephalography. Synthetic aperture magnetometry analysis was used to localize sources of increased power in the theta band during the encoding phases of a feature-binding task in the left and right medial frontal gyri (Brodmann's area 10) and left and right anterior cingulate gyri. Theta band synchronization was observed in many of these same areas, but also in other areas not noted to have increased theta band power suggesting a broad network of regions subserving the encoding phase of feature binding.