Trey Sunderland

Mood Disorders in the Medically Ill: Scientific Review and Recommendations

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.

Clock Drawing in Alzheimer's Disease: A Novel Measure of Dementia Severity

We have tested a simple and reliable measure of visuospatial ability in Alzheimer patients — the Clock Drawing Test. To determine the usefulness of this measure, we asked 67 Alzheimer patients and 83 normal controls to draw the face of a clock reading the time of 2:45. Six independent observers blindly evaluated the results with ratings from 10 (best) to 1 (worst). The mean performance score of Alzheimer subjects was 4.9 ± 2.7 compared to 8.7 ± 1.1 for normal controls (P < .001). Inter‐rater reliability for the clocks drawn by Alzheimer patients was highly significant (r = 0.86; P < .001), and there was relatively little overlap between ratings for Alzheimer patients and normal controls. Furthermore, correlations were highly significant (P < .001) between the mean score of clock drawings and three independent global measures of dementia severity. Although the Clock Drawing Test is certainly not a definitive indicator of Alzheimers disease, the test is easy to administer and provides a useful measure of dementia severity for both research and office settings where sophisticated neuropsychological testing is not available.

Participation of Presenilin 2 in Apoptosis: Enhanced Basal Activity Conferred by an Alzheimer Mutation

Overexpression of the familial Alzheimers disease gene Presenilin 2 (PS2) in nerve growth factor-differentiated PC12 cells increased apoptosis induced by trophic factor withdrawal or β-amyloid. Transfection of antisense PS2 conferred protection against apoptosis induced by trophic withdrawal in nerve growth factor-differentiated or amyloid precursor protein-expressing PC12 cells. The apoptotic cell death induced by PS2 protein was sensitive to pertussis toxin, suggesting that heterotrimeric GTP-binding proteins are involved. A PS2 mutation associated with familial Alzheimers disease was found to generate a molecule with enhanced basal apoptotic activity. This gain of function might accelerate the process of neurodegeneration that occurs in Alzheimers disease, leading to the earlier age of onset characteristic of familial Alzheimers disease.

Intravenous nicotine in Alzheimer's disease: a pilot study

In the first study to examine direct nicotinic augmentation of central cholinergic functioning in Alzheimers disease, six patients were studied in an intensive pilot study with three doses (0.125, 0.25, and 0.5 μg/kg/min) of intravenous nicotine and placebo. Cognitive tests showed a decrease in intrusion errors on the middle (0.25 μg) dose. Prominent behavioral effects were noted, with significant dose-related increases in anxiety and depressive affect. These results suggest that central nicotinic cholinergic stimulation deserves further investigation as a treatment in Alzheimers disease and that nicotine may also be a useful investigative tool in other populations as a probe of central cholinergic function, especially in regard to the modulation of affect.

Increased cognitive sensitivity to scopolamine with age and a perspective on the scopolamine model

18 older normal volunteers (mean age = 66.5 +/- 7.9 years) and 46 younger volunteers (mean age = 27.0 +/- 6.1 years) were administered the anticholinergic drug scopolamine (0.5 mg i.v.) followed by a battery of cognitive tests evaluating attention, learning and memory. The older subjects were significantly more impaired than the younger by scopolamine on some tests of learning and memory. This increased sensitivity of the older group to scopolamine is consistent with studies in animals and humans showing decreased cholinergic system function with age. The findings also indicate that age is an important variable to consider in using the scopolamine model of memory impairment. The cognitive impairment caused by scopolamine in younger subjects in this and prior studies is similar to some, but not all aspects of the impairment which occurs in normal aging. Scopolamine also caused impairments on digit span and word fluency tasks, which are not consistent with normal aging changes. In the older group of subjects, scopolamine produced aspects of the cognitive impairment which occurs in AD on tests of episodic memory and learning, vigilance-attention, category retrieval, digit span, and number of intrusions. Other areas of cognition that are of relevance to aging and AD such as psychomotor speed, praxis, concept formation and remote memory were not evaluated in this study. Some of these are being evaluated in ongoing studies, along with additional and more specific tests of retrieval from knowledge memory, implicit memory and attention. The scopolamine model has provided a fruitful pharmacologic starting point for the study of a number of cognitive operations. The idea of dissecting apart aspects of memory systems pharmacologically depends on the availability of neurochemically specific drugs and on the specificity and sensitivity of neuropsychological tests for distinct cognitive operations or domains. Further studies using such tools will aid not only in the understanding of the impairments which occur in aging and in AD, but also of the conceptualization of memory and other cognitive operations and ultimately the physiological mechanisms involved in memory and learning.

Further studies of the putative serotonin agonist, m-chlorophenylpiperazine: evidence for a serotonin receptor mediated mechanism of action in humans.

To further evaluate the effects and mechanism of action of the putative serotonin agonist m-chlorophenylpiperazine (m-CPP) in humans, changes in plasma prolactin, cortisol, growth hormone, ACTH and body temperature were studied in a group of 10 healthy volunteers following oral administration of m-CPP (0.75 mg/kg), before and after pretreatment with the serotonin receptor antagonist metergoline (MTG).M-CPP produced transient significant increases in plasma prolactin, cortisol, ACTH and in body temperature, but did not significantly alter plasma growth hormone concentration. Moreover, pretreatment with the 5HT antagonist metergoline blocked the m-CPP-induced hormonal and temperature changes.These findings provide strong support for m-CPPs effects in humans being mediated through an interaction with 5HT receptors, and thus support the usefulness of m-CPP as a pharmacologic tool for studying disease and drug-induced alterations in serotonin function in man.

Cerebrospinal fluid β-amyloid1–42 and tau in control subjects at risk for Alzheimer’s disease: The effect of APOE ε4 allele

Background Cerebrospinal fluid (CSF) measures of β-amyloid 1–42 and tau are linked with the known neuropathology of Alzheimers disease (AD). Numerous lines of evidence have also suggested that individuals with at least one APOE e4 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 e4 allele as a predictive variable in the search for possible prognostic biomarkers of AD. Methods We assessed the levels of β-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. Results When divided according to the absence or presence of the APOE e4 allele, the control subjects with at least one e4 allele had significantly lower CSF β-amyloid 1–42 but not tau levels than control subjects without an APOE e4 allele ( p 1–42 and higher CSF tau levels than the normal control group ( p Conclusions The association of APOE e4 allele and lower, more AD-like levels of CSF β-amyloid 1–42 in older control subjects is consistent with previous studies showing possible neuroimaging and cognitive abnormalities with e4 carriers and suggests that CSF β-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.

Effect of apolipoprotein E genotype on hippocampal volume loss in aging healthy women

Objective: To determine whether the presence of a single ε4 allele of the APOE gene is associated with an increased rate of hippocampal volume loss or decline in cognition in healthy women in their sixth decade of life. Methods: Nine APOE-ε4 allele–negative (mean age ± SD, 60.6 ± 10.2 years) and 16 APOE-ε4 allele–positive (mean age ± SD, 55.1 ± 6.0 years) healthy women underwent neurocognitive testing and MRI at the time of entry into the study (baseline) and 2 years later. Neurocognitive testing consisted of the Buschke-Fuld Free Recall, verbal fluency tests, the Rey Figure Test, the Wechsler Memory Scale–Revised, and the Wechsler Adult Intelligence Survey–Revised Block Design. Hippocampal volume determinations were based on manual outlining of sagittal slices aided by axial, coronal, and three-dimensional views of high-resolution 124-slice whole-brain scans; the scans were obtained with a 1.5-tesla scanner using a T1-weighted three-dimensional gradient echo sequence with RF spoiling (TR/TE/flip angle, 24 msec/3 msec/30 °). Results: The percent change in hippocampal volume per year was greater in the APOE-ε4 allele–positive group (mean ± SD, 2.32 ± 1.75%) than in the APOE-ε4 allele–negative group (mean ± SD, 0.77 ± 1.02%; t = 2.41; p < 0.03, two-tailed test). There were no significant differences between the two groups in terms of any of the cognitive measures, and hippocampal volume loss was not correlated with changes in any of the above-mentioned cognitive measures. Conclusions: The presence of a single APOE-ε4 allele is associated with an increased rate of hippocampal volume loss in healthy women in their sixth decade of life that is not related to any detectable memory changes.

Differential responsivity of mood, behavior, and cognition to cholinergic agents in elderly neuropsychiatric populations.

To evaluate the possible differential responsivity of Alzheimer patients to cholinergic agents, a series of pharmacologic challenge studies in 83 neuropsychiatric patients and controls were performed contrasting a cholinergic antagonist (scopolamine) with two cholinergic agonists (arecoline and nicotine). Alzheimer patients displayed significantly greater behavioral and cognitive responses to central cholinergic blockade at lower scopolamine doses than age-matched controls or elderly depressives. These differential changes could not be explained by group differences in the sedative, physiologic, or pharmacokinetic effects of the drug. In addition, the elderly, age-matched control subjects did reveal a profile of cognitive deficits at the highest dose (0.5 mg), which temporarily mimicked the baseline impairments found in early Alzheimers disease. Together, these findings with scopolamine suggest an increased sensitivity to cholinergic blockade in Alzheimers disease and demonstrate the first direct evidence of anticholinergic modelling of dementia in normal elderly subjects. To investigate further the postsynaptic cholinergic responsivity in Alzheimers disease, patients were studied with arecoline and nicotine. While the cognitive effects of both agents were modest at best, there were significant differences in mood and behavioral responses between arecoline and nicotine in Alzheimer subjects. These behavioral changes occurred at much lower doses in the Alzheimer patients than those required in normal controls, once more supporting the notion of increased behavioral sensitivity to cholinergic agents in Alzheimers disease. In addition, the differential mood effects between these two cholinergic agonists raise new questions about receptor selectivity in the cholinergic regulation of mood.

The Apolipoprotein E Gene, Attention, and Brain Function

The epsilon4 allele of the apolipoprotein E (ApoE) gene is associated with alterations in brain function and is a risk factor for Alzheimers disease (AD). Changes in components of visuospatial attention with ApoE-epsilon4, aging, and AD are described. Healthy middle-aged adults without dementia who have the ApoE-epsilon4 gene show deficits in spatial attention and working memory that are qualitatively similar to those seen in clinically diagnosed AD patients. The findings support an association between ApoE polymorphism and specific components of visuospatial attention. Molecular mechanisms that may mediate the ApoE-attention link by modulating cholinergic neurotransmission to the posterior parietal cortex are discussed. Studies of attention and brain function in ApoE-epsilon4 carriers without dementia can advance knowledge of the genetics of visual attention, may enhance understanding of the preclinical phase of AD, and may lead to better methods for early AD detection.