Alan M. Mellow

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.

Neuroendocrine, physiologic, and behavioral responses following intravenous nicotine in nonsmoking healthy volunteers and in patients with Alzheimer's disease.

In separate studies, nonsmoking nicotine-naive subjects (11 young and middle-aged normal volunteers and 11 nonsmoking patients with Alzheimers disease) received up to three doses of intravenous nicotine bitartrate (0.125, 0.25, and 0.5 micrograms/kg/min) and placebo for 60 min. Measurement of plasma ACTH, cortisol, and prolactin showed that nicotine produced in both groups a dose-dependent increase in cortisol, with ACTH in both groups and prolactin in the Alzheimers group significantly elevated only by the 0.5 micrograms dose. Physiologic measures showed dose-dependent increases that were consistent with previous reports of nicotinic cholinergic stimulation. Behavioral effects included increases in anxiety and decreases in mood, especially following the 0.5 micrograms dose. Physical side effects were modest. The results indicate that nicotinic cholinergic stimulation can activate pituitary hormonal secretion in the human and suggest that nicotinic cholinergic stimulation may constitute an important part of cholinesterase inhibitor-induced endocrine stimulation and behavioral activation.

Acute effects of high-dose thyrotropin releasing hormone infusions in Alzheimer's disease

Thyrotropin releasing hormone (TRH) was administered intravenously to ten patients with Alzheimers Disease (AD) in a high-dose paradigm, thought to maximize central nervous system effects and potentially produce facilitation of cholinergic function, a known property of the neuropeptide. Acute effects of TRH on behavioral, cognitive and physiologic measures were assessed after patients received 0.1 mg/kg TRH, 0.3 mg/kg TRH and placebo, the higher TRH dose and placebo being given in a randomized, double-blind fashion. Patients showed statistically significant increases in arousal and improvement in affect, as well as a modest improvement in semantic memory, all after receiving the higher TRH dose. Both TRH doses produced transient rises in systolic blood pressure, with no effect on diastolic blood pressure, heart rate or temperature. This study suggests that high-dose TRH can be safely administered to AD patients and is neurobehaviorally active; further studies are needed to determine the extent and mechanism of the cognitive and psychobiological properties of this peptide in AD and other neuropsychiatric disorders.

Race, Psychiatric Diagnosis, and Mental Health Care Utilization in Older Patients

To evaluate the impact of race on mental health care utilization among older patients within given clinical psychiatric diagnoses, the authors examined a retrospective sample of 23,718 elderly veterans treated in Department of Veterans Affairs inpatient facilities in 1994. Significant racial differences in mental health care utilization found over a subsequent 2-year period were related to outpatient (but not inpatient) care; for instance: 1) African American patients with psychotic disorders had significantly fewer outpatient psychiatric visits; and 2) African American patients with substance abuse disorders had significantly more psychiatric visits than Caucasian patients in their respective groups. Although inpatient utilization appeared to be similar among races, findings related to outpatient utilization may be associated with such factors as compliance, treatment efficacy, access to health care, or possible clinician bias.

Galanin Immunoreactivity in Human CSF: Studies in Eating Disorders and Alzheimer’s Disease

Galanin is a peptide which stimulates feeding behavior in animals and is found within those basal forebrain cholinergic neurons which degenerate in Alzheimers disease. Galanin was measured in cerebrospinal fluid (CSF) by radioimmunoassay. The nature of the immunoreactivity was characterized chromatographically as authentic galanin. CSF galanin levels were determined in subjects with Alzheimers disease, involutional depression, anorexia nervosa and bulimia. No differences between any diagnostic group and age and sex-matched controls were found.

Antidepressant treatment of veterans with Parkinson's disease and depression: analysis of a national sample.

We examined the impact of comorbid Parkinsons disease (PD) on depression treatment. Using national Veterans Affairs (VA) databases, fiscal year 2002 data were examined for 283 273 elderly males seen for depression. We compared 2 matched depression groups, one with (N = 7868) and one without (N = 7868) PD. In the 12-month period following a depression-related clinic visit, PD and non-PD patients were equally likely to fill an antidepressant prescription (77.8% vs. 77.4%), most commonly for a selective serotonin re-uptake inhibitor (SSRI) (62.9% vs 62.6%). Depressed PD patients had slightly higher rates of newer non-SSRI use (20.6% vs 19.2%, P < .05) and lower rates of tricyclic antidepressant use (7.4% vs 8.9%, P < .001). The presence of a PD diagnosis appears to have little impact on the frequency and type of antidepressant treatment. Efforts to improve the care of depressed PD patients should focus instead on improving recognition, ensuring adequacy of treatment, and evaluating the efficacy of existing antidepressants. (J Geriatr Psychiatry Neurol 2007;20:161-165)

Evidence for a decline with age in behavioral responsivity to the serotonin agonist, m-chlorophenylpiperazine, in healthy human subjects

The functional significance of alterations in brain serotonin (5HT) associated with normal aging in both animals and humans is largely unknown. Using the effects of the 5HT agonist, m-chlorophenylpiperazine (m-CPP), as a measure of central serotonergic responsivity, we compared the behavioral and neuroendocrine responses of older normal volunteers (mean age +/- SD = 62.4 +/- 4.12) to those of younger normal volunteers (mean age +/- SD = 31.6 +/- 5.52). When m-CPP was administered intravenously, older subjects showed decreased behavioral responses but similar neuroendocrine responses, compared to younger subjects. The decreased behavioral responsivity was unrelated to pharmaco-kinetic differences between the groups, since m-CPP plasma levels were similar in both groups. This report is the first in vivo study in humans to demonstrate decreased behavioral responsivity with age following serotonergic stimulation, and may indicate a functionally less responsive 5HT subsystem in older subjects.

A preliminary study of the effects of intravenous m-chlorophenylpiperazine, a serotonin agonist, in elderly subjects

m-Chlorophenylpiperazine (m-CPP), a serotonin receptor agonist, is currently being investigated as a probe of serotonergic responsivity in various neuropsychiatric disorders. The safety of m-CPP in elderly populations and its potential usefulness in exploring possible serotonergic dysfunction in Alzheimers disease and normal aging were assessed by examining the behavioral, neuroendocrine, and physiological effects of this agent in 15 elderly subjects (mean age 69 +/- 2 years): 9 Alzheimer patients and 6 healthy normal volunteers. Intravenous m-CPP (0.08 mg/kg) was well tolerated in all subjects and produced no serious adverse effects. The behavioral effects were modest; in particular, minimal anxiety was observed, a finding that contrasted to results from an earlier study reporting that intravenous m-CPP at a slightly higher dose induced marked anxiety and panic attacks in younger subjects. m-CPP produced significant increases in plasma cortisol and prolactin, and significant changes in blood pressure and temperature in these elderly subjects. The results of this preliminary study suggest that intravenous m-CPP is safe and well-tolerated in elderly subjects. Future studies at higher doses can now proceed to study more definitively the question of possible age- and disorder-related reductions in central nervous system (CNS) serotonergic responsivity.

The effects of thyrotropin-releasing hormone and scopolamine in Alzheimer's disease and normal volunteers.

Thyrotropin-releasing hormone (TRH), a neuromodulator and possibly a neurotransmitter in the central nervous system, was shown in a prior study of young normal volunteers to attenuate the memory impairment induced by the anticholinergic drug scopolamine. In the present study, the cognitive, behavioral and physiologic effects of high dose TRH (0.5 mg/kg), both alone and following administration of scopolamine, were examined in 10 Alzheimers disease (AD) patients (mean age±SD=63.5 years) and 12 older normal volunteers (mean age=64.9±8.8 years). On the day AD subjects received TRH alone, modest but statistically significant improvement from baseline performance was documented on some tests of learning and memory, especially in those with mild dementia severity. In comparing cognitive test performance between the scopolamine alone and scopolamine+TRH conditions, only two test scores were significantly higher in the latter condition. In the group of older volunteers, TRH did not attenuate scopolamine-induced cognitive impairment, contrary to prior findings in a group of younger controls. In fact, older subjects performed worse after receiving scopolamine followed by TRH than after receiving scopolamine alone. In addition, no change from baseline cognitive performance was detected after subjects received TRH alone. These findings raise several questions and speculations on possible age-related changes in the cholinergic system, as well as on the mechanism of the interaction of TRH with the cholinergic system.

Automatic Memory Processes in Patients with Dementia-Alzheimer's Type (DAT)

We examined patients with Dementia-Alzheimers Type, depression, and matched controls on tasks designed to compare automatic (monitoring frequency and modality) and effortful (free recall) processing of words and pictures. The results demonstrated that depressed patients performed poorly only when conditions required effortful processing, but DAT patients performed poorly under all conditions. There was almost no overlap in scores between DAT and elderly depressed patients on one of the measures of automatic processing suggesting that this measure may be clinically useful. The results suggest that automatic memory processes can be partially dissociated from effortful memory processes, but that both types of operations are impaired in DAT patients.