Paul A. Newhouse

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.

Nicotinic system involvement in Alzheimer's and Parkinson's diseases : Implications for therapeutics

SummaryAdvances in our understanding of the structure, function and distribution of nicotinic acetylcholine receptors in the CNS have provided the impetus for new studies examining the role(s) that these receptors and associated processes may play in CNS functions. Further motivation has come from the realisation that such receptors must be involved in the maintenance of cigarette smoking, and from clues provided by studies of degenerative neurological diseases such as Alzheimer’s disease and Parkinson’s disease, in which the loss of nicotinic receptors has been described.Ongoing investigations of the molecular substructure of central nicotinic receptors and their pharmacology have begun to open up new possibilities for novel CNS therapeutics with nicotinic agents. Exploiting these possibilities will require understanding of the role(s) that these receptor systems play in human cognitive, behavioural, motor and sensory functioning. Clues from careful studies of human cognition are beginning to emerge and will provide direction for studies of potentially therapeutic novel nicotinic agents.Despite the promising results of acute studies, few long term studies with nicotine or nicotinic drugs have been performed in dementing disorders. Thus, there is uncertainty as to whether long term nicotinic treatment will provide sustained cognitive benefit. It is even more uncertain whether such cognitive benefit will have a significant clinical impact on patients and their families. To maximise the potential benefit of long term treatment with nicotinic agonists (or other cholinergic drugs), we suggest that drug treatment should be combined with cognitive rehabilitation strategies. This will enable patients and/or their families to focus on the particular cognitive domains that may be improved.

Acute effects of the selective cholinergic channel activator (nicotinic agonist) ABT-418 in Alzheimer's disease.

Abstract To explore further the potential for cognitive enhancement utilizing nicotinic stimulation in Alzheimer’s disease (AD), six otherwise healthy subjects with moderate AD received placebo and three doses (6, 12, and 23 mg) of the novel selective cholinergic channel activator (ChCA) (nicotinic agonist) ABT-418 over 6 h in a double-blind, within-subjects, repeated-measures design. Subjects showed significant improvements in total recall and a decline in recall failure on a verbal learning task. Qualitatively similar improvements were seen in non-verbal learning tasks such as spatial learning and memory, and repeated acquisition. No significant behavioral, vital sign, or physical side effects were seen. These results confirm that stimulating central nicotinic receptors has acute cognitive benefit in AD patients. These findings suggest that selective ChCAs have a potential therapeutic role in dementing disorders, and that further studies with this or similar agents in AD and/or Parkinson’s disease are warranted.

Effects of acute nicotine administration on behavioral inhibition in adolescents with attention-deficit/hyperactivity disorder

RationaleAdolescents with attention-deficit/hyperactivity disorder (ADHD) become cigarette smokers at twice the rate of non-ADHD adolescents, and this finding continues into adulthood. Abnormal cognitive/behavioral inhibition is one core cognitive symptom of ADHD, leading to impulsive behavior in people with this disorder. Nicotine, contained in tobacco smoke, is known to improve attention, vigilance, and short-term memory. However, little is known about how nicotine might effect cognitive/behavioral inhibition.ObjectiveThis study tested the hypothesis that acute nicotine administration would improve cognitive/behavioral inhibition in non-smoking adolescents with ADHD.MethodsThis single-dose, acute, repeated-measures, double blind study in adolescents (13–17 years) with DSM-IV confirmed ADHD assessed the effects of transdermal nicotine, oral methylphenidate, and placebo on inhibition in non-smoking adolescents with ADHD. Dependent measures included tests of cognitive/behavioral inhibition (the stop signal task), cognitive interference control (the Stroop task), and a measure of verbal learning and recognition (the hi–low imagery task).ResultsResults from five subjects indicated that stop signal reaction time (SSRT), an estimate of the speed of inhibiting a response, was significantly (P<0.01) improved following both nicotine and methylphenidate treatment as compared to placebo treatment. Neither “go” reaction time nor accuracy showed any effect of drug. In the Stroop task, another task of cognitive inhibition, nicotine but not methylphenidate significantly (P<0.05) decreased the Stroop effect compared to placebo.ConclusionsThese results indicate that nicotine administration has measurable positive effects on cognitive/behavioral inhibition in adolescents with ADHD. The size of the effect is at least comparable to methylphenidate. Positive effects of nicotine on inhibitional performance may contribute to higher rates of cigarette use in adolescents with ADHD.

Acute nicotinic blockade produces cognitive impairment in normal humans

Single oral doses of the central and peripheral nicotinic antagonist mecamylamine were administered to healthy young normal males in doses of 5, 10, and 20 mg in a placebo-controlled, double-blind study. The 20 mg dose caused a significant increase in errors in the learning condition of the Repeated Acquisition task, producing a slower acquisition curve. The lower doses produced less errors, but more than in the placebo condition. There was no effect of drug on the performance component (retrieval of previously learned information). On the recognition memory task, dose-related increases in false-alarms during the delay period were seen, with little effect on misses or hits. Reaction time measures suggested a dose-related slowing of RT on several tasks. Behavioral effects were minimal and physiologic measures were consistent with dose-related ganglionic blockade. We interpret these results to indicate that acute blockade of nicotinic receptor function can produce measurable and significant cognitive impairment, even in non-smoking normals.

Nicotinic treatment of Alzheimer’s disease

Approximately 20 years after the formulation of the cholinergic hypothesis to explain the cognitive symptoms of Alzheimers disease, cholinesterase therapy remains the mainstay of treatment for this disorder, Although partially effective, currently available agents have limited effects on cognitive function and long-term efficacy appears modest. Direct or indirect stimulation of nicotinic cholinergic receptors may offer an additional therapeutic strategy. Ongoing investigations of the molecular substructure of central nervous system nicotinic receptors, their accompanying pharmacology, and the effects of nicotinic agents on cognitive function have suggested the possibility that nicotinic stimulation may have beneficial effects in Alzheimers disease and other neuropsychiatric disorders. Studies from our laboratory and others have explored the role of central nervous system nicotinic mechanisms in normal human cognitive and behavioral functioning as well as their role in Alzheimers disease. Results from acute therapeutic trials with nicotine arid novel nicotinic agents suggest that nicotinic stimulation in Alzheimers disease patients can improve the acquisition and retention of verbal and visual information and decrease errors in cognitive tasks, as well as improve accuracy and response time, Whether such results will translate into improved clinical functioning remains to be fully tested. Development of subtype-selective nicotinic agonists with an improved safety profile will enable long-term testing of the efficacy of nicotinic stimulation on cognitive performance as well as potential cytoprotective effects. Direct or indirect (allosteric) modulation of nicotinic receptor function offers a new opportunity for Alzheimers disease therapeutics.

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.

Age-Related Effects of the Nicotinic Antagonist Mecamylamine on Cognition and Behavior

Studies of the neurochemical pathology of Alzheimers disease and Parkinsons disease reveal a severe and specific loss of central nicotinic cholinergic receptors. We have investigated the functional significance of this finding for cognitive functioning by studying the effects of the centrally active nicotinic antagonist mecamylamine. Single oral doses of mecamylamine were administered to 12 healthy young males and 15 healthy elderly subjects in doses of 5, 10, and 20 mg in a placebo-controlled, double-blind study. In both groups, the 20-mg dose caused a significant increase in errors in the learning condition of the Repeated Acquisition Task, producing a slower acquisition curve. There was no effect of drug on the performance component (retrieval of previously learned information). However, elderly subjects showed enhanced sensitivity to mecamylamine, with lO-mg dose producing significant impairment of learning not seen in the young normals. On a recognition memory task, there was an age-associated shift in response bias, with the elderly subjects becoming more liberal with increasing dose. Reaction-time measures suggested a dose-related slowing of reaction time on several tasks. Behavioral effects were minimal and physiologic effects were consistent with dose-related ganglionic blockade. These results indicate that acute blockade of nicotinic receptor function can produce measurable and significant cognitive impairment similar to some deficits seen in dementing illnesses, and that there is an age-related increase in sensitivity to nicotinic blockade.

The Cholinergic Hypothesis of Cognitive Aging Revisited Again: Cholinergic Functional Compensation

It is now possible to reevaluate the cholinergic hypothesis of age-related cognitive dysfunction based on a synthesis of new evidence from cholinergic stimulation studies and cognitive models. We propose that a change of functional circuitry that can be observed through a combination of pharmacologic challenge and functional neuroimaging is associated with age-related changes in cholinergic system functioning. Psychopharmacological manipulations using cholinergic agonists and antagonists have been consistent in replicating patterns of aging seen in functional imaging studies. In addition, studies of anticholinesterase drugs in patients with Alzheimers disease and mild cognitive impairment show support for the proposal that cholinergic compensation causes alterations in task-related brain activity. Thus, the cholinergic hypothesis of age-related cognitive dysfunction deserves further consideration as new methodologies for evaluating its validity are increasingly being used. Future directions for testing hypotheses generated from this model are presented.

Nicotine Treatment of Mild Cognitive Impairment: a 6-Month Double-Blind Pilot Clinical Trial

Objective: To preliminarily assess the safety and efficacy of transdermal nicotine therapy on cognitive performance and clinical status in subjects with mild cognitive impairment (MCI). Methods: Nonsmoking subjects with amnestic MCI were randomized to transdermal nicotine (15 mg per day or placebo) for 6 months. Primary outcome variables were attentional improvement assessed with Connors Continuous Performance Test (CPT), clinical improvement as measured by clinical global impression, and safety measures. Secondary measures included computerized cognitive testing and patient and observer ratings. Results: Of 74 subjects enrolled, 39 were randomized to nicotine and 35 to placebo. 67 subjects completed (34 nicotine, 33 placebo). The primary cognitive outcome measure (CPT) showed a significant nicotine-induced improvement. There was no statistically significant effect on clinician-rated global improvement. The secondary outcome measures showed significant nicotine-associated improvements in attention, memory, and psychomotor speed, and improvements were seen in patient/informant ratings of cognitive impairment. Safety and tolerability for transdermal nicotine were excellent. Conclusion: This study demonstrated that transdermal nicotine can be safely administered to nonsmoking subjects with MCI over 6 months with improvement in primary and secondary cognitive measures of attention, memory, and mental processing, but not in ratings of clinician-rated global impression. We conclude that this initial study provides evidence for nicotine-induced cognitive improvement in subjects with MCI; however, whether these effects are clinically important will require larger studies. Classification of evidence: This study provides Class I evidence that 6 months of transdermal nicotine (15 mg/day) improves cognitive test performance, but not clinical global impression of change, in nonsmoking subjects with amnestic MCI.