Larry E. Tune

Driving in Patients with Dementia

These pilot data suggest that driving among individuals with incapacitating dementing illness may be an unrecognized, potentially serious problem. A simple 20‐item screening questionnaire was administered to 72 referrals to the Dementia Research (outpatient) Clinic of the Johns Hopkins Hospital. Thirty percent of the patient sample had at least one accident since the onset of symptoms of dementia. An additional 11% were reported by caregivers to have “caused” accidents.

Acetylcholine and Delirium

The neurotransmitter acetylcholine has been implicated in animal and human studies of delirium. This chapter will briefly review the clinical studies focussing on measurement of serum levels of anticholinergic activity in delirious states. Three approaches have been taken. First, to identify medications currently prescribed that have subtle anticholinergic effects. The current ‘list’ includes 48 commonly prescribed medications. Second, to associate serum anticholinergic activity with delirium in various clinical states including postcardiotomy delirium, postelectroconvulsive delirium, delirious elderly medical inpatients, and nursing home patients. Third, to intervene in patients with elevated anticholinergic activity by reducing known anticholinergics and correlating this reduction with clinical measures of cognition and delirium. Our most recent data investigates the impact of anticholinergics on demented patients. Rates of delirium were significantly higher in patients receiving larger numbers of anticholinergics.

Donepezil HCl (E2020) maintains functional brain activity in patients with Alzheimer disease: Results of a 24-week, double-blind, placebo-controlled study

OBJECTIVE The authors evaluated the effects of donepezil (10 mg/day) versus placebo on brain glucose metabolism. METHODS This was a randomized, double-blind, parallel-group, 24-week pilot study in 28 patients with mild-to-moderate Alzheimer disease (AD). Functional brain activity was quantified by measuring average glucose metabolism in an axial brain slice and regional brain glucose metabolism using positron emission tomography. RESULTS At Week 24, relative to the pons metabolic rate, mean brain glucose metabolism in an axial slice at the level of the striatum was maintained within 0.5% of mean baseline levels for donepezil-treated patients, whereas it declined by an average of 10.4% in placebo-treated patients. This observation was confirmed by an analysis of differences in the mean slopes of glucose metabolism in the striatal slice in donepezil- and placebo-treated patients during the 24-week period. Significant treatment differences at Week 24 favoring donepezil for the mean percentage change from baseline in regional brain glucose metabolism were observed in four predefined regions of interest: the right parietal lobe 1, left temporal lobe 2, right frontal lobe 2, and left frontal lobe 2. CONCLUSION Placebo-treated patients with AD show a decline in functional brain activity, relative to the pons, in several regions, and treatment with donepezil may slow this decline.

Effects of anticholinergic medication on memory in schizophrenia.

Verbal memory and reaction time of ten schizophrenic patients were compared at two different serum anticholinergic levels. Verbal recall was worse at higher drug levels, while reaction time tended to be improved by anticholinergic treatment. Implications for studies of memory in schizophrenia are considered.

Chronic Exposure to Anticholinergic Medications Adversely Affects the Course of Alzheimer Disease

OBJECTIVE Authors examined the effect of chronic exposure to anticholinergics in a cohort of Alzheimer disease (AD) patients. METHODS All patients were examined annually with standard neuropsychologic tests and received the cholinesterase inhibitor donepezil hydrochloride at a dose of 10 mg/day. The study population (N=69) was divided into two groups: those receiving one or more concomitant medications with significant anticholinergic properties (N=16) and those receiving no concomitant medications with anticholinergic properties (N=53). RESULTS At 2 years, MMSE scores were significantly worse for patients receiving anticholinergic medications than for those not on anticholinergics. CONCLUSION Although very preliminary, these data suggest that concomitant therapy with anticholinergics may be associated with significant deleterious effects on acetylcholinesterase therapy, or, more speculatively, that chronic exposure to anticholinergics may have adverse effects on the clinical course of AD.

Quantification of neuroreceptors in the living human brain: IV. Effect of aging and elevations of D2-like receptors in schizophrenia and bipolar illness

In a previous study of 10 drug-naive schizophrenic patients, the density of D2 dopamine receptors was found to be elevated in the caudate nucleus. The study raised questions about the influence of the age of the patients, the relationship of receptor density to psychosis, and the accuracy of the method used to obtain this evidence. Using positron emission tomography and constrained analysis of the brain uptake of the radioligand N-[11C] methylspiperone ([11C]NMSP), we tested four questions: Were the assumptions underlying the quantitation valid? Is there an age decline of the density of D2-like dopamine receptors in drug-naive schizophrenia and bipolar illness? If so, is it different from that observed in normal aging? Are D2-like dopamine receptors elevated at any age in either drug-naive schizophrenic or psychotic bipolar illness patients? NMSP and haloperidol partition volumes and plasma protein fractions were not significantly different among patient groups and normal volunteers. The model-derived assay of radioligand metabolites in plasma was confirmed by high-performance liquid chromatography in the patient groups. D2-like dopamine receptors declined with age, and the slope did not differ significantly between the schizophrenic patients, bipolar affective illness patients, and normal controls. Taking the effect of age into account, increases in D2 dopamine receptor density were found in seven psychotic patients with bipolar affective illness compared with seven nonpsychotic patients and 24 control subjects as well as in 22 drug-naive schizophrenic patients compared with the 24 control subjects.

Cognitive, Behavioral, and Physiological Changes in Alzheimer Disease Patients as a Function of Incontinence Medications

OBJECTIVE Authors evaluated the cognitive, neurophysiologic, and behavioral effects of incontinence medications in patients with Alzheimer disease (AD). METHODS Nine patients were evaluated, both on and off incontinence medication, for cognitive status, neuropsychiatric status, activities of daily living, and serum anticholinergic level. Caregivers were interviewed to evaluate behavioral status and caregiver burden. RESULTS Patients showed better performance on specific measures of cognition and behavior when not taking medication for incontinence. A significant, inverse correlation was found between mental status and anticholinergic level. CONCLUSION Although the sample size was small, the findings suggest that, in patients with AD, incontinence medications with anticholinergic properties may have detrimental effects on mental status and behavior.

Benzodiazepine-Induced and Anticholinergic-Induced Delirium in the Elderly

Encompassing the range from subtle cognitive impairments to frank delirium, toxicity due to benzodiazepines and to anticholinergic-containing compounds is reviewed. For benzodiazepines, an extensive literature suggests that they impair immediate and delayed memory, psychomotor performance, and subjective complaints of station. This, in several studies, results in increased patient morbidity (e.g., increasing risk of hip fractures). Anticholinergic compounds are widely utilized in managing elderly patients, particularly nursing home residents. Toxicity from anticholinergic compounds, detected by anticholinergic drug levels, is significantly correlated with the presence and severity of delirium in a number of settings including postoperative patients and elderly nursing home residents. Possible means of identifying the syndrome by prediction of dose and type of medication, as well as by quantitative EEG, are reviewed.

Quantitative MRI volume changes in late onset schizophrenia and Alzheimer's disease compared to normal controls ☆

Volumes of medial and lateral temporal lobe structures were assessed using magnetic resonance imaging (MRI) in 11 patients with late-life onset schizophrenia (LOS), 18 normal elderly controls and 12 patients with moderate cognitive impairment due to Alzheimers disease (AD) who had no non-cognitive symptoms. While both patient groups had smaller volumes of several medial temporal regions (e.g. entorhinal cortex, left hippocampus), schizophrenics had significantly smaller anterior superior temporal gyri (STG) than normal controls, but AD patients did not. We have previously demonstrated anterior STG volume to be reduced in early life onset schizophrenia.

Striatal dopamine D2 receptor quantification and superior temporal gyrus: Volume determination in 14 chronic schizophrenic subjects

Chronic schizophrenic (n = 14) and normal subjects (n = 15) were studied with resonance imaging (MRI) and positron emission tomography (PET). Two PET scans were carried out to estimate caudate dopamine D2 receptor densities. MRI was used to measure the volume of the superior temporal gyrus. Average striatal D2 receptor density (Bmax) was significantly higher in the schizophrenic group than in the normal group. Average left superior temporal gyral volume was significantly smaller in the schizophrenic group than in the normal group, and the same tendency was found for the right superior temporal gyrus. Thus, the main finding of this combined analysis of functional and structural neuroimaging techniques was an inverse relationship between reduced superior temporal gyral volume and elevated striatal D2 receptor Bmax values. These preliminary findings require confirmation in larger groups of patients and control subjects.