Medical decision-making capacity in mild cognitive impairment: a 3-year longitudinal study.

OBJECTIVE: To investigate longitudinal change in the medical decision-making capacity (MDC) of patients with amnestic mild cognitive impairment (MCI) under different consent standards. METHODS: Eighty-eight healthy older controls and 116 patients with MCI were administered the Capacity to Consent to Treatment Instrument at baseline and at 1 to 3 (mean = 1.7) annual follow-up visits thereafter. Covariate-adjusted random coefficient regressions were used to examine differences in MDC trajectories across MCI and control participants, as well as to investigate the impact of conversion to Alzheimer disease on MCI patients' MDC trajectories. RESULTS: At baseline, MCI patients performed significantly below controls only on the three clinically relevant standards of appreciation, reasoning, and understanding. Compared with controls, MCI patients experienced significant declines over time on understanding but not on any other consent standard. Conversion affected both the elevation (a decrease in performance) and slope (acceleration in subsequent rate of decline) of MCI patients' MDC trajectories on understanding. A trend emerged for conversion to be associated with a performance decrease on reasoning in the MCI group. CONCLUSIONS: Medical decision-making capacity (MDC) decline in mild cognitive impairment (MCI) is a relatively slow but detectable process. Over a 3-year period, patients with amnestic MCI show progressive decline in the ability to understand consent information. This decline accelerates after conversion to Alzheimer disease (AD), reflecting increasing vulnerability to decisional impairment. Clinicians and researchers working with MCI patients should give particular attention to the informed consent process when conversion to AD is suspected or confirmed.

Cognitive models of medical decision-making capacity in patients with mild cognitive impairment.

This study investigated cognitive predictors of medical decision-making capacity (MDC) in patients with amnestic mild cognitive impairment (MCI). A total of 56 healthy controls, 60 patients with MCI, and 31 patients with mild Alzheimer's disease (AD) were administered the Capacity to Consent to Treatment Instrument (CCTI) and a neuropsychological test battery. The CCTI assesses MDC across four established treatment consent standards--S1 (expressing choice), S3 (appreciation), S4 (reasoning), and S5 (understanding)--and one experimental standard [S2] (reasonable choice). Scores on neuropsychological measures were correlated with scores on each CCTI standard. Significant bivariate correlates were subsequently entered into stepwise regression analyses to identity group-specific multivariable predictors of MDC across CCTI standards. Different multivariable cognitive models emerged across groups and consent standards. For the MCI group, measures of short-term verbal memory were key predictors of MDC for each of the three clinically relevant standards (S3, S4, and S5). Secondary predictors were measures of executive function. In contrast, in the mild AD group, measures tapping executive function and processing speed were primary predictors of S3, S4, and S5. MDC in patients with MCI is supported primarily by short-term verbal memory. The findings demonstrate the impact of amnestic deficits on MDC in patients with MCI.

Medical decision-making capacity in patients with mild cognitive impairment.

OBJECTIVES: To empirically assess the capacity of patients with amnestic mild cognitive impairment (MCI) to consent to medical treatment under different consent standards (Ss). METHODS: Participants were 56 healthy controls, 60 patients with MCI, and 31 patients with mild Alzheimer disease (AD). Each participant was administered the Capacity to Consent to Treatment Instrument (CCTI) and a comprehensive neuropsychological battery. Group differences in performance on the CCTI and neuropsychological variables were examined. In addition, the capacity status (capable, marginally capable, or incapable) of each MCI participant on each CCTI standard was examined using cut scores derived from control performance. RESULTS: Patients with MCI performed comparably to controls on minimal consent standards requiring merely expressing a treatment choice (S1) or making the reasonable treatment choice [S2], but significantly below controls on the three clinically relevant standards of appreciation (S3), reasoning (S4), and understanding (S5). In turn, the MCI group performed significantly better than the mild AD group on [S2], S4, and S5. Regarding capacity status, patients with MCI showed a progressive pattern of capacity compromise (marginally capable and incapable outcomes) related to stringency of consent standard. CONCLUSIONS: Patients with amnestic mild cognitive impairment (MCI) demonstrate significant impairments on clinically relevant abilities associated with capacity to consent to treatment. In obtaining informed consent, clinicians and researchers working with patients with MCI must consider the likelihood that many of these patients may have impairments in consent capacity related to their amnestic disorder and related cognitive impairments.

Dietary factors and cognitive impairment in community-dwelling elderly.

BACKGROUND: Diet may play a role in cognitive impairment. OBJECTIVE: To examine the relationship between dietary factors and cognitive impairment. DESIGN AND METHODS: All subjects (n=1056) were participants in the State-wide Survey of Alabama's Elderly (1986-87). Basic demographic information, Mental Status Questionnaire (MSQ) score, and dietary intake frequency of meat (pork, beef, lamb), fish, chicken or turkey, vegetables, fruit, milk, cheese, desserts, bread or cereal, and dried beans and peas were ascertained during an inhome interview. RESULTS: Most participants were female (67%) and white (73%) with a mean age of 69 years (SD 8.9, min 55 max 94) and mean years of education of 10.7 (SD 3.8, min 1 max 18). Intake of cheese was found to be inversely associated with cognitive impairment in a simple logistic regression analysis, (OR = 0.59; 95% CI: 0.42, 0.84; p=0.003) and in a multiple logistic regression analysis (OR=0.68; 95% CI: 0.47, 0.99; p=0.04), after adjusting for basic socio-demographic factors and for other dietary factors. Increased frequency of cheese intake was associated with decreased cognitive impairment (p=0.0034). In the multiple logistic regression analysis bread or cereal (OR= 0.37, 95% CI: 0.14, 0.97; p=0.044) was inversely associated with, and dessert intake (OR= 1.70, 95% CI: 1.12, 2.59; p=0.013) positively associated with cognitive impairment. CONCLUSION: Dietary intake of cheese is associated with a lower prevalence of cognitive impairment, with a dose-response effect, while intake of dessert is associated with a higher prevalence of cognitive impairment. Possible reasons for a potential protective effect of cheese ingestion are discussed.

Idebenone treatment fails to slow cognitive decline in Alzheimer's disease.

OBJECTIVE: To determine the effect of idebenone on the rate of decline in Alzheimer's disease (AD). METHODS: A 1-year, multicenter, double-blind, placebo-controlled, randomized trial was conducted. Subjects were over age 50 with a diagnosis of probable AD and had Mini-Mental State Examination (MMSE) scores between 12 and 25. Subjects were treated with idebenone 120, 240, or 360 mg tid, each of which was compared with placebo. Primary outcome measures were the Alzheimer's Disease Assessment Scale-Cognitive Subcomponent (ADAS-Cog) and a Clinical Global Impression of Change (CGIC). Secondary outcome measures included measurements of activities of daily living, the Behavioral Pathology in Alzheimer's Disease Rating Scale, and the MMSE. RESULTS: Five hundred thirty-six subjects were enrolled and randomized to the four groups. Except for a slight difference in age, there were no differences in patient characteristics at baseline. For the primary outcome measures, there were no significant overall differences between the treatment groups in the prespecified four-group design. In an exploratory two-group analysis comparing all three treated groups combined with placebo, drug-treated patients performed better on the ADAS-Cog in both the intent-to-treat (ITT) and completers analyses. There were no differences in the CGIC scores for the ITT or completers analyses in either the four-group or the two-group analyses. There were no overall differences on any of the secondary outcome measures in any of the analyses. CONCLUSION: Idebenone failed to slow cognitive decline in AD that was of sufficient magnitude to be clinically significant.

Impaired financial abilities in mild cognitive impairment: a direct assessment approach.

OBJECTIVES: To assess financial capacity in patients with mild cognitive impairment (MCI) using a standardized psychometric capacity measure. METHODS: Participants were 21 cognitively normal older controls, 21 patients with amnestic MCI, and 22 patients with mild AD. The Financial Capacity Instrument (FCI), a psychometric capacity measure consisting of 18 financial ability tests (tasks), 9 domains (activities), and 2 total scores, was administered to participants along with a battery of neuropsychological tests sensitive to dementia. Group differences were examined on the neuropsychological and financial capacity variables. RESULTS: Relative to controls, the MCI group demonstrated impairments in episodic memory, and also semantic knowledge, executive function, written arithmetic, and spatial attention. MCI participants demonstrated impairments in FCI domains of conceptual knowledge, cash transactions, bank statement management, and bill payment, and in overall financial capacity. The control and MCI groups performed significantly better than patients with AD on most financial capacity and cognitive measures. CONCLUSIONS: On direct assessment, patients with amnestic MCI as a group demonstrate impairments across a range of financial abilities. These impairments are mild and may only apply to a subset of patients with MCI. However, existing diagnostic criteria for MCI should be applied flexibly to include mild impairments in higher order activities of daily life such as financial capacity.

Apoptotic-like changes in Lewy-body-associated disorders and normal aging in substantia nigral neurons.

In Parkinson's disease and other Lewy-body-associated disorders, the substantia nigra pars compacta undergoes degeneration, but the mechanism of cell death has not been previously described. The substantia nigra of normal and Alzheimer's disease cases were compared with substantia nigra from patients with Lewy-body-associated disorders (Parkinson's disease, concomitant Alzheimer's/Parkinson's disease, and diffuse Lewy body disease) using in situ end labeling to detect fragmented DNA. In situ end-labeled neurons demonstrated changes resembling apoptosis: nuclear condensation, chromatin fragmentation, and formation of apoptotic-like bodies. Ultrastructural analysis confirmed nuclear condensation and formation of apoptotic-like bodies. Apoptotic-like changes were seen in the substantia nigra of both normal and diseased cases; concomitant Alzheimer's/Parkinson's disease and diffuse Lewy body disease cases had significantly higher amounts of apoptotic-like changes than normal controls or Alzheimer patients. The finding of neuronal death by apoptosis may have relevance for the development of new treatment strategies for Parkinson's disease and related disorders.

Preliminary findings of high-dose thiamine in dementia of Alzheimer's type.

Thiamine is important not only in the metabolism of acetylcholine but also in its release from the presynaptic neuron. Pathologic, clinical, and biochemical data suggest that thiamine deficiency is detrimental to the cholinergic system and that thiamine-dependent enzymes may be altered in Alzheimer's disease. Two previous studies reported contradictory results in patients with dementia of Alzheimer's type treated with 3 g/day of thiamine. In the present study, we examined the effects of 3 to 8 g/day thiamine administered orally. Our results suggest that thiamine at these pharmacologic dosages may have a mild beneficial effect in dementia of Alzheimer's type. The mechanism of the observed effect is unknown, but the findings warrant further investigation, not only for their therapeutic implications but for their possible etiologic clues. In addition, the results suggest long-term carry-over effects that should be considered in the design of future studies.

The role of cholinergic systems in visuospatial processing and memory.

Few studies have specifically addressed the cholinergic role in visuospatial memory. In the present study, we employed a randomized double-blind repeated measures design to investigate the effects of scopolamine on Judgement of Line Orientation (JLO) and two distinct visuospatial memory tasks. Complex Figures (CF) is a test of drawn reproduction similar to the Rey complex figure. The Spatial Array Memory Test (SAMT) is a two-dimensional free-recall visuospatial test which minimizes constructive skills and allows sensitive measurement of placement errors. Scopolamine impaired performance on JLO and CF. However, no effects of scopolamine on SAMT were apparent even though the SAMT is sensitive to aging and right temporal-lobe lesions. Selective effects of scopolamine on focused versus distributed attention may account for these differential results.

Effects of carbamazepine and phenytoin on EEG and memory in healthy adults.

Using a randomized, double-blind, cross-over design, we investigated the effects of carbamazepine (CBZ) and phenytoin (PHT) on memory and spectral EEG components in 15 healthy adults. Each subject was treated with each drug for 1 month, separated by a 1-month washout. Evaluations were conducted at baseline, at the end of each treatment month, and 1 month after the last treatment phase. EEG was collected during an eyes-closed resting condition and a verbal memory activation task. Spectral analysis of the EEG in the nondrug conditions showed that the memory task significantly reduced theta components and increased delta components. As compared with nondrug conditions, the antiepileptic drugs (AEDs) significantly impaired memory performance and produced mild EEG slowing. Memory performance did not differ statistically between the AEDs, but minor differences in spectral EEG components were noted. The results suggest that differences in the cognitive and EEG effects of CBZ and PHT are not clinically significant.

Central anticholinergic hypersensitivity in aging.

Although neurochemical reductions in cholinergic systems have been found to occur during aging, such changes do not necessarily translate to functional deficits. The cognitive deficits of normal aging have been attributed in part to hypocholinergic function, but anticholinergic hypersensitivity in the elderly has not been systematically documented. To test the cholinergic hypothesis of aging, we investigated the effects of scopolamine on memory and attention in healthy young and elderly subjects. Treatments included intramuscular glycopyrrolate (0.0044 mg/kg) and scopolamine (0.002, 0.004, and 0.007 mg/kg) in a randomized double-blind design. The test battery included the Selective Reminding Task (SRT), Digit Span, Paired Associates Learning (PAL), Symbol Digit Modalities Test (SDMT), and the Continuous Performance Task. Elderly controls were more impaired at lower scopolamine doses than were the young on SRT, PAL, and SDMT. These results demonstrate anticholinergic hypersensitivity and are consistent with decremental changes in cholinergic status during normal aging.

Reproducibility of P3.

The P3 event-related potential has been widely employed in both clinical and research investigations. In the present study, P3 latency and amplitude intersession reliability were evaluated in 4 sessions over an average of 33 days in 24 healthy adults using the P3 tonal oddball paradigm. Mean group latencies ranged from 302-305 ms and mean amplitudes ranged from 7.75-8.87 microV. No significant group differences were found across sessions for latency or amplitude. Intrasubject variability was large; the 95% confidence interval for the difference between the means of two combined sessions was +/- 20 ms for latency and +/- 4.63 microV for amplitude. The results suggest that P3 latency and amplitude are reliable and reproducible over weeks for groups, but have greater variability for individuals.

Comparative cognitive effects of carbamazepine and phenytoin in healthy adults.

We investigated neuropsychological effects of carbamazepine and phenytoin in 21 healthy adults using a randomized, double-blind, double-crossover design and treating each subject with each drug for 1 month, separated by a 1-month washout. There were neuropsychological evaluations at baseline, the end of each treatment month, and 1 month after the last treatment phase. Cognitive measures included Symbol Digit Modalities Test, Selective Reminding Test, Complex Figures, Paced Auditory Serial Addition Test, Stroop, Finger Tapping, Grooved Pegboard, Choice Reaction Time, P3 Event-Related Potential, Hopkins Symptom Checklist, and Profile of Mood States (POMS). Compared with nondrug conditions, the anticonvulsants significantly impaired Stroop, Choice Reaction Time, Grooved Pegboard, Hopkins, and POMS. Employing anticonvulsant blood levels as covariates, there were only two significant differences between drugs, one in favor of carbamazepine (ie, Finger Tapping) and one in favor of phenytoin (ie, Stroop). The results suggest that differences in cognitive effects of carbamazepine and phenytoin are not clinically significant.

Effects of scopolamine on visual evoked potentials in aging and dementia.

The unusual combination of a normal pattern reversal VEP and a delayed flash VEP has been reported in patients with dementia of Alzheimer's type (DAT). Hyoscine hydrobromide has been reported to produce a similar VEP abnormality in young, healthy subjects. In the present study, we assessed the relative sensitivity of DAT patients and healthy young, middle-aged and elderly subjects to temporary cholinergic blockade. We report VEP latency values following 3 doses of scopolamine and after a peripheral anticholinergic agent. Flash P2 latency was not significantly slower in DAT patients than in the healthy elderly. Scopolamine increased P2 latency in the young controls but did not affect any other group. The pattern reversal P100 was normal in DAT, and a significant increase in latency occurred following scopolamine administration in both the control and patient groups.

Unilateral cerebral inactivation produces differential left/right heart rate responses.

We studied heart rate following unilateral hemispheric inactivation by intracarotid amobarbital in 25 patients undergoing preoperative evaluation for epilepsy surgery. Heart rate increased after left hemisphere inactivation, but decreased following right hemisphere inactivation. The results are consistent with differential left/right cerebral hemispheric effects on autonomic function, and appear related to functional and anatomic asymmetries in both the central and peripheral nervous systems.

Asymmetry in clinical features of drug-induced parkinsonism.

In clinical practice, distinguishing drug-induced parkinsonism from Parkinson's disease may be difficult. Asymmetry is generally not felt to be common in drug-induced parkinsonism. The authors investigated asymmetry of signs and symptoms in 20 patients with drug-induced parkinsonism. Tremor was identified in seven patients, slowness in five, and mixed symptoms in eight. A notable asymmetry of signs was seen in six patients. As in Parkinson's disease, subgroups seem to exist within the group of patients with drug-induced parkinsonism, and an asymmetry of signs and symptoms is not uncommon.