Donepezil improved memory in multiple sclerosis in a randomized clinical trial.

OBJECTIVE: To determine the effect of donepezil in treating memory and cognitive dysfunction in multiple sclerosis (MS). METHODS: This single-center double-blind placebo-controlled clinical trial evaluated 69 MS patients with cognitive impairment who were randomly assigned to receive a 24-week treatment course of either donepezil (10 mg daily) or placebo. Patients underwent neuropsychological assessment at baseline and after 24 weeks of treatment. The primary outcome was change in verbal learning and memory on the Selective Reminding Test (SRT). Secondary outcomes included other tests of cognitive function, patient-reported change in memory, and clinician-reported impression of cognitive change. RESULTS: Donepezil-treated patients showed significant improvement in memory performance on the SRT compared to placebo (p = 0.043). The benefit of donepezil remained significant after controlling for various covariates including age, Expanded Disability Status Scale, baseline SRT score, reading ability, MS subtype, and sex. Donepezil-treated patients did not show significant improvements on other cognitive tests, but were more than twice as likely to report memory improvement than those in the placebo group (p = 0.006). The clinician also reported cognitive improvement in almost twice as many donepezil vs placebo patients (p = 0.036). No serious adverse events related to study medication occurred, although more donepezil (34.3%) than placebo (8.8%) subjects reported unusual/abnormal dreams (p = 0.010). CONCLUSIONS: Donepezil improved memory in MS patients with initial cognitive impairment in a single center clinical trial. A larger multicenter investigation of donepezil in MS is warranted in order to more definitively assess the efficacy of this intervention.

Cognitive dysfunction lateralizes with NAA in multiple sclerosis.

Recent studies have demonstrated the utility of magnetic resonance (MR) spectroscopic imaging to evaluate axonal integrity in patients with multiple sclerosis (MS). Patient status in MS is frequently assessed by the Expanded Disability Status Scale, which emphasizes ambulation but underestimates the contribution of cognitive factors. Yet, cognitive functions of memory and processing are known to be impaired in MS. We used quantitative MR spectroscopy to determine this relation between cognitive function and N-acetyl aspartate (NAA) levels. We find a significant correlation (r = .63, p < .005) for the left periventricular (PV) NAA concentrations with performance on the verbal Selective Reminding Test. Right PVNAA was significantly (p < .02) correlated with the Tower of Hanoi performance, with r = .58.

Fatigue and declines in cognitive functioning in multiple sclerosis.

OBJECTIVE: To determine whether cognitive fatigue, defined as a decline in cognitive performance over a single testing session, could be identified in MS. METHODS: Forty-five individuals with MS and 14 healthy control participants completed a 4-hour session of cognitive testing that involved a baseline neuropsychological battery, a continuous effortful cognitive task (completing mental arithmetic problems administered on a computer), and a repeat neuropsychological battery. Self-report measures of fatigue and affect were completed before each step of the testing session. RESULTS: The pattern of change in cognitive performances over the testing session significantly differed between the MS and control participants. Individuals with MS showed declines on measures of verbal memory and conceptual planning, whereas the control participants showed improvement. Although there were no significant differences between the groups on any of the baseline cognitive measures, the MS participants performed worse than the control subjects on tests of visual memory, verbal memory, and verbal fluency that were repeated following the continuous effortful cognitive task. Both MS and control participants reported increased mental and physical fatigue across the testing session compared with their baseline values. CONCLUSION: Individuals with MS show declines in cognitive performance during a single testing session and fail to show the improvement exemplified by healthy control subjects.

Psychological states and neuropsychological performances in chronic Lyme disease.

The neuropsychiatric sequelae of chronic Lyme disease remains unclear. This study sought to characterize the psychological status of a group of participants who met criteria for post-Lyme syndrome (PLS). These measures were then used to examine the influence of psychological status on neuropsychological performances. Thirty PLS participants completed a structured psychiatric interview, the Positive and Negative Affect Schedule, the Lyme Symptom Checklist, and a battery of neuropsychological tests. As a group, the PLS participants did not appear to have an elevated incidence of psychiatric disorders, and psychiatric history was not useful for understanding neuropsychological performances or symptom reports. The mood of the PLS participants was characterized by lowered levels of positive affect (PA) and typical levels of negative affect. This combination can be distinguished from depression and is consistent with previous findings of affect patterns in individuals with chronic fatigue syndrome. PA was also linked to both total symptom severity and severity of cognitive complaints, but not to duration of illness, neurological manifestations at initial diagnosis, or treatment history. Relative to published normative data, neuropsychological performances were not in the impaired range on any measure. Neither psychological status nor symptom report were useful for understanding any aspect of cognitive functioning. It is concluded that decreased PA is the most useful marker of psychological functioning in PLS.

Does process-specific slowing account for cognitive deficits in Lyme disease?

Although several studies have suggested that cognitive slowing is a symptom in Lyme disease, it is not clear whether this slowing is general or relates to specific cognitive tasks. This study examined cognitive speed in 25 Lyme disease patients using a mental arithmetic task. These patients showed significant impairments when initiating the cognitive processes involved in counting, but performed as well as healthy participants (n = 23) when the number of counting increments increased. Lyme patients also performed a speeded perceptual-motor matching task as well as healthy participants. Lyme-related initiation speed deficits were significantly correlated with performance on standardized neuropsychological tests, including the Trail Making Test and the Digit Symbol Test, but not with self-reported depression. These results suggest that the cognitive deficits seen on speeded tasks are process specific in the Lyme patient group, and are not the result of generalized slowing.

Pharmacokinetics and pharmacodynamics of the monoamine oxidase B inhibitor mofegiline assessed during a phase I dose tolerance trial.

The safety, pharmacokinetics, and pharmacodynamics of single oral doses of up to 48 mg and daily (for 28 days) doses of up 24 mg mofegiline were investigated in healthy male volunteers. Plasma pharmacokinetics indicated rapid absorption and elimination: time to reach maximum concentration occurred at about 1 hour; half-life ranged from 1 to 3 hours. Maximal plasma concentration and area under the plasma concentration-time curve increased and oral clearance decreased disproportionately with dose. Mofegiline rapidly and markedly inhibited platelet monoamine oxidase B (MAOB) activity, which returned to baseline within 14 days. Urinary excretion of phenylethylamine increased proportionately with doses up to 24 mg. No changes in urinary elimination of catecholamines, blood pressure, heart rate, or ECG were observed. A classic maximum tolerated dose was not achieved in these studies. However, the 48 mg single dose and the 24 mg multiple daily dose far exceeded the dose (1 mg) that was associated with > 90% platelet MAOB inhibition.

Amplification of doxorubicin mutagenicity by cupric ion.

There is a presumption that copper and anthracycline drugs will interact with DNA to produce genotoxicity. This is of concern because serum copper levels are increased in certain neoplastic diseases. To test the interaction, it was determined if the metal ion could alter the mutagenesis of doxorubicin and related drugs in the Salmonella microsome test. In the standard form of the test, doxorubicin was strongly mutagenic against frameshift-sensitive strain TA98. When cupric acetate was added with doxorubicin it amplified the mutagenesis of the antineoplastic with an increase of approximately 19% in peak mutagenic values. This apparent "chemoactivation" was evaluated by additional applications of the Salmonella test. Preincubation of cupric acetate, drug, and bacteria (+/- rat liver S9 fraction) also resulted in a copper-amplifying effect. In the preincubation method copper produced a drug concentration-related increase of more than 700% in the mutagenicity of doxorubicin. This large an increase occurred without S9 in the test. The effects observed in TA98 were not seen with TA102, a strain sensitive to oxidation mechanisms. Copper amplification in the mutagenicity of a positive control, aflatoxin B1, was also observed with TA98 but these effects were not seen with the chelator, EDTA, the antifolate antineoplastic drug, methotrexate, or a test negative amino acid, methionine. Results point to a direct frameshift mechanism to explain the increase in mutagenicity with copper. Amplification of mutagenicity found in this study provides initial experimental support that anthracycline-metal ion-DNA associations might contribute to genotoxicity as has been inferred in the literature.

Total mesh wrapping for parenchymal liver injuries--a combined experimental and clinical study.

This study examined a mesh wrap technique that provides effective hepatic tamponade and clinical experience with the technique in 6 patients is reported. Technical feasibility and effectiveness were investigated in 8 miniature swine. The animals were divided into two groups: group A (n = 4), control animals; stellate liver lacerations without mesh wrap or other measures for hemostasis, and group B (n = 4); stellate liver laceration with synthetic absorbable mesh wrap applied for hepatic hemostasis. Except for mesh application, all variables were held constant for both groups. All animals in the control group died within 20 to 120 minutes (mean: 65 minutes). All animals in group B survived (p = 0.029). The livers were harvested for gross and microscopic examinations. No abscess, bile leak, or hematoma was noted. Clinically, total mesh wrapping was attempted in 6 patients with blunt exsanguinating liver injuries. The technique failed intraoperatively in two patients with juxtacaval lacerations and hepatic vein avulsion injuries. One patient with a bilobar gunshot wound died later of sepsis. In three patients with bursting injuries, the technique successfully controlled bleeding and resulted in long-term survival. In conclusion, the total hepatic mesh wrap (1) is geometrically, technically, and mechanically feasible, (2) was not associated with complications in this series, and (3) can effectively secure hemostasis following parenchymal liver injury.