Sandra Vicari

Double-blind, placebo-controlled study of metrifonate, an acetylcholinesterase inhibitor, for Alzheimer disease

Summary:Fifty patients with probable Alzheimer disease (AD) completed a 3-month double-blind study to compare metrifonate to placebo. We dosed metrifonate to achieve a 40–60% inhibition of red blood cell acetylcholinesterase activity. The Alzheimer Disease Assessment Scale cognitive subscale score (ADAS-C) served as the primary outcome measure. At the completion of 3 months of treatment, the metrifonate group ADAS-C score differed significantly from the placebo group score by 2.6 points (p<0.01). A 0.75-point trend toward improvement occurred during treatment in the ADAS cognitive performance of the metrifonate group (p=0.15), and a 1.10-point deterioration in cognitive performance was found in the placebo group (p<0.02). On the Global Improvement Scale (GIS), the two groups differed significantly on their changes from baseline to treatment phase (p<0.02). Significant deterioration occurred in GIS scores (p<0.01) and in Mini Mental State Examination (MMSE) scores (p<0.03) in the placebo-treated group. Adverse effects were uncommon and did not require adjustment of the dose of metrifonate or discontinuation of treatment. We achieved a mean of 52.3% decrease in red blood cell acetylcholinesterase activity. During up to 18 months of subsequent open metrifonate treatment of patients, we found a deterioration of 1.68 points per year in MMSE performance. These findings support further study of the effects of metrifonate on deterioration rate in AD.

Alzheimer disease assessment scale: useful for both early detection and staging of dementia of the Alzheimer type.

The Alzheimer Disease Assessment Scale (ADAS) was administered to 61 patients with dementia of the Alzheimer type (DAT) and 52 elderly controls. The DAT group was subdivided into different severity levels of dementia based on scores from the Mini-Mental State Exam: very mild (≥24), mild (20 to 23), moderate (10 to 19), and severe (0 to 9). The mean scores on the ADAS Cognitive subscale for the four levels of dementia (very mild = 23.1 ± 7.7, mild = 22.9 ± 8.9, moderate = 38.6 ± 9.8, severe = 54.8 ± 7.6) were statistically different from one another (p < 0.0001, except very mild vs. mild) and were significantly worse than the scores of the elderly control group (5.5 ± 2.7, p < 0.0001, ANOVA). Furthermore, the ADAS Cognitive subscale was highly effective in discriminating individual Alzheimer patients from elderly controls. The ADAS Cognitive score correctly classified 100% of the very mild group, 91% of the entire mild group, and 100% of the moderate and severe groups when a cutoff score of 2 SDs above the control group mean was used. Age and education had only minimal effects on the ADAS Cognitive score. The ADAS is a valuable screening test that only takes 30 min to administer and has utility in both early detection and staging of DAT.

Assessing Alzheimer severity with a global clinical scale.

Diagnosis of dementia needs to be complemented by precise determination of disease severity across the broad spectrum of disease progression. The Mini-Mental State Exam (MMS), the Activities-of-Daily-Living assessment (ADL) and the Clinical Dementia Rating scale (CDR) were modified for direct comparability and administered to 112 outpatients and 45 nursing home residents with a range of dementia severity from mild to profound. The scales showed the highest correlations for the probable Alzheimers disease patient group (62) (Global Assessment of Dementia; GAD vs. ADL: r = 0.91; Extended Mini-Mental Assessment; EMA vs. GAD: r = 0.91; ADL vs. EMA: r = 0.86). For these patients, scores on the individual scales tended to be similar. Disparity among the three scores for individual cases was associated with the presence of comorbidities. The high correlations and correspondence among these scales demonstrate their reliability, validity, and utility in the assessment of dementia severity. The use of an average of these measures, with their increased precision, may give a more accurate indication of dementia severity over a broader range of impairment.

Alzheimer disease assessment scale : a subtest analysis

SummaryThe Alzheimer Disease Assessment Scale (ADAS) was administered to 61 Alzheimer patients, 52 elderly controls, and 80 controls between age 7 and 54 years. The Alzheimer group was categorized into different severity levels of dementia based on MMSE scores: very mild (≥ 24), mild (≥20), moderate (10–19), and severe (0–9). All 11 ADAS Cognitive subtest scores for the mild, moderate, and severe dementia groups were statistically worse than the elderly control group. This was also the case for the very mild group, except for Naming, Commands, Constructional Praxis, and Ideational Praxis. In terms of magnitude of effect, memory and spontaneous language items were the earliest indicators on the ADAS, while praxis, commands, and naming items were only sensitive later in the course of the disorder. The best single indicators of progression throughout the severity continuum of dementia (i.e., from normal to severe) were the Orientation subtest, the ADAS Cognitive score, and the ADAS Total score. The ADAS Noncognitive subtests generally did not show the progression with increasing dementia that was evident on the ADAS Cognitive subtests. Differences in educational level had no statistically significant effects on any of the ADAS subtest scores, and age differences were few and small in magnitude. The differential rate of decline of the various ADAS subtests appears to reflect both the changing pattern of cognitive impairments as a function of severity of DAT and also to some extent the psychometric limitations of some of the subtests.

Effects of Metrifonate on Cognitive Decline in Alzheimer Disease: A Double-Blind, Placebo-Controlled, 6-Month Study

Forty-seven patients with probable Alzheimer disease (AD) completed a 6-month double-blind study to compare metrifonate with placebo. The Alzheimer Disease Assessment Scale cognitive subscale score of the metrifonate group treated to a 50-70% inhibition of red blood cell acetylcholinesterase activity differed significantly from the placebo group score by 1.8 points (p < 0.03) due to a deterioration in cognitive performance in the placebo group (p < 0.01). Statistically significant deterioration also occurred in the Mini-Mental State Examination scores (p < 0.01) in the placebo-treated group. Adverse effects were uncommon and did not require adjustment of the dose of metrifonate or discontinuation of treatment. These findings extend our previous report of a favorable effect of metrifonate on cognitive symptoms in AD by showing clinical, not only statistical, significance.

Better exercise adherence after treatment for cancer (BEAT Cancer) study: Rationale, design, and methods

Most breast cancer survivors do not engage in regular physical activity. Our physical activity behavior change intervention for breast cancer survivors significantly improved physical activity and health outcomes post-intervention during a pilot, feasibility study. Testing in additional sites with a larger sample and longer follow-up is warranted to confirm program effectiveness short and longer term. Importantly, the pilot intervention resulted in changes in physical activity and social cognitive theory constructs, enhancing our potential for testing mechanisms mediating physical activity behavior change. Here, we report the rationale, design, and methods for a two-site, randomized controlled trial comparing the effects of the BEAT Cancer physical activity behavior change intervention to usual care on short and longer term physical activity adherence among breast cancer survivors. Secondary aims include examining social cognitive theory mechanisms of physical activity behavior change and health benefits of the intervention. Study recruitment goal is 256 breast cancer survivors with a history of ductal carcinoma in situ or Stage I, II, or IIIA disease who have completed primary cancer treatment. Outcome measures are obtained at baseline, 3 months (i.e., immediately post-intervention), 6 months, and 12 months and include physical activity, psychosocial factors, fatigue, sleep quality, lower extremity joint dysfunction, cardiorespiratory fitness, muscle strength, and waist-to-hip ratio. Confirming behavior change effectiveness, health effects, and underlying mechanisms of physical activity behavior change interventions will facilitate translation to community settings for improving the health and well-being of breast cancer survivors.

Biobehavioral Factors Mediate Exercise Effects on Fatigue in Breast Cancer Survivors

PURPOSE This study aimed to examine mediators of fatigue response to an exercise intervention for breast cancer survivors in a pilot randomized controlled trial. METHODS Postmenopausal breast cancer survivors (n = 46; ≤stage 2), off primary treatment, and reporting fatigue and/or sleep dysfunction were randomized to a 3-month exercise intervention (160 min·wk of moderate-intensity aerobic walking, twice weekly resistance training with resistance bands) or control group. Six discussion group sessions provided behavioral support to improve adherence. Fatigue, serum cytokines, accelerometer physical activity, cardiorespiratory fitness, sleep dysfunction, and psychosocial factors were assessed at baseline and 3 months. RESULTS The exercise intervention effect sizes for fatigue were as follows: fatigue intensity d = 0.30 (P = 0.34), interference d = -0.38 (P = 0.22), and general fatigue d = -0.49 (P = 0.13). Using the Freedman-Schatzkin difference-in-coefficients tests, increase in fatigue intensity was significantly mediated by interleukin 6 (IL-6) (82%), IL-10 (94%), IL-6/IL-10 (49%), and tumor necrosis factor-α (TNF-α):IL-10 (78%) with reduced sleep dysfunction increasing the relationship between intervention and fatigue intensity rather than mediating intervention effects (-88%). Decrease in fatigue interference was mediated by sleep dysfunction (35%), whereas IL-10 and pro-anti-inflammatory cytokine ratios increased the relationship between intervention and interference (-25% to -40%). The reduction in general fatigue was significantly mediated by minutes of physical activity (76%), sleep dysfunction (45%), and physical activity enjoyment (40%), with IL-10 (-40%) and IL-6/IL-10 (-11%) increasing the intervention-fatigue relationship. In the intervention group, higher baseline fatigue, anxiety, depression, and perceived exercise barrier interference predicted a greater decline in fatigue interference and/or general fatigue during the intervention. CONCLUSIONS Biobehavioral factors mediated and enhanced intervention effects on fatigue, whereas psychosocial factors predicted fatigue response. Further study is warranted to confirm our results and to improve understanding of relationships that mediate and strengthen the intervention-fatigue association.

The Consultation Conference: A New Model of Collaboration for Child Psychiatry and Primary Care

Because of the relative shortage of available child psychiatrists, primary-care providers are increasingly expanding their role in the provision of mental health care. Accordingly, there is an increased need to develop a standardized approach to teaching specialized skills to these providers. One method of doing so is to expand the child psychiatrist’s consultative role to include the structured discussion of patient cases. By emphasizing the reasoning behind treatment recommendations, the psychiatrist can assist the primary-care provider in applying this knowledge to other patients in his or her practice. A group setting, or “consultation conference,” can be used to involve more providers—who, in turn, become resources for each other. This model of a group conference adapts principles of adult learning (1–5) to facilitate the dual consultative and educational goals. Providers who care for patients in the same (or similar) setting come together as a group to share their experience and knowledge. The psychiatrist assists in that group setting, functioning both as expert resource and facilitator. Participants discuss problem cases, thus learning in their own context while receiving assistance in the understanding and management of actual patients (indirect consultation).

Cholinesterase Inhibitors as Therapy in Alzheimer’s Disease: Benefit to Risk Considerations in Clinical Application

Currently available data about cholinesterase inhibitors in Alzheimer’s disease (AD) indicate that knowledge of differences in pharmacology among the inhibitors is essential to physicians to maximize clinical benefits to patients. We express the concern that commercial promotion may not recognize the relevant issues. We caution physicians to consider carefully the rationale of their use of compounds from this class.

Inflammation and psychosocial factors mediate exercise effects on sleep quality in breast cancer survivors: Pilot randomized controlled trial

To improve mechanistic understanding, this pilot randomized controlled trial examined mediators of an exercise intervention effects on sleep in breast cancer survivors (BCS).