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    QUEST - Cognitive Disorders

 

AUTHOR

Johnny Lee 

Development and evaluation of evidence based risk assessment tool (STRATIFY) to predict which elderly inpatients will fall: case-control and cohort studies.  

Chairman’s Rounds, March 5, 2007 

Reference: Development and evaluation of evidence based risk assessment tool (STRATIFY) to predict which elderly inpatients will fall: case-control and cohort studies. D Oliver, M Britton, P Seed, CF Martin, AH Hopper. British Medical Journal. Oct 25, 1997; 315, 7115. Research Library p 1049-1053. 

Clinical Questions for Diagnostic Test: Phase 1 (Prospective Case-Control): What clinical characteristics of elderly inpatients predict their chance of falling? Phase 2 and 3 (Validation Cohort studies): What is the power of a risk assessment tool in predicting falls? 

Background: Falls are common among elderly inpatients. Falls can lead to fractures, fear of falling, anxiety, depression, and loss of confidence. Falls are associated with increased LOS, readmission, and need for nursing home care. Various clinical characteristics have been associated with increased incidence of falls. However, there had been little evidence from British acute hospital wards for elderly patients. 

Validity: Did the clinicians face diagnostic uncertainty? Falls were recorded in ward incident books. There could have been undocumented falls. Nursing judgments were NOT standardized. Fallers and control patients were NOT matched by sex or age. One patient could contribute 2 or more sets of data by falling >1 with each week treated as a separate datum.

Was the tested population representative of that for which the diagnostic test will be use in practice? Yes. Goal was to create an assessment tool for British elderly inpatients.

Was there a blind comparison between the test and an independent gold standard? No.

STRATIFY has 5 risk factors a/w falls: fall as presenting complaint, transfer and mobility score of 3 or 4, nurse’s judgment that patient was agitated, frequent toileting, and visually impaired. Unstable gait and antiarrhythmics were not included for methodological reasons. (Refer to Table 1.)

Was there blinding of those performing and those undergoing the tests? Nurses were not made aware of the risk scores when they provided weekly nursing judgments.

Was follow-up complete? Yes.

Design: Setting: Phase 1 and 2: Elderly care units of St. Thomas’s Hospital, a 700-bed teaching hospital in London, England. Phase 3: Kent and Canterbury Hospital, a 500-bed district gen. hospital with acute/rehab.

Population: Elderly hospitalized patients (≥65 yo). Phase 1: 116 cases/events and 116 controls. Phase 2: 217 patients with 71 fallers. Phase 3: 331 patients with 79 fallers.

Methods: Student’s T test, Wilcoxon’s non-parametric test, logistic regression, OR.

Outcomes: Phase 1: Association of 21 clinical characteristics (e.g.: abbreviated mental test score, modified Barthel index, transfer and mobility score, nursing judgments) with falls by odds ratio (95% CI).

Phase 2 and 3: STRATIFY assessment tool to predict falls.

Follow-up Period: Phase 1: 3 months. Phase 2: 8 weeks. Phase 3: 8 weeks. 

Results: Phase 1: Seven risk factors were associated with falls: agitation (OR 20.9), frequent toileting (OR 2.48), unstable gait (OR 6.58), visual impairment (OR 3.56) as judged by primary nurse; fall as a presenting complaint (OR 4.64), transfer and mobility score of 3 or 4 (OR 2.10), and use of antiarrhythmics. Five of 7 risk factors were used in assessment tool. Phase 2: Sens 93%, Spec 88%, PPV 62%, NPV 98%, LR+ 7.75, LR- 0.0795 for risk score ≥2. Phase 3: Sens 92%, Spec 68%, PPV 39%, NPV 98%, LR+ 2.875, LR- 0.11 for risk score ≥2. 

Conclusions: STRATIFY can be a clinically useful tool for predicting falls among the elderly in British hospital wards. However, 3 of 5 factors are subjective and not standardized. Medications may play a more significant role in falls than reported.

 Synopsis: In Phase 1 (3 months), a prosp case-control study of 116 cases-116 controls (of elderly inpatients ≥65 yo) found 5 factors A/W a higher risk of falls. In Phases 2 and 3 (8 weeks each) with cohort studies of 217 and 331 patients, risk score ≥2 had clinically useful sens. and spec. in predicting falls. Of note, inpatients in the study were at British hospitals with characteristics which may differ from US inpatients.

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AUTHOR:
Dan McCabe

Haloperidol Prophylaxis For Delirium

Chairman’s Rounds, August 7, 2006

 Citation: Kalixvaart K, Jonghe J, et al. Haloperidol Prophylaxis for Elderly Hip-Surgery Patients at Risk for Delirium: A Randomized Placebo-Controlled Study. JAGS. 2005; 53; 1658-1666

Clinical Question: To study the effectiveness of haloperidol prophylaxis on incidence, severity, and duration of post operative delirium in elderly hip-surgery patients at risk for delirium

Clinical Case or Background Info: Multiple times per week consult service at the VA is asked to assist with treatment of delirium in elderly post-op veterans in ICU setting.  Should high risk surgical patients for post-op delirium be placed on prophylactic haloperidol?

Question Type: Therapy

 Validity Criteria Therapy: Follow-up: 11 in Haloperidol group lost to follow up, 24 in the placebo group.  All patients who entered trial were accounted for and attributed at its conclusion. Randomization: Patients were randomized by computer randomized code.  The research team and all participants were blinded and checked by assessors.  Intention to treat: Patients analyzed in the groups to which they were randomized See Figure 1.  Similar groups: Yes see Table 1 Blinding: Patients and clinicians were unaware of allocation, unsure whether assessors were aware of group allocation?  Equal treatment: both groups received equal treatment.

 Study Design Type: Randomized Controlled Trial

Allocation: Patients who met inclusion criteria were randomized to group receiving 0.5mg of Haloperidol TID, versus Placebo group

Follow Up Period: Minimum of 1 day vs. Maximum of 6 days depending on the onset of delirium

Setting: 915 bed teaching hospital in the Netherlands (Holland)

Patients/Population: Men and women aged 70 years and older admitted for acute or elective hip surgery.  Must have been at intermediate or high risk for post op delirium based on four predictive risk factors (as previously described) Visual impairment, severity of illness measured using the APACHE II, cognitive impairment MMSE score less then 24, and the index of dehydration.  Intermediate risk was 1or 2 risk factors, high risk 3 or 4.

Intervention/exposure: Medication started on admission and continued until 3 days after surgery, a maximum delay for surgery of 72 was permitted, Haloperidol dosage was based on the average starting dose for treatment of older patients with delirium in the department and recommendations by the American Psychiatric Association.  All patients received consultation from geriatric service providing them with enhancement of orientation and cognition; sensory and mobility-improving advice; attention to pain and sleeping complaints; extra attention to fluid and food intake; and patient education

Outcomes: Primary Outcome Post-op delirium as determined by DSM-IV criteria.  Secondary Outcome severity of delirium, delirium duration, and length of hospital stay.

 Main Results: Primary Outcome: 430 patients both Haloperidol and Placebo groups 15.8% developed delirium, 15.1% (32/212) of Haloperidol group and 16.5% (36/218) in placebo group, no significant difference.

Secondary Outcomes: During episode of delirium Haloperidol group DRS-R-98 was significantly lower then the placebo group. See figure 2

During day 5 until Day 8 the proportion of patients still having delirium was significantly lower after haloperidol prophylaxis. See figure 3

Mean duration of delirium in the haloperidol group was 5.41 days, 6.4 days shorter then the placebo group 11.8 days.  Mean difference of days spent in the hospital until patients were ready for transfer to a rehabilitation unit or home was 5.5 days shorter in the Haloperidol group. 

No drug related side effects were seen during the study period.

Conclusions:  Overall the post-op delirium rate was much less thn expected given known delirium rates in this population.  This study likely indicates that primary prevention is an effective strategy for preventing delirium which was provided to both groups in this study.  Significant benefits in secondary outcomes indicate that when applied in clinical practice the strategy of combining non-pharmacologic and pharmacologic interventions may lead to smaller numbers of patients who will have delirium and that it may shorten the severity and duration of delirium.  One limitation of the study was the dosage of Haldol administered 1.5mg/24 hours this was based on the average starting dose for treatment of delirious older patients and the minimal chance of EPS side effects.  Higher doses of Haldol may be necessary for primary prevention of delirium.  Based on this study I would treat high risk post-op patients with prophylactic Haloperidol. 

Two Teaching Points:  

1. Though no significant difference in primary outcome NNT can be calculated as 71, the number of people which would receive prophylactic haloperidol to cause one less person develop delirium. 

2. Required sample size based on assumption that haloperidol prophylaxis would reduce delirium rate from 40% to 27%, based on comparable studies with 40% delirium rate.  13% reduction in delirium rate found with non-pharmacologic interventions.  Based on statistical data sample size of 206 patients would be needed to find effect based on these assumptions.  Based on delirium rates in this study was underpowered.  

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Author:
Anne Lin

A MULTICOMPONENT INTERVENTION TO PREVENT DELIRIUM IN HOSPITALIZED OLDER PATIENTS

Authors: Inouye, Sharon K.; Bogardus, Sidney T. Jr.; Charpentier, Peter A. 

Summary: Controlled clinical trial using prospective individual matching strategy to evaluate effectiveness of multi component protocol for the prevention of delirium. Potential participants in the study were consecutive patients admitted to 3 general medicine units: 1 intervention and 2 usual care units. 2434 patients were potentially eligible to participate, >70yo, no delirium at baseline, and were intermediate or high risk for delirium at baseline (based on screening). 1265 were excluded b/c of inability to participate in interviews, profound dementia, aphasia, intubation, respiratory isolation or hospital stays of <48 hrs. 250 eligible patients refused to be in study. 67 cases could not be matched (criteria age within 5 years, sex, and base-line risk of delirium). 852 patients were matched into 426 pairs. Intervention consisted of standardized protocols to manage six risk factors for delirium: cognitive impairment, sleep deprivation, immobility, visual impairment, hearing impairment, and dehydration. Delirium was assessed daily by structured interview with MMSE, Digit Span Test, Confusion Assessment Method. Delirium defined by Confusion Assessment Method.

  1. Are the results of the study valid?
    1. Was the assignment of patients to treatments randomized? No. Patients were matched according to age, sex and delirium risk at baseline.
    2. Were all patients who entered the trial properly accounted for and attributed at its conclusion? Yes. Was follow up complete? Yes.
    3. Were patients, health workers, and study personnel "blind" to treatment? Yes. Assessments of delirium were done by research staff who were unaware of the intervention, nature of the study or group assignments.
    4. Were the groups similar at the start of the trial? Yes.
    5. Aside from the experimental intervention, were the groups treated equally? Yes. Same attending and residents provided care for both groups.

  2. What were the results? 
    Outcome n=106/852 Intervention Usual Care Statistical Analysis
    First episode of delirium 42 (9.9%) 64 (15.0%) OR 0.6 (0.39-0.92) p=0.02
    days of delirium 105 161  p=0.02
    no. episodes of delirium 62 90 p=0.03
    mean delirium score  3.85 +1.27 3.52 + 1.44 p=0.25
    recurrence, >2 episodes 13 (13.0%) 17 (26.6%) p=0.62

    1. How large was the treatment effect?
      Incidence of delirium significantly lower in intervention group 9.9% v. 15.0%, p=0.02.
    2. How precise was the estimate of the treatment effect?
      The 95% confidence interval for the absolute risk reduction (increase in response rate) is 39% to 92% .

  3. Can the results be applied to my patient care?
    Yes. Can apply some elements of protocols. May not have resources or control.

    Are the likely treatment benefits worth the potential harms and costs?
    Yes.

Results and Bottom Line:
This multicomponent strategy was effective in prevention of delirium in older medical patients. After delirium has occurred the intervention did not decrease the severity of delirium or likelihood of recurrence. Focus should be on prevention in at risk patients.

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Author:
Anne Lin

EFFECTS OF ROFECOXIB OR NAPROXEN VS. PLACEBO ON ALZHEIMER DISEASE PROGRESSION: A RANDOMIZED CONTROLLED TRIAL

Clinical Question: Does treatment with a selective cyclooxygenase (COX) -2 inhibitor (rofecoxib) or a traditional nonselective NSAID (naproxen) slows cognitive decline in patients with mild-to-moderate AD?

Reference: JAMA. 2003 Jun 4; 289(21): 2819-26. Aisen PS, Schafer KA, Grundman M, Pfeiffer E, Sano M, Davis KL, Farlow MR, An S, Thomas RG, Thal LJ.

Methods
Design - Multi center, randomized, double blind, placebo controlled, parallel group trial with 1-year exposure to study medications.

Patient Population included individuals with probable AD recruited from clinic populations. (See Patient Flowchart pg. 2821) Exclusion criteria: hypersensitivity to NSAIDS, CHF, bleeding disorders, poorly controlled HTN, renal insufficiency. Also co morbid conditions that might respond to NSAIDS or NSAIDs, neuroleptics, antidepressant use w/in 2 months of the trial. Inclusion criteria: age older than 50, MMSE 13­26. Stable use of cholinesterase inhibitors was permitted. Analysis included assessment of treatment groups for age, sex, APO E genotype.

Intervention /Control-Rofecoxib 25mg QD or Naproxen 220mg BID or placebo. Groups stratified by site with randomization sequence generated by the ADCS data center with masking assessed by questionnaires. Analysis/Outcomes - Analysis was conducted on an intention to treat basis including all randomized participants. LOCF was not used. An alternative impution scheme was whereby a participant's missing score at 52 weeks was imputed based on the data from all individuals with completed data, as applied to the participant's last observed score. Primary outcome was the 1-year change in score on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) which evaluates memory, attention, reason, language, orientation and praxis. 50% reduction in cognitive decline was considered significant as suggested by data from a small pilot study. Secondary Outcome measures included the Clinical Dementia Rating-sum of boxes, ADCS-ADL scale, Neuropsychiatric Inventory and QOL, time to obtain significant endpoints. Endpoints' 4point decline in the ADAS-cog, death, institutionalization. 1 step worsening on the global CDR scale, 15pt decline on the ADCS-ADL scale.

Follow-up - duration / completeness, accounting of patients

Validity
Study was randomized with randomization list concealed. All treatment groups similar at baseline. Patients starting trial were accounted for at conclusion. Patients analyzed in groups to which they were randomized. Patients and clinicians blinded to treatment. Groups treated similarly outside of intervention.

 Results
The primary outcome measure was the 1-year change in the Alzheimer Disease Assessment Scale­Cognitive (ADAS-Cog) subscale score. Secondary outcome measures included the Clinical Dementia Rating scale sum-of-boxes, the Neuropsychiatric Inventory, the Quality of Life-AD, and the time to attainment of significant end points (4-point decline from baseline ADAS-Cog score, 1-step worsening on the global Clinical Dementia Rating scale, 15-point decline on the ADCS activities of daily living inventory, institutionalization, or death). The 1-year mean (SD) change in ADAS-Cog scores in participants treated with naproxen (5.8 [8.0]) or rofecoxib (7.6 [7.7]) was not significantly different from the change in participants treated with placebo (5.7 [8.2]). Results of secondary analyses showed no consistent benefit of either treatment. Fatigue, dizziness, and hypertension were more commonly reported in the active drug groups, and more serious adverse events were found in the active treatment group than in the placebo group

Comments
Naproxen chosen because of BID dosing and low dose was selected to avoid serious adverse events and high dropout rate compared to placebo. Insufficient dose? Other drugs in the same class may have different activity. Exposure greater than 1 year or earlier in disease course may be necessary. Primary prevention trial may be useful.

 

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DOES SELEGILINE IMPROVE THE WELL BEING OF PATIENTS WITH ALZHEIMER'S DISEASE?

Citation: Birks, J; Flicker, L. Selegiline for Alzheimer's disease, Issue 4, 2002.

Background:
"Alzheimer's disease is the most common cause of dementia in older people accounting for 60% of cases. Selegiline (L-Depreny) is a levotory acetylenic deriative of phenylethylamine initially developed in Hungary as an antihypertensive."
-low doses l0mg/day - MAO-B inhibitor
-high doses 40mg/day-MAO A and B
-inhibits uptake of dopamine in pre synaptic nerve endings, increasing its synthesis -fluctuations in dopamine levels cause measurable variations in operations of working memory

Selegiline was proposed for treatment of AD following reports of elevated MAO-B activity in patients with AD versus healthy older people.
-thought to be due to increased proportion of glial cells
-highest level of MAO-B in hippocampus, a pivotal structure in Alzheimer's.
-MAO-B accounts for some 80% of human brain MAO (dopamine and phenylethylamine as substrates)

Currently, selegiline remains controversial and has a low rate of prescription as well as the lack of approval by several authorities in Europe etc. No formal statistical review had been done until recently due to variations in scales with regards to efficacy. The data still remains difficult to combine.

Methods:
1. Search Strategy: Medline, PsycLIT, EMBASE as well as a Cochrane Dementia and Cognitive Impairment Group Register of Clinical Trials
2. Study Selection: All un confounded, double-blind, randomized controlled trials in which selegiline was administered for more than one day and compared to placebo in the setting of dementia.

a. All studies included had allocation concealment criteria A or B. Only one study Freedman 1998 met criteria for Category A.
b. Reviewed 29 selegiline trials over past 10 years. 8 short term crossover studies, 9 in combination with another dementia drug. Of these, 15 were included in this study.
c. Size of trials varied from 10 to 341 patients, average being 50. Duration of treatment was from 3 wks and 2 years, with 3 months being the average.
d. Scales - MMSE 12-24 (moderate dementia), also Gottfries-Branne-Steen and Ferm's dementia scale. Average age 70, duration of disease 2.9 years.
e. Outcome criteria divided into "domains" - dependency (institutionalization), global impression, functional performance, behavioral disturbance, quality of life, cognition function, effect on career, death, safety, acceptability of treatment.

Results:
15 included trials. 12 of these addressed behavioral and mood effects along with cognitive effects. The results of 8 trials reported some beneficial effect of selegiline on cognition, and 3 showed some benefit with regard to mood and behavior.

1. Cognitive: Meta analysis revealed benefits on memory function as evidenced by improvement in several tests (Randt Memory Index, Wechsler Memory Scale, etc). The combined tests showed improvement with selegiline compared to placebo (SMD 0.56, 95%; Cl - -0.88 --- -0.24). One study found an estimated 11.8 point difference in the ADAS -Cog test and another found further benefits (another 4.8 points) when selegiline was combined with another cholinergic medication.
2. Mood/Behavior: 3 studies showed improvement in mood and behavior using the brief psychiatric rating scale and the Dementia Mood Assessment Scale. However, other scales (Cornell Scale for Depressed, Global Deterioration Scale etc.), showed no effect of selegiline vs. placebo (SMD - 0.11, 95%; CI -0.49--- - 0.27).
3. Few patients left the trials and there were few major side effects (anxiety, agitation, dizziness, nausea, dyspepsia).

Comments:
There is some evidence that selegiline improves the mental function of people with Alzheimer's disease without detrimental effects. The evidence is best for memory function. Unfortunately, the evidence cannot be standardized very well (MMSE, ADAS-Cog) because of the variety of studies administered and how the reports were published. Much of the data is presented in a way that makes extraction of standardized data difficult.

There is also evidence that selegiline improves behavior and mood in Alzheimer's disease, but no evidence to support Clinical Global Impression of Change benefits. There is limited evidence for dependence (placement in nursing homes etc.).

Bottom line:
The evidence is promising for the beneficial effects of selegiline, but there is not enough evidence to recommend its use in everyday practice. Improvements in methods of reporting and standardization of scales would provide greater availability for incorporating various data.

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Author:
C. Feltner

DONEPEZIL FOR MILD AND MODERATE ALZHEIMER'S DISEASE

  Bottom line: This review of randomized, double-blind, placebo-controlled trials finds evidence that treatment with donepezil in people with Alzheimer’s disease, for 12, 24, or 52 weeks, is associated with improvements in cognitive function and clinician-rated global clinical state.

Background: Alzheimer's disease is the most common cause of dementia affecting older people and is associated with loss of cholinergic neurons in parts of the brain involved in memory. Acetylcholinesterase inhibitors (such as donepezil) delay the breakdown of acetylcholine released into synaptic clefts and may enhance cholinergic neurotransmission.

Clinical Question: Does donepezil improve cognitive function and well being in patients with mild or moderate Alzheimer's disease?

Reference: Birks JS, Melzer D, Beppu H. Donepezil for mild and moderate Alzheimer's disease (Cochrane Review). In: The Cochrane Library, Issue 4: 2002. Oxford: Update Software.

Search terms: E2020, donepezil and Aricept.

Methods: All double-blind, randomized controlled trials in which treatment with donepezil was compared with placebo for patients with Alzheimer's disease were reviewed. Eight trials are included involving 2664 participants, all reported since 1996. The studies all used similar criteria for diagnosis: either NINCDS­ADRDA criteria/ DSM-III-R. The severity of the disease was measured by the MMSE. Exclusion criteria were consistent across studies. Patients with the following medical disorders were excluded: insulin­dependent DM or other endocrine d/o, asthma, COPD or uncontrolled GI, hepatic or cardiovascular disease. Also, no use of anti cholinergics, anticonvulsants, antidepressants or anti psychotics was permitted. Data were extracted by one reviewer, pooled, and the weighted mean differences (or Peto odds ratios) estimated. Analysis was conducted using the intent-to-treat principle with last observation carried forward. Primary outcomes included cognitive function (tested by either ADAS-Cog), and global impression (CIBIC-plus or GBS). Secondary outcomes included MMSE, patient-rated QOL and function (or ADLs).

Results: The meta-analysis reveals benefits on cognitive function as shown by improvement in the ADAS-Cog and MMSE scores using weighted mean differences (with 95%CI in parentheses).

                   ADAS-COG                       MMSE

weeks

10mg

5 mg

12

-3.1(-4.2,-1.9)

-2.3(-3.2,-1.5)

24

-1.9(-3.6,-2.2)

-.19(-2.6,-1.1)

12

-1.3(-1.8,-0.8)

-0.9(1.5,-0.4)

24

-1.4(-2.1,-0.7) 

-1.2(-1.9,-0.5)

54

-1.7(-2.6,-0.8)

X

The results of three studies show some improvement in global clinical state (assessed by an independent clinician) in those treated with 5 and 10mg/day of donepezil compared with placebo at 12 and 24 weeks. The patient's own ratings of their quality of life showed no benefit of donepezil compared with placebo. There were significantly more withdrawals before the end of treatment from the 10mg/day (but not 5mg/day) donepezil group compared with placebo.

Comments:
1. Study groups are likely to be healthier than patients typically seen in practice.
2. The outcome of the study could be enhanced because the data was reported on an ITT basis with LOCF. Those who drop out, on average, would be expected to show further decline by the end of the study and more patients in the treatment group (10mg donepezil qd) dropped out than placebo.
3. There is controversy concerning whether what cognitive tests measure is of everyday importance.
4. The duration of treatment is short; trial evidence of longer term effects is not currently available. 
5. No evidence was found that donepezil improves patient-rated quality of life. Also, no available outcome measures address dependency and effects on caregivers.

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Author:
Matthew Soulier

GINKGO BILOBA FOR COGNITIVE IMPAIRMENT AND DEMENTIA

Bottom Line: A systematic review of trials of Ginkgo biloba in the treatment of acquired cognitive impairment showed promising evidence of efficacy, but there is a need for further trials to confirm and extend the findings.

Background: Medicinal products derived from the tree, Ginkgo biloba, are some of the most widely used of any plant-based products. A well-defined extract, EGb 761, is produced from the ground-up leaves. EGb 761 is one of the top five prescription medicines in Germany. It is believed that the medicinal properties of Ginkgo biloba are due to a combination of effects and that it acts by increasing blood supply by dilating blood vessels, reducing blood viscosity, by modification of neurotransmitter systems, and by reducing the density of oxygen free radicals.

Reference: Birks J, Grimley Evans J, Van Dongen M. Ginkgo Biloba for Cognitive Impairment and Dementia (Cochrane Review). In: The Cochrane Library, Issue 4, 2002.

Methods: All relevant, randomized, double-blind controlled studies, in which extracts of Ginkgo biloba at any strength and over any period were compared with placebo for their effects on people with acquired cognitive impairment, including dementia, of any degree of severity. There are 33 included studies in this meta-analysis. The duration of the studies varies from 3 weeks to 52 weeks, with the majority being of 12 weeks duration. The participants of the studies were diagnosed either with dementia of any type or age related cognitive impairment. All studies except one, use a Ginkgo preparation based on the standard extract. Thus the doses in mg/day are comparable across trials. The daily dose ranged from 80 to 600 mg/day, usually less than 200 mg/day.

Results:

1. Overall, there are no significant differences between Ginkgo and placebo in the proportions of participants dropping out or experiencing adverse events before the scheduled end of treatment.

2. The CGI scale: There are benefits associated with Ginkgo (dose less than 200mg/day) compared with placebo at less than 12 weeks (54/63 showed improvement compared with 20/63, OR 15.32, 95% CI 5.90 to 39.80, P=<.0001), and Ginkgo (dose greater than 200mg/day) at 24 weeks (57/79 compared with 42/77, OR 2.16, 95% CI 1.11 to 4.20, P=.02).

3. Cognition: Shows benefit for Ginkgo (dose less than 200mg/day) compared with placebo at 12 weeks (SMD -0.57, 95% CI -1.09, -0.05, P=0.03, random effects model), Ginkgo (greater than 200 mg/day) at 12 weeks (SMD -0.56,95% CI -1.12 to -0.0, P=0.05), at 12 weeks (Ginkgo any dose) (SMD -0.71, 95% CI - 1.23 to -0.19 P=0.008, random effects model) at 24 weeks (Ginkgo any dose) (SMD -0.17, 95% CI -0.32 to -0.02 P=0.03) and at 52 weeks (Ginkgo less than 200 mg/day) (SMD -0.41, 95% CI -0.71 to -0.11, P=<.01).

4. Activities of Daily Living (ADL): Shows benefit for Ginkgo (dose less than 200mg/day) compared with placebo at 12 weeks (SMD -1.10, 95% CI -1.79,441, P=<.01), Ginkgo (dose less than 200 mg/day) at 24 weeks (SMD -0.25, 95% CI -0.49 to -0.00, P=.05), and at 52 weeks (Ginkgo less than 200 mg/day) (SMD - 0.41, 95% CI -0.71 to -0.11, P=<.01).

5. Measures of mood and emotional function: Show benefit for Ginkgo (dose less than 200 mg/day) compared with placebo at less than 12 weeks (SMD -0.51, 95% CI -0.99 to -0.03, P=.04) and Ginkgo (dose less than 200mg/day) at 12 weeks (SMD -1.94, 95% CIs -2.73, -1.15 P=<.0001).

Validity: These studies, though randomized controlled, are flawed due to the few attempts at ITT analyses. Multiple different scales and outcome measures were used, some which were explicitly described, some which were vague. Inclusion/exclusion criteria were quite variant among the studies. It was unclear what percentage had which type of cognitive impairment, and often studies include a mixture of categories.

Comments: Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo. Many of the early trials used unsatisfactory methods, were small, and cannot exclude publication bias. Overall there is promising evidence of improvement in cognition and function associated with Ginkgo. There is need for a large trial using modern methodology and permitting an intention-to-treat analysis to provide more robust estimates of the effects.

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Author:
Julie Adams, MD

ERT OR HRT IN COGNITIVE FUNCTION IN POST-MENOPAUSAL WOMEN  

Bottom line: ERT or HRT does very little to prevent decline of or improve cognitive function in post­menopausal women and further studies of better design are needed to elucidate what little evidence of effect does exist.

Background: Estrogen have been associated with maintenance and protection of brain structures in animal models. It has been hypothesized that maintaining high levels of estrogen in post-menopausal women using ERT or HRT would protect against cognitive decline.

Search Method: Trials for this analysis were identified through a search of the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, MEDLINE (1996-2002), EMBASE (1985-2000), PsycINFO (1967-2002), and CINAHL (1982-2001) databases using the terms ORT, PORT, ERT, HRT, estrogen, oestrogen, progesterone.

Clinical question: Can hormone replacement therapy (estrogen and progesterone) or estrogen replacement therapy slow cognitive decline in post-menopausal women?

Reference: Hogervorst, E; Yaffe, K, Richards, M; Huppert, F. Hormone replacement therapy for cognitive function in postmenopausal women (Cochrane Review). The Cochrane Library, (Issue 4), 2002.

Methods: Fifteen double-blind randomized controlled trials were read by two reviewers and deemed adequate for inclusion. They then underwent quality assessment according to Cochrane Collaboration guidelines (all were either A or B) and, if data were adequate as was the case in 9 of 15, they were included in meta-analysis.

Validity: Review admitted studies only on healthy post-menopausal women (whether natural or surgical) who were treated with ERT or HRT and had subsequent cognitive testing. Heterogeneity was great as to educational level; mood or other psychiatric co-morbidity; age, mode, dose and duration of treatment; and method of compliance check. Furthermore cognitive tests employed varied greatly between trials. Meta­analysis is therefore limited.

Results:
Verbal memory tests: Paired associate immediate recall was significantly in favor of treatment for surgically menopausal women treated with E2 IM x2-3months (z=2.40, p<0.05, chi square=1.12, p=0.29, SMD 1.02, 95% C.I. 0.19-1.85). The same test scored differently showed no effect in older women treated with CEE+MPA PO x9months. Paired associate delayed recall showed no significant effect in either group. No other verbal memory test showed significance in any group. Visual memory tests: None of the studies that used this test (E2 IM x2-3months, E2 transdermal x2-3 weeks, E2 oral x 2months, CEE oral xlmonth) showed significant effect of treatment on visiospatial memory. Speed of information processing: Treatment with CEE+MPA PO x9months showed significant effect in complex information processing speed on the TMT-B (z=1.3, p<0.05, SMD=-0.57, 95% C.I.=1.16 to 0.01). No other test in this category showed improvement with this therapy or transdermal E2 x2-3 weeks. Abstract reasoning: Young surgically menopausal women treated with E2 IM x2-3months showed significantly better performance on an abstract reasoning test (z=10.45, p<0.0001, WMD=6.80, 95% C.I.=5.52-8.08) and on the Clerical Speed and Accuracy test (z=9.16, p<0.0001, WMD=6.00, 95% C.I.=4.27-7.28). No other test in this category with any other intervention showed effect.

Comments: This review and analysis of the body of literature on estrogen therapy for cognitive protection is limited by the studies it employs. The studies are heterogeneous (age; type of menopause; treatment method, mode and duration; pre-morbid functioning; co-morbid psych diagnoses; presence of menopausal symptoms) and six lack data to include. Despite these shortcomings, the analysis presented is reliable and gaps in study designs are easily recognized. As the authors themselves address, looking more closely at the specific variables listed above might produce a more reliable or more promising study. For the most part, the data presented are discouraging with the exception of E2 10mg IM used in young surgically post­menopausal women that showed significant improvement for three tests after 2-3months of treatment.

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DHEA SUPPLEMENTATION FOR COGNITIVE FUNCTION

Bottom Line: There is limited evidence from controlled trials that dehydroepiandrosterone (DHEA) enhances cognitive function in normal middle-aged or elderly people.

Background: DHEA/DHEAS are the most abundant steroid hormones in women and men. They reach their highest levels in young adults and decrease markedly with age. There is some epidemiologic evidence suggesting high levels of DHEAS in males may protect against heart disease and prolong life. It is plausible that elevated DHEA would protect neurons by lowering cortisol levels. In the USA, over the counter DHEA supplementation is increasingly popular.

Clinical Question: Does DHEA improve cognitive function or slow cognitive decline in older adults with or without dementia?

Reference: Huppert FA, Van Niekerk JK. DHEA supplementation for cognitive function. The Cochrane Library, Volume (Issue 4) 2002.

Methods: Study sources: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group, personal communications, conference abstracts, hand-searched journals. --Designs of studies: Double-blind, randomized, placebo-controlled trials -- two using parallel groups and two using cross-over. Durations were 6 months, 6 weeks, 5 weeks, and 2 weeks (with stressor at end). 
--Study selection criteria: Subjects were older adults with or without cognitive impairment; the interventions were DHEA or DHEAS; outcomes were performance on objective cognitive tests; allocation of treatment was rated "adequate" or "intermediate" following Cochrane Collaboration guidelines 
--Number of studies screened/accepted: Of six studies passing the screen two were excluded, one because the subjects were a poorly defined group of young adults, the other because the subjects were young adults given only one dose of DHEA. In the end four studies were selected, three on cognition in normal older adults and one on cognition in perimenopausal women with impaired well-being.
--Subject population: 210 (66+46+17+81) subjects were randomized and 21 (-6-6-3-6) were excluded from analysis. Selection criteria varied widely, but none of the 189 analyzed subjects carried a psychiatric diagnosis.
--Intervention: DHEA 50mg PO qd versus placebo. Analysis: There was no data pooling. 
--Outcomes: Various objective cognitive tests. Follow-up: None.

Validity: The clinical question was focused.
--Study inclusion criteria were straightforward and appropriate, and it is unlikely that a relevant, significant study was missed.
--The quality of each study's allocation of treatment was evaluated using a standard protocol.
--The four selected studies were heterogeneous, but three were by the same author, they were all done between 1997 and 1999, none of the subjects had a diagnosis, and each study used the same dose of DHEA. 
--The proportion of randomized subjects later excluded from analysis (overall 10%) was acceptable.

Results: There was no meta-analysis.
--Only one of the four studies provided significant, but conflicting, results: testing before and after a "laboratory psychosocial stressor" showed deterioration (p<0.05) only in the placebo group on a symbol cancellation test, but also showed deterioration (p<0.01) in only the DHEA group on a visual memory test. 
--Interestingly, another study found significant superiority in the DHEA group on a visual memory test compared to a placebo group.
--There were no significant side-effects.

Comments: No studies were found of cognitively impaired patients receiving DHEA.
--The longest study was three months, whereas the neuroprotective effect of DHEA may be a long-term phenomenon. The sample sizes were small. DHEA 50mg qd may not be an optimal dose.
--The couple significant results are likely the product of using multiple outcome measures or the use of a stressor in that particular study.  

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ELEVATED HOMOCYSTEINE LEVELS AND RISK FOR STROKE, VASCULAR DEMENTIA AND ALZHEIMER DISEASE

Author: Matthew Soulier, MD

Reference: Mcllroy, Stephen P. et al (2002). Moderately Elevated Plasma Homocysteine, Methylenetetrahydrofolate Reductase Genotype, and Risk for Stroke, Vascular Dementia, and Alzheimer Disease in Northern Ireland. Stroke. 33: 2351-2356.

Methods:
Design: Case Control.
Setting: Subjects were `randomly recruited' from the Memory Clinic, Stroke Unit, and Day Hospital, Belfast City Hospital. Healthy controls were recruited from the local podiatry clinic and volunteers previously known to the department.
Patient Population: AD n=83; mean age, 77.2 years; SD=8.1 years; 30% male; Val): n=78; mean age, 77.3 years; SD=9.3 years; 33% male; NDS: n=64; mean age, 73.8 years; SD=8.1 years; 58% male; `Healthy' controls: n=7 1; mean age, 74.3 years; SD=7.6 years; 20% male. Does not report how many screened vs number enrolled.
Inclusion Criteria: Only inclusion criteria described: Patients and controls were white and were ascertained to have at least parents and grandparents born in Northern Ireland to ensure ethnicity.
Exclusion Criteria: A strong family history of dementia (>1 first-degree relative). 
Blinding: No blinding
Analysis: Subject groups were compared on quantitative characteristics by use of 1-way ANOVA and on qualitative characteristics by use of Pearson's [chi]2 test. Multiple regression analysis was used to adjust for possible confounders in the comparison of homocysteine levels between groups. Primary Exposures: fasting levels of homocysteine, apolipoprotein E (APOE), and Methylenetetrahydrofolate Reductase (MTHFR) genotypes.
Secondary Exposures: age, sex, hypertension, cholesterol, smoking, creatinine, and nutritional measures, history of cardiovascular disease/peripheral vascular disease, smoking, educational status, and socioeconomic status (childhood and adult), vitamin B6, vitamin B12, and folate. 
Method: One single fasting venous blood sample was collected.

Validity:
Did the experimental and control groups begin the study with a similar prognosis? This is obviously the toughest question to answer as we do not know all determinants or their secondary mechanisms for the given outcomes. The groups did differ significantly between ages, sex, smoking status, and mean serum folate, but the authors did adjust for differences via multiple regression analysis. 
Exposure was equally likely to be identified in the two groups.
The outcomes and exposures were measured in the same way in all groups.

Results:
- OR's for all 3 patient groups were significant, even as they were adjusted for confounding variables OR for homocys>13 in the 3 disease groups relative to the control group
- As expected, significant increase in the carriage of APOE [epsilon]4 was observed in the AD group compared with controls: [chi]2=10.5, df=1, P=0.001, OR=3.32 (95% CI, 1.49 to 7.50). However, there was only a trend toward increased carriage of [epsilon]4 in the VaD group.
 -Analysis of the distribution of the MTHFR genotypes between groups revealed that CT and TT were significantly overrepresented in the VaD group compared with controls (59.2% versus 29.6%; [chi]2= 13.0;df =1;P <0.001) and AD patients (59.2% versus 28.9%; [chi]2=14.8;df =1;P <0.001). The difference between the VaD and the NDS groups (59.2% versus 38.1%; [chi]2 =6.14;df =1;P =0.019) failed to reach significance. The frequency of the T allele was also significantly increased in the VaD group compared with the other subject groups.
-Mean homocysteine levels increased non significantly from the CC genotype (15.4 µmol/L; SD 8.0) through the CT genotype (15.9.tmol/L; SD 6.9) to the TT genotype (19.5 µmol/L; SD 13.1). However, there was no association between MTHFR genotype and homocysteine levels in any subject group.

Comments: The main finding in this case control study was the significant increase in plasma homocysteine levels in all disease groups compared with controls. This difference remained significant after adjustment for conventional vascular risk factors and other possible confounders. This indicates that mildly elevated homocysteine levels nay therefore significantly increase risk for VaD, AD, or stroke. The results from this study also indicate that possession of the T allele of the MTHFR C677T polymorphism significantly increases risk for VaD. When the VaD group was compared with the NDS group, the T allele was significantly over represented in the former, leading to the possibility that this allele confers increased risk for dementia after stroke. The effect of the APOE polymorphism on the risk for AD was as expected. The present report indicates that possession of the APOE [epsilon]4 allele may increase risk for VaD in those patients who suffer stroke. These results argue for a randomized trial of the efficacy of folate, vitamin B12, and/or vitamin B6 in subjects who are designated as being at high risk for stroke or dementia. However, it has finally been driven into my head that correlation can not be taken to indicate causation. Thus, hyperhomocysteinemia should, at the present time, be regarded only as an indicator of susceptibility to disease, and therapies that could reduce homocysteine levels are not guaranteed to reduce the incidence of either strokes or dementia.

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ESTROGEN AND PROGESTIN INCREASES DEMENTIA RISK

 

Bottom Line: Women taking estrogen plus progestin are at a two-fold higher risk for developing dementia that those taking placebo (relative risk=2.05). While the actual number of women developing dementia over the course of this study was small, the difference between groups shows that estrogen plus progestin is not useful for protecting against memory loss. The number needed to harm, NNH, for dementia in postmenopausal women exposed to E+P compared to placebo over one year is 435. These findings, coupled with previously reported WHI data, support the conclusion that the risks of estrogen plus progestin outweigh the benefits.

 

Background: The WHI E-plus-P trial, involving over 16,000 women across the country, is the largest clinical trial of postmenopausal hormones ever undertaken. Its findings have contrasted with previously detected protective effects for hormones found in case-control and observational studies, including a meta-analysis of 14 studies assessing the risk of AD, in which the overall odds ratio associated with estrogen use was 0.56 (Hogervorst 2000).

 

Clinical Case/Question: Is estrogen + progestin effective in preventing dementia in women?

 

Reference: Shumaker, S. et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003 May 28;289(20):2651-62.

 

Methods:

The Women's Health Initiative Memory Study (WHIMS) was funded by Wyeth Pharmaceuticals, which manufactures PremproTM, which it provided for use in the WHI trials. WHIMS is a randomized, double-blind, placebo-controlled clinical trial, began enrolling participants from the Women's Health Initiative (WHI) estrogen plus progestin trial in May 1996. Of the 4894 eligible participants of the WHI study, 4532 (92.6%) postmenopausal women free of probable dementia, aged 65 years or older recruited from 39 of 40 WHI clinical centers were enrolled in the WHIMS. Participants received either I daily tablet of 0.625 mg of conjugated equine estrogen plus 2.5 mg of medroxyprogesterone acetate (n = 2229), or a matching placebo (n = 2303). Main outcome measures: Incidence of probable dementia (primary outcome) and mild cognitive impairment (secondary outcome) were identified through a structured clinical assessment.

  Validity:

Potential sources of bias and/or threats to the validity of this study include:

- A small number of events of interest (61 cases of dementia) compared with a larger number of dropouts (151 cases)

- Groups were similar at baseline on all important prognostic factors, with the exception of a slightly lower prevalence of previous stroke and slightly higher percentage of participants using statins in the E+P group. These differences would potentially bias the study in favor of the E+P group.

Otherwise, all important validity criteria were met by the study, including concealed randomization, blinding of all important groups, good follow-up, and near intention-to-treat analysis. Both groups were treated similarly outside of the experimental intervention. Generalizability may be limited by the characteristics of the study population, who appeared to represent a higher than average socioeconomic group.

 

Results:
Most of the dementia found among women participating in the study was classified as probably Alzheimer's disease, with vascular dementia ranking second. There were 20 cases of Alzheimer's disease among the 40 dementia cases in the women in the combination therapy group (50 percent of the cases); in women on placebo, 12 of the 21 cases (57 percent) of dementia were deemed Alzheimer's disease. The two groups began to diverge one year after randomization; the differences continued through 5 years of follow-up.

 

Comments:
In a companion analysis, the WHIMS trial also found that combination estrogen plus progestin does not protect women from normal declines in cognitive function when compared with placebo. WHIMS investigator Stephen Rapp, Ph.D., Wake Forest University School of Medicine, and colleagues at the other sites examined the participants' performance on an often-used test, the Modified Mini-Mental State Exam (3MS). All participants' average performance on the cognitive tests actually improved over time, which researchers suggest may be due to a "practice effect" as a result of taking the same tests every year. However, the rate of increase in the performance of women on the 3MS was somewhat lower for women in the combination therapy group when compared with women receiving placebo. "Because of possible harm in some areas and lack of a demonstrated benefit in others, we have concluded that combination hormone therapy should not be prescribed at this time for older, postmenopausal women to maintain or improve cognitive function," says Judith A. Salerno, M.D., M.S., Deputy Directory of the National Institute on Aging (NIA) at the National Institutes of Health (NIH), U.S. Department of Health and Human Services.

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THIAMINE DEFICIENCY IN ALZHEIMER'S DEMENTIA

Author: Kelly Clouse , MD

Clinical Question: Are patients with Alzheimer's dementia more likely to have thiamine deficiency than patients with other types of dementia or patients wt out dementia? (and further, is thiamine deficiency a risk factor for Alzheimer's dementia?)

Reference: Gold, M, Chen MF, Johnson K (1995) Plasma and red blood cell thiamine deficiency in patients with dementia of the Alzheimer's type. Arch Neurol 52:1081-1086.

Methods
Design - case-control study
Setting - Univ. of S. Florida Memory Disorder Clinic
Patient Population - 34 patients (17 with probable SDAT, 17 patients undergoing cognitive impairment evaluation thought to have other forms of dementia); patients identified consecutively, any other inclusion/exclusion criteria and #screened vs. enrolled not described
Exposure - patients were analyzed for thiamine deficiency as measured by plasma levels and RBC levels, noting both numerical averages and identifying "low" values based on age adjusted levels. 
Analysis - age, MMSE scores, plasma and RBC thiamine levels compared non-parametrically, using Kruskall-Wallis one-way analyses of variance. Sex ratios and proportions of patients with abnormalities in thiamine levels analyzed with Pearson chi-squared statistics. One-way analysis of variance done to analyze the difference in MMSE scores between normal controls and patients with SDAT who had low plasma thiamine levels. Stats by SYSTAT for Windows.
Outcomes - average thiamine levels (plasma and RBC), proportion of patients with abnormally low thiamine levels (age adjusted), MMSE scores between SDAT group with and without low thiamine levels, vitamin supplementation,
Follow-up - all 34 patients accounted for in the data, except missing a MMSE in one SDAT patient.

Validity
Were the comparison groups clearly delineated and treated similarly outside of the putative exposure?

•  Controls and case