ADAS cog flawed

PLYMOUTH, United Kingdom -- December 19, 2012 -- New research suggests that the cognitive test used in Alzheimer's disease (AD) drug trials is flawed.

The current standard cognitive test for the disease is the ADAS Cog. The new research, published as 2 studies in the journal Alzheimer's & Dementia: The Journal of the Alzheimer's Association, investigates the role of the test and questions its effectiveness.

The studies show that the ADAS Cog is not subtle enough to properly track changes in the early stages of AD. This is important because data from this key stage is required to show whether or not a new drug is working.

Researchers also showed that the modern method of "Rasch analysis" confirmed the flaw.

In the first study, researchers examined 675 measurements from people aged 53 to 90 years with mild Alzheimer's disease across 5 time points -- 0, 6, 12, 18 and 24 months.

In terms of final patient score the ADAS-cog seemed sound. But by breaking down all the data to component level, a different story emerged: a "ceiling effect" was exposed for 8 out of the 11 parts of the ADAS-cog with many patients, ranging from 32% to 83%, passing the section when in reality much greater variance between the patients almost certainly existed and needed scoring.

In the second study, the research team moved on to use the modern method of Rasch analysis to further test the data. This confirmed the flaw. The more sophisticated method of analysis also suggested a number of possible pathways to improvement including making parts of the ADAS-cog test more difficult as well as re-thinking the scoring structure.

As a consequence, the Plymouth-based research team is suggesting urgent changes to the ADAS Cog and is not ruling out the need for a new test.

"It is impossible to say precisely the extent to which the ADAS Cog's flaws have undermined the numerous clinical trials in which it has been used," said Jeremy Hobart, MD, Plymouth University Peninsula Schools of Medicine and Dentistry, Plymouth, United Kingdom. "It has been used, unchanged, for many years and its apparent contribution to suboptimal trials has led a number of drug companies to rethink their strategies."

"However, it is very clear that in its current form the ADAS Cog underestimates cognitive differences between people and changes over time," he said. "To determine if treatments, developed from painstaking years of research, work in expensive studies we need to invest in developing measurement instruments that are fit for purpose. This requires the routine use of different methods. In its current form, the ADAS Cog is not working in people with mild Alzheimer's disease."

raloxifene and cognition

Raloxifene improves verbal memory in late postmenopausal women: a randomized, double-blind, placebo-controlled trial; Jacobsen DE, Samson MM, Emmelot-Vonk MH, Verhaar HJ; Menopause (Nov 2009)

OBJECTIVE:: The aim of this study was to examine the effects of raloxifene compared with those of placebo on verbal memory, mental processing speed, depression, anxiety, and quality of life. METHODS:: A randomized, double-blind, placebo-controlled trial of 213 healthy women 70 years or older was conducted between July 2003 and January 2008 at the University Medical Centre Utrecht, the Netherlands. Participants were randomly assigned to receive raloxifene (60 mg) or placebo daily for 12 months. Measurements were taken at baseline and after 3, 6, and 12 months. The change in scores from baseline was calculated. The main outcome measures were direct and delayed verbal memory (Groningen 15 Words test), mental processing speed (Trails B test), mood/depression (Geriatric Depression Scale), anxiety (State-Trait Anxiety Inventory 1 and 2), and quality of life (Women's Health Questionnaire and EuroQol-5 dimensional questionnaire). RESULTS:: Direct verbal memory improved significantly with raloxifene compared with placebo: the women receiving raloxifene repeated more words in the words A + B test than did the women receiving placebo (P = 0.025). At 12 months, the change from baseline was 16 words in the raloxifene group and 10 words in the placebo group. In the words A test, direct repetition was also significantly better among women receiving raloxifene than among women receiving placebo (P = 0.023), with the change from baseline in the number of words repeated being nine words in the raloxifene group and six words in the placebo group at 12 months. CONCLUSIONS:: In postmenopausal women, raloxifene gave significantly improved verbal memory when compared with placebo.

AFIB and cognitive decline without stroke

Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ONTARGET and TRANSCEND studies; Marzona I, O'Donnell M, Teo K, Gao P, Anderson C, Bosch J, Yusuf S; Canadian Medical Association Journal (CMAJ) (Feb 2012)

BACKGROUND:The role of atrial fibrillation in cognitive impairment and dementia, independent of stroke, is uncertain. We sought to determine the association of atrial fibrillation with cognitive and physical impairment in a large group of patients at high cardiovascular risk. METHODS:We conducted a post-hoc analysis of two randomized controlled trials involving 31 546 patients, the aims of which were to evaluate the efficacy of treatment with ramipril plus telmisartan (ONTARGET) or telmisartan alone (TRANSCEND) in reducing cardiovascular disease. We evaluated the cognitive function of participants at baseline and after two and five years using the Mini-Mental State Examination (MMSE). In addition, we recorded incident dementia, loss of independence in activities of daily living and admission to long-term care facilities. We used a Cox regression model adjusting for main confounders to determine the association between atrial fibrillation and our primary outcomes: a decrease of three or more points in MMSE score, incident dementia, loss of independence in performing activities of daily living and admission to long-term care. RESULTS:We enrolled 31 506 participants for whom complete information on atrial fibrillation was available, 70.4% of whom were men. The mean age of participants was 66.5 years, and the mean baseline MMSE score was 27.7 (standard deviation 2.9) points. At baseline, 1016 participants (3.3%) had atrial fibrillation, with the condition developing in an additional 2052 participants (6.5%) during a median follow-up of 56 months. Atrial fibrillation was associated with an increased risk of cognitive decline (hazard ratio [HR] 1.14, 95% confidence interval [CI]1.03-1.26), new dementia (HR 1.30, 95% CI 1.14-1.49), loss of independence in performing activities of daily living (HR 1.35, 95% CI 1.19-1.54) and admission to long-term care facilities (HR 1.53, 95% CI 1.31-1.79). Results were consistent among participants with and without stroke or receiving antihypertensive drugs. INTERPRETATION:Cognitive and functional decline are important consequences of atrial fibrillation, even in the absence of overt stroke.

mitazepine for weight loss in AD

Can Mirtazapine Counteract the Weight Loss Associated With Alzheimer Disease? A Retrospective Open-label Study; Segers K, Surquin M; Alzheimer Disease & Associated Disorders (Jul 2012)

Weight loss is a frequent complication of Alzheimer disease (AD), associated with increased morbidity and mortality. Increased appetite and weight gain are known side effects of the antidepressant mirtazapine. This analysis was undertaken to assess the safety and potential utility of mirtazapine to counteract weight loss in patients with AD or mixed AD (AD with cerebrovascular lesions). We performed a retrospective analysis of the clinical records of all outpatients attending our memory clinic for AD or mixed AD, who had received mirtazapine (30 mg daily) with the specific purpose of inducing weight or appetite gain. Data were available for a total of 22 patients (mean age, 80.9 y, 86.4% female). The mean weight at baseline was 52.4 kg and the mean BMI was 20.5 kg/m. 77.3% of the patients had gained weight after 3 months (mean gain, 1.93 kg or 3.9% of initial body weight) and 82.3% after 6 months (2.11 kg or 4.6%). One patient had to discontinue mirtazapine because of daytime sleepiness. Mirtazapine seems to be a safe and useful approach to counteract weight loss in AD, if possible in combination with nonpharmacological interventions. Body weight should be monitored during treatment to avoid excessive weight gain.

donepezil for LBD

Donepezil for dementia with Lewy bodies: A randomized, placebo-controlled trial; Mori E, Ikeda M, Kosaka K, on behalf of the Donepezil-DLB Study Investigators; Annals of Neurology 72 (1), 41-52 (Jul 2012)

 

OBJECTIVE: Because cholinergic deficits are prominent in dementia with Lewy bodies (DLB), we investigated the effects of a cholinesterase inhibitor, donepezil, in such patients in a randomized, double-blind, placebo-controlled exploratory phase 2 trial. METHODS: One-hundred forty patients with DLB, recruited from 48 specialty centers in Japan, were randomly assigned to receive placebo or 3, 5, or 10mg of donepezil hydrochloride daily for 12 weeks (n = 35, 35, 33, and 37, respectively). Effects on cognitive function were assessed using the Mini-Mental State Examination (MMSE) and several domain-specific neuropsychological tests. Changes in behavior were evaluated using the Neuropsychiatric Inventory, caregiver burden using the Zarit Caregiver Burden Interview, and global function using the Clinician's Interview-Based Impression of Change-plus Caregiver Input (CIBIC-plus). Safety measures included the Unified Parkinson's Disease Rating Scale part III. RESULTS: Donepezil at 5 and 10mg/day was significantly superior to placebo on both the MMSE (5mg: mean difference, 3.8; 95% confidence interval [CI], 2.3-5.3; p<0.001; 10 mg: mean difference, 2.4; 95% CI, 0.9-3.9; p = 0.001) and CIBIC-plus (p<0.001 for each); 3mg/day was significantly superior to placebo on CIBIC-plus (p<0.001), but not on the MMSE (p = 0.017). Significant improvements were found also in behavioral measures (p<0.001) at 5 and 10mg/day and caregiver burden (p = 0.004) at 10 mg/day. The safety results were consistent with the known profile of donepezil and similar among groups. INTERPRETATION: Donepezil at 5 and 10mg/day produces significant cognitive, behavioral, and global improvements that last at least 12 weeks in DLB patients, reducing caregiver burden at the highest dose. Donepezil is safe and well tolerated. ANN NEUROL 2012;72:41-52.

 

Comment-- donepezil-- which is available as a once daily generic, is effective in LBD, therefore the more expensive rivastigmine patch is not needed.

Higher vitamin D level protective against AD?

Higher Vitamin D Dietary Intake Is Associated With Lower Risk of Alzheimer's Disease: A 7-Year Follow-up; Annweiler C, Rolland Y, Schott AM, Blain H, Vellas B, Herrmann FR, Beauchet O; Journals of Gerontology: Series A, Biological Sciences and Medical Sciences (Apr 2012)

 

BACKGROUND: Hypovitaminosis D is associated with cognitive decline among older adults. The relationship between vitamin D intakes and cognitive decline is not well understood. Our objective was to determine whether the dietary intake of vitamin D was an independent predictor of the onset of dementia within 7 years among women aged 75 years and older. METHODS: Four hundred and ninety-eight community-dwelling women (mean, 79.8 ± 3.8 years) free of vitamin D supplements from the EPIDemiology of OSteoporosis Toulouse cohort study were divided into three groups according to the onset of dementia within 7 years (ie, no dementia, Alzheimer's disease [AD], or other dementias). Baseline vitamin D dietary intakes were estimated from self-administered food frequency questionnaire. Age, body mass index, initial cognitive performance, education level, physical activity, sun exposure, disability, number of chronic diseases, hypertension, depression, use of psychoactive drugs, and baseline season were considered as potential confounders. RESULTS: Women who developed AD (n = 70) had lower baseline vitamin D intakes (mean, 50.3 ± 19.3 μg/wk) than nondemented (n = 361; mean intake = 59.0 ± 29.9 μg/wk, p = .027) or those who developed other dementias (n = 67; mean intake = 63.6 ± 38.1 μg/wk, p = .010). There was no difference between other dementias and no dementia (p = .247). Baseline vitamin D dietary intakes were associated with the onset of AD (adjusted odds ratio = 0.99 [95% confidence interval = 0.98-0.99], p = .041) but not with other dementias (p = .071). Being in the highest quintile of vitamin D dietary intakes was associated with a lower risk of AD compared with the lower 4 quintiles combined (adjusted odds ratio = 0.23 [95% confidence interval = 0.08-0.67], p = .007). CONCLUSIONS: Higher vitamin D dietary intake was associated with a lower risk of developing AD among older women.

 

Comment see associated article about treating with memantine and vitamin D

Memantin plus vitamin D in Alzheimer's disease

Effectiveness of the combination of memantine plus vitamin d on cognition in patients with Alzheimer disease: a pre-post pilot study; Annweiler C, Herrmann FR, Fantino B, Brugg B, Beauchet O; Cognitive and Behavioral Neurology 25 (3), 121-7 (Sep 2012)

 

OBJECTIVE: To determine whether treatment with memantine plus vitamin D is more effective than memantine or vitamin D alone in improving cognition among patients with Alzheimer disease (AD). METHODS: We studied 43 white outpatients (mean 84.7±6.3 years; 65.1% women) with a new diagnosis of AD, who had not taken anti-dementia drugs or vitamin D supplements. We prescribed memantine alone (n=18), vitamin D alone (n=17), or memantine plus vitamin D (n=8) for an average of 6 months. We assessed cognitive change with the Mini-Mental State Examination (MMSE). We used age, sex, pre-treatment MMSE score, and duration of treatment as covariables. RESULTS: Before treatment, the 3 groups had comparable MMSE scores. At 6 months, participants taking memantine plus vitamin D increased their MMSE score by 4.0±3.7 points (P=0.034), while participants taking memantine alone remained stable (change of 0.0±1.8 points; P=0.891), as did those taking vitamin D alone (-0.6±3.1 points; P=0.504). Treatment with memantine plus vitamin D was associated with improvement in the MMSE score compared to memantine or vitamin D alone after adjustment for covariables (P<0.01). Mixed regression analysis showed that the visit by combined treatments (memantine plus vitamin D) interaction was significant (P=0.001), while memantine or vitamin D alone showed no effect. CONCLUSIONS: Patients with AD who took memantine plus vitamin D for 6 months had a statistically and clinically relevant gain in cognition, underlining possible synergistic and potentiating benefits of the combination.

High dose rivastigmine in Alz disease

Randomized, Double-Blind, Parallel-Group, 48-Week Study for Efficacy and Safety of a Higher-Dose Rivastigmine Patch (15 vs. 10 cm) in Alzheimer's Disease; Cummings J, Froelich L, Black SE, Bakchine S, Bellelli G, Molinuevo JL, Kressig RW, Downs P, Caputo A, Strohmaier C; Dementia and Geriatric Cognitive Disorders 33 (5), 341-353 (Jul 2012)

Aim: Determine whether patients with Alzheimer's disease demonstrating functional and cognitive decline, following 24-48 weeks of open-label treatment with 9.5 mg/24 h (10 cm(2)) rivastigmine patch, benefit from a dose increase in a double-blind (DB) comparative trial of two patch doses. Methods: Patients meeting prespecified decline criteria were randomized to receive 9.5 or 13.3 mg/24 h (15 cm(2)) patch during a 48-week, DB phase. Coprimary outcomes were change from baseline to week 48 on the Instrumental Activities of Daily Living domain of the Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-IADL) scale and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). Safety and tolerability were assessed. Results: Of 1,584 patients enrolled, 567 met decline criteria and were randomized. At all timepoints, ADCS-IADL and ADAS-cog scores favoured the 13.3 mg/24 h patch. The 13.3 mg/24 h patch was statistically superior to the 9.5 mg/24 h patch on the ADCS-IADL scale from week 16 (p = 0.025) onwards including week 48 (p = 0.002), and ADAS-cog at week 24 (p = 0.027), but not at week 48 (p = 0.227). No unexpected safety concerns were observed. Conclusions: The 13.3 mg/24 h rivastigmine patch significantly reduced deterioration in IADL, compared with the 9.5 mg/24 h patch, and was well tolerated.

CSF profiles and variant dementia

Neurology 2012; 78:47 -54

CSF profiles of tau and abeta are extremely effective differentiating some dementias but not others. Markers were t(total) tau, p (phosphorylated) tau, and Abeta42 in CSF.  " AD profile" of  markers was seen in AD, but also in many autopsy proven cases of  DLB, CBD, FTLD and VaD (about 30-50 % of respective types of dementia patients had :AD profile."  Psychiatric patients and those with subjective complaints of memory loss had normal CSF results.  PSP patients had normal results also.  CJD patients had very high t tau and normal p tau