Cognition and neuropsychiatry in behavioral variant FTD by disease stage

Ranasinghe KG, Rankin KP, Loach IV et al. Neurology, 2016; 86: 600-610.

 

authors examined a cohort of 204 patients with clinical dementia rating. 

 

Early stages of the disease were characterized by profound neuropsychiatric symptoms, insensitivity to errors, slower response times and poor naming.

 

Stepwise declines that occurred in later stages included free recall, visuoconstruction, set shifting, error insensitivity, semantic and design fluency, emotion naming, calculations, syntax comprehension and verbal agility. 

 

Error insensitivity is called a highly sensitive index of early bv FTD and is likely attributed to the right lateral prefrontal cortex which is responsible for response inhibition and sensitivity to rule violations (esp IFG). Early patients show impaired processing speed and fluency tasks, but are adequate on attention and working memory, and visuoperceptual processing.

 

bvFTD patients get "denkfaulheit" or an early amotivational syndrome sometimes called emotional laziness.   They may score poorly due to noncooperation and disruption of the "ventral salience network stuctures" to identify pedrsonally salient stimuli. 

Vascular risk factors in suspected NPH

Jaraj D, Agerskov A, Rabiei K et al. Vascular risk factors in suspected normal pressure hydrocephalus. A population based study.  Neurology 2016; 86: 592-599 

 

Authors found that hypertension, white matter lesions on MRI and diabetes were related to clinical and imaging features of NPH suggesting vascuar mechanisms;

 

 

and  editorial 

Graff-Radford NR. Is normal pressure hydrocephalus becoming less idiopathic?  Neurology 2016; 86: 588-89.

 

Dr. Graff Radford discusses that the problem usually cited, resistance to CSF outflow, is problematic as an etiology as some patients with normal CSF outflow resistance  also present with hydrocephalus.  He points out that more than 10 %of patients with iNPH have congenital hydrocephalus, and more than 10 % have a head size above the 98th percentile. 

Ventricular pulse pressure is related to iNPH, and ligating the choroid plexus in dogs unilaterally (prventing pulse pressure) prevents hydrocephalus in that but not the other ventricle. 

 

In a human study, patients with iNPH but without an absorption problem underwent shunting; these patients had severe vascular risk factors.  They improved with shunting.  The small study (n=14) was blinded and randomized sothe control group had their shunts ligated for three months in the neck and only improved after un-ligation. 

 

He regards the question of vascular risk factors as etiologic to be unresolved.

 

Alz biomarkers in normal pressure hydrocephalus

Graff-Radford NR.  Alzheimer CSF biomarkers may be misleading in normal-pressure hydrocephalus.  Neurology 2014; 83:1573-1575.

Preshunt in NPH have low Ab42 and tau protein, that improve post shunt.  Author attributes to impaired clearance of these proteins in NPH,  same is true for tau protein.  After shunting, "room for the ICF space increases during sleep and ability for the proteins to better drain into the CSF (increases).  Physicians should not rely on CSF biomarkers to look for Alz disease among patients being assessed for Alzheimer's disease. 

 

Blogger comment

nice clinical practical pearl.  In NPH the whole idea of evaluation is to separate out bad surgical candidates from good ones by identifying Alzheimer's patients and others. 

posterior cortical atrophy review paper

http://ac.els-cdn.com/S1474442211702897/1-s2.0-S1474442211702897-main.pdf?_tid=63b29014-f231-11e3-9c1c-00000aab0f26&acdnat=1402578149_2d87bf974149da4f3ae868083858a9fd

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

Brain reserve, education and Alzheimer's disease

The balance between cognitive reserve and brain imaging biomarkers of cerebrovascular and Alzheimer's diseases; Murray AD, Staff RT, McNeil CJ, Salarirad S, Ahearn TS, Mustafa N, Whalley LJ; Brain (Nov 2011)

The cognitive reserve hypothesis explains the disparity between clinical and pathological phenotypes and why, in two individuals with the same extent of neuropathology, one may be demented while the other remains cognitively intact. We examined the balance between brain magnetic resonance imaging measures of the two most common pathologies associated with brain ageing, cerebrovascular disease and Alzheimer's disease, and parameters of cerebral reserve in well-characterized participants born in 1936, for whom childhood intelligence is known. Brain magnetic resonance imaging was carried out at 1.5T using fluid attenuation inversion recovery and T(1)-weighted volumetric sequences in 249 participants. Cerebrovascular disease was quantified by measuring brain white matter hyperintensities on fluid attenuation inversion recovery images using Scheltens' scale and Alzheimer's disease was measured from volumetric data using FreeSurfer to extract whole brain volume and hippocampal volumes in turn. The effect of these measures of brain burden on life-long cognitive ageing from the age of 11 to 68 years was compared with the effect of educational attainment and occupational grade using structural equation modelling. Complete brain burden and reserve data were available in 224 participants. We found that educational attainment, but not occupation, has a measurable and positive effect, with a standardized regression weight of +0.23, on late life cognitive ability in people without cognitive impairment aged 68 years, allowing for the influence of childhood intelligence and the two most common subclinical brain pathological burdens in the ageing brain. In addition, we demonstrate that the magnitude of the contribution of education is greater than the negative impact of either neuropathological burden alone, with standardized regression weights of -0.14 for white matter hyperintensities and -0.20 for hippocampal atrophy. This study illustrates how education counteracts the deleterious effects of cerebrovascular disease and Alzheimer's disease and highlights the importance of quantifying cognitive reserve in dementia research.
 
Blogger note:  Education is known to be very important in Alzheimer's development, but is now more important than pathology?  I agree that it affects dementia research but might do so because education affects performance on tools used in dementia research, more than the biologic process of disease.  One could conclude, equally valid-ly, that this proves we need new tools to measure Alzheimer's that are less reflective of educational attainment.

Vitamin D and risk of cognitive decline in elderly persons

Llewellyn DJ, Lang IA, Langa KM, Muniz-Terrera G, Phillips CL, Cherubini A, Ferrucci L, Melzer D; Archives of Internal Medicine 170 (13), 1135-41 (Jul 2010)

BACKGROUND: To our knowledge, no prospective study has examined the association between vitamin D and cognitive decline or dementia. METHODS: We determined whether low levels of serum 25-hydroxyvitamin D (25[OH]D) were associated with an increased risk of substantial cognitive decline in the InCHIANTI population-based study conducted in Italy between 1998 and 2006 with follow-up assessments every 3 years. A total of 858 adults 65 years or older completed interviews, cognitive assessments, and medical examinations and provided blood samples. Cognitive decline was assessed using the Mini-Mental State Examination (MMSE), and substantial decline was defined as 3 or more points. The Trail-Making Tests A and B were also used, and substantial decline was defined as the worst 10% of the distribution of decline or as discontinued testing. RESULTS: The multivariate adjusted relative risk (95% confidence interval [CI]) of substantial cognitive decline on the MMSE in participants who were severely serum 25(OH)D deficient (levels<25 nmol/L) in comparison with those with sufficient levels of 25(OH)D (>/=75 nmol/L) was 1.60 (95% CI, 1.19-2.00). Multivariate adjusted random-effects models demonstrated that the scores of participants who were severely 25(OH)D deficient declined by an additional 0.3 MMSE points per year more than those with sufficient levels of 25(OH)D. The relative risk for substantial decline on Trail-Making Test B was 1.31 (95% CI, 1.03-1.51) among those who were severely 25(OH)D deficient compared with those with sufficient levels of 25(OH)D. No significant association was observed for Trail-Making Test A. CONCLUSION: Low levels of vitamin D were associated with substantial cognitive decline in the elderly population studied over a 6-year period, which raises important new possibilities for treatment and prevention.

Treating Neuropsychiatric Symptoms in Dementia With Lewy Bodies: A Randomized Co

Culo S, Mulsant BH, Rosen J, Mazumdar S, Blakesley RE, Houck PR, Pollock BG; Alzheimer Disease & Associated Disorders (Jul 2010)

Sensitivity to psychotropic medications presents a therapeutic challenge when treating neuropsychiatric symptoms in patients with dementia with Lewy bodies (DLB). We compared under randomized, double-blinded conditions the tolerability and efficacy of citalopram and risperidone in the treatment of behavioral and psychotic symptoms in patients with DLB and Alzheimer disease (AD). Thirty-one participants with DLB and 66 with AD hospitalized for behavioral disturbance were treated under randomized, double-blind conditions with citalopram or risperidone for up to 12 weeks. Neuropsychiatric symptoms were assessed with the nursing home version of the Neuropsychiatric Inventory (NPI) and the Clinical Global Impression of Change (CGIC). Side effects were measured using the UKU Side Effect Rating Scale. A significantly higher proportion of participants with DLB (68%) than with AD (50%) discontinued the study prematurely. Discontinuation rates were comparable in DLB participants treated with citalopram (71%) or risperidone (65%). However, participants with DLB randomized to risperidone experienced a higher overall burden of side effects. Scores on the NPI and the CGIC worsened in DLB participants and improved in those with AD. Most patients with behavioral disturbances or psychosis associated with DLB tolerate citalopram or risperidone poorly and do not seem to benefit from either medication.

donepezil and apathy

Effect of donepezil on emergence of apathy in mild to moderate Alzheimer's disease; Waldemar G, Gauthier S, Jones R, Wilkinson D, Cummings J, Lopez O, Zhang R, Xu Y, Sun Y, Knox S, Richardson S, Mackell J; International Journal of Geriatric Psychiatry (Jul 2010)


OBJECTIVE: To determine whether donepezil treatment (10 mg/day over 24 weeks) is associated with delayed emergence of apathy in patients with mild to moderate Alzheimer's disease (AD) and to explore relationships between donepezil's effects on apathy and other Neuropsychiatric Inventory (NPI)-measured behavioural symptoms. METHODS: Two randomised, double-blind, parallel-group, placebo-controlled studies that met prespecified criteria and were sufficiently similar to allow data pooling were derived from all donepezil AD clinical trials. Patients scoring from 10 to 26 on baseline Mini-Mental Status Examination were included. A clinical milestone for apathy and other NPI items was defined as the first emergence of a composite score (frequency x severity)>/=3. Differences in time to event (i.e. milestone) between donepezil- and placebo-treated groups were assessed using the Kaplan-Meier method and log-rank test. Shift tables were constructed to evaluate clinical milestone status for apathy and other NPI items at baseline and endpoint, and were analysed using the Cochran-Mantel-Haenszel (CMH) test, stratified by baseline status. RESULTS: Of all NPI items, apathy had the highest proportion of subjects scoring>/=3 at baseline. Donepezil was superior to placebo on both apathy milestone analyses (time-to-event log-rank test and shift table CMH test, p = 0.01). Aberrant motor behaviour demonstrated similar benefit. CONCLUSIONS: Donepezil treatment appears to have resulted in a significant reduction over 6 months of the emergence of apathy in patients with AD. These data suggest that a prospective clinical trial in patients with early AD that includes apathy as a primary outcome measure may be warranted. Copyright (c) 2010 John Wiley&Sons, Ltd.

Cholinesterase inhibitor minutiae

1.  oral donepezil is not affected by food, unlike rivastigmine and galanthamine
2.  donepezil has 3-5 hours to peak onnset v. 0.5-1 for galanthamine and rivastigmine (oral) and 8-10 hours for rivastigmine patch
3. serum half life is 70-80 hours for oral donepezil, 5-7 hours for galantamine, 2-8 hours for oral rivastigmine, 3-4 hours for rivastigmine patch and 60-80 hours for memantine

GOVERNMENT REPORT ON RISK FACTORS FOR ALZ DISEASE

http://www.ahrq.gov/downloads/pub/evidence/pdf/alzheimers/alzcog.pdf

 

UPSHOT

GOOD:  PHYSICAL ACTIVITY, COGNITIVE ENGAGEMENT

BAD; SMOKING, E4 ALLELE, DIABETES,HYPERTENSION

 

LONG REPORT IF YOU WANT DETAILS.

Frontotemporal dementia- clinical pearls

1.  Frontotemporal dementia is a clinical term, frontolobar degeneration is a pathologic term

2.  Preservation of memory, ability to keep track of day events, timing of spouse coming to and leaving home, and lack of getting lost (intact visuospatial) are characteristic, as is young age at onset (is second most common presentation before age 65, third after).

3. FTD-bv is more common than FTD-lang presentation.  See other post for criteria.  Presentation of FTD-bv includes difficulty with modulating behaviors (disinhibition, perseveration, lack of initiative), personality change, emotional blunting and loss of insight.  Language presentation  can be a problem with expression and naming, or word meaning (semantic dementia).  Later, dementia becomes more global.  Patients have frontal lobe release signs and in some cases, evidence of MND or Parkinson's. 

4.  Web resources
www.ftd-picks.org
www.aphasia.org