Alzheimer Disease: Lane R

Staekenborg SS, van der Flier WM, van Straaten EC, Lane R, Barkhof F, Scheltens P. · Department of Neurology and Alzheimer Centre, Vrije University Medical Centre, Amsterdam, The Netherlands. · Stroke. · Pubmed #18096841 links to  free full text

Abstract: BACKGROUND AND PURPOSE: The aim of this study was to describe the prevalence of a number of neurological signs in a large population of patients with vascular dementia (VaD) and to compare the relative frequency of specific neurological signs dependent on type of cerebrovascular disease. METHODS: Seven hundred six patients with VaD (NINDS-AIREN) were included from a large multicenter clinical trial (registration number NCT00099216). At baseline neurological examination, the presence of 16 neurological signs was assessed. Based on MRI, patients were classified as having large vessel VaD (18%; large territorial or strategical infarcts on MRI), small vessel VaD (74%; white matter hyperintensities [WMH], multiple lacunes, bilateral thalamic lesions on MRI), or a combination of both (8%). RESULTS: A median number of 4.5 signs per patient was presented (maximum 16). Reflex asymmetry was the most prevalent symptom (49%), hemianopia was most seldom presented (10%). Measures of small vessel disease were associated with an increased prevalence of dysarthria, dysphagia, parkinsonian gait disorder, rigidity, and hypokinesia and as well to hemimotor dysfunction. By contrast, in the presence of a cerebral infarct, aphasia, hemianopia, hemimotor dysfunction, hemisensory dysfunction, reflex asymmetry, and hemiplegic gait disorder were more often observed. CONCLUSIONS: The specific neurological signs demonstrated by patients with VaD differ according to type of imaged cerebrovascular disease. Even in people who meet restrictive VaD criteria, small vessel disease is often seen with more subtle signs, including extrapyramidal signs, whereas large vessel disease is more often related to lateralized sensorimotor changes and aphasia.

Feldman HH, Ferris S, Winblad B, Sfikas N, Mancione L, He Y, Tekin S, Burns A, Cummings J, del Ser T, Inzitari D, Orgogozo JM, Sauer H, Scheltens P, Scarpini E, Herrmann N, Farlow M, Potkin S, Charles HC, Fox NC, Lane R. · Division of Neurology, University of British Columbia Hospital, Vancouver, Canada. · Lancet Neurol. · Pubmed #17509485 No free full text.

Abstract: OBJECTIVE: To assess the effect of rivastigmine in patients with mild cognitive impairment (MCI) on the time to clinical diagnosis of Alzheimer's disease (AD) and the rate of cognitive decline. METHODS: The study was a double-blind, randomised, placebo-controlled trial of up to 48 months. All patients had MCI operationally defined by having cognitive symptoms, a global clinical dementia rating stage of 0.5, a score of less than 9 on the New York University delayed paragraph recall test, and by not meeting the diagnostic criteria for AD. Primary efficacy variables were time to clinical diagnosis of AD, and change in performance on a cognitive test battery. This study is registered with the US National Institutes of Health clinical trials database (ClinicalTrials.gov), number NCT00000174. FINDINGS: Of 1018 study patients enrolled, 508 were randomly assigned to rivastigmine and 510 to placebo; 17.3% of patients on rivastigmine and 21.4% on placebo progressed to AD (hazard ratio 0.85 [95% CI 0.64-1.12]; p=0.225). There was no significant difference between the rivastigmine and placebo groups on the standardised Z score for the cognitive test battery measured as mean change from baseline to endpoint (-0.10 [95% CI -0.63 to 0.44], p=0.726). Serious adverse events were reported by 141 (27.9%) rivastigmine-treated patients and 155 (30.5%) patients on placebo; adverse events of all types were reported by 483 (95.6%) rivastigmine-treated patients and 472 (92.7%) placebo-treated patients. The predominant adverse events were cholinergic: the frequencies of nausea, vomiting, diarrhoea, and dizziness were two to four times higher in the rivastigmine group than in the placebo group. INTERPRETATION: There was no significant benefit of rivastigmine on the progression rate to AD or on cognitive function over 4 years. The overall rate of progression from MCI to AD in this randomised clinical trial was much lower than predicted. Rivastigmine treatment was not associated with any significant safety concerns.

Vincent S, Lane R. · Novartis Pharmaceuticals, Surrey, UK. · Int Psychogeriatr. · Pubmed #16191241 No free full text.

Abstract: Vascular dementia (VaD), like Alzheimer's disease (AD), is associated with cholinergic deficits. Rivastigmine provides sustained, brain-selective inhibition of acetylcholinesterase and butyrylcholinesterase. Preliminary data suggest that rivastigmine may provide significant benefits in patients with AD and cerebrovascular disease (mixed dementia), and in patients with VaD. Open-label rivastigmine treatment has been associated with improved cognitive and functional abilities, behavioral symptoms, and reduced caregiver stress in a small pilot study in these patients. Larger, prospective, double-blind studies of rivastigmine in patients with VaD are under way. These studies will confirm whether rivastigmine is an efficacious treatment option for a range of patients for whom, until now, there have been few symptomatic therapies.

Feldman H, Scheltens P, Scarpini E, Hermann N, Mesenbrink P, Mancione L, Tekin S, Lane R, Ferris S. · Division of Neurology, University of British Columbia, Vancouver Hospital and Health Sciences Center, Vancouver, British Columbia, Canada. · Neurology. · Pubmed #15079026 No free full text.

Abstract: The authors investigated neuropsychiatric symptoms in mild cognitive impairment (MCI) from baseline data of the Investigation in the Delay to Diagnosis of AD with Exelon (InDDEx) study (n = 1,010). Neuropsychiatric symptoms were reported in 59% of subjects (Neuropsychiatric Inventory [NPI]). NPI+ subjects had significantly greater impairment on global, cognitive, and functional scores than NPI- subjects. The presence of neuropsychiatric symptoms appears to be a marker of MCI severity.

Erkinjuntti T, Skoog I, Lane R, Andrews C. · Department of Neurology, Helsinki University Central Hospital, Hyks, Finland. · Int J Clin Pract. · Pubmed #14686563 No free full text.

Abstract: Alzheimer's disease patients with hypertension or other vascular risk factors have been shown to receive greater symptomatic benefits than patients with strictly Alzheimer's disease following short-term treatment with rivastigmine, an inhibitor of acetylcholinesterase and butyrylcholinesterase. We evaluated the long-term efficacy of rivastigmine in Alzheimer's disease patients with or without hypertension. Subjects in a 26-week placebo-controlled trial of rivastigmine entered an open-label extension study for 104 weeks. Efficacy measures included the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), Progressive Deterioration Scale (PDS) and Global Deterioration Scale (GDS). Subjects were stratified by the presence or absence of hypertension at baseline. At 104 weeks, there was a trend for hypertensive patients from the original rivastigmine 6-12 mg/day group (early starters), who received rivastigmine for the full 104 weeks) to have better ADAS-cog scores than the original placebo group (late starters), who received open-label rivastigmine for the last 78 weeks only). Significant treatment differences were observed in the hypertensive subgroup on the PDS and GDS. In non-hypertensive patients, changes from baseline at week 104 were similar in 'early' and 'late' starters of rivastigmine treatment. The additional apparent benefits on disease progression detected in patients with hypertension and Alzheimer's disease may be linked to drug effects on cerebrovascular factors. These findings may have an important influence on the way cholinesterase inhibitors are prescribed.

Erkinjuntti T, Skoog I, Lane R, Andrews C. · Department of Neurology, Helsinki University Central Hospital, Hyks, Finland. · Int J Clin Pract. · Pubmed #12510954 No free full text.

Abstract: Rivastigmine has demonstrated significant benefits in patients with mild to moderate Alzheimer's disease (AD). We aimed to confirm whether rivastigmine was effective in patients with or without concurrent vascular risk factors (VRF), as previously suggested. We chose to stratify the 725 patients involved in an international dose-ranging study according to the presence of arterial hypertension (a marker of VRF) at baseline. Efficacy in each subgroup was assessed using the ADAS-cog, a measure of cognitive performance, the Progressive Deterioration Scale (PDS) and the Clinician's Interview-Based Impression of Change (CIBIC) with caregiver input. Patients receiving rivastigmine 6-12 mg/day showed better outcomes on the ADAS-cog than those receiving placebo, in both the hypertensive and non-hypertensive subgroups. Hypertensive patients receiving rivastigmine 6-12 mg/day also showed improvement over those receiving 1-4 mg/day (p = 0.023). Rivastigmine 6-12 mg/day also provided better outcomes than placebo on the PDS in the hypertensive (p = 0.031) and non-hypertensive (p = 0.035) subgroups. All patients receiving rivastigmine 6-12 mg/day had superior CIBIC-plus scores than those receiving placebo. There was a trend for lower incidences of nausea and vomiting in rivastigmine-treated patients with hypertension than in those without hypertension. No cardiac adverse events or drug-drug interactions were reported. Our data support the hypothesis that rivastigmine provides benefits to patients with or without hypertension, and contribute to the evidence that particular benefits may be observed in those with vascular risk factors.

Nordberg A, Darreh-Shori T, Peskind E, Soininen H, Mousavi M, Eagle G, Lane R. · Karolinska Institute, Division of Alzheimer Neurobiology, Karolinska University Hospital Huddinge, Stockholm, Sweden. · Curr Alzheimer Res. · Pubmed #19199870 No free full text.

Abstract: BACKGROUND: The current study aimed to compare the effects of different cholinesterase inhibitors on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities and protein levels, in the cerebrospinal fluid (CSF) of Alzheimer disease (AD) patients. METHODS AND FINDINGS: AD patients aged 50-85 years were randomized to open-label treatment with oral rivastigmine, donepezil or galantamine for 13 weeks. AChE and BuChE activities were assayed by Ellman's colorimetric method. Protein levels were assessed by enzyme-linked immunosorbent assay (ELISA). Primary analyses were based on the Completer population (randomized patients who completed Week 13 assessments). 63 patients were randomized to treatment. Rivastigmine was associated with decreased AChE activity by 42.6% and decreased AChE protein levels by 9.3%, and decreased BuChE activity by 45.6% and decreased BuChE protein levels by 21.8%. Galantamine decreased AChE activity by 2.1% and BuChE activity by 0.5%, but increased AChE protein levels by 51.2% and BuChE protein levels by 10.5%. Donepezil increased AChE and BuChE activities by 11.8% and 2.8%, respectively. Donepezil caused a 215.2% increase in AChE and 0.4% increase in BuChE protein levels. Changes in mean AChE-Readthrough/Synaptic ratios, which might reflect underlying neurodegenerative processes, were 1.4, 0.6, and 0.4 for rivastigmine, donepezil and galantamine, respectively. CONCLUSION: The findings suggest pharmacologically-induced differences between rivastigmine, donepezil and galantamine. Rivastigmine provides sustained inhibition of AChE and BuChE, while donepezil and galantamine do not inhibit BuChE and are associated with increases in CSF AChE protein levels. The clinical implications require evaluation.

Staekenborg SS, van Straaten EC, van der Flier WM, Lane R, Barkhof F, Scheltens P. · Dept. of Neurology and Alzheimer Centre, Vrije Universiteit Medical Centre, 7057, 1007 MB Amsterdam, The Netherlands. · J Neurol. · Pubmed #18677637 No free full text.

Abstract: OBJECTIVE: The aim of this study was a cross-sectional comparison of clinical and MRI characteristics and risk factor profiles between patients with small vessel disease (lacunae and white matter hyperintensities) and large vessel disease (large territorial or strategical infarcts) in a large cohort of VaD patients. METHODS: Patients with VaD (NINDS-AIREN) were included in a large multicenter treatment trial (the VantagE study). All patients were examined by a neurologist and interviewed about their medical history. Based on MRI, patients were classified as having large vessel VaD, small vessel VaD, or a combination. Other MRI characteristics included white matter hyperintensities (WMH), medial temporal lobe atrophy (MTA) and general cortical atrophy. RESULTS: Of the 706 patients, 522 (74 %) had small vessel disease, 126 (18 %) had large vessel disease and 58 (8 %) had both. Patients with small vessel disease were older and less educated, and showed more cortical and medial temporal lobe atrophy than patients with large vessel disease. The most prevalent vascular risk factors (hypertension, diabetes and smoking) were equally distributed between the different types of VaD. However, patients with large vessel disease had more hypercholesterolemia and cardiac risk factors compared to patients with small vessel disease. CONCLUSION: Cerebrovascular disease underlying VaD consists in the majority of small vessel disease and in about one fifth of large vessel disease. This study demonstrates heterogeneity between these two groups with regard to risk factor profile and atrophy scores on MRI.

Ballard C, Sauter M, Scheltens P, He Y, Barkhof F, van Straaten EC, van der Flier WM, Hsu C, Wu S, Lane R. · Wolfson Centre for Age-Related Diseases, King's College, London, UK. · Curr Med Res Opin. · Pubmed #18674411 No free full text.

Abstract: OBJECTIVE: The aim was to evaluate the efficacy, safety and tolerability of rivastigmine capsules in patients diagnosed with probable vascular dementia (VaD). METHODS: VantagE (Vascular Dementia trial studying Exelon) was a 24-week, multicentre, double-blind study. VaD patients aged 50-85 years were randomized to rivastigmine capsules (3-12 mg/day) or placebo. Efficacy assessments included global and cognitive performances, activities of daily living and neuropsychiatric symptoms. Adverse events were recorded. Additional exploratory analyses determined whether heterogeneity in pathologies and symptoms extended to differential treatment effects. TRIAL REGISTRATION: NCT00099216. RESULTS: 710 patients were randomized. Rivastigmine demonstrated superiority over placebo on three measures of cognitive performance (Vascular Dementia Assessment Scale, Alzheimer's Disease Assessment Scale cognitive subscale, Mini-Mental State Examination; all p< or = 0.05, intent-to-treat population [ITT]), but not other outcomes. Predominant adverse events were nausea and vomiting. Exploratory analyses indicated that older patients (> or =75 years old), assumed more likely to also have Alzheimer's disease (AD) pathology, demonstrated significant cognitive responses to rivastigmine and a safety profile similar to that seen in AD patients. Younger patients, assumed less likely to have concomitant AD pathology, showed no efficacy response and were associated with slight elevations of blood pressure, cerebrovascular accidents and mortality. Rivastigmine-placebo differences in patients with, versus those without, medial temporal atrophy (also suggestive of concomitant AD) showed a numerical difference similar to that seen between the older versus younger patients, but did not attain statistical significance. CONCLUSION: Consistent with trials evaluating other cholinesterase inhibitors, rivastigmine did not provide consistent efficacy in probable VaD. The efficacy apparent on cognitive outcomes was derived from effects in older patients likely to have concomitant Alzheimer pathology. This is supportive of an existing argument that the putative cholinergic deficit in VaD reflects the presence of concomitant Alzheimer pathology.

Ivinson AJ, Lane R, May PC, Hosford DA, Carrillo MC, Siemers ER. · Harvard NeuroDiscovery Center, Harvard Medical School, Boston, MA, USA. · Alzheimers Dement. · Pubmed #18631952 No free full text.

Abstract: Drug discovery has traditionally been almost exclusively the purview of pharmaceutical and biotechnology companies, whereas universities have focused on basic research. However, given the challenges involved in discovering and developing truly effective, symptomatic treatments and disease-modifying drugs for Alzheimer's disease, there is a need to reassess this simple division of labor. Whereas each sector is likely to retain a core interest and expertise at either end of the drug discovery spectrum, there is room for closer cooperation at the intersection of the for-profit and not-for-profit sectors. The Alzheimer's Association Research Roundtable convened a meeting of senior industry researchers and academic investigators to discuss this intersection and to assess the opportunity for closer partnership on Alzheimer's disease drug discovery and development.

Lane R, Feldman HH, Meyer J, He Y, Ferris SH, Nordberg A, Darreh-Shori T, Soininen H, Pirttilä T, Farlow MR, Sfikas N, Ballard C, Greig NH. · Novartis Pharmaceuticals Corporation, East Hanover, New Jersey 07936-1080, USA. · Pharmacogenet Genomics. · Pubmed #18334913 No free full text.

Abstract: OBJECTIVE: To evaluate the synergistic effects of the apolipoprotein E (APOE) epsilon4 and butyrylcholinesterase K-variant (BCHE-K) alleles on progression to Alzheimer's disease (AD) in individuals with mild cognitive impairment (MCI). METHODS: This was a post-hoc exploratory analysis from a 3-4-year, randomized, placebo-controlled study of rivastigmine in participants with MCI (InDDEx study). Participants who consented to genetic testing were included in the current analyses. The incidence of progression to AD, cognitive decline and changes in MRI brain volumes were investigated in participants from the placebo arm of the InDDEx study. RESULTS: Of the 1018 participants in the overall study, 464 were successfully genotyped for both APOE and butyrylcholinesterase. Of these, 68 (14.7%) carried > or =1 APOE epsilon4 and > or =1 BCHE-K allele. The presence of APOE epsilon4 was associated with a significantly higher incidence of progression to AD whereas the presence of BCHE-K had no independent effect on progression. A synergistic effect of the combined presence of APOE epsilon4 and BCHE-K on the time to clinical diagnosis of AD and on MRI brain volumes was seen. Progression to AD and hippocampal volumetric loss was greatest in participants who carried both APOE epsilon4 and BCHE-K alleles and lowest in BCHE-K carriers without the APOE epsilon4 allele. CONCLUSION: In MCI, the risk of cognitive decline, hippocampal volumetric loss and progression to AD seems to be the greatest in individuals who carry at least one copy of both the BCHE-K and APOE epsilon4 alleles.

Blesa R, Ballard C, Orgogozo JM, Lane R, Thomas SK. · Hospital de la Sta Creu i Sant Pau, Barcelona, Spain. · Neurology. · Pubmed #17646620 No free full text.

Abstract: Alzheimer disease (AD) has a significant impact on caregivers. Administering and managing medications is one of their many daily tasks. More effective modes of drug administration may benefit patient and caregiver, and may improve compliance. A prospective outcome of the IDEAL (Investigation of TransDermal Exelon in ALzheimer's disease) trial was to evaluate caregiver preference for rivastigmine patches compared with capsules. The 24-week, randomized, double-blind, double-dummy, placebo- and active-controlled IDEAL trial investigated once-daily rivastigmine patches vs twice-daily capsules in moderate AD patients. Caregivers rated patch adhesion throughout. The AD Caregiver Preference Questionnaire (ADCPQ) assessed patch vs capsule from caregivers' perspective, based on expectations, preferences, and satisfaction with treatment. A total of 1,059 caregivers completed the ADCPQ while their respective patients were on study drug. More than 70% of caregivers preferred the patch to capsules overall. The patch was preferred to capsules with respect to ease of use (p < 0.0001) and ease of following the schedule (p < 0.0001). Caregivers indicated greater satisfaction overall (p < 0.0001) and less interference with daily life (p < 0.01) with the patch vs capsules. The preference substudy of the IDEAL trial demonstrated that caregivers of AD patients preferred patches to capsules for drug delivery. Preference for the patch may indicate reduced caregiver stress, substantiated by greater satisfaction and less interference with daily life. These benefits may lead to improved compliance.

Winblad B, Grossberg G, Frölich L, Farlow M, Zechner S, Nagel J, Lane R. · Karolinska Institutet Alzheimer Research Center, Stockholm, Sweden. · Neurology. · Pubmed #17646619 No free full text.

Abstract: The rivastigmine patch is the first transdermal treatment for Alzheimer disease (AD). By providing continuous delivery of drug into the bloodstream over 24 hours, transdermal delivery may offer benefits superior to those of oral administration. This study compared the efficacy, safety and tolerability of rivastigmine patches with capsules and placebo. IDEAL (Investigation of transDermal Exelon in ALzheimer's disease) was a 24-week, double-blind, double-dummy, placebo- and active-controlled study. Patients with AD were randomized to placebo or one of three active treatment target dose groups: 10-cm(2) rivastigmine patch (delivering 9.5 mg/24 hours); 20-cm(2) rivastigmine patch (17.4 mg/24 hours); or 6-mg BID rivastigmine capsules. Primary efficacy measures were the Alzheimer's Disease Assessment Scale-Cognitive subscale and Alzheimer's Disease Cooperative Study-Clinical Global Impression of Change. Secondary outcome measures assessed a range of domains, including behavior, cognitive performance, attention, executive functions, and activities of daily living. A total of 1,195 AD patients participated. All rivastigmine treatment groups showed significant improvement relative to placebo. The 10-cm(2) patch showed similar efficacy to capsules, with approximately two-thirds fewer reports of nausea (7.2% vs 23.1%) and vomiting (6.2% vs 17.0%), incidences statistically not significantly different from placebo (5.0% and 3.3% for nausea and vomiting, respectively). The 20-cm(2) patch showed earlier improvement and numerically superior cognitive scores vs the 10-cm(2) patch with similar tolerability to capsules. Local skin tolerability was good. The transdermal patch with rivastigmine may offer additional therapeutic benefits and may prove to be the best delivery system for this drug to treat AD.

Winblad B, Kawata AK, Beusterien KM, Thomas SK, Wimo A, Lane R, Fillit H, Blesa R. · Karolinska Institutet Alzheimer Research Center, Huddinge, Sweden. · Int J Geriatr Psychiatry. · Pubmed #17407176 No free full text.

Abstract: BACKGROUND: Family caregivers comprise a critical component in the care of Alzheimer's disease (AD) patients. Among their many tasks, caregivers are responsible for administering and managing medications. Effective interventions incorporate the needs of both the AD patient and the caregiver, and understanding treatment preferences may maximize intervention effectiveness. Transdermal patches may offer advantages over conventional oral formulations. METHODS: A 24-week randomized controlled trial compared the rivastigmine patch to the rivastigmine capsule and placebo in patients with probable AD. At baseline and Weeks 8 and 24, the AD Caregiver Preference Questionnaire (ADCPQ) was used to evaluate caregiver expectations, preferences and satisfaction with treatment. Double-dummy treatment blinding ensured that caregiver preference for the patch or capsule was not confounded by perceptions of efficacy or tolerability. Reasons for preference were also elicited. The analytic sample included caregivers who completed the ADCPQ at Weeks 8 and/or 24. RESULTS: One thousand and fifty-nine caregivers completed the ADCPQ. More than 70% of caregivers preferred the rivastigmine patch to the capsule. The patch was significantly preferred to the capsule with respect to ease of following the schedule and ease of use. Caregivers indicated greater satisfaction overall, greater satisfaction with administration, and less interference with daily life with the patch versus the capsule (all p<or=0.01). CONCLUSION: Caregivers of AD patients preferred the patch to the capsule for drug delivery. Preference for the rivastigmine patch could potentially lead to improved compliance and improved clinical benefits.

Winblad B, Cummings J, Andreasen N, Grossberg G, Onofrj M, Sadowsky C, Zechner S, Nagel J, Lane R. · Karolinska Institutet Alzheimer Research Center, Stockholm, Sweden. · Int J Geriatr Psychiatry. · Pubmed #17380489 No free full text.

Abstract: OBJECTIVES: To compare the efficacy, safety and tolerability of a novel rivastigmine transdermal patch with conventional rivastigmine capsules and placebo in patients with Alzheimer's disease (AD). METHODS: In this 24-week, multicenter, double-blind, double-dummy, placebo- and active-controlled trial, patients with probable AD were randomized to one of four treatment groups: 12 mg/day rivastigmine capsules; 10 cm2 (9.5 mg/24 h) rivastigmine patch; 20 cm(2) (17.4 mg/24 h) rivastigmine patch; or placebo. Primary efficacy measures were the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog) and Alzheimer's Disease Cooperative Study--Clinical Global Impression of Change (ADCS-CGIC). RESULTS: One thousand one hundred and ninety five AD patients from 21 countries participated in the study. Treatment differences (vs placebo) on the ADAS-Cog at Week 24 in 10 cm2 patch, 20 cm2 patch and capsule groups were 1.6 (p=0.005), 2.6 (p<0.001) and 1.6 (p=0.003). Treatment differences on the ADCS-CGIC were 0.3 (p=0.01), 0.2 (p=0.054) and 0.3 (p=0.009). Comparison between the 10 cm2 patch and the capsule revealed non-inferiority. Rates of nausea in the 10 cm2 patch and capsule groups were 7.2% and 23.1%, respectively; rates of vomiting were 6.2% and 17.0%, respectively. Moderate or severe skin irritation occurred in<or=10% patients across the four patch sizes (5, 10, 15 and 20 cm2). CONCLUSIONS: The target dose of 10 cm2 rivastigmine patch provides efficacy similar to the highest doses of capsules with a superior tolerability profile. The transdermal patch with rivastigmine may offer convenience important to many caregivers and patients.

Feldman HH, Lane R, Anonymous00147. · Division of Neurology, University of British Columbia, Clinic for Alzheimer's Disease and Related Disorders, Vancouver, British Columbia, Canada. · J Neurol Neurosurg Psychiatry. · Pubmed #17353259 No free full text.

Abstract: OBJECTIVE: To evaluate the efficacy and safety of rapidly titrated rivastigmine administered twice (BID) or three times (TID) daily in patients with mild to moderate Alzheimer's disease (AD). METHODS: This was a 26 week international, randomised, double blind, placebo controlled study in which 678 patients with probable AD received placebo or rivastigmine 2-12 mg/day BID or TID. Primary outcome measures included the cognitive subscale of the AD Assessment Scale (ADAS-cog) and categorical analysis of the Clinician Interview Based Impression of Change incorporating caregiver information (CIBIC-Plus). Secondary outcomes were the CIBIC-Plus change from baseline, Progressive Deterioration Scale, ADAS-cogA, Mini-Mental State Examination and Global Deterioration Scale. RESULTS: At week 26, mean rivastigmine dose was 9.6 (2.76) mg/day in the TID group and 8.9 (2.93) mg/day in the BID group. Mean ADAS-cog changes from baseline in the TID and BID rivastigmine treated groups were -0.2 (SD 7.3) and 1.2 (SD 7.2) versus 2.8 (SD 7.2) for the placebo group (p<0.05). Differences between rivastigmine TID and placebo on the CIBIC-Plus categorical responder analysis were significant (31% vs 19%; p<0.05, intention to treat). No significant differences were seen between BID and placebo for this outcome measure. Adverse events were predominantly gastrointestinal, occurring mainly during dose titration. Withdrawal because of adverse events accounted for 17% of BID, 11% of TID and 9% of placebo patients. CONCLUSIONS: Rivastigmine administered as a BID or TID regimen significantly benefited cognitive, function and global performances in AD patients. The TID regimen showed a tendency for superior tolerability and permitted titration to higher doses, an outcome that is significant as the efficacy of rivastigmine is dose related.

Bronnick K, Emre M, Lane R, Tekin S, Aarsland D. · Norwegian Centre for Movement Disorders, Stavanger University Hospital, Helse Stavanger, Norway. · J Neurol Neurosurg Psychiatry. · Pubmed #17287236 No free full text.

Abstract: OBJECTIVE: To compare the profile of cognitive impairment in Alzheimer's disease (AD) with dementia associated with Parkinson's disease (PDD). METHODS: Neuropsychological assessment was performed in 488 patients with PDD and 488 patients with AD using the Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog). Logistic regression analysis was used to investigate whether the diagnosis could be accurately predicted from the cognitive profile. Additionally, the cognitive profiles were compared with a normative group using standardised effect sizes (Cohen's d). RESULTS: Diagnosis was predicted from the cognitive profile, with an overall accuracy of 74.7%. Poor performance of the AD patients on the orientation test in ADAS-cog best discriminated between the groups, followed by poor performance of the PDD patients on the attentional task in MMSE. Both groups showed memory impairment, AD patients performing worse than PDD patients. CONCLUSION: The cognitive profile in PDD differs significantly from that in AD. Performance on tests of orientation and attention are best in differentiating the groups.

Blesa R, Bullock R, He Y, Bergman H, Gambina G, Meyer J, Rapatz G, Nagel J, Lane R. · Hospital Sta Creu i Sant Pau, Barcelona, Spain. · Pharmacogenet Genomics. · Pubmed #17047484 No free full text.

Abstract: A randomized double-blind trial evaluated the efficacy and tolerability of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and donepezil, an AChE-selective inhibitor, in patients with Alzheimer's disease over a 2-year period. A retrospective analysis showed differential responses to cholinesterase inhibitors (ChE-Is) in patients younger than 75 years. This analysis investigated the effect of BuChE genotype on response to ChE-I therapy in these patients. In a retrospective analysis, patients younger than 75 who had consented to pharmacogenetic analysis were divided into groups according to BuChE genotype. Efficacy measures were the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI), Global Deterioration Scale (GDS), Mini-Mental State Examination (MMSE) and the Alzheimer's Disease Cooperative Study-Activities of Daily Living Scale (ADCS-ADL). Changes on efficacy parameters were calculated for rivastigmine-treated and donepezil-treated patients in both groups. Of 114 (34.1%) patients younger than 75 who were successfully assessed for BuChE genotype, 76 (66.7%) were homozygous for wild-type BuChE, and 38 (33.3%) carried at least one BuChE K-variant allele. Wild-type BuChE carriers showed significantly greater responses to rivastigmine than to donepezil on the SIB, ADCS-ADL, GDS and NPI. No significant between-treatment differences in efficacy were observed in BuChE K-variant carriers, although adverse events were more frequent in rivastigmine-treated patients. In this retrospective analysis, Alzheimer's disease patients younger than 75 with wild-type BuChE exhibited differential efficacy to rivastigmine, while BuChE K-variant carriers experienced similar long-term treatment effects with both agents. These differences may reflect rivastigmine's ability to inhibit BuChE and AChE.

Bullock R, Bergman H, Touchon J, Gambina G, He Y, Nagel J, Lane R. · Kingshill Research Centre, Swindon, UK. · Curr Med Res Opin. · Pubmed #16574032 No free full text.

Abstract: BACKGROUND: Younger Alzheimer's disease (AD) patients appear to differ genetically and neuropathologically from older AD patients, and may experience a more aggressive disease course compared with older patients. A randomised trial investigated the efficacy and tolerability of rivastigmine, an inhibitor of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), and donepezil, an AChE-selective inhibitor, in patients with AD over a 2-year period. This retrospective analysis investigated whether younger and older patients showed differential tolerability and efficacy responses to cholinesterase inhibitor treatment. METHODS: For the current analysis, patients were divided according to age at baseline: those aged < 75 years and those aged >or= 75 years. Efficacy measures were the Severe Impairment Battery (SIB), Neuropsychiatric Inventory (NPI), Global Deterioration Scale (GDS), Mini-Mental State Examination (MMSE) and the AD Cooperative Study Activities of Daily Living scale (ADCS-ADL). Changes in efficacy parameters and adverse event frequencies were calculated for rivastigmine and donepezil-treated patients in both age groups. Exploratory analyses were also conducted on SIB, ADCS-ADL and NPI in patients who consented to pharmacogenetic testing at baseline. Genotyping of the apolipoprotein E (APOE) epsilon4 allele and the BuChE K-variant was conducted using the TaqMan assay. Main efficacy analyses were based on an intent-to-treat last observation carried forward (ITT-LOCF) population. RESULTS: Of the 994 patients who received the study drug, 362 (36.4%) were younger than 75 years and 632 (63.6%) were aged 75 years or over. Rivastigmine provided significant benefits in younger patients compared with donepezil on the NPI-10, NPI-12, NPI-D, GDS and ADCS-ADL (all p < 0.05, ITT-LOCF). With the exception of the NPI-D in favour of donepezil (p < 0.05, ITT-LOCF), no significant treatment differences were observed in older patients. Younger patients with two wild-type BuChE alleles had a significantly greater response to rivastigmine than donepezil on the ADCS-ADL (p < 0.01, ITT-LOCF) and SIB (p < 0.05, ITT-LOCF). The most common adverse events were nausea and vomiting and these were more frequent in rivastigmine-treated patients. CONCLUSION: In this sub group analysis, patients younger than 75 years of age showed greater treatment responses to rivastigmine than donepezil. Analysis of response by BuChE genotype suggests that this differential effect may be due to the inhibition of BuChE, in addition to AChE, by rivastigmine.

Touchon J, Bergman H, Bullock R, Rapatz G, Nagel J, Lane R. · CHU, INSERM 361, Montpellier, France. · Curr Med Res Opin. · Pubmed #16393430 No free full text.

Abstract: BACKGROUND: A double-blind randomized trial evaluated the efficacy and tolerability of rivastigmine and donepezil in patients with Alzheimer's disease (AD) over 2 years. Baseline data indicated that some patients had symptoms suggestive of concomitant Lewy body disease. This retrospective analysis investigated whether AD patients with and without symptoms suggesting concomitant Lewy body pathology demonstrated different responses to therapy. METHODS: AD patients were divided by the presence/absence of symptoms suggestive of concomitant Lewy body disease. These were identified by a concomitant diagnosis of dementia with Lewy bodies and/or use of anti-parkinsonian medication at baseline. Baseline characteristics, demographics, changes on efficacy parameters and adverse event (AE) frequencies were calculated for rivastigmine- and donepezil-treated patients. Efficacy parameters were the Severe Impairment Battery (SIB), Mini-Mental State Examination (MMSE), Global Deterioration Scale (GDS), Neuropsychiatric Inventory (NPI) and AD Cooperative Study Activities of Daily Living scale (ADCS-ADL). Main efficacy analyses were based on an intent-to-treat last observation carried forward (ITT-LOCF) population. RESULTS: Both populations reached mean doses of rivastigmine and donepezil that were within therapeutic ranges. Nine hundred and ninety-four AD patients received study drug, of whom 49 (4.9%) had symptoms suggestive of concomitant Lewy body disease (25 rivastigmine, 24 donepezil). In this subpopulation, changes from baseline after 2 years of treatment with rivastigmine were significantly better than those seen with donepezil on the SIB, MMSE and ADCS-ADL (ANCOVA or Wilcoxon analyses, p < 0.05, ITT-LOCF). Statistical significance was not maintained in non-ITT-LOCF analyses, except for EP analyses on the SIB and ADCS-ADL (both p < 0.05). Rivastigmine also provided significantly better functioning than donepezil in patients without Lewy body pathology, as shown by a significant treatment difference at endpoint on the ADCS-ADL (p < 0.05, ITT-LOCF; not maintained in non-ITT-LOCF analyses). NPI changes from baseline did not differ significantly between treatment groups. AD patients with symptoms suggestive of concomitant Lewy body disease receiving rivastigmine or donepezil experienced fewer gastrointestinal side effects, leading to fewer discontinuations due to AEs, compared with patients without Lewy body pathology. CONCLUSION: In this retrospective analysis, AD patients who had symptoms suggestive of concomitant Lewy body disease appeared to show greater treatment responses to rivastigmine than to donepezil, and experienced fewer adverse events under either drug, compared with patients without Lewy body pathology.

Bullock R, Touchon J, Bergman H, Gambina G, He Y, Rapatz G, Nagel J, Lane R. · Kingshill Research Centre, Victoria Hospital, Swindon, UK. · Curr Med Res Opin. · Pubmed #16083542 No free full text.

Abstract: OBJECTIVES: Randomised controlled trials that directly compare cholinesterase inhibitors for the treatment of Alzheimer's disease have been characterised by significant methodological limitations. As a consequence, they have failed to establish whether there are differences between agents in this class. To help address this question, a double-blind, randomised, controlled, multicentre trial was designed to evaluate the efficacy and tolerability of cholinesterase inhibitor treatment in patients with moderate to moderately-severe Alzheimer's disease over a 2-year period. METHODS: Patients were randomly assigned to rivastigmine 3-12 mg/day or donepezil 5-10 mg/day. Efficacy measures comprised assessments of cognition, activities of daily living, global functioning and behavioural symptoms. Safety and tolerability assessments included adverse events and measurement of vital signs. RESULTS: In total, 994 patients received cholinesterase inhibitor treatment (rivastigmine, n = 495; donepezil, n = 499), and 57.9% of patients completed the study. The most frequent reason for premature discontinuation in both treatment groups was adverse events, primarily gastrointestinal. Adverse events were more frequent in the rivastigmine group during the titration phase, but similar in the maintenance phase. Serious adverse events were reported by 31.7% of rivastigmine- and 32.5% of donepezil-treated patients, respectively. Rivastigmine and donepezil had similar effects on measures of cognition and behaviour, but rivastigmine showed a statistically significant advantage on measures of activities of daily living and global functioning in the ITT-LOCF population. However, this was not maintained in the non-ITT-LOCF populations. In secondary subgroup analyses, AD patients who had genotypes that encoded for full expression of the butyrylcholinesterase enzyme (BuChE wt/wt; n = 226/340), who were < 75 years of age (n = 362/994) or who had symptoms suggestive of concomitant Lewy body disease (n = 49/994) showed significantly greater benefits from rivastigmine treatment. CONCLUSIONS: Cholinesterase inhibitor treatment may offer continued therapeutic benefit for up to 2 years in patients with moderate AD. Although both drugs performed similarly on cognition and behaviour, rivastigmine may provide greater benefit in activities of daily living and global functioning.

Farlow MR, He Y, Tekin S, Xu J, Lane R, Charles HC. · Department of Neurology, Indiana University School of Medicine, Clinical Building, Room 299, 541 Clinical Drive, Indianapolis, IN 46202-5111, USA. · Neurology. · Pubmed #15557508 No free full text.

Abstract: OBJECTIVE: The authors aimed to use baseline data of an ongoing large, prospective study in subjects with mild cognitive impairment (MCI) to investigate the impact of APOE genotype on the symptom profile of the condition. METHODS: Cognitive assessments included the AD Assessment Scale cognitive subscale (ADAS-cog), the Mini-Mental State Examination (MMSE), and a cognitive battery for assessment of memory, attention, and executive function. Behavioral assessments included the Neuropsychiatric Inventory and Beck Depression Inventory. Activities of daily living were assessed by the AD Cooperative Study Activities of Daily Living (ADCS-ADL) scale. Hippocampal volumes were measured with MRI. RESULTS: A total of 494 of 1,018 study subjects provided APOE data. Approximately 40% of the subjects were APOE epsilon4 carriers. APOE epsilon4 carriers had lower MMSE (p = 0.01) and higher ADAS-cog (p < 0.0001) scores than noncarriers, indicating worse cognitive impairment. APOE epsilon4 carriers also had greater deficits on New York University delayed paragraph recall and Buschke free and cued selective reminding tests, and on the ADCS-ADL scale (p < 0.001). They also had smaller hippocampal volumes (p = 0.002). Behavioral scores were similar across the subgroups. CONCLUSION: MCI subjects carrying the APOE epsilon4 allele showed distinct cognitive and imaging profiles, which appeared to resemble those of early Alzheimer patients. APOE epsilon4 genotype was associated with greater impairments in memory and functional activities as well as hippocampal atrophy.

Farlow M, Lane R, Kudaravalli S, He Y. · Department of Neurology, Indiana University School of Medicine, Indianapolis, IN, USA. · Pharmacogenomics J. · Pubmed #15289797 No free full text.

Abstract: This retrospective analysis of two double-blind, placebo-controlled studies in patients with mild to moderately severe AD investigated the efficacy of rivastigmine 6-12 mg/day on cognitive outcomes in patients with or without the apolipoprotein (APOE) epsilon4 allele. APOE data were collected from patients who consented to pharmacogenetic testing. Treatment differences within each subgroup were compared, using the Observed Case (OC) population. The APOE epsilon4 and non-APOE epsilon4 subgroups comprised 246 and 121 patients, respectively. Overall, APOE epsilon4 noncarriers showed greater decline than carriers (P<0.05). However, at 26 weeks, placebo-treated APOE epsilon4 patients declined 3.04 points below baseline on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), and rivastigmine-treated patients improved by 1.67 points. Non-APOE epsilon4 placebo-treated patients declined by 4.59 points and rivastigmine-treated patients declined by 0.48 points. Thus, non-APOE epsilon4 carriers showed a less favorable course under either placebo or rivastigmine, but both genotype-defined subgroups showed quantitatively similar responses to therapy (both P<0.05 vs placebo).