Keith Wesnes

Efficacy of rivastigmine in dementia with Lewy bodies: a randomised, double-blind, placebo-controlled international study

BACKGROUND Dementia with Lewy bodies is a common form of dementia in the elderly, characterised clinically by fluctuating cognitive impairment, attention deficits, visual hallucinations, parkinsonism, and other neuropsychiatric features. Neuroleptic medication can provoke severe sensitivity reactions in patients with dementia of this type. Many deficits in cholinergic neurotransmission are seen in the brain of patients with Lewy-body dementia; therefore, drugs enhancing central cholinergic function represent a rationally-based therapeutic approach to this disorder. Rivastigmine, a cholinesterase inhibitor, was tested in a group of clinically characterised patients with Lewy-body dementia. METHODS A placebo-controlled, double-blind, multicentre study was done in 120 patients with Lewy-body dementia from the UK, Spain, and Italy. Individuals were given up to 12 mg rivastigmine daily or placebo for 20 weeks, followed by 3 weeks rest. Assessment by means of the neuropsychiatric inventory was made at baseline, and again at weeks 12, 20, and 23. A computerised cognitive assessment system and neuropsychological tests were also used, and patients underwent close medical and laboratory safety analysis. FINDINGS Patients taking rivastigmine were significantly less apathetic and anxious, and had fewer delusions and hallucinations while on treatment than controls. Almost twice as many patients on rivastigmine (37, 63%), than on placebo (18, 30%), showed at least a 30% improvement from baseline. In the computerised cognitive assessment system and the neuropsychological tests, patients were significantly faster and better than those on placebo, particularly on tasks with a substantial attentional component. Both predefined primary efficacy measures differed significantly between rivastigmine and placebo. After drug discontinuation differences between rivastigmine and placebo tended to disappear. Known adverse events of cholinesterase inhibitors (nausea, vomiting, anorexia) were seen more frequently with rivastigmine than with placebo, but safety and tolerability of the drug in these mostly multimorbid patients were judged acceptable. INTERPRETATION Rivastigmine 6-12 mg daily produces statistically and clinically significant behavioural effects in patients with Lewy-body dementia, and seems safe and well tolerated if titrated individually.

AROMAS OF ROSEMARY AND LAVENDER ESSENTIAL OILS DIFFERENTIALLY AFFECT COGNITION AND MOOD IN HEALTHY ADULTS

This study was designed to assess the olfactory impact of the essential oils of lavender (Lavandula angustifolia) and rosemary (Rosmarlnus officinalis) on cognitive performance and mood in healthy volunteers. One hundred and forty-four participants were randomly assigned to one of three independent groups, and subsequently performed the Cognitive Drug Research (CDR) computerized cognitive assessment battery in a cubicle containing either one of the two odors or no odor (control). Visual analogue mood questionnaires were completed prior to exposure to the odor, and subsequently after completion of the test battery. The participants were deceived as to the genuine aim of the study until the completion of testing to prevent expectancy effects from possibly influencing the data. The outcome variables from the nine tasks that constitute the CDR core battery feed into six factors that represent different aspects of cognitive functioning. Analysis of performance revealed that lavender produced a significant decrement in performance of working memory, and impaired reaction times for both memory and attention based tasks compared to controls. In contrast, rosemary produced a significant enhancement of performance for overall quality of memory and secondary memory factors, but also produced an impairment of speed of memory compared to controls. With regard to mood, comparisons of the change in ratings from baseline to post-test revealed that following the completion of the cognitive assessment battery, both the control and lavender groups were significantly less alert than the rosemary condition; however, the control group was significantly less content than both rosemary and lavender conditions. These findings indicate that the olfactory properties of these essential oils can produce objective effects on cognitive performance, as well as subjective effects on mood.

Visual perception in Parkinson disease dementia and dementia with Lewy bodies.

Objective: To quantify visual discrimination, space-motion, and object-form perception in patients with Parkinson disease dementia (PDD), dementia with Lewy bodies (DLB), and Alzheimer disease (AD). Methods: The authors used a cross-sectional study to compare three demented groups matched for overall dementia severity (PDD: n = 24; DLB: n = 20; AD: n = 23) and two age-, sex-, and education-matched control groups (PD: n = 24, normal controls [NC]: n = 25). Results: Visual perception was globally more impaired in PDD than in nondemented controls (NC, PD), but was not different from DLB. Compared to AD, PDD patients tended to perform worse in all perceptual scores. Visual perception of patients with PDD/DLB and visual hallucinations was significantly worse than in patients without hallucinations. Conclusions: Parkinson disease dementia (PDD) is associated with profound visuoperceptual impairments similar to dementia with Lewy bodies (DLB) but different from Alzheimer disease. These findings are consistent with previous neuroimaging studies reporting hypoactivity in cortical areas involved in visual processing in PDD and DLB.

Safety, Pharmacokinetics, and Effects on Cognitive Function of Multiple Doses of GTS-21 in Healthy, Male Volunteers *

This study was designed to determine the safety, tolerability, pharmacokinetics and effects on cognitive function of GTS-21 in healthy, male volunteers. A total of 18 subjects were randomized to GTS-21 (25, 75 and 150 mg) or placebo administered three times daily (first 4 days, once on Day 5) for three, 5-day sessions. GTS-21 was well tolerated up to doses of 450 mg/day, with no clinically significant safety findings. Cmax and the area under the plasma concentration of GTS-21 and the metabolite 4-OH-GTS-21 increased in a dose-related fashion; although considerable intersubject variability occurred, it decreased with continued dosing. GTS-21 showed statistically significant enhancement of three measures of cognitive function (attention, working memory, episodic secondary memory) compared to placebo. A relationship between exposure to GTS-21 and the magnitude of the cognitive response was apparent, with maximal effect approached for doses between 75 and 150 mg three times a day. These data indicate that GTS-21 may represent a novel treatment for dementia.

Breakfast reduces declines in attention and memory over the morning in schoolchildren

Twenty-nine schoolchildren were tested throughout the morning on 4 successive days, having a different breakfast each day (either of the cereals Cheerios or Shreddies, glucose drink or No breakfast). A series of computerised tests of attention, working memory and episodic secondary memory was conducted prior to breakfast and again 30, 90, 150 and 210 min later. The glucose drink and No breakfast conditions were followed by declines in attention and memory, but the declines were significantly reduced in the two cereal conditions. This study provides objective evidence that a typical breakfast of cereal rich in complex carbohydrates can help maintain mental performance over the morning.

Effects of rivastigmine on cognitive function in dementia with lewy bodies: a randomised placebo-controlled international study using the cognitive drug research computerised assessment system.

This study was designed to assess the effects of rivastigmine (Exelon®) on the cognitive functioning of patients suffering from dementia with Lewy bodies. This was a prospective, multi-centre, randomised, double-blind, placebo-controlled exploratory study conducted at sites in the UK, Spain and Italy. The treatment period was 20 weeks with a 3-week posttreatment follow-up. The primary outcome measures were the Cognitive Drug Research (CDR) computerised assessment system and the Neuropsychiatric Inventory. Testing was conducted prior to dosing and then again at weeks 12, 20 and 23. Analysis of the data from the 92 patients who completed the study identified a significant pattern of benefits of rivastigmine over placebo on the CDR system. These benefits were seen on tests of attention, working memory and episodic secondary memory. Taking attention for example, patients given placebo showed a significant deterioration from predosing scores at 12 and 20 weeks, whereas patients on rivastigmine performed significantly above their predosing levels. These effects were also large in magnitude, the decline under placebo at week 12 being 19%, while the improvement under rivastigmine was 23%. The clinical relevance of this 23% improvement was that it took the patients 33% towards being normal for their age on this assessment of attention. These benefits to cognitive function were accompanied by a significant improvement of the other primary outcome measure, the Neuropsychiatric Inventory. Three weeks after discontinuation of rivastigmine, most parameters of cognitive performance returned to predrug levels.

Characterizing mild cognitive impairment in incident Parkinson disease: The ICICLE-PD Study

Objective: To describe the frequency of mild cognitive impairment (MCI) in Parkinson disease (PD) in a cohort of newly diagnosed incident PD cases and the associations with a panel of biomarkers. Methods: Between June 2009 and December 2011, 219 subjects with PD and 99 age-matched controls participated in clinical and neuropsychological assessments as part of a longitudinal observational study. Consenting individuals underwent structural MRI, lumbar puncture, and genotyping for common variants of COMT, MAPT, SNCA, BuChE, EGF, and APOE. PD-MCI was defined with reference to the new Movement Disorder Society criteria. Results: The frequency of PD-MCI was 42.5% using level 2 criteria at 1.5 SDs below normative values. Memory impairment was the most common domain affected, with 15.1% impaired at 1.5 SDs. Depression scores were significantly higher in those with PD-MCI than the cognitively normal PD group. A significant correlation was found between visual Pattern Recognition Memory and cerebrospinal β-amyloid 1–42 levels (β standardized coefficient = 0.350; p = 0.008) after controlling for age and education in a linear regression model, with lower β-amyloid 1–42 and 1–40 levels observed in those with PD-MCI. Voxel-based morphometry did not reveal any areas of significant gray matter loss in participants with PD-MCI compared with controls, and no specific genotype was associated with PD-MCI at the 1.5-SD threshold. Conclusions: In a large cohort of newly diagnosed PD participants, PD-MCI is common and significantly correlates with lower cerebrospinal β-amyloid 1–42 and 1–40 levels. Future longitudinal studies should enable us to determine those measures predictive of cognitive decline.

Cognitive performance in hypertensive and normotensive older subjects

Longitudinal studies suggest that hypertension in midlife is associated with cognitive impairment in later life. Cross-sectional studies are difficult to interpret because blood pressure can change with onset of dementia and the inclusion of subjects on treatment and with hypertensive end-organ damage can make analysis difficult. We examined cognitive performance in hypertensive and normotensive subjects without dementia or stroke ≥70 years of age. Cognitive performance was determined with the use of a computerized assessment battery in 107 untreated hypertensives (55 women, age 76±4 years, blood pressure, 164±9/89±7; range, 138 to 179/68 to 99 mm Hg) and 116 normotensives (51 female, age 76±4 years, 131±10/74±7; 108 to 149/60 to 89 mm Hg). Older subjects with hypertension were significantly slower in all tests (reaction time, milliseconds; simple, 346±100 versus 318±56, P <0.05; memory scanning, 867±243 versus 789±159, P <0.01; immediate word recognition, 947±261 versus 886±192, P <0.05; and delayed word recognition, 937±230 versus 856±184, P <0.05; picture recognition, 952±184 versus 894±137, P <0.01; spatial memory, 1390±439 versus 1258±394, P <0.01; excepting choice reaction time, 510±75 versus 498±72, P =0.08). Accuracy was also impaired in tests of number vigilance, 99.2±2.5% versus 99.9±0.9, P <0.01; delayed word recognition, 83.5±16 versus 87.9±9.8, P <0.01; and spatial memory 64±32 versus 79±20, P <0.001. Hypertension in older subjects is associated with impaired cognition in a broad range of areas in the absence of clinically evident target organ damage.

Chewing gum selectively improves aspects of memory in healthy volunteers.

CognitiveDrugResearchLtd.,ReadingRG301EA,UKMany people chew gum partly due to the belief that itincreases aspects of mental performance, including concen-tration. To the best of our knowledge no empirical evidenceexists to support this contention. The present experiment,therefore, examined the effects of chewing gum using acomprehensive and sensitive cognitive assessment batteryand two tasks manipulating cognitive load. Heart rateresponses were also measured.Seventy-five healthy adult participants (mean age 246years) were randomly assigned to one of three experimentalconditions (N‹25 per group): ‘‘chewing’’ – a piece of sugar-free chewing gum (Wrigley’s Extra Spearmint) was chewednaturally and constantly throughout the procedure; ‘‘shamchewing’’ – participants mimicked chewing movements in theabsence of gum; ‘‘quiet control’’ – no chewing behaviour wasperformed.Aspects of attention, working memory and long-termmemory were assessed using the Cognitive Drug Research(CDR) computerised battery. Stimuli were presented on acolour monitor and, except for two written word recall tasks,responses were collected automatically using a ‘‘Yes’’/‘‘No’’responsemodule.Thetaskswerepresentedintheorder:Wordpresentation, Immediate Word Recall, Picture Presentation,SimpleReactionTime,DigitVigilance,ChoiceReactionTime,Spatial Working Memory, Numeric Working Memory,Delayed Word Recall, Word Recognition and PictureRecognition (for details, e.g. see Kennedy et al. 2000).Following the CDR battery, participants performed compu-terised Serial Subtractions tasks. These assess concentrationand working memory and allow manipulation of cognitiveload (see Scholey et al., 2001 for details). In the present studySerialThrees(involvingtherepeatedsubtractionofthreefroma randomly generated starting number using the computer’snumerickeypad)thenSerialSevens(subtractionofseven)wereused, each for 2min.Eachcognitive taskoutcome measurewasanalysedby one-wayanalysisofvariance,withDunnettcomparisonstoisolatebetween-group effects where appropriate. The most strikingfindingwasasignificanteffectonbothimmediateanddelayedword recall, with more words being recalled in the chewingconditioncomparedwiththequietcontrolcondition(Table1).The Spatial Working Memory sensitivity index and Numericworkingmemoryreactiontimeweresimilarlyimprovedinthechewingcondition,andalsointheshamchewingconditionforthe latter measure (which reflects the efficiency of workingmemory operations). In addition, simple reaction times wereslowerintheshamchewingconditionthaninthequietcontrolcondition.Baseline heart rate recordings (sampled at 30-s intervals)began 240s prior to treatment and continued during a 180-speriod of chewing, sham chewing or sitting quietly prior tocognitive assessment (which lasted about 30min in all). Heartrate (mean bpm) was calculated during baseline, treatment,each of the 10 CDR tasks and both Serial Subtraction tasks.Heart rate changes relative to baseline were subjected to a3(Condition) 14(Phase) factorial ANOVA with repeatedmeasures on the latter factor. The main effect of conditionapproached significance, F(2,936)‹30, p‹006; heart ratesweresignificantlyhigherinthechewingconditionthaninquietcontrols, p<005 (Fig. 1). There was also a significant maineffect oftask,F(13,936)‹130,p<001:with theexceptionofSimple Reaction Time and Delayed Word Recall, all taskphasesofthestudywereassociatedwithsignificantincreasesinheart rate. There was also a significant task conditioninteraction, F(26,936)‹256, p<001.Theseresultsprovidedthefirstevidencethatthechewingofgum can improve episodic memory (involving the learning,storage and retrieval of information) and working memory(where information is held ‘‘on line’’). They did not indicatethat gum-chewing improves aspects of attention, at least asmeasured here.The impaired Simple Reaction Time during sham chewingmay reflect diversion of attentional resources during initialstages of performing this unfamiliar behaviour. This is con-sistent with the elevated heart rate observed while shamchewing in earlierphases of the experiment (Fig. 1). Althoughanactivecontrolisimportant,shamchewingmaynotbeidealfor this purpose, because most cognitive scores (except, nota-E-mail: a.scholey@unn.ac.uk bly, Numeric Working Memory Reaction Time) in this group0195–6663/02/

Modulation of Mood and Cognitive Performance Following Acute Administration of Single Doses of Melissa Officinalis (Lemon Balm) with Human CNS Nicotinic and Muscarinic Receptor-Binding Properties

– see front matter # 2002 Elsevier Science Ltd. All rights reserved.