The role of automated cognitive function testing in contemporary drug development is assessed here, from the early stages as an aid to translational medicine, through pivotal trials of cognition enhancers to post-marketing studies. Properly automated cognitive function assessments have considerable benefits over traditional pencil and paper tests, and can bring additional value to all stages of drug development.
Cognitive function testing was first introduced into drug development to assess the unwanted side effects of many medicines to produce impairments to mental functioning, and is still widely utilised to establish whether newer medicines are relatively free from such effects. However, the opportunities for medicines to improve cognitive function in the dementias and other disorders have led to the widespread incorporation of such testing into efficacy trials, sometimes as the primary outcome.
Cognitive function refers to mental processes which are crucial for the conduct of the activities of daily living. These processes include attention (concentration, vigilance), the ability to hold information temporarily 'on line' (working memory), the ability to store, retain and retrieve information over hours, days and years (episodic secondary memory) and the coordination of movement. While there are many other facets of cognitive function, these are particularly important because they can be influenced by a wide variety of factors, including trauma, fatigue, stress, nutrition, ageing, disease (both physical and mental), and, of course, medicines and drugs. The efficiency with which these processes operate has a direct influence on how effectively everyday activities are conducted; essentially, the quality of everyday behaviour is underpinned by cognitive function.
Our appreciation of the importance of cognitive function depends on the appropriateness and also the quality of the measurements. The only direct way to assess aspects of cognitive function is to require an individual to perform mental tasks whose successful performance is dependent upon those aspects. Thus, if a researcher wished to assess memory, the test would involve the subject remembering some kind of information with the outcome measure reflecting how successfully this information was memorised and subsequently retrieved. Equally, if the object of study was to assess the ability to maintain attention, the test would involve sustaining attention to a set of pre-defined stimuli and the outcome measures would reflect both the accuracy and speed of the responses. Ultimately, the quality of the measurement of cognitive processes depends on how well the tasks have been designed and implemented.
In the past, many aspects of cognitive dysfunction have been difficult to assess, not because they are subtle or have little relevance to everyday behaviour, but generally because they have not been subject to the diligent application of appropriate tests. Even when testing has shown cognitive dysfunction to be present, its clinical relevance can be questioned; sometimes because the tests have not been demonstrated to have relevance to everyday activities, or because the psychologists who have developed them have failed to convince physicians of either the importance of the construct they are measuring, and / or the ability of the test to measure the particular construct. Thus, while it has long been demonstrated that Alzheimer's patients perform poorly on tests of attention, the importance of attention deficits in the profile of dementia has only become widely accepted in recent years. Even when there is widespread agreement, for example, that pronounced memory loss is a major characteristic of Alzheimer's disease, and this memory loss can be observed non-clinically and without the need to quantify it; such observation is not sufficient if we are to chart the progression of the disease or identify improvements which may be conferred by medication, and thus precise tests of memory are essential.
Automation - Rationale and benefits
There are a number of reasons for automating tests of cognitive function. One is to improve the overall quality of testing by standardising and facilitating test administration while also automatically collecting and processing the responses in an unbiased manner. Another is to precisely capture the speed of each response, something which cannot be done with non-automated tests and, therefore, limits the sensitivity of such pencil and paper methods. A further advantage is that automation can enable tests to definitively and objectively measure particular aspects of cognitive function that traditional procedures cannot unequivocally assess.
The diverse range of cognitive tests available makes it hard to generalise findings from one study to another, and most researchers would agree that the standardisation of tests is desirable. It is well established that the manner in which a test is administered will have a consequence on how it is performed. It must also be acknowledged that different test administrators, no matter how professional, will adopt varying manners of test administration. Automation can go a long way towards minimising the influence of these factors; standardised instructions can be administered via the computer screen and the test stimuli (pictures, words and other information) can be presented for precisely controlled durations and at specific rates. Further, test administrators being human, make mistakes and, in some procedures, there are also judgements to be made. These judgements, by their nature, can be subjective and will always be a potential source of variability. Such problems can be largely overcome with the proper automation of tests.
Automation of testing can also provide the opportunity to facilitate the process of test administration in various ways. For example, automated test systems can cue both experimenter and subject for the various stages of tests and introduce the next test in sequence. When testing is repeated on subsequent occasions, computerised tests can automatically select the appropriate parallel (or alternate) forms. A further benefit in volunteer trials is that groups can be tested simultaneously using multiple computer set-ups, often administered by a single experimenter. Widely used systems like the Cognitive Drug Research (CDR) System have the further benefit that non-specialists can administer the tests.
Most of the advantages described above serve to reduce the variability associated with test administration, which improves the precision of the assessment and thus the sensitivity of the test. The ability to measure, to the nearest millisecond, the time, as well as the accuracy, of each response, is one of the most significant advances to the sensitivity and quality of cognitive assessment which automation has brought to the field. This comprehensive measurement confers huge advantages; not only can trade-offs between speed and accuracy be identified (and thus changes in response style can be differentiated from changes to mental ability), but also improvements to both accuracy and speed can be unequivocally interpreted as reflecting enhanced performance. The security and integrity of cognitive data can also be guaranteed by automated tests, responses being stored in encrypted files which can only be accessed by authorised personnel.
Some automated systems have been in use since the 1980s and the advantages have been repeatedly identified. In 1996, researchers from the Canadian Institute of Mental Health compared the CDR System to a range of non-automated tests including the Mini-Mental State Examination (MMSE), the Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog) and the Wechsler Memory Scale. They found that the CDR System was not only superior in detecting dementia but was the only test that could reliably differentiate patients with Alzheimer's disease from those with Huntington's dementia.
Translational Medicine - The value in phase I and II drug development
Traditional drug development simply assessed the safety, tolerability of pharmacokinetics of novel compounds in phase I and sought evidence of efficacy in large phase II, or in some cases phase III, trials. A widespread trend over recent years has been to seek evidence of the desired effects of a compound as early of possible in the development process using procedures sometimes called biomarkers. This work is termed translational medicine and permits the early selection of compounds that show more potential for further development and reduces the likelihood of wasted resources due to candidate drugs failing later in the clinical development cycle. Cognitive testing can serve drug development by either identifying the ability of a compound to enhance cognitive function, or by ensuring that a compound is relatively free of the unwanted side-effect of cognitive impairment. Although phase I studies are by their nature busy, intensive and often invasive, cognitive function testing can be integrated into the study design, provided the appropriate types of cognitive tests are employed. In most phase I Units, volunteers are housed in wards and the majority of study procedures are performed there. Properly computerised tests are ideal, as auditory instructions or responses are not required and a single administrator can simultaneously test several volunteers, whereas many pencil and paper techniques by their interactive nature are inappropriate and / or impractical. Brief but sensitive tests are the ideal, measuring a range of cognitive domains within 15-20 minutes. These tests can be repeated a number of times over the study day to assess any time profile of effects and can be done by the bedside if necessary.
Evidence of cognition enhancement has been identified in routine phase I safety and tolerability trials by simply introducing appropriately sensitive computerised tests into the study procedure, without compromising the primary safety objectives of the trials or requiring larger sample sizes. These findings have subsequently been confirmed using the same procedures in small phase II trials in a number of conditions including adult ADHD, Alzheimer's disease and schizophrenia. Other work in phase I has established the absence of cognitive impairment for compounds such as darifenacin, a selective M3 antagonist targeted to treat urge incontinent in the elderly without the cognitive impairment known to result from traditional medications like oxybutynin. This absence of impairment was followed up in larger phase I trails and has since been confirmed in clinical practice.
Computerised testing has also been used in phase I models, for example the scopolamine model of dementia which has identified a range of compounds that can potentially treat the symptoms of Alzheimer's disease, including Debio 9902 a third - generation anti-Alzheimer's compound now in phase II trials. Sleep deprivation models in volunteers have also been used to identify the wake promoting properties of compounds, for example armodafinil, which was subsequently approved by the FDA for the treatment of narcolepsy and shift-work sleep disorder.
There are cognitive assessment systems that can be used in virtually any environment with any population. The benefits of identifying wanted or unwanted effects as soon as possible in development are now widely recognised and accepted. Many companies have many compounds to choose from and they can stop the development of inferior compounds as soon as possible. Smaller companies developing cognition enhancers need to demonstrate potential efficacy as soon as possible in the development process to enable them to establish licensing or co-development programmes with larger companies. With these considerations in mind, there is now little justification or excuse for not properly assessing cognitive function throughout the drug development process.
Alzheimer's disease and other dementias
The search for drugs to treat the cognitive dysfunction associated with Alzheimer's disease and other dementias is now well into its third decade, yet progress has been slow. In part, this has been due to the unofficial acceptance of the ADAS-cog as the gold-standard for measuring cognition in pivotal Alzheimer's trials, despite there being no regulatory mandate for this. The limitations of the ADAS-cog are numerous and have been described widely elsewhere; many relating to the problems inherent in non-automated tests, but a particularly serious limitation is the failure of the ADAS-cog to assess attention, now established to be a core cognitive deficit in Alzheimer's disease. The highly controversial decision by the UK's National Institute of Clinical Excellence (NICE) in 2005 to recommend that currently available anti-dementia drugs (the anticholinesterases) not be given to patients with mild to moderate Alzheimer's disease was based on their judgement that the available evidence of efficacy was limited. As the ADAS-cog was the sole cognitive outcome assessment in the regulatory trials of the anticholinesterases, the potential of the compounds to also improve attention went unaddressed. Had attention tests been included in such work and improvements been identified, this extra evidence may have helped address NICE's reservations. More recent work using computerised tests, has shown that the attention benefits of anticholinesterases such as galantamine in Alzheimer's disease can be profound in magnitude, representing up to 40 per cent reversals of these attentional deficits. The improvements to attention were also favourably reflected in Clinicians' Global Clinical Impressions, and had implications for everyday behaviour and also for carer burden.
The treatable cognitive deficits in other major forms of dementia are also being profiled and recent consensus criteria for Parkinson's Disease Dementia (PDD) and Dementia with Lewy Bodies (DLB) have established that the profound attention deficits identified in both dementias using the CDR System are central to the symptomatology of the both diseases and of greater significance potential than the memory deficits. The criteria recommend that automated attention measures should be part of assessments of therapeutic outcomes in the disorders. The first randomised clinical trials in DLB and PDD have identified that rivastigmine can produce large and clinically meaningful reversals of attention deficits of up to 50 per cent in DLB and 68 per cent in PDD. Furthermore, work in PDD has shown that CDR attention tests predict the capabilities of conducting the activities of daily living far more strongly than does the ADAS-cog.
The European Medicines Agency (EMEA) 2008 Guidelines for Development of Medicines for Alzheimer's disease and Parkinson's Disease have stressed that attention should be one of the domains assessed in the dementias, and has also provided a green light for properly validated alternatives to the ADAS-cog to be incorporated into future trials. Therefore, automated tests such as the CDR System which have satisfied the various validation requirements stipulated by the guidelines can now be introduced into pivotal Alzheimer's trials, if not immediately to replace the ADAS-cog, but at least to supplement it. In the case of other dementias such as PDD and DLB as well as Huntington's and Vascular dementia, there is or never has been any rationale for using the ADAS-cog and future trials can proceed with alternative methodologies more suitable to the deficit profiles in these dementias.
The growing recognition that cognitive dysfunction in schizophrenia plays a major role in the poor rehabilitation rates of otherwise successfully treated psychotic patients into functional roles in society, has led to the development of the MATRICS Consensus Cognitive Battery (MCCB). The initiative identified seven target domains covering core aspects of cognitive function including attention, speed of processing, working memory and verbal and visual learning. Unfortunately the developers included mainly traditional pencil and paper neuropsychological tests and not surprisingly, the first trial to be published using the MCCB, identified training effects on the various tasks which obscured the potential treatment effects the study was designed to identify. However, the positive contribution the MATRICS initiative has brought to the field is the establishment of the core cognitive domains which should be targeted in schizophrenia research, which has opened the door for properly validated automated test systems such as the CDR System to be used in such research.
Other clinical conditions in which cognitive disorder is present
Coronary Artery Bypass Graft (CABG) surgery has long been associated with residual cognitive dysfunction. Recently, a worldwide pivotal trial sponsored by Neuren used the CDR System as one of the two primary outcome variables to test Glypromate. The FDA approved trial was terminated early due to the lower than expected variability in the cognitive data resulting from the use of computerised testing. The sponsors argued that the reduction in variability meant that the study objectives could be adequately tested with 320 patients as opposed to the originally planned 600. Sadly, the initial reports are that the study compound did not provide a protective cognitive effect to the patents, but this trial does provide the rationale for other trials to address this topic with markedly smaller sample sizes than would be required with traditional neuropsychological tests.
Cognitive dysfunction is widely recognised to occur in a variety of clinical conditions. A core benefit cognitive testing can bring to such work is to establish the benefits which can accrue from therapies which alleviate the symptoms in the conditions and / or enhance cognitive function. Benefits with the CDR System have been identified in depression with reboxetine; cancer with fentanyl, epoetin alpha, and modafinil; sleep apnea with armodafinil; narcolepsy with armodafinil; fibromyalgia with galantamine; hypertension with candesartan; epilepsy with remacemide; ispronicline in Age-Associated Memory Impairment; and ABT-089 and NS2359 in adult ADHD.
The application to herbal medicines
As herbal medicines become more widely available and get subjected to regulatory scrutiny, the requirement to properly assess their purported benefits becomes overwhelming. Many have been traditionally believed to enhance cognitive function and the CDR System was used in one of the first randomised trials of ginkgo biloba in elderly patients with mild cognitive impairment. Over the last 20 years, clinical trials using the CDR System have been able to confirm many of these purported cognitive benefits in the young and elderly for a variety of substances including gingko biloba, panax ginseng, Sage, guarana, Bacopa Monniera, Melissa and rosemary. Such work has been used to support product claims, advertising and patents.
Paediatric clinical trials
Children as young as six can be tested using the CDR System and a variety of trials have been conducted including the cognitive effects of breakfast cereals, classroom ventilation and mobile phones, as well as clinical trials including one assessing the effects of anti-epileptic medications in adolescents with epilepsy. The worldwide moves to increase the regulatory requirement to establish safety data in children for medicines they are likely to receive will provide the opportunity to assess the cognitive risks or benefits children may experience from a range of novel and existing drugs.
Interest is growing in combining cognitive testing with other techniques in phase I trials which measure various aspects of activity in the CNS, such as EEG, PET and fMRI. While these hugely sensitive measures reveal vast amounts about CNS function and activity, it must be remembered that they are not in themselves direct measures of cognitive function. Instead, they identify patterns of activity, which may be the neural substrates for various aspects of function, and these measures are thus indirect assessments. However, when such assessments are directly integrated with tests of cognitive function, these co-joint evaluations of performance and CNS activity become extremely powerful instruments which are, for example, capable of functionally linking drug-induced changes in cognitive function with activation of various brain areas, or in the case of SPECT, with receptor occupancy.
It is time to act
The importance of cognitive function assessments in contemporary drug development makes a strong case for the proper automation of test procedures. Much of the benefits of automated testing in translational medicine and many other areas of drug development which have been discussed have been based on the extensive experience gained with an automated cognitive test system which has been used in clinical trials worldwide since the 1980s. The ability to definitively assess changes in cognitive function in clinical trials opens up possibilities in numerous areas, including paediatric studies, studies of herbal medicines, imaging studies, as well as more mainstream areas of drug development including dementia, schizophrenia and numerous other neurological, psychiatric or clinical conditions. Computerised assessment of cognitive function has now come of age in drug development, and the pharmaceutical industry has a range of systems and technologies available to better characterise and develop its products.
The case for Internet-based cognitive testing the potential value for phase IV
Cognitive testing can now be delivered via the Internet which will enable cognitive testing to be introduced in phase IV programmes. Such trials will enable the benefits of medicines on cognitive function to be captured in large post-marketing studies, patients either logging on at home to perform testing, or having testing conducted while making visits to the clinic. It will also enable medical practitioners to test patients prior to recommending medications, and then to conduct follow up testing at regular intervals. This will enable clinicians to determine for themselves whether cognition enhancers are having their desired positive cognitive effects, or conversely, that other compounds are indeed free from unwanted cognitive effects. Evidence-based prescribing will thus be feasible in clinical settings, which would enhance the credibility of many potential treatments for cognitive disorders.
Keith Wesnes is the owner and Chief Executive of Cognitive Drug Research (CDR) Ltd., which he founded in 1986. He trained at Reading University, Indiana University and Guy's Hospital Medical School, has published over 200 peer reviewed papers and holds Professorships at Northumbria University, Newcastle, UK and Swinburne University, Melbourne, Australia.
Rianne Stacey has been working for CDR for just over a year as a member of the Research and Development Team. She has a strong academic background gaining a masters degree from the University of Cambridge in 2002 before embarking on a PhD at the University of Manchester, which she completed in 2007.
Bradford E, Nield H, Wesnes K. (2006) An internet survey of the cognitive differences between self-reported users and non-users of a standardised combination of ginseng, vitamins and minerals. Journal of Psychopharmacology 20 (5): A30
Bronnick K, Ehrt U, Emre M, De Deyn P P, Wesnes K, Tekin S and Aarsland D (2006). Attentional deficits affect activities of daily living in dementia associated with PD. J Neurol Neurosurg Psychiatry 77:1136-1142.
Coley DA, Greeves R, Saxby BK (2007) The Effect of Low Ventilation Rates on the Cognitive Function of a Primary School Class. International Journal of Ventilation 6: 1473-3315.
Dunbar G C, Inglis F, Kuchibhatla R, Sharma T, Tomlinson M and Wamsley J (2007). Effect of ispronicline, a neuronal nicotinic acetylcholine receptor partial agonist, in subjects with age associated memory impairment (AAMI). Journal of Psychopharmacology 21: 171-178.
Edgar CJ, Wesnes KA (2008) Cognition assessment in paediatric clinical trials. Drug Discovery Today 13 :79-85.
Emre M (2003). Dementia associated with Parkinson’s disease. THE LANCET Neurology 2: 229-236.
Emre M, Aarsland D, Albanese A, et al. (2004). Rivastigmine for Dementia Associated with Parkinson’s Disease. New England Journal of Medicine 351: 2509-18.
Ferguson J, Wesnes K, Schwartz G (2003). Reboxetine versus paroxetine versus placebo: Effects on cognitive functioning in depressed patients. International Clinical Psychopharmacology 18: 1-6.
Ferris S, Lucca U, Mohs R, Dubois B, Wesnes K, Erzigkeit H, Geldmacher D, Bodick N. (1997). Objective Psychometric Tests in Clinical Trials of Dementia Drugs. Position paper from the International Working Group on Harmonisation of Dementia Drug Guidelines. Alzheimer Disease and Associated Disorders 11: Suppl. 3, 34-38.
Freedman R, Olincy A, Buchanan R, et al (2008). Initial Phase 2 Trial of a Nicotinic Agonist in Schizophrenia. Am. J. Psychiatry, doi: 10.1176/appi.ajp.2008.07071135.
Galvin J, Cornblatt B, Newhouse P, Ancoli-Israel S, Wesnes K, Williamson D, Zhu Y, Sorra K, Amatniek J (2008). Effects of Galantamine on Measures of Attention: Results From two Clinical Trials in Alzheimer’s Disease Patients With Comparisons to Donepezil. Alzheimer’s Disease and Related Disorders 22: 30-38.
Harsh J R, Hayduk R, Rosenberg R, Wesnes K A, Walsh J K, Arora S, Niebler G E and Roth T (2006). The efficacy and safety of armodafinil as treatment for adults with excessive sleepiness associated with narcolepsy. Current Medical Research Opinion 22: 761-74.
Haskell CF, Kennedy DO, Wesnes KA, Milne AL, Scholey AB. (2007). A double-blind, placebo-controlled, multi-dose evaluation of the acute behavioural effects of guarana in humans. Journal of Psychopharmacology 21: 65-70.
Hassman H, Brownstein L, Satek S et al. (2007). The Use of the CDR Schizophrenia Test Battery to Measure Cognitive Function Deficits in Schizophrenics. Poster presented at 47th Annual Meeting NCDEU, Boca Raton, Florida.
Hirshkowitz M, Black JE, Wesnes K, Niebler G, Arora S & Roth T (2006). Adjunct armodafinil improves wakefulness and memory in obstructive sleep apnea/hypopnea syndrome. Respiratory Medicine 101: 616-627.
Ingwersen J, Defeyter MA, Kennedy DO, Wesnes KA, Scholey AB. (2007) A low glycaemic index breakfast cereal preferentially prevents children's cognitive performance from declining throughout the morning. Appetite 49: 240-244.
Kennedy DO, Scholey AB, Wesnes K (2002). Modulation of cognition and mood following administration of single doses of ginkgo biloba, ginseng and a ginkgo/ginseng combination to healthy young adults. Physiology & Behaviour 75:1-13.
Kennedy DO, Scholey AB, Wesnes KA (2000). The dose-dependent cognitive effects of acute administration of ginkgo biloba to healthy young volunteers. Psychopharmacology 151: 416-423.
Kennedy DO, Wake G, Savelev S, Tildesley NTJ, Perry EK, Wesnes KA, Scholey AB (2003). 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. Neuropsychopharmacology 28: 1871–1881.
Kohli S, Fisher SG, Tra Y, Adams MA, Mapstone MM, Wesnes KA, Jean-Pierre P, Roscoe JA, Morrow GR (2009). The Effect of Modafinil on Cognitive Function in Breast Cancer Survivors. Cancer in press
McKeith I, Del Ser T, Spano P, Emre M, Wesnes K, Anand R, Cicin-Sain A, Ferrara R, Spiegel R (2000). Efficacy of rivastigmine in dementia with Lewy bodies: A randomised, double-blind, placebo-controlled international study. The Lancet 356: 2031-2036.
McKeith I, Mintzer J, Aarsland D, Burn D, Chiu H, Cohen-Mansfield J, Dickson D, Dubois B, Duda J, Feldman H, Gauthier S, Halliday G, Lawlor B, Lippa C, Lopez O, Machado JC, O’Brien J, Playfer J, Reid W (2004). Dementia With Lewy Bodies The Lancet 3: 19 28.
McNamara (2002). Opioid switching from morphine to transdermal fentanyl for toxicity reduction in palliative care. Palliative Medicine 16: 425-434.
Mohr E, Walker D, Randolph C, Sampson M, Mendis T (1996). The utility of clinical trial batteries in the measurement of Alzheimer’s and Huntington’s dementia. International Psychogeriatrics 8: 397-411.
Moss M, Cook J, Wesnes K, Duckett P (2003). Aromas of rosemary and lavender essential oils differentially affect cognition and mood in healthy adults. International Journal of Neuroscience 113:15-38.
Preece AW, Iwi G, Davies-Smith A, Wesnes K, Butler S, Lim E, Varey A (1999). Effect of a 915-MHz simulated mobile phone signal on cognitive function in man. International Journal of Radiation Biology 75: 447-456.
Roth T, White D, Schmidt-Nowara W, Wesnes KA, Niebler G, Arora S, Black J (2006) Effects of armodafinil in the treatment of residual excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome: a 12-week multicentre, double-blind, randomised, placebo-controlled study in nCPAP-adherent adults. Clinical Therapeutics 28: 689-706
Saxby BK, Harrington F, Wesnes KA, McKeith IG, Ford GA (2008) Candesartan and cognitive decline in older patients with hypertension: A substudy of the SCOPE trial. Neurology 70:1858-1866.
Scholey A, Tildesley N, Ballard C, Wesnes KA, Tasker A, Perry EK, Kennedy DO (2008). An extract of Salvia (sage) with anticholinesterase properties improves memory and attention in healthy older volunteers. Psychopharmacology DOI 10,1007/s00213-008-1101-3.
Simpson PM, Surmon DJ, Wesnes KA and Wilcock GR (1991). The Cognitive Drug Research computerised assessment system for demented patients: A validation study. International Journal of Geriatric Psychiatry, 6: 95-102.
Stough C, Downey LA, Lloyd J, Silber B, Redman S, Hutchison C, Wesnes K, Mathan P (2008) Examining the nootropic effects of Bacopa Monneria on Human Cognitive Functioning: 90 day , double-blind, placebo-controlled randomized trial. Phytotherapy Research 22: In press
Tesch H, Liberati IM, et al. (2006). Assessment of the cognitive effects of once weekly epoetin alfa in anemic patients with hematologic malignancies receiving chemotherapy: results of the EPOLYM trial [Abstract]. The Hematology Journal 91 (suppl 1): 8-9.
Vellas B, Cunha L, Gertz HJ, De Deyn PP, Wesnes K, Hammond G, Schwalen S (2005) Early onset effects of galantamine treatment on attention in patients with Alzheimer's disease. Curr Med Res Opin 21: 1423-1429.
Wesnes K (2001). The role of attention deficits in the cognitive pathology of dementia. Alzheimer Insights 7: 1-4.
Wesnes KA (2008). Assessing Change in Cognitive Function in Dementia: The Relative Utilities of the Alzheimer’s Disease Assessment Scale – Cognitive Subscale and the Cognitive Drug Research System. Neurodegenerative Dis; 5:261–263.
Wesnes K, Faleni RA, Hefting NR, Hoogsteen G, Houben JJG, Jenkins E, Jonkman JHJ, Leonard J, Petrini O, Van Lier JJ (1997). The cognitive, subjective and physical effects of a ginkgo biloba/ panax ginseng combination in healthy volunteers with neurasthenic complaints. Psychopharmacology Bulletin 33: 677-683.
Wesnes K, Ferguson J, Petrini O (2004) The memory enhancing effects of gingko biloba in healthy middle-aged volunteers [Abstract]. International Journal of Neuropsychopharmacology 7 (Suppl): 271
Wesnes KA, Harrison JE (2003) The evaluation of cognitive function in the dementias: methodology and regulatory considerations. Dialogues in Clinical Neuroscience 5: 77-88.
Wesnes K, Pincock C, Richardson D, Helm G, Hails S (2003). Breakfast reduces declines in attention and memory over the morning in school children. Appetite 41: 329-331.
Wesnes K, Simmons D, Rook M, Simpson PM (1987). A double blind placebo controlled trial of tanakan in the treatment of idiopathic cognitive impairment in the elderly. Human Psychopharmacology 2: 159-169.
Wesnes KA, Edgar C, Wroe SJ, Dean ADP (2009). Comparative Cognitive and Psychological Profiles of Remacemide and Carbamazepine and Validation of Measures: Data from the SEReNE Trial. Epilepsy & Behavior doi:10.1016/j.yebeh.2008.11.012
Wesnes KA, McKeith IG, Edgar C, Ferrara R, Emre M, Lane R. (2005). Benefits of rivastigmine on attention in dementia associated with Parkinson disease. Neurology 65: 1654-1656.
Wesnes KA, McKeith IG, Ferrara R, Emre M, Del Ser T, Spano PF, Cicin-Sain A, Anand R, Spiegel R (2002). 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. Dementia and Geriatric Cognitive Disorders 13: 183-192.
Wesnes KA, Snorrason E, Valsson A, Bragee B, Greenwood D (2001). The cognitive effects of galanthamine in patients suffering from fibromyalgia. Journal of Psychopharmacology 15 (Suppl.): A58.
Wesnes KA, Ward T, McGinty A, Petrini O (2000). The memory enhancing effects of a ginkgo biloba/ panax ginseng combination in healthy middle aged volunteers. Psychopharmacology 152: 353-361.
Wilens TE, Verlinden MH, Adler LA, Wozniak PJ, West SA (2006) ABT-089, A Neuronal Nicotinic Receptor Partial Agonist, for the Treatment of Attention-Deficit/Hyperactivity Disorder in Adults: Results of a Pilot Study. Biological Psychiatry 59: 1065–1070.