Alzheimer Disease: Wesnes K

Wesnes K. · Cognitive Drug Research, Ltd., Goring-on-Thames, and Human Cognitive Neuroscience Unit, Northumbria University, Newcastle-on-Tyne, UK. · Drugs Today (Barc). · Pubmed #17612707 No free full text.

Abstract: Parkinson's disease is associated with dementia in about 40% of cases, and in time up to 80% of patients will develop dementia. This dementia is characterized by deficits in attention, executive function and memory. While, as in Alzheimer's disease, cholinergic dysfunction has long been identified to be related to the cognitive impairment in Parkinson's dementia, the fear of exacerbating the motor symptoms of the disorder has greatly hindered research into the anticholinesterases as symptomatic treatments for the cognitive and psychiatric deficits. However, following a number of successful open-label trials with anticholinesterases, a large, international, randomized, double-blind, placebo-controlled trial of the effects of rivastigmine in the dementia associated with Parkinson's disease has been conducted. Rivastigmine was found to significantly improve all of the primary and secondary endpoints in the study, showing benefits to cognitive function, neuropsychiatric complaints and activities of daily living. Cognitive improvements were seen on the Alzheimer's Disease Assessment Scale cognitive subscale, the Mini Mental State Examination, the attention battery of the Cognitive Drug Research computerized assessment system, word fluency and clock drawing. An open-label extension to the study suggested that the beneficial effects persisted up to 48 weeks. While the improvements seen with rivastigmine on the various measures have been described as modest by some commentators, rivastigmine is now widely registered for the symptomatic treatment of mild to moderate dementia associated with Parkinson's disease. A treatment is now available for a previously unmet medical need.

Walker MP, Ayre GA, Perry EK, Wesnes K, McKeith IG, Tovee M, Edwardson JA, Ballard CG. · MRC Neurochemical Pathology Unit, Newcastle General Hospital, Newcastle upon Tyne, UK. · Dement Geriatr Cogn Disord. · Pubmed #11044778 No free full text.

Abstract: Fluctuating cognition (FC) is a common and important symptom in dementia, particularly dementia with Lewy bodies (DLB), although it has not been empirically quantified or characterised. Forty subjects (15 DLB, 15 AD, 10 elderly controls) were evaluated using a clinical FC severity scale, as well as receiving measures of variability in attentional performance and slow EEG rhythms across 90 s, 1 h and 1 week. DLB patients had significantly more severe FC and more severe variability in attentional and slow electrocortical measures than either AD patients or normal controls in all time frames. Attentional and EEG variability also correlated significantly with independent clinical ratings of FC. Clinical quantification and measures of attention and EEG variability can therefore make an important and standardised contribution to the assessment of FC in dementia, facilitating future treatment studies with important implications for the potential causative mechanisms and differential diagnosis.

Walker MP, Ayre GA, Cummings JL, Wesnes K, McKeith IG, O'Brien JT, Ballard CG. · Medical Research Council Neurochemical Pathology Unit, Institute for the Health of the Elderly, Newcastle, UK. · Neurology. · Pubmed #10762503 No free full text.

Abstract: BACKGROUND: Case reports and clinical observations suggest that fluctuating cognition (FC) is common in the major dementias, particularly dementia with Lewy bodies (DLB), where it is one of three core clinical diagnostic features. OBJECTIVES: To examine the frequency, characteristics, and diagnostic utility of FC in dementia using clinical, attentional, and EEG markers. Method:- A total of 155 subjects (61 with AD, 37 with DLB, 22 with vascular dementia [VaD], 35 elderly controls) received clinical evaluation for FC using a semiquantified measure applied by experienced clinicians and 90-second cognitive choice reaction time (CRT) and vigilance reaction time (VIGRT) trials. Forty subjects also received an evaluation of mean EEG frequency across 90 seconds. RESULTS: Patients with DLB had a greater prevalence and severity of FC than did patients with AD or VaD rated using clinical, attentional, and EEG measures. The 90-second cognitive and EEG trials demonstrated that FC occurs on a second-to-second basis in patients with DLB. Patients with VaD had a higher prevalence of FC than did those with AD, although the profile of FC was different from that expressed by DLB cases. Optimal cutoff values on the clinical scale achieved good discrimination between the dementia groups (sensitivity 81%, specificity 92%, DLB versus AD; sensitivity 81%, specificity 82%, DLB versus VaD; sensitivity 64%, specificity 77%, VaD versus AD). CONCLUSION: Standardized assessment methods demonstrate that FC is significantly more common and severe in DLB than in other major dementias. The periodicity of FC is different in DLB and VaD cases, with important implications for the underlying causal mechanisms and for differential diagnosis.

Galvin JE, Cornblatt B, Newhouse P, Ancoli-Israel S, Wesnes K, Williamson D, Zhu Y, Sorra K, Amatniek J. · Department of Neurology, Washington University School of Medicine, St Louis, MO 63110, USA. · Alzheimer Dis Assoc Disord. · Pubmed #18317244 No free full text.

Abstract: Deficits in attention are present early in the course of Alzheimer disease (AD). Acetylcholine receptors are appealing molecular targets for intervention as cholinergic pathways are involved in the neurobiology of attention. For this reason, measures of attention were included in 2 independent, multicenter, randomized, parallel, controlled trials in subjects with AD comparing the effects of galantamine, an acetylcholinesterase inhibitor and postulated nicotinic receptor modulator, and donepezil, an acetylcholinesterase inhibitor. The attention battery of the Cognitive Drug Research computerized assessment system was used in both trials. Small magnitude, positive signals were observed for simple and choice reaction times for both compounds. Attention task performance tended to improve early for galantamine-treated subjects. A consistent temporal pattern of improvement was not observed in donepezil-treated subjects. Quantitative findings appeared more pronounced in subjects with moderate AD. Galantamine's proposed action as a nicotinic receptor modulator may bear on these findings. Improved attention may have positive effects on cognitive and functional outcomes for AD patients, although this hypothesis requires further study and validation.

Vellas B, Cunha L, Gertz HJ, De Deyn PP, Wesnes K, Hammond G, Schwalen S, Anonymous00189. · Memory Research Resource Center for Alzheimer's Disease, Service de gériatrie, CHU Hôpital Lagrave Casselardit, Toulouse, France. · Curr Med Res Opin. · Pubmed #16197661 No free full text.

Abstract: INTRODUCTION: Exploratory pilot studies and knowledge of its mode of action suggested that galantamine, a cholinesterase inhibitor and modulator of nicotinic receptors, can improve attention. This study was designed to test the effects of galantamine on attention in patients with mild-to-moderate Alzheimer's disease (AD) and to see how changes in attention affected their caregivers. METHODS: This was an open-label, multicentre study. Patients received galantamine (up to 24 mg/day) for 12 weeks. Attention was assessed after 1, 4, 8 and 12 weeks using computerized tests including Choice Reaction Time (CRT), and caregiver, physician and patient ratings. RESULTS: Data were available from 373 patients (mean age 75 years, mean baseline MMSE score 21). Attention as measured by CRT improved significantly from baseline to study endpoint (p < 0.001), improvements were observed after 1 week and statistical significance was maintained from 8 weeks. Physicians rated 67% of patients as globally improved and 5% as worsened. Caregivers reported improved attention in 57% of patients and worsening in 6%; 62% of patients considered they had improved and 3% considered themselves to be worse. Caregiver stress, time spent caring for patients and patients' interactions with others all improved from baseline to endpoint. Galantamine was generally well tolerated; the most common adverse events were gastrointestinal. CONCLUSION: Previous controlled trials have demonstrated that galantamine has a positive effect on cognition, activities of daily living, behaviour and global condition, but this is the first study to suggest that galantamine may specifically improve attention (according to both objective and subjective measures) in patients with AD. These effects may be a consequence of galantamine's potentiating action at nicotinic receptors.

Pomara N, Willoughby L, Wesnes K, Greenblatt DJ, Sidtis JJ. · Geriatric Psychiatry Program, Nathan S. Kline Institute for Psychiatric Research, Orangeburg, NY 10962, USA. · Arch Gen Psychiatry. · Pubmed #15699298 links to  free full text

Abstract: CONTEXT: The apolipoprotein E (APOE) epsilon4 allele has been implicated as a significant risk factor in the development of late-onset Alzheimer disease, but the evidence of cognitive sequelae in healthy individuals has been mixed. OBJECTIVE: To determine if the APOE epsilon4 allele increases susceptibility to lorazepam-induced verbal learning impairment in nondemented older adults. DESIGN: A placebo-controlled crossover design. SETTING: A community-based sample of subjects. PARTICIPANTS: Sixty-four cognitively intact and highly educated (>12 years) adults. Twenty-four subjects (mean age, 66.3 years) were carriers of an APOE epsilon4 allele (epsilon4 positive) and 40 (mean age, 66.0 years) were not (epsilon4 negative). INTERVENTIONS: All subjects received a single oral dose of placebo and lorazepam (0.5 and 1.0 mg) 1 week apart. MAIN OUTCOME MEASURE: We used the Buschke Selective Reminding Test to assess verbal learning during a 5-hour period after placebo or lorazepam administration. RESULTS: We found a time-related, dose-dependent effect of lorazepam, with long-term recall generally decreasing with higher doses of lorazepam at up to 2.5 hours. At 5 hours, the epsilon4-negative group showed significant improvement in long-term memory, but the epsilon4-positive group demonstrated a persistent deficit. Subsequent analysis revealed that the poor performance at 5 hours was found in an epsilon4-positive subgroup with lower baseline performance. CONCLUSIONS: In cognitively intact, older adults, the effect of the APOE epsilon4 allele is not necessarily seen in the immediate response to benzodiazepine challenge. Rather, the APOE epsilon4 allele appears to affect the carrier's ability to recover from a cognitive challenge in a normal fashion, at least in a subgroup of subjects with relatively low baseline performance. This suggests that although carrying an APOE epsilon4 allele increases the risk for cognitive toxic effects, allele status alone is not a sufficient predictor of such effects. Studying the response to and the recovery from cognitive challenges may provide insights into the role of the APOE epsilon4 allele and its interaction with other factors in the development of Alzheimer disease and other age-related cognitive problems.

Zaffalon M, Wesnes K, Petrini O. · IDSIA, Galleria 2, 6928 Manno, (Lugano), Switzerland. · Artif Intell Med. · Pubmed #12957781 No free full text.

Abstract: Dementia is a serious personal, medical and social problem. Recent research indicates early and accurate diagnoses as the key to effectively cope with it. No definitive cure is available but in some cases when the impairment is still mild the disease can be contained. This paper describes a diagnostic tool that jointly uses the naive credal classifier and the most widely used computerized system of cognitive tests in dementia research, the Cognitive Drug Research system. The naive credal classifier extends the discrete naive Bayes classifier to imprecise probabilities. The naive credal classifier models both prior ignorance and ignorance about the likelihood by sets of probability distributions. This is a new way to deal with small and incomplete datasets that departs significantly from most established classification methods. In the empirical study presented here, the naive credal classifier provides reliability and unmatched predictive performance. It delivers up to 95% correct predictions while being very robust with respect to the partial ignorance due to the largely incomplete data. The diagnostic tool also proves to be very effective in discriminating between Alzheimer's disease and dementia with Lewy bodies.

O'Brien KK, Saxby BK, Ballard CG, Grace J, Harrington F, Ford GA, O'Brien JT, Swan AG, Fairbairn AF, Wesnes K, del Ser T, Edwardson JA, Morris CM, McKeith IG. · MRC Building, MRC/University of Newcastle Centre Development for Clinical Brain Ageing, Newcastle upon Tyne, NE1 3BZ, UK. · Pharmacogenetics. · Pubmed #12668920 No free full text.

Abstract: OBJECTIVES: To determine the response of patients with different butyrylcholinesterase genotypes to therapy, and the influence of butyrylcholinesterase on cognition. Acetylcholine plays a key role in attention and memory and reduced cortical acetylcholine is associated with the severity of dementia. Inhibitors of the enzyme acetylcholinesterase are an effective dementia treatment, though the role of the related enzyme butyrylcholinesterase is less well understood. METHODS: We examined the response of a cohort of dementia patients enrolled in a trial of a cholinesterase inhibitor who had been genotyped at the butyrylcholinesterase locus. Additionally a prospectively assessed cohort of dementia patients was genotyped and rate of cognitive decline examined, along with baseline cognitive performance in a group of elderly non-demented individuals. We identified that the presence of reduced-activity butyrylcholinesterase variants correlates with preserved attentional performance and reduced rate of cognitive decline. During cholinesterase inhibitor therapy, patients with normal butyrylcholinesterase show improved attention, though patients carrying reduced-activity enzyme do not, possibly due to being at ceiling performance. Butyrylcholinesterase did not however affect attentional performance in non-demented individuals with mild cognitive impairment. CONCLUSIONS: These findings indicate that the butyrylcholinesterase enzyme is a major regulator of attention especially in cholinergic deficiency states through its ability to hydrolyse acetylcholine. Pharmacologic manipulation of this enzyme may be a viable strategy in dementia treatment and, with butyrylcholinesterase genotyping, may provide pharmacogenomic treatment of dementia.

Ballard C, Stephens S, McLaren A, Wesnes K, Kenny RA, Burton E, O'Brien J, Kalaria R. · Institute for Ageing and Health, Newcastle General Hospital, Westgate Road, Newcastle NE4 6BE, United Kingdom. · Ann N Y Acad Sci. · Pubmed #12480750 No free full text.

Abstract: This paper examines the frequency of CIND, the profile of early cognitive deficits in stroke patients, the differences in the profile of cognitive impairment in people with CIND and those with vascular dementia, and the MRI associations of CIND in older stroke patients.