Neuroimaging data are increasingly being used to predict potential outcomes or groupings, such as clinical severity, drug dose response, and transitional illness states. In these examples, the variable (target) we want to predict is ordinal in nature. Conventional classification schemes assume that the targets are nominal and hence ignore their ranked nature, whereas parametric and/or non-parametric regression models enforce a metric notion of distance between classes. Here, we propose a novel, alternative multivariate approach that overcomes these limitations - whole brain probabilistic ordinal regression using a Gaussian process framework. We applied this technique to two data sets of pharmacological neuroimaging data from healthy volunteers. The first study was designed to investigate the effect of ketamine on brain activity and its subsequent modulation with two compounds - lamotrigine and risperidone. The second study investigates the effect of scopolamine on cerebral blood flow and its modulation using donepezil. We compared ordinal regression to multi-class classification schemes and metric regression. Considering the modulation of ketamine with lamotrigine, we found ordinal regression significantly outperformed multi-class classification and metric regression in terms of accuracy and mean absolute error. However, for risperidone ordinal regression significantly outperformed metric regression but performed similarly to multi-class classification both in terms of accuracy and mean absolute error. For the scopolamine dataset, ordinal regression was found to outperform both multi-class and metric regression techniques considering the regional cerebral blood flow in the anterior cingulate cortex. Ordinal regression was thus the only method that performed well in all cases. Our results indicate the potential of an ordinal regression approach for neuroimaging data while providing a fully probabilistic framework with elegant approaches for model selection.

Donepezil, a member of the acetylcholinesterase inhibitor family, is approved for management of cognitive impairments as well as behavioral complications in patients with neurodegenerative Alzheimer's disease. Generally, donepezil is regarded as a safe medication in patients with Alzheimer's disease although there have been reports of several minor adverse events including gastrointestinal disturbances. Herein we describe a patient with Alzheimer's disease who demonstrated delirious behavior upon treatment with donepezil.

To investigate the long-term effects of cholinesterase inhibitor (ChEI) therapy and the influence of sociodemographic and clinical factors on the use of community-based home help services (HHS) by patients with Alzheimer's disease (AD).This 3-year, prospective, multicenter study included 880 AD patients treated with donepezil, rivastigmine, or galantamine in a routine clinical setting. At baseline and every 6 months, the patients were assessed with several rating scales, including the Mini-Mental State Examination, Instrumental Activities of Daily Living (IADL), and Physical Self-Maintenance Scale. Doses of ChEI and amounts of HHS per week were recorded. Cox regression models were used to predict the time to HHS, and multiple linear regression was used to predict the volume of HHS used.During the study, 332 patients (38%) used HHS. Factors that both postponed HHS use and predicted lower amounts of HHS were higher doses of ChEIs, better IADL ability, and living with family. Men, younger individuals, and those with a slower IADL decline showed a longer time to HHS, whereas female sex, a lower cognitive status, or more medications at baseline predicted fewer hours of HHS.Higher doses of ChEI might reduce the use of HHS, possibly reducing the costs of community-based care. Female spouses provide more informal care than do male spouses, so the likelihood of using HHS is greater among women with AD. The "silent group" of more cognitively impaired and frail elderly AD patients receives less HHS, which might precipitate institutionalization.

INTRODUCTION:

Despite years of research, there are no disease-modifying drugs for Alzheimer's disease (AD), a fatal, age-related neurodegenerative disorder. Screening for potential therapeutics in rodent models of AD has generally relied on testing compounds before pathology is present, thereby modeling disease prevention rather than disease modification. Furthermore, this approach to screening does not reflect the clinical presentation of AD patients which could explain the failure to translate compounds identified as beneficial in animal models to disease modifying compounds in clinical trials. Clearly a better approach to pre-clinical drug screening for AD is required.

METHODS:

To more accurately reflect the clinical setting, we used an alternative screening strategy involving the treatment of AD mice at a stage in the disease when pathology is already advanced. Aged (20-month-old) transgenic AD mice (APP/swePS1[increment]E9) were fed an exceptionally potent, orally active, memory enhancing and neurotrophic molecule called J147. Cognitive behavioral assays, histology, ELISA and Western blotting were used to assay the effect of J147 on memory, amyloid metabolism and neuroprotective pathways. J147 was also investigated in a scopolamine-induced model of memory impairment in C57Bl/6J mice and compared to donepezil. Details on the pharmacology and safety of J147 are also included.

RESULTS:

Data presented here demonstrate that J147 has the ability to rescue cognitive deficits when administered at a late stage in the disease. The ability of J147 to improve memory in aged AD mice is correlated with its induction of the neurotrophic factors NGF (nerve growth factor) and BDNF (brain derived neurotrophic factor) as well as several BDNF-responsive proteins which are important for learning and memory. The comparison between J147 and donepezil in the scopolamine model showed that while both compounds were comparable at rescuing short term memory, J147 was superior at rescuing spatial memory and a combination of the two worked best for contextual and cued memory.

CONCLUSION:

J147 is an exciting new compound that is extremely potent, safe in animal studies and orally active. J147 is a potential AD therapeutic due to its ability to provide immediate cognition benefits, and it also has the potential to halt and perhaps reverse disease progression in symptomatic animals as demonstrated in these studies.

OBJECTIVE:

Chronic use of the acetylcholinesterase inhibitor donepezil has been found to improve mood or to induce mania/hypomania in many neuropsychiatric patients with altered cholinergic and dopaminergic tone. Our aim was to determine whether acutely administered donepezil would alter mood in volunteers with no such alterations.

METHODS:

This investigation was a double-blind, crossover design study of 15 young, healthy male participants who were allocated in random order to three oral treatments: placebo and 5-mg and 7.5-mg donepezil (doses which exert clinical and acute cognitive effects without considerable peripheral side effects). At the theoretical peak-plasma concentrations of donepezil, volunteers rated how they felt on validated questionnaires, which included various dimensions of subjective feelings. We also assessed changes in brain-derived neurotrophic factor (BDNF), which is increased by donepezil after chronic regimes and is related to modulation of mood.

RESULTS:

Donepezil significantly increased ratings of vigour and anxiety symptoms (medium effect sizes). No changes in bodily symptoms or BDNF were observed.

CONCLUSIONS:

Acute donepezil administration in participants with unaltered cholinergic and dopaminergic tone led to positive and negative changes in affect. These results call for further research on the direct mood effects of donepezil. Copyright © 2013 John Wiley & Sons, Ltd.

As nicotinic acetylcholine receptor (nAChR) agonists directly address cholinergic neurotransmission with potential impact on glutamatergic function, they are considered as potential new symptomatic treatment options for Alzheimer's disease compared to the indirectly operating acetylcholinesterase inhibitors such as the current gold standard donepezil. In order to evaluate the therapeutic value of nAChR activation to ameliorate cognitive dysfunction, a direct comparison between α4β2, α7 nAChR agonists, and donepezil was performed on the level of an ex vivo experimental model of impaired memory formation. First, we demonstrated that amyloid beta (Aβ)42 oligomers, which are believed to be the synaptotoxic Aβ-species causally involved in the pathophysiology of Alzheimer's disease, have a detrimental effect on long-term potentiation (LTP) in the CA1 region of rat hippocampal slices, a widely used cellular model of learning and memory. Second, we investigated the potential of donepezil, the α4β2 nAChR agonist TC-1827 and the α7 nAChR partial agonist SSR180711 to reverse Aβ42 oligomer induced LTP impairment. Donepezil showed only a slight reversal of Aβ42 oligomer induced impairment of early LTP, and had no effect on Aβ42 oligomer induced impairment of late LTP. The same was demonstrated for the α4β2 nAChR agonist TC-1827. In contrast, the α7 nAChR partial agonist SSR180711 completely rescued early as well as late LTP impaired by Aβ42 oligomers. As activating α7 nAChRs was found to be most efficacious in restoring Aβ42 oligomer induced LTP deficits, targeting α7 nAChRs might represent a powerful alternative approach for symptomatic treatment of AD.

Objectives:

There is discussion about the effect of cholinesterase inhibitors (CERs) on weight of patients with Alzheimer's disease (AD). Given the adverse outcomes of weight loss in AD patients, it is important to establish the effect of CERs on weight. This study aimed tot assess the long-term effect of galantamine on weight of AD patients. Design, setting and participants: This longitudinal study was performed at a large memory clinic in the North of the Netherlands. During the period 2002 to 2010, 303 community-dwelling AD patients, aged 65 years or older who started using a cholinesterase inhibitor (CER), were included. Measurements: Socio-demographic characteristics and data on comorbidity, number of medications, type and dosage of CER, use of care, cognitive function, behaviour and nutritional status (weight, Body Mass Index (BMI)) were recorded at the time the diagnosis AD was made and at subsequent outpatient clinic visits. The Generalized Estimating Equations (GEE) model was used to determine the effect of galantamine of 16 mg and 24 mg on weight. The effect of galantamine in a dose of 16 and 24 mg was investigated because the other groups (rivastigmine, galantamine 8 mg) were too small to determine the effect on weight by GEE analysis. Donepezil is not available in the Netherlands.

Results:

The median follow-up time between the moment patients started using a CER (T0) and the 1st visit was 6 months (n=300); between T0 and the 2nd visit 13 months (n=212); between T0 and the 3rd visit 25 months (n=117) and between T0 and the 4th visit 37 months (n=58). Galantamine 16 mg and 24 mg, corrected for age, gender, social status, informal care, professional care, comorbidity, number of medications, cognition, behaviour and appetite, had no effect on weight (p > 0.05). Male patients had a higher average weight compared to female patients (p=0.000, B=8.333). Patients without an informal caregiver (p=0.01, B=-3.697) or partner (p=0.042, B=-3.197) had a lower average weight compared to patients with an informal caregiver or partner.

Conclusion:

Weight loss in AD patients should not be attributed to long-term treatment with galantamine. This is in accordance with the French guideline. If AD patients are losing weight, other causes, including insufficient care, should be investigated.

Donepezil 10 mg/day has been a modestly successful therapeutic agent for the palliative treatment of Alzheimer disease dementia. In 2011, seeking greater efficacy and an extension of the Aricept brand, a 23-mg formulation of donepezil was introduced. A large-scale trial, organized by Eisai, the sponsor, failed to show superiority in their primary analyses of donepezil 23 mg/day in patients with moderate to severe Alzheimer disease dementia vs 10 mg, but the published report used post hoc analyses to claim "statistically significant benefits." There was greater than a 3 times higher rate of gastrointestinal side effects with 23 mg of donepezil compared to 10 mg. Thus, not only does donepezil 23 mg/day increase the likelihood of unacceptable gastrointestinal side effects, it provides no clinical benefits. Aricept 23 mg is about 10 times more costly per pill than donepezil 10 mg.

Cholinesterase inhibitors and memantine are prescribed to slow the progression dementia. Although the efficacy of these drugs has been demonstrated, their effectiveness, from the perspective of patients and caregivers, has been questioned. Little is known about whether the demand for cholinesterase inhibitors and memantine are sensitive to out-of-pocket cost. Using the 2006 implementation of Medicare Part D as a natural experiment, this study examines the impact of changes in drug coverage on use of cholinesterase inhibitors and memantine by comparing use before and after Medicare Part D implementation among older adults who did and did not experience a change in coverage.Retrospective analyses of claims data from 35,102 community-dwelling Medicare beneficiaries in Pennsylvania aged 65 or older. Beneficiaries were continuously enrolled in a Medicare Advantage plan from 2004 to 2007. Outcome variables were any use of donepezil (Aricept®), galantamine (Razadyne®), rivastigmine (Exelon®), tacrine (Cognex®), or memantine (Namenda®) each year and the number of 30-day prescriptions filled for these drugs. Independent variables included type of drug benefit pre-Part D (No coverage, $150 cap, $350 cap, and No cap as the reference group), time period, and their interaction. Sensitivity analyses were conducted to test if there are differences in use by drug class or if beneficiaries with a diagnosis of dementia pre-Part D experienced an increase in use post-Part D.The No coverage group had a 38% increase in the odds ratio of any use of antidementia medications (P = 0.0008) post-Part D relative to the No cap group. All four coverage groups had significant increases in number of 30-day prescriptions (P < 0.001) over the study period. In adjusted models that included the sub-sample with any use pre-Part D, the No coverage group had a 36% increase in prescriptions (P = 0.002) and the $350 cap group had a 15% increase (P = 0.003) after adjusting for trends in the No cap group. Results from the sensitivity analysis for the sub-sample with a diagnosis of dementia pre-Part D show that each group had significant increases in 30-day prescriptions compared to the No cap control group (P < 0.05).Use of cholinesterase inhibitors and memantine in our sample increased and a greater increase in use was observed among Medicare beneficiaries who experienced improvements in drug coverage under Medicare Part D.