therapeutic strategies in dementia

PETERSEN, PhD, MD, Consultant, Department of Neurology, Alzheimer's Disease Research Center, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. WARNER, MD, MRCPsych, Senior Lecturer/Honorary Consultant in Geriatric Psychiatry, Department of Psychological Medicine, Imperial College, London, UK.

Preface

However, much remains to be done, and given the rapid expansion of the population of people with dementia and those who care for them, it will be necessary for health care providers and those involved in dementia research to run very hard indeed if only we would stand still and not be submerged by the rising tide of need. We also thank the individual contributors whose on-schedule submission of the high-quality chapters that follow have made our work as editors an easy and enjoyable task.

Current pharmacological approaches in dementia

Cholinesterase inhibitors: synthesis of meta-analysis/randomized controlled trials

A comparison of donepezil and galantamine in the treatment of cognitive symptoms of Alzheimer's disease: a meta-analysis. Lanctot KL, Herrmann N, Yau KK et al. Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis.

Figure 1.1 Advantages and disadvantages of level of evidence in determining efficacy and effectiveness.

Cholinesterase inhibitors: long-term studies

Long-term efficacy and safety of donepezil in the treatment of Alzheimer's disease: final analysis of a US multicenter open-label study. Wilcock G, Howe I, Coles H et al. Long-term comparison of galantamine and donepezil in the treatment of Alzheimer's disease.

Figure 2.1 Delayed start model to show 1-year effects of rivastigmine on cognition: ADAS-Cog

Cholinesterase inhibitors: head-to-head studies

For example, even in the maintenance phase of the study (ie excluding all subjects who withdrew in the titration phase), 15.3% of rivastigmine-treated patients reported vomiting compared to 4.4% of donepezil-treated patients . The published study abstract concludes that significant advantages were found in treatment response to galantamine (compared to donepezil) in cognition, as measured by response rates on the MMSE and ADAS-Cog.

Table 3.1 Satisfaction/ease of use questionnaires

Ginkgo biloba

Additionally, one of the two Gingko trials included [27] did not use the assessment of cognitive functioning, ADAS-Cog [21], which is the primary outcome measure in the review. A randomized, double-blind, placebo-controlled trial of two doses of ginkgo biloba extract in dementia of the Alzheimer type.

Memantine

A subanalysis of the NPI showed a significant advantage of memantine in the domains of delusions and agitation/aggression. Results of a randomized, placebo-controlled 6-month study of memantine in the treatment of mild to moderate Alzheimer's disease in Europe.

Figure 5.1 Differentiation from other NMDA antagonists (with permission from [23]).

Anti-oxidant drugs

Klatte et al.[44] Population and design: 130 subjects Results: Subjects taking vitamin E dropped in the clinic for memory impairment, significantly lower than those in the CERAD cohort, probably AD according to NINCDS-ADRDA Comment: Many limitations of the CERAD cohort (criterions for drop- outs, donepezil intake not included and vitamin E use not available and (at least 5 mg per day) and vitamin E age differences). Fillenbaum et al.[43] Population and design: 616 subjects from a Results: 8% subjects used vitamins; 141 subjects from the secondary analysis of a subsample of cases had dementia (93 AD). Therapeutic strategies in dementia Sano et al.[45] Subjects and study design:342 subjects with results:Delay in time to primary outcome for.

Thal et al.[58] Subjects and Study Design: 536 subjects, age Results: There were no significant differences between. Petersen et al.[46] Subjects and Study Design: 769 subjects with Results: No effect of vitamin E on primary outcome. Nathan et al.[64] Subjects and Study Design: 11 healthy Results: No acute effects of Ginkgo biloba berries were found for volunteers receiving Ginkgo biloba (120 mg) or for any of the memory tests investigated.

Maurer et al.[68] Subjects and study design: 20 subjects with Results: Gingko treated group performed better than AD.

Pharmacoeconomic studies

All but two of the cost-effectiveness studies used the model as the analytical framework for the analysis. A brief summary of the modeling method used in the reported studies has been provided above. In most cost-effectiveness studies of AD drugs, the structure of the model is not elaborated (if at all).

As part of the detailed investigation into the cost-effectiveness of Alzheimer's disease drugs, a systematic search of the literature has been undertaken to identify the methods available to model disease progression over time. The cost-effectiveness studies of AD drugs have limitations due to the methods used to model disease progression, but this may reflect the general literature available to inform the field of AD. The focus of the literature on quality of life (QOL) for AD is on cognitive function and not on quality of life per se [47].

Donepezil and rivastigmine in the treatment of Alzheimer's disease: a best-evidence synthesis of published data on their efficacy and cost-effectiveness.

Table 7.3 reports basic data from a critical appraisal of the published economic evalu- evalu-ations

Biological developments and future therapies

Disease-modifying therapeutic strategies for Alzheimer’s disease: targeting the

Anti-inflammatory drugs

The main trial to test this hypothesis has been the Alzheimer's Disease Prevention Trial (ADAPT). Inverse association of anti-inflammatory treatments and Alzheimer's disease: initial results of a co-twin control study. APOE-'4 predicts but anti-inflammatory drugs do not prevent Alzheimer's disease in an elderly community sample.

Nonsteroidal anti-inflammatory drug use and Alzheimer's disease: a case-control study in Rochester, Minnesota, 1980 to 1984. No support for a protective effect of NSAIDs against Alzheimer's disease from a follow-up population-based study. Effect of nonsteroidal anti-inflammatory drugs on the risk of Alzheimer's disease: systematic review and meta-analysis of observational studies.

Results of a double-blind, randomized, placebo-controlled trial of celecoxib for the treatment of Alzheimer's disease progression.

Figure 9.1 Relative risk of Alzheimer’s disease (with permission from reference [43]).

Nicotine and amyloid-!

Mucke L, Masliah E, Yu GQ et al. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. Schenk D, Barbour R, Dunn W et al. Immunization with amyloid-beta attenuates Alzheimer's disease-like pathology in the PDAPP mouse. Nordberg A, HellströmLindahl E, Lee M, et al. Chronic nicotine treatment reduces beta-amyloidosis in the brain of a mouse model of Alzheimer's disease (APPsw).

Figure 10.1 Schematic picture of the suggested pathological processes in AD. Age, genetics and lifestyle are all important factors that might determine the risk of developing AD

Butyrylcholinesterase

The G4 form of AChE, which is predominantly at the synapse in the normal brain, may be reduced in AD by as much as 90% in some areas of the brain. This reduction is primarily due to loss of the G4 form at presynaptic sites of cholinergic synapses in the brain [14]. In normal brains, the ratio of BuChE-positive glia to AChE-positive glia is highest in the entorhinal and in the frontotemporal cortices (two areas highly susceptible to AD) [18].

Indeed, the improvement in cognitive performance after cholinesterase inhibitor treatment may best correlate with inhibition of BuChE activity in the central nervous system [54]. This evidence further suggests that inhibition of BuChE in the central nervous system (as with rivastigmine in this study) may be a therapeutically beneficial mechanism that is clinically useful in the treatment of AD. Neurological cholinesterases in normal brain and in Alzheimer's disease: relation to plaques and selective vulnerability of patients.

Giacobini E, Spiegel R, Veroff AE et al. Inhibition of acetyl and butyryl cholinesterases in the cerebrospinal fluid of patients with Alzheimer's disease by rivastigmine: correlation with cognitive benefits.

Figure 11.1 AChE activity decreases, and relative BuChE activity increases in the AD brain

Sex hormones in the treatment of Alzheimer’s disease

In the Women's Health Initiative randomized controlled trial (WHIMS), 2229 women were treated with placebo or conjugated equine estrogen plus methoxyprogesterone acetate (HRT) for a median period of 4 years. Lu PH, Masterman DA, Mulnard R et al. Effects of testosterone on cognition and mood in male patients with mild Alzheimer's disease and healthy older men. Postmenopausal estrogen replacement therapy and risk of Alzheimer's disease: a population-based case-control study.

Prospective study of estrogen replacement therapy and risk of developing Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Risk factors for Alzheimer's disease: a prospective analysis from the Canadian Study of Health and Aging. Mulnard RA, Cotman CW, Kawas C et al. Estrogen therapy for the treatment of mild to moderate Alzheimer's disease: a randomized controlled trial.

Cherrier MM, Matsumoto AM, Amory JK et al. Testosterone improves spatial memory in men with Alzheimer's disease and mild cognitive impairment.

Allosteric sensitization of brain nACh receptors as a treatment strategy in Alzheimer’s dementia

The functional significance of the different subtypes and their different distribution in the brain are not yet fully understood. In electrophysiological studies of cell current, APL action causes a leftward shift and increase in the slope of the agonist dose-response curve [69]. The action of APL can be described as (i) an allosteric increase in agonist binding affinity to nicotinic receptors and (ii) an increase in agonist-induced channel probability.

In the concentration range tested, none of the AChE inhibitors, with the exception of galantamine, significantly affected ACh-induced currents. In the case of APL galantamine, this picture is clouded by the facts that galantamine (i) exhibits further modest AChE inhibitory activity and (ii) does not penetrate well into the brain, resulting in excessive peripheral side effects (see disclaimer). - full stop in the section: What can be improved?). Cellular expression of α7 nicotinic acetylcholine receptor protein in the temporal cortex in Alzheimer's and Parkinson's disease - a stereological approach.

Expression of nicotinic acetylcholine receptor units in Alzheimer's disease cerebral cortex: histotopographic correlation with amyloid plaques and hyperphosphorylated tau protein.

Figure 13.1 Differences between a nicotinic agonist and an allosteric modulator of nicotinic receptors.

The utility of biomarkers in the diagnosis and monitoring of Alzheimer’s disease

Amyloid precursor protein-mediated free radicals and oxidative damage: implications for the development and progression of Alzheimer's disease. CSF biomarkers of Alzheimer's disease: levels of beta-amyloid, tau, phosphorylated tau relate to clinical symptoms and survival. Serum or cerebrospinal fluid levels of glyceraldehyde-derived advanced glycation end products (AGEs) may be a promising biomarker for early detection of Alzheimer's disease.

The effect of simvastatin treatment on amyloid precursor protein and cholesterol metabolism in the brain in patients with Alzheimer's disease. Mapping the evolution of regional atrophy in Alzheimer's disease: unbiased analysis of fluid-registered serial MRI. Comparison of the diagnostic performance of FDG-PET and VBM-MRI in very mild Alzheimer's disease.

Follow-up SPECT study of cerebral blood flow change during donepezil treatment in patients with Alzheimer's disease.

Figure 14.1 Non-genetic diagnostic biomarkers.

Management of non-cognitive issues in dementia

Non-pharmacological interventions for BPSD

Cleanliness can sometimes conflict with personal autonomy, as an individual with dementia may choose not to bathe. Providing information to caregivers of persons with dementia is an essential non-pharmacological intervention. Ongoing caregiver support that provides ongoing opportunities to seek advice has been shown to help caregivers and delay institutionalization of persons with dementia [12].

Although an individual's ability to communicate declines in advanced dementia, communication skills are crucial to maintaining quality of life and understanding the perspective of the person with dementia. Others have advised using broad opening sentences, treating the person with dementia as an equal, sharing experiences and feelings, and finding topics that are meaningful [15]. Providing maximum autonomy to the person with dementia is a central guiding principle, placing greater importance on the person's habits or preferences than on the convenience of the care system.

The intervention may target a change in the environment, the behavior of the worker, the care system or the person with dementia.