THERAPEUTIC STRATEGIES IN DEMENTIA

PETERSEN, PhD, MD, Consultant, Department of Neurology, Alzheimer's Disease Research Center, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. MARY SANO, PhD, Director of the Alzheimer's Disease Research Center, Professor of Psychiatry, Department of Psychiatry, Mount Sinai Medical Center, New York, Research and Development Program, James J.

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. A 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 during 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 treatment response advantages were found with galantamine (compared to donepezil) on cognition as measured by MMSE and ADAS-Cog response rates.

Table 3.1 Satisfaction/ease of use questionnaires

Ginkgo biloba

Furthermore, one of the two included Gingko studies [27] does not use the assessment of cognitive functioning, the 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 Alzheimer's-type dementia.

Memantine

The NPI sub-analysis showed a significant advantage for memantine in the domain of delusions and agitation/aggression. Results of a 6-month randomized, placebo-controlled trial 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 had a reduction in clinical memory impairment, a significantly lower rate than those in the CERAD cohort NINCDS-ADRDA probable AD Comment: Several limitations of the CERAD cohort (dropout criteria , taking donepezil is not included and vitamin E use is not available and (at least 5 mg daily) and vitamin E age differences). Fillenbaum et al.[43] Population and design: 616 subjects from a Results: 8% of subjects used vitamins; 141 subjects of the secondary analysis of the subsample of cases had dementia (93 AD). Therapeutic strategies in dementia Sano et al.[45] Subjects and study design: 342 subjects Outcomes: 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] Study subjects and design: 769 subjects 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 were found volunteers received Ginkgo biloba (120 mg) or for any of the memory tests examined.

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 a model as the analytical framework for analysis. A brief overview of the modeling approach used in the reported studies is provided above. In most cost-effectiveness studies on AD drugs, the structure of the model is not discussed in any detail (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 drugs for AD 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 the 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

Results of a double-blind, randomized, placebo-controlled trial of celecoxib in the treatment of Alzheimer's disease progression. Decreased protein levels of nicotine receptor subunits in the hippocampus and temporal cortex of patients with Alzheimer's disease. A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid.

Mucke L, Masliah E, Yu GQ et al. High neuronal expression of abet 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 reduces Alzheimer's disease-like pathology in PDAPP mice. 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 9.1 Relative risk of Alzheimer’s disease (with permission from reference [43]).

Butyrylcholinesterase

The G4 form of AChE which is predominantly at the synapse in the normal brain can be reduced in AD by as much as 90% in some areas of the brain. This reduction is mainly 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 frontotemporal cortex (two areas highly susceptible to AD) [18].

Indeed, improvement in cognitive function after treatment with a cholinesterase inhibitor 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 by rivastigmine in this study) may be a therapeutically beneficial mechanism that is clinically useful in the treatment of AD. Neurological cholinesterases in the normal brain and in Alzheimer's disease: relationship to plaques and patients with selective vulnerability.

Giacobini E, Spiegel R, Veroff AE et al. Inhibition of acetyl- and butyryl-cholinesterase in the cerebrospinal fluid of Alzheimer's disease patients 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 Memory (WHIMS) randomized controlled trial, 2229 women were treated with either placebo or conjugated equine estrogen and methoxyprogesterone acetate (HRT) for an average 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 elderly 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 differential distribution in the brain is not yet fully understood. In whole-cell current electrophysiological studies, the APL action produces a shift to the left and an increase in the slope of the agonist dose-response curve [ 69 ]. The action of APL can be described as (i) allosteric enhancement of the binding affinity of agonist to nicotinic receptors, and (ii) increase in the probability of agonist-induced channel.

In the concentration range tested, none of the AChE inhibitors, with the exception of galantamine, significantly affected ACh-induced currents. In the case of the APL-galantamine, this picture is obscured by the facts that galantamine (i) exhibits additional modest AChE inhibitory activity, and (ii) does not penetrate well into the brain, resulting in excessive peripheral side effects ( see it - topic in section: What can be improved?). Cellular expression of a7 nicotinic acetylcholine receptor protein in the temporal cortex in Alzheimer's and Parkinson's disease - a stereological approach.

Expression of nicotinic acetylcholine receptor subunits in Alzheimer's disease cerebral cortex: histotopographical 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 for Alzheimer's disease: levels of beta-amyloid, tau, and phosphorylated tau are associated with clinical symptoms and survival. Serum or cerebrospinal fluid levels of glyceraldehyde-derived advanced glycation end products (AGEs) may be a promising biomarker for the early detection of Alzheimer's disease.

Effect of simvastatin treatment on amyloid precursor protein and brain cholesterol metabolism in patients with Alzheimer's disease. Mapping the development of regional atrophy in Alzheimer's disease: an unbiased analysis of serial fluid-registered 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 changes during donepezil therapy 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 be at odds with personal autonomy, as someone with dementia may prefer not to bathe. Providing information to caregivers of persons with dementia is an essential non-pharmacological intervention. Ongoing support for caregivers, which provides continuous opportunities to seek advice, has been shown to assist caregivers and delay institutionalization of persons with dementia [12].

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

The intervention can focus on a change in the environment, the behavior of the employee, the care system or the person with dementia.