Turning Principles into Practice in Alzheimer's Disease

J. Lindesay; R. Bullock; H. Daniels; M. Emre; H. Förstl; L. Frölich; T. Gabryelewicz; P. Martínez-Lage; A. U. Monsch; M. Tsolaki; T. van Laar


Int J Clin Pract. 2010;64(10):1198-1209. 

In This Article

Stress the Importance of Optimal Diagnosis and Treatment

International Alzheimer's Associations and practice guidelines encourage timely detection and diagnosis of dementia, and subsequent treatment initiation.[14] The importance and advantages of early diagnosis have already been discussed. The European Federation of Neurological Societies (EFNS) has recently published recommendations on the diagnosis of dementia.[14] Clinical diagnosis should be based on agreed criteria [e.g., Diagnostic and Statistical Manual of Mental Disorders 4th edition/National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimers Disease and Related Disorders Association (DSM-IV/NINCDS-ADRDA) for Alzheimer's disease;[27] Consortium criteria for dementia with Lewy bodies;[28] National Institute of Neurological Disorders and Stroke and Association Internationale pour la Recherché et l'Enseignement en Neurosciences (NINDS-AIREN) for vascular dementia.][29] Extending these criteria, the EFNS guidelines state that neuroimaging is now the most important investigation in the work-up of dementia to aid in differential diagnosis and management decisions.[14] Structural brain imaging (computer tomography or magnetic resonance imaging [MRI]) should be used in the evaluation of every patient suspected of dementia. Figure 1 shows structural MRI in Alzheimer's disease, where hippocampal, medial-temporal and whole brain atrophy, with resulting ventricular enlargement, are key features. Other techniques may be used if uncertainty remains after clinical and structural work-up. For example, single photon emission computed tomography (SPECT) provides a measurement of regional cerebral blood flow, which is reflective of neuronal activity. Bilateral temporal, parietal and posterior cingular hypoperfusion tend to be apparent in Alzheimer's disease (Figure 2). Fluorodeoxyglucose positron emission tomography (FDG-PET) imaging, a more refined investigational technique, can also be used to measure brain metabolism, and in Alzheimer's disease it will typically show bilateral temporoparietal hypometabolism (Figure 3); however, this has yet to be made clinically widely available. In addition, growing evidence supports the added diagnostic value of specific cerebrospinal fluid biomarkers (e.g., amyloid-β, total tau and phospho-tau) for evaluation of patients with atypical presentations of Alzheimer's disease.[27]

Figure 1.

Structural magnetic resonance imaging (MRI) in Alzheimer's disease: whole brain atrophy and ventricular enlargement are key features. (Reproduced with the kind permission of Dr P. Martínez-Lage, Fundacion CITA-Alzheimer, San Sebastian, Spain)

Figure 2.

Functional imaging (SPECT) showing bilateral temporal, parietal and posterior cingular hypoperfusion in a 76-year-old patient with mild Alzheimer's disease. (Reproduced with the kind permission of Drs P. Martínez-Lage and I. Roca, Fundacion CITA-Alzheimer, San Sebastian and Hospital Vall d'Hebron, Barcelona, Spain, respectively)

Figure 3.

Functional imaging (FDG-PET) in Alzheimer's disease: bilateral temperoparietal hypometabolism. (Reproduced with the kind permission of Drs P. Martínez-Lage and J. Arbizu, Fundacion CITA-Alzheimer, San Sebastian and Clinica Universidad de Navarra, Pamplona, Spain, respectively)

The EFNS also recommends that medical history (including co-morbidities) should be collected from patients, and supplemented by an independent informant when possible.[14] Assessments of cognitive performance, activities of daily living (ADLs), behavioural and psychological symptoms are central to the diagnosis of dementia and should be performed in all patients.[14] A general neurological and physical examination should also be performed, and screening blood tests should be used to identify potential reversible causes and aggravators of cognitive impairment (e.g., metabolic, infectious and toxic conditions), and any physical co-morbidities.[14]

Once diagnosed with Alzheimer's disease, all patients and their caregivers should be offered the opportunity to benefit from non-pharmacological and pharmacological therapies. Non-pharmacological options include 'cognitive training' exercises. Typically, these focus on specific domains of cognitive functioning, although more general cognitively-mediated domains of functioning (e.g., ADLs, instrumental ADLs, social skills and behavioural disturbances) can also be targeted.[30] Cognitive training involves guided practice on a set of standard tasks designed to reflect particular cognitive functions, such as memory, attention, or problem-solving ('executive functions'). The underlying assumption is that practice has the potential to improve or at least maintain functioning in the given domain, and that any effects of practice will generalise beyond the immediate training context. A meta-analysis of 17 controlled studies identified suggests that patients with Alzheimer's disease may derive some cognitive and functional benefits from cognitive training.[30] Restorative cognitive training strategies demonstrate larger effect sizes than compensatory strategies. The largest effect sizes were seen in the domains of learning, memory, executive functioning, ADLs, general cognition, depression and general functioning.

Amongst pharmacological options (Table 2), the available treatments for Alzheimer's disease offer symptomatic improvements with meaningful benefits. Cholinesterase inhibitors (rivastigmine, donepezil and galantamine) are widely approved for the treatment of mild to moderate Alzheimer's disease[14] (Table 2). As a class, these agents can offer benefits in three main affected areas, the ABCs of Alzheimer's disease: ADLs; behaviour; and cognitive function.[31–33] Recent guidance from the Committee for Medicinal Products for Human Use (CHMP) acknowledge the particular importance of ADLs as an outcome criterion for any future clinical trials in Alzheimer's disease. For the purpose of drug approval, they suggest that two primary outcomes should be used, assessing cognition and ADLs.[34] While cognitive dysfunction is the hallmark of Alzheimer's disease, and can be measured objectively, ADL assessment is useful to evaluate the meaningful impact of a treatment on everyday functioning. For the demonstration of patient-related clinical benefits, outcome parameters related to ADL function, behavioural symptoms or quality of life should be followed. Furthermore, clinical endpoints such as functional worsening or nursing home placement might be useful, despite their methodological difficulties.[34,35]

In principle, initiation of treatment in early (mild to moderate) stages of dementia has the greatest potential to improve long-term outcomes, by delaying symptomatic decline while the cognitive reserve is still relatively preserved.[36] The benefits of early cholinergic treatment are suggestive, but not proven, across separate open-label extension studies of rivastigmine (oral and transdermal),[37,38] donepezil[39] and galantamine[40] in patients with Alzheimer's disease. In each of these trials, patients who received placebo initially in the core double-blind phase (i.e. a delayed treatment start) did not appear to 'catch up' with those who received treatment for the entire study period. The EFNS guidelines recommend treatment with cholinesterase inhibitors be considered at the time of diagnosis in patients with Alzheimer's disease, taking into account expected therapeutic benefits and potential safety issues.[14] This guidance is also being followed at the national level. For example, the UK Department of Health National Dementia Strategy, which includes a summary of National Institute for Clinical Excellence (NICE) and Social Care Institute for Excellence (SCIE) evidence for dementia services, specifies 'good quality early diagnosis and intervention for all' as one of their 17 objectives.[41] However, in the absence of firm evidence of cost-effectiveness, the NICE treatment guidelines do not yet support cholinesterase inhibitor therapy in mild Alzheimer's disease. Treatment at later disease stages is also important. Neocortical cholinergic deficits still progress in the disease course,[42] and patients with more advanced Alzheimer's disease, who may have greater cholinergic deficits, have been shown to derive particularly strong benefits from cholinesterase inhibitor therapy.[43,44]

Advanced Alzheimer's disease is typically associated with the emergence of behavioural and psychotic problems. Cholinesterase inhibitors have demonstrated some efficacy in behavioural symptoms,[45] although their role in more severely disturbed patients may be limited.[46] This is important because the safety of antipsychotic use in elderly dementia populations has been called into question in recent years. Trials have shown an increased likelihood of serious cerebrovascular adverse events such as stroke and transient ischaemic attack (TIA) in elderly patients taking some atypical antipsychotic agents.[47] Effective use of cholinesterase inhibitors can delay the onset and decrease the severity of neuropsychiatric symptoms in dementia, and may reduce the requirement for antipsychotic and other psychotropic medications.[48,49] In elderly subjects with behavioural and psychotic symptoms of dementia, cholinesterase inhibition may provide a more appropriate therapeutic option than conventional antipsychotic or neuroleptic agents.[47]

It is important that adequate doses of cholinesterase inhibitors are prescribed. Although statistically significant differences have been demonstrated, the benefits demonstrated in clinical trials of these agents may be below clinically-relevant thresholds.[50] However, a study based on standard clinical practice in Italy showed that 65% of patients taking cholinesterase inhibitors – which exhibit dose–response relationships – are taking suboptimal doses.[51] at least partially explaining a lack of response in some patients. Physicians should encourage patients to reach target therapeutic doses of these agents, in order to provide optimal benefits. If patients are unable to reach target therapeutic doses due to associated side effects, slower dose escalation, taking oral agents with food or the use of a transdermal patch therapy may improve tolerability.[52] A careful clinical search for co-morbid medical conditions, which may induce a rapid cognition decline, is also warranted before depriving patients of the potential benefits of treatment altogether.[53]

For patients already receiving target recommended doses but still not responding to treatment, switching to an alternative cholinesterase inhibitor may provide benefits.[53] For example, in one open-label French study, amongst 382 Alzheimer's disease patients who had previously failed to benefit from treatment with donepezil, over half subsequently responded to treatment after switching to rivastigmine, as assessed using a global function scale.[54] In severe Alzheimer's disease, the addition of memantine to a cholinesterase inhibitor regimen may also offer some symptom relief. In a trial of 404 patients with moderate to severe Alzheimer's disease, who were already receiving stable doses of donepezil, the addition of memantine resulted in a 0.9-point improvement on the Severe Impairment Battery, while patients receiving placebo (on top of donepezil) declined by 2.5 points.[55]

Unfortunately, adherence to Alzheimer's disease therapies is notoriously low. Alzheimer's disease is a chronic disease, yet the average pharmacological treatment duration is estimated to be a mere 4–5 months.[56] Ensuring patients stay on any medication long-term is difficult, but amongst the Alzheimer's disease population (including caregivers) non-compliance due to forgetfulness and difficulties coping with multiple medication regimens is particularly common.[4] Some patients or caregivers voluntarily discontinue treatment because of a perceived lack of efficacy, and it is important to always communicate realistic expectations. For example, the disease will inevitably progress despite treatment, and while treatment effects with current therapies are modest they may impact on cognition as well as behaviour. With long-term treatment, a less-than-expected decline despite further clinical worsening may be regarded as a clinical benefit. Patients and caregivers who understand the potential benefits and limitations of treatment may be more likely to stay on treatment for longer. Families of patients with Alzheimer's disease are continually seeking the most promising treatment for their loved ones, and a better commitment to ensuring treatment compliance and adherence may be expected if they understand fully all issues surrounding the effects of treatment.


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