Joanne Rodda

Are cholinesterase inhibitors effective in the management of the behavioral and psychological symptoms of dementia in Alzheimer's disease? A systematic review of randomized, placebo-controlled trials of donepezil, rivastigmine and galantamine

BACKGROUND The study aim was to conduct a systematic review of the evidence from randomized, placebo controlled trials related to the efficacy of donepezil, rivastigmine and galantamine in the treatment of behavioral and psychological symptoms of Alzheimers disease. METHODS Electronic database searches of MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials were carried out using multiple search terms. Articles included were original publications of randomized, placebo-controlled trials of monotherapy of donepezil, rivastigmine or galantamine that reported a behavioral outcome measure. RESULTS 14 studies were identified that matched inclusion criteria. Nine were of donepezil, three of galantamine and two of rivastigmine. Median study treatment length was 24 weeks (range 12-170). Most studies used the Neuropsychiatric Inventory as a behavioral outcome measure although three used specific scales for either agitation or apathy. Four studies were specifically designed to assess behavioral outcomes whilst in the majority of studies behavioral outcomes were only secondary measures. Three studies found statistically significant, albeit modest, differences in the change of NPI total score between drug and placebo. The interpretation of the results of many studies is limited by methodological considerations, including generally low NPI scores at baseline and the investigation of behavioral and psychological symptoms of dementia (BPSD) as secondary outcomes. CONCLUSIONS The evidence base regarding the efficacy of cholinesterase inhibitors in BPSD is limited, in part due to methodological considerations. In the absence of alternative safe and effective management options, the use of cholinesterase inhibitors is an appropriate pharmacological strategy for the management of BPSD in Alzheimers disease.

Depression in older adults

#### Summary points Depression is a major contributor to healthcare costs and is projected to be the leading cause of disease burden in middle and higher income countries by the year 2030.w1 Depression in later life, traditionally defined as age older than 65, is associated with disability, increased mortality, and poorer outcomes from physical illness. Most clinicians will encounter older patients with depression in their day to day practice, but although treatment is as effective for older patients as for younger adults, the condition is often under-recognised and under-treated. According to WHO data, proportionately more people aged over 65 commit suicide than any other age group, and most have major depression. Older people who attempt suicide are more likely to die than younger people, while in those who survive, prognosis is worse for older adults.1 With a progressively ageing population worldwide, identification and treatment of depression in older adults becomes increasingly important, especially as older patients may have different presentations and needs than younger ones. We consider recent systematic reviews, meta-analyses, and randomised controlled trials to …

Subjective cognitive impairment: increased prefrontal cortex activation compared to controls during an encoding task

Subjective cognitive impairment (SCI) has been proposed as a clinical stage which may precede mild cognitive impairment in the clinical continuum of AD, and is characterised by the presence of subjective memory complaints in the absence of objective cognitive deficits. Specific memory‐related brain activation differences have been reported in mild cognitive impairment and in cognitively normal individuals at known genetic risk of AD; our objective was to determine whether similar differences are present in people with SCI.

Cholinesterase inhibitors and memantine for symptomatic treatment of dementia

A 78 year old woman is assessed in the memory clinic. Her family feel that she has become increasingly forgetful over the past two years, misplacing objects around the house and forgetting her drugs. Her speech is repetitive, and she struggles with day to day activities such as cooking. Routine blood tests are normal, and she scores 21/30 on the mini-mental state examination (MMSE) with deficits in orientation, attention and concentration, and recall. Magnetic resonance imaging, performed to exclude other pathology, reveals global cerebral atrophy consistent with Alzheimer’s disease. In discussion with her and her family, a management plan is formulated that includes referral to the local dementia advisor and social services for day opportunities as well as prescription of a cholinesterase inhibitor. The most common types of dementia are Alzheimer’s disease, vascular dementia, mixed dementia, dementia with Lewy bodies, and frontotemporal dementia. At present, four drugs are licensed in the UK for the management of Alzheimer’s disease, the cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and memantine, a partial antagonist of NMDA receptors (table 1⇓). The use of these drugs in other types of dementia has been investigated, with the most convincing evidence coming from studies of dementia with Lewy bodies and Parkinson’s disease dementia. There is currently no evidence to support the use of cholinesterase inhibitors or memantine in frontotemporal dementia or mild cognitive impairment. View this table: Table 1  Licensed indications for cholinesterase inhibitors and memantine in the UK Cholinesterase inhibitors increase the availability of acetylcholine at the synaptic cleft by preventing its breakdown by the enzyme acetylcholinesterase. Galantamine also modulates nicotinic acetylcholine receptors, and rivastigmine inhibits butylcholinesterase, but the importance of these additional properties is unknown. Memantine is believed to act by reducing glutamate mediated excitotoxicity. In this review we summarise the evidence and current guidance related to the use of …

Subjective cognitive impairment: Functional MRI during a divided attention task

BACKGROUND Individuals with subjective cognitive impairment (SCI) have persistent memory complaints but normal neurocognitive performance. For some, this may represent a pre-mild cognitive impairment (MCI) stage of Alzheimers disease (AD). Given that attentional deficits and associated brain activation changes are present early in the course of AD, we aimed to determine whether SCI is associated with brain activation changes during attentional processing. METHODS Eleven SCI subjects and 10 controls completed a divided attention task during functional magnetic resonance imaging. RESULTS SCI and control groups did not differ in sociodemographic, neurocognitive or behavioural measures. When group activation during the divided attention task was compared, the SCI group demonstrated increased activation in left medial temporal lobe, bilateral thalamus, posterior cingulate and caudate. CONCLUSION This pattern of increased activation is similar to the pattern of decreased activation reported during divided attention in AD and may indicate compensatory changes. These findings suggest the presence of early functional changes in SCI; longitudinal studies will help to further elucidate the relationship between SCI and AD.

Comparison of cognitive decline between dementia with Lewy bodies and Alzheimer's disease: a cohort study

Objectives Dementia with Lewy bodies (DLB) accounts for 10%–15% of dementia cases at autopsy and has distinct clinical features associated with earlier institutionalisation and a higher level of carer distress than are seen in Alzheimers disease (AD). At present, there is on-going debate as to whether DLB is associated with a more rapid cognitive decline than AD. An understanding of the rate of decline of cognitive and non-cognitive symptoms in DLB may help patients and carers to plan for the future. Design In this cohort study, the authors compared 100 AD and 58 DLB subjects at baseline and at 12-month follow-up on cognitive and neuropsychiatric measures. Setting Patients were recruited from 40 European centres. Participants Subjects with mild–moderate dementia. Diagnosis of DLB or AD required agreement between consensus panel clinical diagnosis and visual rating of 123I-FP-CIT (dopamine transporter) single photon emission computed tomography neuroimaging. Outcome measures The Cambridge Cognitive Examination including Mini-Mental State Examination and Neuropsychiatric Inventory (NPI). Results The AD and DLB groups did not differ at baseline in terms of age, gender, Clinical Dementia Rating score and use of cholinesterase inhibitors or memantine. NPI and NPI carer distress scores were statistically significantly higher for DLB subjects at baseline and at follow-up, and there were no differences between AD and DLB in cognitive scores at baseline or at follow-up. There was no significant difference in rate of progression of any of the variables analysed. Conclusions DLB subjects had more neuropsychiatric features at baseline and at follow-up than AD, but the authors did not find any statistically significant difference in rate of progression between the mild–moderate AD and DLB groups on cognitive or neuropsychiatric measures over a 12-month follow-up period.

Ten years of cholinesterase inhibitors

In this editorial we have summarised ten years of evidence relating to the use of cholinesterase inhibitors in Alzheimers and other dementias. We have presented this evidence in the context of the evolution of public and professional awareness of dementia and its management and prescribing patterns over this time frame. We also briefly outline recent political and legal events surrounding the 2007 NICE guidance and the possible long‐term impact of cholinesterase inhibitors on clinical practice. Whilst cholinesterase inhibitors continue to play a part in the management of Alzheimers disease, it is possible that their most important legacy will be their contribution to the increased awareness and recognition of dementia as a neurodegenerative disease and the resulting transformation of old age psychiatry services. Copyright

Memory complaints with and without memory impairment: the impact of leukoaraiosis on cognition.

White matter alterations, leukoaraiosis (LA) on structural MRI, are associated with cognitive deficits and increased risk of dementia. LA may also impact on subjective memory complaints in otherwise healthy older adults. Little is known about the interplay between LA memory complaints and cognition. We investigated cognitive phenotypes associated with LA in 42 non-demented older adults categorized as having subjective cognitive complaints with no objective cognitive impairment-the subjective cognitive impairment group (SCI; n = 12), amnesic mild cognitive impairment (aMCI; n = 20), or healthy controls (HC; n = 11). We measured LA severity on MRI with a 40-point visual rating scale. Controlling for age and Mini-Mental State Examination (MMSE) score, analyses revealed multiple between-group differences. Follow-up linear regression models investigating the underlying contributors to each clinic groups cognitive profile indicated that LA contributed to learning slope variance (after accounting for age and MMSE) but only for the SCI group. Although the SCI group showed a significantly steeper learning slope when compared to HC and aMCI, increasing LA severity negatively impacted this groups rate of learning. This, in conjunction with the significant contribution of age on SCI learning slope performance variance suggests that greater LA burden at a younger age may contribute to subtle changes in learning for individuals with subjective cognitive complaints.

Dopaminergic imaging: clinical utility now and in the future.

Over the past ten years, dopaminergic imaging has become increasingly part of the assessment and diagnosis of dementia. There are numerous PET and SPECT ligands available that target different steps in the process of neurotransmission. Abnormalities in dopaminergic imaging measures are consistent features of dementia with Lewy bodies (DLB) and other parkinsonian syndromes, and can be used to facilitate diagnosis, particularly in distinguishing between DLB and Alzheimers disease. This review summarizes present knowledge in this area and the implications for current and future clinical practice.

Attitudes of UK psychiatrists to the diagnosis of MCI in clinical practice.

BACKGROUND Mild cognitive impairment (MCI) may represent a transitional stage between normal functioning and dementia. Following the initial criteria developed by Petersen et al. in 1999, which focused on memory deficit in the context of otherwise normal cognition and general functioning, the concept has evolved with the introduction of subtypes of MCI and improved understanding of etiology. Our aim was to investigate current practice as well as familiarity with and attitudes toward the concept of MCI amongst UK old age psychiatrists. METHOD We sent an anonymized postal survey to all clinicians on the Royal College of Psychiatrists Old Age Psychiatry register. Questions covered attitudes toward the concept of MCI in addition to diagnostic criteria and assessment tools used. RESULTS The response rate was 39% (453 of 1,154 questionnaires returned completed). The majority of respondents were consultants (83%) and 91% diagnosed MCI. Only 4.4% of the respondents thought that the concept of MCI was not useful and 79% of them required a memory complaint from either the patient or an informant for a diagnosis, but the majority did not have a specific cut-off on cognitive testing. Eighty-two percent reported that they required no or minimal impairment in activities of daily living for a diagnosis of MCI. The two most frequently used tools for assessment were the Mini-Mental State Examination and the Addenbrookes Cognitive Examination-Revised. CONCLUSIONS Our survey shows that in the United Kingdom, the term MCI has become part of everyday clinical practice in psychiatry, suggesting that clinicians find it a useful term to conceptualize the transitional stage between normal aging and dementia. However, there is variability in diagnostic practice.