Editorial: Alzheimer's Disease and the Fornix

This e-book focuses primarily on the role of the fornix as a functional, prognostic, and diagnostic marker of Alzheimer’s disease (AD), and the application of such a marker in clinical practice. Researchers have long been focused on the cortical pathology of AD, since the most important pathologic features are the senile plaques found in the cortex, and the neurofibrillary tangles and neuronal loss that start from the entorhinal cortex and the hippocampus. In addition to gray matter structures, histopathological studies indicate that the white matter is also altered in AD. The fornix is a white matter bundle that constitutes a core element of the limbic circuits, and is one of the most important anatomical structures related to memory. The fornices originate from the bilateral hippocampi, merge at the midline of the brain, again divide into the left and right side, and then into the precommissural and the postcommissural fibers, and terminate at the septal nuclei, nucleus accumbens (precommissural fornix), and hypothalamus (postcommissural fornix). These functional and anatomical features of the fornix have naturally captured researchers’ attention as possible diagnostic and prognostic markers of AD. Growing evidence indicates that the alterations seen in the fornix are potentially a good marker with which to predict future conversion from mild cognitive impairment to AD, and even from a cognitively normal state to AD. The degree of alteration is correlated with the degree of memory impairment, indicating the potential for the use of the fornix as a functional marker. Moreover, there have been attempts to stimulate the fornix to recover the cognitive function lost with AD. Our goal is to provide information about the status of current research and to facilitate further scientific and clinical advancement in this topic

Systematic review of psychological approaches to the management of neuropsychiatric symptoms of dementia

Objective: The authors systematically reviewed the literature on psychological approaches to treating the neuropsychiatric symptoms of dementia.Method: Reports of studies that examined effects of any therapy derived from a psychological approach that satisfied prespecified criteria were reviewed. Data were extracted, the quality of each study was rated, and an overall rating was given to each study by using the Oxford Centre for Evidence-Based Medicine criteria.Results: A total of 1,632 studies were identified, and 162 satisfied the inclusion criteria for the review. Specific types of psychoeducation for caregivers about managing neuropsychiatric symptoms were effective treatments whose benefits lasted for months, but other caregiver interventions were not. Behavioral management techniques that are centered on individual patients' behavior or on caregiver behavior had similar benefits, as did cognitive stimulation. Music therapy and Snoezelen, and possibly sensory stimulation, were useful during the treatment session but had no longer-term effects; interventions that changed the visual environment looked promising, but more research is needed.Conclusions: Only behavior management therapies, specific types of caregiver and residential care staff education, and possibly cognitive stimulation appear to have lasting effectiveness for the management of dementia-associated neuropsychiatric symptoms. Lack of evidence regarding other therapies is not evidence of lack of efficacy. Conclusions are limited because of the paucity of high-quality research ( only nine level-1 studies were identified). More high-quality investigation is needed

Comparing proxy rated quality of life of people living with dementia in care homes

Background: Improving quality of life (QOL) for people with dementia is a priority. In care homes, we often rely on proxy ratings from staff and family but we do not know if, or how, they differ in care homes. Methods: We compared 1056 pairs of staff and family DEMQOL-Proxy ratings from 86 care homes across England. We explored factors associated with ratings quantitatively using multilevel modelling and, qualitatively, through thematic analysis of 12 staff and 12 relative interviews. Results: Staff and family ratings were weakly correlated (ρs = 0.35). Median staff scores were higher than family's (104 v. 101; p < 0.001). Family were more likely than staff to rate resident QOL as ‘Poor’ (χ2 = 55.91, p < 0.001). Staff and family rated QOL higher when residents had fewer neuropsychiatric symptoms and severe dementia. Staff rated QOL higher in homes with lower staff:resident ratios and when staff were native English speakers. Family rated QOL higher when the resident had spent longer living in the care home and was a native English. Spouses rated residents’ QOL higher than other relatives. Qualitative results suggest differences arise because staff felt good care provided high QOL but families compared the present to the past. Family judgements centre on loss and are complicated by decisions about care home placement and their understandings of dementia. Conclusion: Proxy reports differ systematically between staff and family. Reports are influenced by the rater:staff and family may conceptualise QOL differently

Management of Neuropsychiatric Symptoms of Dementia in Clinical Settings: Recommendations from a Multidisciplinary Expert Panel

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/106983/1/jgs12730.pd

What is the therapeutic value of antidepressants in dementia? A narrative review

Objectives: Antidepressants are commonly used in dementia. Depression is a frequent and important co-morbidity in dementia and antidepressants are often used to treat depression and more widely. However there are questions about their utility in depression in dementia and other behavioural and psychological symptoms of dementia (BPSD). The aim of this narrative review is to summarise the evidence on whether there is therapeutic value in prescribing antidepressants to people with dementia. Methods: A PubMed search was performed to identify RCTs that prescribed antidepressants to people with dementia, either in the treatment of BPSD (depression, anxiety, agitation/aggression, psychosis, apathy) or for secondary outcomes (quality of life, carer burden, activities of daily living, cognition, clinical severity, adverse events). Results: Thirty-six RCTs were identified (participant n=3,386). A consistent finding in well-designed blinded placebo controlled trials in dementia is the lack of positive effect of antidepressants on outcomes of interest including depression. One large well-designed study has reported a significant reduction in agitation in people with dementia, but at the expense of clinically significant adverse events. Otherwise change observed in open trials is also seen in the placebo group, suggesting any effect is not attributable to the prescription of antidepressants. Conclusions: It is striking how few data there are on indications other than depression. We should question the use of antidepressants in dementia. Definitive trials of clinical effectiveness of specific indications such as anxiety and agitation in dementia and discontinuation of antidepressants in dementia are needed

Empirically Defining Trajectories of Late-Life Cognitive and Functional Decline

Background: Alzheimer’s disease (AD) is associated with variable cognitive and functional decline, and it is difficult to predict who will develop the disease and how they will progress. Objective: This exploratory study aimed to define latent classes from participants in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database who had similar growth patterns of both cognitive and functional change using Growth Mixture Modeling (GMM), identify characteristics associated with those trajectories, and develop a decision tree using clinical predictors to determine which trajectory, as determined by GMM, individuals will most likely follow. Methods: We used ADNI early mild cognitive impairment (EMCI), late MCI (LMCI), AD dementia, and healthy control (HC) participants with known amyloid-β status and follow-up assessments on the Alzheimer’s Disease Assessment Scale - Cognitive Subscale or the Functional Activities Questionnaire (FAQ) up to 24 months postbaseline. GMM defined trajectories. Classification and Regression Tree (CART) used certain baseline variables to predict likely trajectory path. Results: GMM identified three trajectory classes (C): C1 (n = 162, 13.6%) highest baseline impairment and steepest pattern of cognitive/functional decline; C3 (n = 819, 68.7%) lowest baseline impairment and minimal change on both; C2 (n = 211, 17.7%) intermediate pattern, worsening on both, but less steep than C1. C3 had fewer amyloid- or apolipoprotein-E ɛ4 (APOE4) positive and more healthy controls (HC) or EMCI cases. CART analysis identified two decision nodes using the FAQ to predict likely class with 82.3% estimated accuracy. Conclusions: Cognitive/functional change followed three trajectories with greater baseline impairment and amyloid and APOE4 positivity associated with greater progression. FAQ may predict trajectory class

Coordinated analysis of age, sex, and education effects on change in MMSE scores

Objectives. We describe and compare the expected performance trajectories of older adults on the Mini-Mental Status Examination (MMSE) across six independent studies from four countries in the context of a collaborative network of longitudinal studies of aging. A coordinated analysis approach is used to compare patterns of change conditional on sample composition differences related to age, sex, and education. Such coordination accelerates evaluation of particular hypotheses. In particular, we focus on the effect of educational attainment on cognitive decline.Method. Regular and Tobit mixed models were fit to MMSE scores from each study separately. The effects of age, sex, and education were examined based on more than one centering point.Results. Findings were relatively consistent across studies. On average, MMSE scores were lower for older individuals and declined over time. Education predicted MMSE score, but, with two exceptions, was not associated with decline in MMSE over time.Conclusion. A straightforward association between educational attainment and rate of cognitive decline was not supported. Thoughtful consideration is needed when synthesizing evidence across studies, as methodologies adopted and sample characteristics, such as educational attainment, invariably differ. © 2012 The Author

The relationship between changes in quality of life outcomes and progression of Alzheimer's disease: results from the Dependence in AD in England 2 longitudinal study

Objective: The relationship between conventional indicators of Alzheimer’s disease (AD) progression and quality of life (QoL) outcomes is unclear. Dependence on others has been recommended as a unifying construct in defining AD severity. This study examined the relationship between indicators of disease severity (including dependence) and changes in QoL and utility over 18-months. Methods: A multi-centre, cohort study was conducted across 18 UK sites. One hundred and forty five patients with possible/probable AD and their caregivers completed assessments of disease severity (Dependence Scale, Mini-Mental State Examination, Neuropsychiatric Inventory, Disability Assessment for Dementia), dementia-specific QoL (DEMQOL, DEMQOL-Proxy) and generic health-related utility (EQ-5D) at both time points. Results: There was evidence of individual change in QoL over 18 months, with over 50% of patients reporting either maintenance or improvement of life quality. The EQ-5D proxy suggested a mean decline in QoL whilst the DEMQOL-Proxy indicated overall improvement. In the subsample of people who self-reported QoL and utility, no mean change was evident. Changes in dependence did not explain changes on any QoL or utility outcome. There was a weak association between the EQ-5D proxy and changes in cognition, whereas changes on the DEMQOL-Proxy were partly explained by changes in behavioural disturbance. Conclusions: The natural progression of AD over 18-months does not lead to inevitable decline in QoL or utility. There are no clear or consistent direct relationships between changes in disease severity and QoL outcomes. The impact of increasing dependence and worsening disease severity is likely buffered by a combination of psychological, social and environmental factors

Sertraline and mirtazapine versus placebo in subgroups of depression in dementia: findings from the HTA-SADD randomized controlled trial

Objective Studies have shown that antidepressants are no better than placebo in treating depression in dementia. The authors examined antidepressant efficacy in subgroups of depression in dementia with different depressive symptom profiles. Methods This study focuses on exploratory secondary analyses on the randomized, parallel-group, double-blind, placebo-controlled Health Technology Assessment Study of the Use of Antidepressants for Depression in Dementia (HTA-SADD) trial. The setting included old-age psychiatry services in nine centers in England. The participants included 326 patients meeting National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association probable/possible Alzheimer disease criteria, and Cornell Scale for Depression in Dementia (CSDD) scores of 8 or more. Intervention was placebo (n = 111), sertraline (n = 107), or mirtazapine (n = 108). Latent class analyses (LCA) on baseline CSDD items clustered participants into symptom-based subgroups. Mixed-model analysis evaluated CSDD improvement at 13 and 39 weeks by randomization in each subgroup. Results LCA yielded 4 subgroups: severe (n = 34), psychological (n = 86), affective (n = 129), and somatic (n = 77). Mirtazapine, but not sertraline, outperformed placebo in the psychological subgroup at week 13 (adjusted estimate: –2.77 [standard error (SE) 1.16; 95% confidence interval: –5.09 to –0.46]), which remained, but lost statistical significance at week 39 (adjusted estimate: –2.97 [SE 1.59; 95% confidence interval: –6.15 to 0.20]). Neither sertraline nor mirtazapine outperformed placebo in the other subgroups. Conclusion Because of the exploratory nature of the analyses and the small sample sizes for subgroup analysis there is the need for caution in interpreting these data. Replication of the potential effects of mirtazapine in the subgroup of those with depression in dementia with “psychological” symptoms would be valuable. These data should not change clinical practice, but future trials should consider stratifying types of depression in dementia in secondary analyses

Depression symptoms and cognitive function among individuals with advanced HIV infection initiating HAART in Uganda

Background Among patients with HIV infection, depression is the most frequently observed psychiatric disorder. The presence of depressive symptoms and cognitive dysfunction among HIV patients has not been well studied in Sub-Saharan Africa. Initiation of highly active antiretroviral therapy (HAART) may have an effect on the prevalence and the change over time of depression symptoms and cognitive impairment among HIV-positive individuals. Methods We recruited 102 HIV-positive individuals at risk of cognitive impairment who were initiating HAART and 25 HIV-negative individuals matched for age and education. Depression was assessed using the Centre for Epidemiologic Studies Depression Scale (CES-D). Neurocognitive assessment included the International HIV Dementia Scale (IHDS), an 8 test neuropsychological battery and the Memorial Sloan Kettering scale. Assessments were carried out at 0, 3 and 6 months. Results The HIV-positive group had more respondents with CES-D score > 16 than the HIV-negative group at all 3 clinic visits (54%Vs 28%; 36% Vs 13%; and 30% Vs 24% respectively; all p < 0.050 OR 2.86, 95% CI: 1.03, 7.95, p = 0.044). The HIV positive group had higher likelihood for cognitive impairment (OR 8.88, 95% CI 2.64, 29.89, p < 0.001). A significant decrease in the mean scores on the CES-D (p = 0.002) and IHDS (p = 0.001) occurred more in the HIV-positive group when compared to the HIV-negative group. There was no association between clinical Memorial Sloan Kettering score and depression symptoms (p = 0.310) at baseline. Conclusion Depression symptomatology is distinct and common among cognitively impaired HIV patients. Therefore individuals in HIV care should be screened and treated for depression