Pauline Aalten

Proposed diagnostic criteria for apathy in Alzheimer's disease and other neuropsychiatric disorders

There is wide acknowledgement that apathy is an important behavioural syndrome in Alzheimers disease and in various neuropsychiatric disorders. In light of recent research and the renewed interest in the correlates and impacts of apathy, and in its treatments, it is important to develop criteria for apathy that will be widely accepted, have clear operational steps, and that will be easily applied in practice and research settings. Meeting these needs is the focus of the task force work reported here. The task force includes members of the Association Française de Psychiatrie Biologique, the European Psychiatric Association, the European Alzheimers Disease Consortium and experts from Europe, Australia and North America. An advanced draft was discussed at the consensus meeting (during the EPA conference in April 7th 2008) and a final agreement reached concerning operational definitions and hierarchy of the criteria. Apathy is defined as a disorder of motivation that persists over time and should meet the following requirements. Firstly, the core feature of apathy, diminished motivation, must be present for at least four weeks; secondly two of the three dimensions of apathy (reduced goal-directed behaviour, goal-directed cognitive activity, and emotions) must also be present; thirdly there should be identifiable functional impairments attributable to the apathy. Finally, exclusion criteria are specified to exclude symptoms and states that mimic apathy.

Neuropsychiatric syndromes in dementia - Results from the European Alzheimer Disease Consortium: Part I

Background/Aims: The aim of this study was to identify neuropsychiatric subsyndromes of the Neuropsychiatric Inventory in a large sample of outpatients with Alzheimer’s disease (AD). Methods: Cross-sectional data of 2,354 patients with AD from 12 centres from the European Alzheimer’s Disease Consortium were collected. Principal component analysis was used for factor analysis. Results: The results showed the presence of 4 neuropsychiatric subsyndromes: hyperactivity, psychosis, affective symptoms and apathy. The subsyndrome apathy was the most common, occurring in almost 65% of the patients. Conclusion: This large study has provided additional robust evidence for the existence of neuropsychiatric subsyndromes in AD.

Behavioral Problems in Dementia: A Factor Analysis of the Neuropsychiatric Inventory

The aim of this study was to detect behavioral subsyndromes of the 12-item Neuropsychiatric Inventory (NPI). Cross-sectional data of 199 patients with dementia living in the community were collected. Principal component analysis (with Varimax rotation) was used for factor analysis. Results showed the presence of three behavioral subsyndromes: mood/apathy, psychosis, and hyperactivity. Anxiety was regarded as a separate symptom. The subsyndrome mood/apathy was the most common, occurring in almost 80% of the patients, versus psychosis and hyperactivity, which occurred in 37 and 60% of the patients, respectively.

Impact of Behavioural Problems on Spousal Caregivers: A Comparison between Alzheimer’s Disease and Frontotemporal Dementia

Background: Behavioural changes are a key factor in distinguishing frontotemporal dementia (FTD) from Alzheimer’s disease (AD), however, little is known about the impact of these changes on caregivers. The aim of this study was to compare caregivers’ distress related to behavioural symptoms of AD and FTD. Methods: 47 spouse caregivers of consecutively referred patients with AD and 27 spouse caregivers of patients with FTD participated in this study. Behavioural disturbances in the patient and caregivers’ emotional reactions were measured with the Neuropsychiatric Inventory. Results: Patients with FTD had significantly higher levels of agitation, apathy, disinhibition and aberrant motor behaviour than did patients with AD. High distress scores were found for disinhibition, depression and apathy in caregivers of FTD patients whereas caregivers of AD patients reported patient apathy, depression and anxiety as being severely distressing. Higher mean distress scores were found for disinhibition in the FTD group. Furthermore, caregivers of FTD patients reported higher levels of general burden, and felt less competent than AD caregivers. Conclusions: Caregivers of FTD patients were overall more distressed by the behaviour of their partners than were the caregivers of AD patients.Findings from this study underscore the importance of differentiating between diagnostic groups and specific behavioural domains when focusing on caregiver reactions to problem behaviour.

Neuroanatomical correlates of apathy in Parkinson's disease: A magnetic resonance imaging study using voxel-based morphometry.

Apathy is generally defined as a disorder of motivation and is considered one of the most common neuropsychiatric disturbances in Parkinsons disease (PD). Only few studies addressed the neuroanatomical correlates of apathy in PD. The aim of this article was to determine the structural correlates of apathy in PD patients. Fifty‐five PD patients underwent a neuropsychiatric and neuropsychological examination, and a 3 T magnetic resonance imaging scan was acquired. A voxel‐based multiple regression analysis was used to calculate correlation between gray matter density and severity measures of apathy. Apathy correlates with decreased cognitive functioning and more depressive symptoms but not with more severe motor symptoms. High apathy scores were correlated with low gray matter density values in a number of cortical brain areas: the bilateral precentral gyrus (BA 4, 6), the bilateral inferior parietal gyrus (BA 40), the bilateral inferior frontal gyrus (BA 44, 47), the bilateral insula (BA 13), the right (posterior) cingulate gyrus (BA 24, 30, 31), and the right precuneus (BA 31). Apathy in PD correlates with reduced gray matter density in a number of brain regions. The involvement of the cingulate gyrus and inferior frontal gyrus is in line with the results of earlier studies addressing apathy in patients with Alzheimers disease or depressive disorder. Further studies addressing the pathogenesis of apathy are needed.

Awareness in dementia: A review of clinical correlates

This article provides a review of the literature on clinical correlates of awareness in dementia. Most inconsistencies were found with regard to an association between depression and higher levels of awareness. Dysthymia, but not major depression, is probably related to higher levels of awareness. Anxiety also appears to be related to higher levels of awareness. Apathy and psychosis are frequently present in patients with less awareness, and may share common neuropathological substrates with awareness. Furthermore, unawareness seems to be related to difficulties in daily life functioning, increased caregiver burden, and deterioration in global dementia severity. Factors that may be of influence on the inconclusive data are discussed, as are future directions of research.

Impact of molecular imaging on the diagnostic process in a memory clinic

[11C]Pittsburgh compound B ([11C]PIB) and [18F]‐2‐fluoro‐2‐deoxy‐D‐glucose ([18F]FDG) PET measure fibrillar amyloid‐β load and glucose metabolism, respectively. We evaluated the impact of these tracers on the diagnostic process in a memory clinic population.

New MRI Markers for Alzheimer's Disease: A Meta-Analysis of Diffusion Tensor Imaging and a Comparison with Medial Temporal Lobe Measurements

The aim of the present study is to evaluate the diagnostic value of diffusion tensor imaging (DTI) for early Alzheimers disease (AD) in comparison to widely accepted medial temporal lobe (MTL) atrophy measurements. A systematic literature research was performed into DTI and MTL atrophy in AD and mild cognitive impairment (MCI). We included seventy-six studies on MTL atrophy including 8,122 subjects and fifty-five DTI studies including 2,791 subjects. Outcome measure was the effect size (ES) expressed as Hedges g. In volumetric studies, atrophy of the MTL significantly differentiated between AD and controls (ES 1.32-1.98) and MCI and controls (ES 0.61-1.46). In DTI-Fractional anisotropy (FA) studies, the total cingulum differentiated best between AD and controls (ES = 1.73) and the parahippocampal cingulum between MCI and controls (ES = 0.97). In DTI-Mean diffusivity (MD) studies, the hippocampus differentiated best between AD and controls (ES = -1.17) and between MCI and controls (ES = -1.00). We can conclude that in general, the ES of volumetric MTL atrophy measurements was equal or larger than that of DTI measurements. However, for the comparison between controls and MCI-patients, ES of hippocampal MD was larger than ES of hippocampal volume. Furthermore, it seems that MD values have somewhat more discriminative power than FA values with higher ES in the frontal, parietal, occipital and temporal lobe.

Test sequence of CSF and MRI biomarkers for prediction of AD in subjects with MCI

Our aim was to identify the best diagnostic test sequence for predicting Alzheimers disease (AD)-type dementia in subjects with mild cognitive impairment (MCI) using cerebrospinal fluid (CSF) and magnetic resonance imaging (MRI) biomarkers. We selected 153 subjects with mild cognitive impairment from a multicenter memory clinic-based cohort. We tested the CSF beta amyloid (Aβ)1-42/tau ratio using enzyme-linked immunosorbent assay (ELISA) and hippocampal volumes (HCVs) using the atlas-based learning embeddings for atlas propagation (LEAP) method. Outcome measure was progression to AD-type dementia in 2 years. At follow-up, 48 (31%) subjects converted to AD-type dementia. In multivariable analyses, CSF Aβ1-42/tau and HCV predicted AD-type dementia regardless of apolipoprotein E (APOE) genotype and cognitive scores. Test sequence analyses showed that CSF Aβ1-42/tau increased predictive accuracy in subjects with normal HCV (p < 0.001) and abnormal HCV (p = 0.025). HCV increased predictive accuracy only in subjects with normal CSF Aβ1-42/tau (p = 0.014). Slope analyses for annual cognitive decline yielded similar results. For selection of subjects for a prodromal AD trial, the best balance between sample size and number of subjects needed to screen was obtained with CSF markers. These results provide further support for the use of CSF and magnetic resonance imaging biomarkers to identify prodromal AD.

Pharmacological Treatment of Apathy in Neurodegenerative Diseases: A Systematic Review

Objective: To evaluate the efficacy of pharmacological treatment of apathy in patients with neurodegenerative diseases. Methods: Systematic review of studies assessing the effects of pharmacological treatment on apathy in neurodegenerative diseases. Results: Thirty-five studies were included: 2 meta-analyses, 13 randomized controlled trials (RCTs), 14 open-label studies, 5 case series, and 1 single case study. Eight studies included apathy as a primary outcome. A cholinesterase inhibitor was investigated in 24 studies, methylphenidate in 5, and other medications in 6 studies. Most RCTs of cholinesterase inhibitors reported a small but statistically significant improvement of apathetic symptoms. Conclusions: Although some medications are promising candidates for further study, there is as yet insufficient evidence that pharmacological treatment improves apathetic symptoms in patients with neurodegenerative disease. Large-scale, placebo-controlled RCTs with apathy as a primary outcome measure are needed to establish the potential benefit of pharmacological treatment of apathy.