Comparison of neuropsychological rehabilitation techniques for unilateral neglect: an ABACADAEAF single-case experimental design.

Unilateral neglect is a debilitating attentional disorder whereby patients fail to report, respond or orient to information presented on one side of space. Previous studies have demonstrated improvements in neglect symptoms using rehabilitation techniques, such as anchoring or limb activation. We investigated the effectiveness of five interventions in reducing the unilateral neglect observed in patient F.P. A single-case ABACADAEAF design was used to investigate the effectiveness of musical stimulation (B), anchoring (C), vibratory stimulation (D), limb activation (E), and anchoring and vibratory stimulation combined (F), compared to baseline (A). Severity of neglect was measured using star cancellation, line crossing and line bisection tests. Tau-U statistical analyses were used to investigate significant differences between conditions. All interventions resulted in improvements in F.P.'s neglect. Anchoring (C), vibratory stimulation (D) and the combination of these two techniques (F) led to greatest improvements on all three tests of neglect. Musical stimulation led to improvements on the line bisection task only. Anchoring and vibratory stimulation were the most effective techniques for reducing neglect for this patient. Further research is needed to investigate whether the observed gains can be sustained on a longer-term basis, generalised to other tasks, and replicated in larger samples.

Paradoxical improvement of function more than 2 years after onset of tuberculous meningitis.

OBJECTIVE: To document the unexpected improvement made by a 50 year-old patient over 2 years after being diagnosed with tuberculous meningitis (TBM). METHODS: Regular neuropsychological assessments were carried out, initially with a test for patients in reduced states of awareness and later with more demanding tests. RESULTS: The patient was diagnosed with TBM in November 2008 and was mute, stuporous and barely more than minimally conscious for over 2 years. By February 2011, following the cessation of TBM medication, her conscious level had improved and she could be assessed on a range of neuropsychological tests. The patient presented with diffuse cognitive impairments coupled with focal neurological signs, but showed marked improvements in cognitive functioning compared to when admitted. CONCLUSIONS: This study demonstrates that late stage neuropsychological improvement is possible, even after 2 years of showing minimal awareness. Such paradoxical improvement of function is considered in the light of other paradoxical phenomena in TBM, comparisons are offered with similar neurological conditions and possible mechanisms underlying the dramatic improvement that took place are suggested.

Multivariate analysis of MRI data for Alzheimer's disease, mild cognitive impairment and healthy controls.

We have used multivariate data analysis, more specifically orthogonal partial least squares to latent structures (OPLS) analysis, to discriminate between Alzheimer's disease (AD), mild cognitive impairment (MCI) and elderly control subjects combining both regional and global magnetic resonance imaging (MRI) volumetric measures. In this study, 117 AD patients, 122 MCI patients and 112 control subjects (from the AddNeuroMed study) were included. High-resolution sagittal 3D MP-RAGE datasets were acquired from each subject. Automated regional segmentation and manual outlining of the hippocampus were performed for each image. Altogether this yielded volumes of 24 different anatomically defined structures which were used for OPLS analysis. 17 randomly selected AD patients, 12 randomly selected control subjects and the 22 MCI subjects who converted to AD at 1-year follow up were excluded from the initial OPLS analysis to provide a small external test set for model validation. Comparing AD with controls we found a sensitivity of 87% and a specificity of 90% using hippocampal measures alone. Combining both global and regional measures resulted in a sensitivity of 90% and a specificity of 94%. This increase in sensitivity and specificity resulted in an increase of the positive likelihood ratio from 9 to 15. From the external test set, the model predicted 82% of the AD patients and 83% of the control subjects correctly. Finally, 73% of the MCI subjects which converted to AD at 1 year follow-up were shown to resemble AD patients more closely than controls. This method shows potential for distinguishing between different patient groups. Combining the different MRI measures together resulted in a significantly better classification than using them separately. OPLS also shows potential for predicting conversion from MCI to AD.

APOE ε2 allele is associated with larger regional cortical thicknesses and volumes.

BACKGROUND: The protective effect of the apolipoprotein E (APOE) ε2 allele against Alzheimer's disease (AD) is controversial. OBJECTIVE: Our purpose was to clarify if the ε2 allele affects regional cortical thicknesses and volumes. METHODS: Regional cortical thicknesses and volumes were measured with an automated pipeline in 109 subjects with mild cognitive impairment, 114 AD patients and 105 age-matched healthy controls. RESULTS: In the mild cognitive impairment group, the ε2 carriers had thicker regional cortices at the transverse temporal cortex and parahippocampal gyrus than the subjects with ε3/ε3, and a larger cerebral gray matter and smaller lateral ventricles than the ε3/ε3 and ε4 carriers. In the AD group, the ε2 carriers had significantly thicker entorhinal and transverse temporal cortices, a larger whole cerebral gray matter, and smaller lateral ventricles than the subjects with the ε3/ε3 genotype, and a significantly thicker entorhinal cortex and larger cerebral gray matter than ε4 carriers. No APOE2 effect was found in the control group. CONCLUSION: The APOE ε2 allele is associated with larger regional cortical thicknesses and volumes in mild cognitive impairment and AD.

Improving implementation of evidence based practice for people with psychosis through training the wider workforce: Results of the GOALS feasibility randomised controlled trial.

BACKGROUND AND OBJECTIVES: There is a pressing need to improve access to evidence-based practice for people with psychosis. The primary aim of this study was to assess clinical feasibility of a manualised, evidence-based CBT intervention (GOALS) targeting a personalised recovery goal, delivered by the frontline workforce, following brief training. Secondly, we aimed to conduct preliminary statistical analyses of key outcomes and costs. METHODS: The GOALS study is a feasibility randomised controlled trial (ISRCTN 73188383). 75 participants with current psychosis were recruited and randomly allocated to receive either treatment as usual alone or with GOALS therapy. RESULTS: Brief training enabled frontline staff to deliver the therapy according to protocol and 74% of therapy participants partially or fully achieved their goals. There were significant improvements with a moderate effect size of 0.56 on goal attainment. However, preliminary statistical analyses found no significant differences between groups on our primary outcome of activity levels or other secondary outcomes Health economic analysis found that point estimates of costs, controlling for baseline costs, implied savings (even including intervention costs), but the difference was not statistically significant. LIMITATIONS: The study was designed as a feasibility RCT, and therefore the results of secondary estimates of efficacy effects should be treated with caution. CONCLUSIONS: This approach holds promise in supporting people with psychosis to reach personal recovery goals, cost effectively.

Training the Frontline Workforce to Deliver Evidence-Based Therapy to People With Psychosis: Challenges in the GOALS Study.

Improving access to psychotherapies in psychosis requires workforce expansion in resource-challenged systems. The GOALS feasibility randomized controlled trial assessed training and implementation of an evidence-based intervention by frontline workers, targeting recovery goals. Training uptake and therapy fidelity were good. Case managers with crisis management responsibilities were less likely than clinical assistants to deliver therapy. Participants receiving "sufficient therapy" achieved goals, but therapy was usually provided by clinical assistants. This is consistent with implementation science principles, that training must be combined with supportive organizational structures, such as by focusing on roles that already include therapy delivery or developing stronger organizational supports for case managers.

CERAD neuropsychological compound scores are accurate in detecting prodromal alzheimer's disease: a prospective AddNeuroMed study.

The Consortium to Establish a Registry for Alzheimer's Disease Neuropsychological Battery (CERAD-NB) is a widely used tool in screening for Alzheimer's disease (AD), however, it does not include a validated total score for delayed memory. Our aim was to develop clinically applicable memory compound scores for CERAD-NB and examine whether they and global cognitive total scores could detect prodromal AD and cognitive progression in MCI. One year follow-up data of 201 subjects with a baseline diagnosis of MCI (46 progressed to AD; 155 remained stable) and 212 controls in the European multicenter AddNeuroMed study were analyzed. Two previously described cognitive total scores and two memory compound scores were tabulated for CERAD-NB. Receiver Operating Characteristic analysis was applied in the group discrimination at baseline and the annual change for different compound scores was examined. Normative cut-offs for CERAD compound scores were tabulated in the Finnish CERAD sample of 306 controls. Country adjusted CERAD compound scores (AUC 0.95-0.96) were more accurate than Word List Recall (AUC 0.93) and Mini-Mental State Examination (AUC 0.90) in discriminating progressive mild cognitive impairment (MCI) subjects from controls. With normative cut-off values CERAD total scores yielded to 87-89% sensitivity and 84-86% specificity in screening for prodromal AD in a separate multinational population. The annual deterioration in all CERAD compound scores was significant in the progressive (p ≤ 0.001) but not in the stable MCI group (p > 0.08). CERAD total scores are a practical way of screening for prodromal AD and assessing cognitive progression in MCI. The new memory compound scores were more accurate than CERAD subtests in predicting AD conversion.

The impact of childhood adversity on suicidality and clinical course in treatment-resistant depression.

BACKGROUND: Childhood adversity is a risk factor for the development of depression and can also affect clinical course. We investigated this specifically in treatment-resistant depression (TRD). METHODS: One hundred and thirty-seven patients with TRD previously admitted to an inpatient affective disorders unit were included. Clinical, demographic and childhood adversity (physical, sexual, emotional abuse; bullying victimization, traumatic events) data were obtained during admission. Associations between childhood adversity, depressive symptoms and clinical course were investigated. RESULTS: Most patients had experienced childhood adversity (62%), with traumatic events (35%) and bullying victimization (29%) most commonly reported. Childhood adversity was associated with poorer clinical course, including earlier age of onset, episode persistence and recurrence. Logistic regression analyses revealed childhood adversity predicted lifetime suicide attempts (OR 2.79; 95% CI 1.14, 6.84) and childhood physical abuse predicted lifetime psychosis (OR 3.42; 95% CI 1.00, 11.70). LIMITATIONS: The cross-sectional design and retrospective measurement of childhood adversity are limitations of the study. CONCLUSIONS: Childhood adversity was common amongst these TRD patients and was associated with poor clinical course, psychosis and suicide attempts. Routine assessment of early adversity may help identify at risk individuals and inform clinical intervention.

Longitudinal course of symptom severity and fluctuation in patients with treatment-resistant unipolar and bipolar depression.

Little is currently known about the long-term course of symptom severity and fluctuation in patients with treatment-resistant depression (TRD). We assessed this using the longitudinal interval follow-up evaluation in 115 patients with TRD (84 unipolar, 31 bipolar) with 1-7 years (median 36 months) of follow-up. Of the follow-up months, 39.2% were spent asymptomatic and 21.1% at sub-threshold symptom level, while 15.8% were spent at mild, 13.9% at moderate, and 10.0% at severe depressive episode level. Significantly more unipolar than bipolar patients were continuously symptomatic during follow-up (43% vs. 29%). Patients had a mean of 1.0 (S.D.=1.2) symptom severity level fluctuations per year. High fluctuating patients had significantly poorer global functioning and quality of life. Although most patients with TRD achieve an asymptomatic state, they continue to fluctuate and experience depressive symptoms in the majority of months, mostly at subclinical or mild severity. However, there are important differences between unipolar and bipolar TRD, with unipolar patients more likely to experience an unremitting depressive state. Additionally, a more fluctuating longitudinal illness course is associated with poorer function and quality of life, and with a bipolar diagnosis. We suggest that the longitudinal illness course is an important outcome to be considered in future TRD research.

Combination analysis of neuropsychological tests and structural MRI measures in differentiating AD, MCI and control groups--the AddNeuroMed study.

To study the ability of neuropsychological tests, manual MRI hippocampal volume measures, regional volume and cortical thickness measures to identify subjects with Alzheimer's disease (AD), mild cognitive impairment (MCI), and healthy age-matched controls. Neuropsychological tests, manual hippocampal volume, automated regional volume and regional cortical thickness measures were performed in 120 AD patients, 120 MCI subjects, and 111 controls. The regional cortical thickness and volumes in MCI subjects were significantly decreased in limbic/paralimbic areas and temporal lobe compared to controls. Atrophy was much more extensive in the AD patients compared to MCI subjects and controls. The combination of neuropsychological tests and volumes revealed the highest accuracy (82% AD vs. MCI; 94% AD vs. control; 83% MCI vs. control). Adding regional cortical thicknesses into the discriminate analysis did not improve accuracy. We conclude that regional cortical thickness and volume measures provide a panoramic view of brain atrophy in AD and MCI subjects. A combination of neuropsychological tests and regional volumes are important when discriminating AD from healthy controls and MCI.

Prospective evaluation of specialist inpatient treatment for refractory affective disorders.

BACKGROUND: Little data exist to inform the treatment of severe and resistant affective disorders. We report here the effectiveness of specialist multimodal inpatient treatment for refractory affective disorders. METHODS: Prospective evaluation of 225 consecutive patients admitted to the National Affective Disorders Unit between 2001 and 2008. RESULTS: Patients were highly treatment-resistant: most had already received ECT, lithium augmentation and over 10 prior treatment trials. Even so, sequential assessment with the Hamilton Depression Rating Scale found that 69% showed a clinical response (≥ 50% reduction in Hamilton score) to intensive therapy during admission; 50% continued to sustain a full response and 71% at least a partial response on discharge. Patients' self-ratings (57% very much or much improved, 24% slightly improved) and relative and referrer reports (75% and 68% respectively rated patients as improved) gave similar levels of improvement. LIMITATIONS: This was an observational study, without any untreated control group. The generalisability of the findings is limited by the highly specialised nature of the unit. CONCLUSIONS: Most patients with depression highly resistant to prior treatment respond to specialist and intensive multimodal inpatient therapy.

CERAD neuropsychological battery total score in multinational mild cognitive impairment and control populations: the AddNeuroMed study.

An important focus in Alzheimer's disease (AD) research is the development of methods for early diagnosis. Despite progress with some other biomarkers, sensitive and specific neuropsychological measures for identifying subjects in the prodromal phase of AD remain the most promising early diagnostic tool. We evaluated the value of the composite score for the Consortium to Establish a Registry for Alzheimer's disease Neuropsychological Battery (CERAD-NB) in Europeans with mild cognitive impairment (MCI) and in control populations. Baseline clinical data were analyzed from 223 healthy elderly and 224 subjects with MCI from the prospective AddNeuroMed study carried out in Finland, France, Greece, Italy, Poland, and the United Kingdom. The total score for CERAD-NB was calculated by the subtest addition method. The CERAD total score, adjusted for age, gender, education, and country, clearly differentiated the control and MCI groups (p < 0.001). The optimal between-groups cut-off point for the CERAD total score derived from ROC analysis yielded 81.5% sensitivity and 75.4% specificity (AUC = 0.848, p < 0.001). The CERAD total score was superior to the Mini-Mental Status Examination, or any single CERAD subtest in discriminating between the control and MCI groups. While the overall level of the CERAD total score varied between the different countries, it remained accurate in differentiating controls and MCI subjects within each country. We conclude that the CERAD total score is an accurate measure for detecting mild cognitive impairment, but implementing specific cut-off points needs to be based upon country specific normative data.

Effect of APOE ε4 allele on cortical thicknesses and volumes: the AddNeuroMed study.

The apolipoprotein E (APOE) ε4 allele is a risk factor for Alzheimer's disease (AD), but its effect on brain volumes is controversial. We explored the effect of the ε4 allele on regional cortical thickness and volume measurements using an automated pipeline in 111 subjects with mild cognitive impairment (MCI), 115 AD patients, and 107 age-matched healthy controls. The clinical data were used as covariates in the thickness and volume comparisons. The ε4 carriers had significantly smaller volume than non-carriers in caudate (p=0.028) in controls; in amygdala and caudate in the MCI group (p

Analysis of regional MRI volumes and thicknesses as predictors of conversion from mild cognitive impairment to Alzheimer's disease.

We determined predictors of conversion to Alzheimer's disease (AD) from mild cognitive impairment (MCI) with automated magnetic resonance imaging (MRI) regional cortical volume and thickness measures. One hundred amnestic MCI subjects, 118 AD patients, and 94 age-matched healthy controls were selected from AddNeuroMed study. Twenty-four regional cortical volumes and 34 cortical thicknesses were measured with automated image processing software at baseline. Twenty-one subjects converted from MCI to AD determined with the cognitive tests at baseline and 1 year later. The hippocampus, amygdala, and caudate volumes were significantly smaller in progressive MCI subjects than in controls and stable MCI subjects. The cortical volumes achieved higher predictive accuracy than did cognitive tests or cortical thickness. Combining the volumes, thicknesses, and cognitive tests did not improve the accuracy. The volume of amygdala and caudate were independent variables in predicting conversion from MCI to AD. We conclude that regional cortical volume measures are more powerful than those common cognitive tests we used in identifying AD patients at the very earliest stage of the disease.

Association of plasma clusterin concentration with severity, pathology, and progression in Alzheimer disease.

CONTEXT: Blood-based analytes may be indicators of pathological processes in Alzheimer disease (AD). OBJECTIVE: To identify plasma proteins associated with AD pathology using a combined proteomic and neuroimaging approach. DESIGN: Discovery-phase proteomics to identify plasma proteins associated with correlates of AD pathology. Confirmation and validation using immunodetection in a replication set and an animal model. SETTING: A multicenter European study (AddNeuroMed) and the Baltimore Longitudinal Study of Aging. PARTICIPANTS: Patients with AD, subjects with mild cognitive impairment, and healthy controls with standardized clinical assessments and structural neuroimaging. MAIN OUTCOME MEASURES: Association of plasma proteins with brain atrophy, disease severity, and rate of clinical progression. Extension studies in humans and transgenic mice tested the association between plasma proteins and brain amyloid. RESULTS: Clusterin/apolipoprotein J was associated with atrophy of the entorhinal cortex, baseline disease severity, and rapid clinical progression in AD. Increased plasma concentration of clusterin was predictive of greater fibrillar amyloid-beta burden in the medial temporal lobe. Subjects with AD had increased clusterin messenger RNA in blood, but there was no effect of single-nucleotide polymorphisms in the gene encoding clusterin with gene or protein expression. APP/PS1 transgenic mice showed increased plasma clusterin, age-dependent increase in brain clusterin, as well as amyloid and clusterin colocalization in plaques. CONCLUSIONS: These results demonstrate an important role of clusterin in the pathogenesis of AD and suggest that alterations in amyloid chaperone proteins may be a biologically relevant peripheral signature of AD.