Dysexecutive disorders and their diagnosis: A position paper.

Although executive function disorders are among the most prevalent cognitive impairments a consensus on diagnostic criteria has yet to be reached. With a view to harmonizing these criteria, the present position paper (i) focuses on the main dysexecutive disorders, (ii) examines recent approaches in both the behavioral and cognitive domains, (iii) defines diagnostic boundaries for frontal syndrome, (iv) reports on the frequency and profile of the executive function disorders observed in the main brain diseases, and (v) proposes an operationalization of diagnostic criteria. Future work must define the executive processes involved in human adaptive behavior, characterize their impairment in brain diseases, and improve the management of these conditions (including remediation strategies and rehabilitation)

J Alzheimers Dis

BACKGROUND: Pathogenic variants in the autosomal dominant genes PSEN1, PSEN2, or APP, APOE4 alleles, and rare variants within TREM2, SORL1, and ABCA7 contribute to early-onset Alzheimer's disease (EOAD). However, sporadic EOAD patients have been insufficiently studied to define the probability of being a carrier of one of these variants. OBJECTIVE: To describe the proportion of each genetic variation among patients with very young-onset sporadic AD. METHODS: We first screened PSEN1, PSEN2, and APP in 154 EOAD patients with an onset before 51 years and a negative family history. Among 99 patients with no mutation (NMC), whole exome sequencing (WES) was performed. We analyzed the APOE genotype and rare protein-truncating or missense predicted damaging variants of TREM2, SORL1, and ABCA7. Neurological examination and cerebrospinal fluid (CSF) biomarkers were systematically retrieved. RESULTS: Nineteen (12.3%) mutation carriers (MC) harbored an APP or PSEN1 pathogenic or likely pathogenic variant. Among the NMC, 54/99 carried at least one genetic risk factor, including 9 APOE4/E4 homozygous, 37 APOE4 heterozygous, and 14 with a rare variant in another risk factor gene: 3 SORL1, 4 TREM2, and 9 ABCA7. MC presented an earlier disease onset (p < 0.0001) and associated neurologic symptoms more frequently (p < 0.002). All but one patient had at least 2 CSF biomarkers in abnormal ranges. CONCLUSION: The genetic component of very early sporadic EOAD gathers a substantial proportion of pathogenic variants in autosomal dominant genes and an even higher proportion of patients carrying genetic risk factors, suggesting an oligogenic determinism, even at this range of ages

Caregiver burden in amyotrophic lateral sclerosis is more dependent on patients’ behavioral changes than physical disability: a comparative study

<p>Abstract</p> <p>Background</p> <p>Behavioral changes in patients with amyotrophic lateral sclerosis (ALS) mirror those found in frontotemporal dementia (FTD). Considering the high rate of neuropsychiatric symptoms found in ALS patients, this paper examines whether caregiver burden is associated with behavioral changes <it>over and above</it> the physical disability of patients with ALS, and if the presence of caregivers’ depression, anxiety and stress also impacts on caregiver burden.</p> <p>Methods</p> <p>140 caregivers of patients with ALS participated in a postal survey investigating patients’ neuropsychiatric symptoms (Cambridge Behaviour Inventory Revised CBI-R), motor function (Amyotrophic Lateral Sclerosis Functional Rating Scale Revised - ALSFRS-R), caregiver burden (Zarit Burden Interview), and caregiver mood (Depression, Anxiety and Stress Scale- DASS21). Seventy four percent of them were caregivers of patients with limb onset and 25.7% were caregivers of patients with bulbar onset.</p> <p>Results</p> <p>Moderate to severe behavioral changes were reported in 10-40% of patients with ALS. The levels of depression, anxiety and stress in the caregivers reached 20%. Burden was high in 48% of the caregivers. The strongest predictor of high caregiver burden was ALS patients’ abnormal behavior rather than physical disability, with an odds ratio of 1.4, followed by caregivers’ stress.</p> <p>Conclusions</p> <p>Our study has identified that behavioral changes (e.g. disinhibition, impulsivity) and caregiver stress have greater impact on caregiver burden than level and pattern of physical disability.</p

Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia

Based on the recent literature and collective experience, an international consortium developed revised guidelines for the diagnosis of behavioural variant frontotemporal dementia. The validation process retrospectively reviewed clinical records and compared the sensitivity of proposed and earlier criteria in a multi-site sample of patients with pathologically verified frontotemporal lobar degeneration. According to the revised criteria, 'possible' behavioural variant frontotemporal dementia requires three of six clinically discriminating features (disinhibition, apathy/inertia, loss of sympathy/empathy, perseverative/compulsive behaviours, hyperorality and dysexecutive neuropsychological profile). 'Probable' behavioural variant frontotemporal dementia adds functional disability and characteristic neuroimaging, while behavioural variant frontotemporal dementia 'with definite frontotemporal lobar degeneration' requires histopathological confirmation or a pathogenic mutation. Sixteen brain banks contributed cases meeting histopathological criteria for frontotemporal lobar degeneration and a clinical diagnosis of behavioural variant frontotemporal dementia, Alzheimer's disease, dementia with Lewy bodies or vascular dementia at presentation. Cases with predominant primary progressive aphasia or extra-pyramidal syndromes were excluded. In these autopsy-confirmed cases, an experienced neurologist or psychiatrist ascertained clinical features necessary for making a diagnosis according to previous and proposed criteria at presentation. Of 137 cases where features were available for both proposed and previously established criteria, 118 (86%) met 'possible' criteria, and 104 (76%) met criteria for 'probable' behavioural variant frontotemporal dementia. In contrast, 72 cases (53%) met previously established criteria for the syndrome (P < 0.001 for comparison with 'possible' and 'probable' criteria). Patients who failed to meet revised criteria were significantly older and most had atypical presentations with marked memory impairment. In conclusion, the revised criteria for behavioural variant frontotemporal dementia improve diagnostic accuracy compared with previously established criteria in a sample with known frontotemporal lobar degeneration. Greater sensitivity of the proposed criteria may reflect the optimized diagnostic features, less restrictive exclusion features and a flexible structure that accommodates different initial clinical presentations. Future studies will be needed to establish the reliability and specificity of these revised diagnostic guidelines

Effect of general anaesthesia on functional outcome in patients with anterior circulation ischaemic stroke having endovascular thrombectomy versus standard care: a meta-analysis of individual patient data

Background: General anaesthesia (GA) during endovascular thrombectomy has been associated with worse patient outcomes in observational studies compared with patients treated without GA. We assessed functional outcome in ischaemic stroke patients with large vessel anterior circulation occlusion undergoing endovascular thrombectomy under GA, versus thrombectomy not under GA (with or without sedation) versus standard care (ie, no thrombectomy), stratified by the use of GA versus standard care. Methods: For this meta-analysis, patient-level data were pooled from all patients included in randomised trials in PuMed published between Jan 1, 2010, and May 31, 2017, that compared endovascular thrombectomy predominantly done with stent retrievers with standard care in anterior circulation ischaemic stroke patients (HERMES Collaboration). The primary outcome was functional outcome assessed by ordinal analysis of the modified Rankin scale (mRS) at 90 days in the GA and non-GA subgroups of patients treated with endovascular therapy versus those patients treated with standard care, adjusted for baseline prognostic variables. To account for between-trial variance we used mixed-effects modelling with a random effect for trials incorporated in all models. Bias was assessed using the Cochrane method. The meta-analysis was prospectively designed, but not registered. Findings: Seven trials were identified by our search; of 1764 patients included in these trials, 871 were allocated to endovascular thrombectomy and 893 were assigned standard care. After exclusion of 74 patients (72 did not undergo the procedure and two had missing data on anaesthetic strategy), 236 (30%) of 797 patients who had endovascular procedures were treated under GA. At baseline, patients receiving GA were younger and had a shorter delay between stroke onset and randomisation but they had similar pre-treatment clinical severity compared with patients who did not have GA. Endovascular thrombectomy improved functional outcome at 3 months both in patients who had GA (adjusted common odds ratio (cOR) 1·52, 95% CI 1·09–2·11, p=0·014) and in those who did not have GA (adjusted cOR 2·33, 95% CI 1·75–3·10, p&lt;0·0001) versus standard care. However, outcomes were significantly better for patients who did not receive GA versus those who received GA (covariate-adjusted cOR 1·53, 95% CI 1·14–2·04, p=0·0044). The risk of bias and variability between studies was assessed to be low. Interpretation: Worse outcomes after endovascular thrombectomy were associated with GA, after adjustment for baseline prognostic variables. These data support avoidance of GA whenever possible. The procedure did, however, remain effective versus standard care in patients treated under GA, indicating that treatment should not be withheld in those who require anaesthesia for medical reasons