Mental Rotation of Faces in Healthy Aging and Alzheimer's Disease

Previous research has shown that individuals with Alzheimer's disease (AD) develop visuospatial difficulties that affect their ability to mentally rotate objects. Surprisingly, the existing literature has generally ignored the impact of this mental rotation deficit on the ability of AD patients to recognize faces from different angles. Instead, the devastating loss of the ability to recognize friends and family members in AD has primarily been attributed to memory loss and agnosia in later stages of the disorder. The impact of AD on areas of the brain important for mental rotation should not be overlooked by face processing investigations – even in early stages of the disorder.This study investigated the sensitivity of face processing in AD, young controls and older non-neurological controls to two changes of the stimuli – a rotation in depth and an inversion. The control groups showed a systematic effect of depth rotation, with errors increasing with the angle of rotation, and with inversion. The majority of the AD group was not impaired when faces were presented upright and no transformation in depth was required, and were most accurate when all faces were presented in frontal views, but accuracy was severely impaired with any rotation or inversion.These results suggest that with the onset of AD, mental rotation difficulties arise that affect the ability to recognize faces presented at different angles. The finding that a frontal view is “preferred” by these patients provides a valuable communication strategy for health care workers

Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA‐Epilepsy study

Objective: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current corticocentric models of this disease. We quantified cross‐sectional regional cerebellar lobule volumes using structural magnetic resonance imaging in 1602 adults with epilepsy and 1022 healthy controls across 22 sites from the global ENIGMA‐Epilepsy working group. Methods: A state‐of‐the‐art deep learning‐based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in (1) all epilepsies, (2) temporal lobe epilepsy with hippocampal sclerosis (TLE‐HS), (3) nonlesional temporal lobe epilepsy, (4) genetic generalized epilepsy, and (5) extratemporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness. Results: Across all epilepsies, reduced total cerebellar volume was observed (d = .42). Maximum volume loss was observed in the corpus medullare (dmax = .49) and posterior lobe gray matter regions, including bilateral lobules VIIB (dmax = .47), crus I/II (dmax = .39), VIIIA (dmax = .45), and VIIIB (dmax = .40). Earlier age at seizure onset ( η ρ max 2 $$\eta {\mathit{\mathsf{\rho}}}_{\mathsf{max}}^{\mathsf{2}}$$ = .05) and longer epilepsy duration ( η ρ max 2 $$\eta {\mathit{\mathsf{\rho}}}_{\mathsf{max}}^{\mathsf{2}}$$ = .06) correlated with reduced volume in these regions. Findings were most pronounced in TLE‐HS and ETLE, with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls. Significance: We provide robust evidence of deep cerebellar and posterior lobe subregional gray matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in nonmotor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellar subregional damage into neurobiological models of epilepsy

Subcutaneous Low Dose Alemtuzumab: Role As a Salvage Therapy in Immune -Mediated Marrow Failure Conditions

Abstract Aplastic anemia (AA), pure red cell aplasia (PRCA), pure white cell aplasia (PWCA), idiopathic neutropenia (IN) and T cell large granular lymphocytic leukemia (LGL) are bone marrow failure (BMF) conditions unified by immune-mediated pathogenesis leading to cytopenias. Intravenous alemtuzumab, a CD52 monoclonal antibody approved for the treatment of chronic lymphocytic leukemia (CLL) and used for relapsed AA, has a response rate in AA of 37-58%. However, dosing and route was likely based on those used in CLL regimens and resulted in significant immunosuppressive complications. Here we summarize our experience with sc alemtuzumab given at the maximum dose of total 100 mg as etiologic treatment (either salvage therapy or preferred therapy) to patients with various BMF. We investigated the therapies administered to patients seen at the Cleveland Clinic or at the University of Naples (NCT00895739) between years 2002-2015. Of 484 patients with BMF conditions (Cleveland: AA: 204, LGL: 174, PRCA: 56; Naples: AA: 24, LGL: 2, PRCA: 14), 65 patients with AA (N=22), PRCA (N=22), LGL (N=18) and 3 cases of IN/PWCA were treated sc alemtuzumab, given according 2 distinct schedules: i. initial dose of 3 mg sc followed by 10 mg once or twice weekly for at least 8 consecutive weeks; ii. 4-5 day dose escalation (3-10-30-30-30 mg) regimen. In both schedules, some patients received a much longer course with maintenance treatment or occasional boosts to prevent or treat relapse. Patients received bactrim and acyclovir prophylaxis, IVIG for hypoglobulinemia and underwent CMV monitoring. The median age of patients was 57.5 years (range: 31-84 years). Alemtuzumab was used as salvage therapy in Cleveland (except for 3 AA cases with contraindication to anti-thymocyte globulin or cyclosporine), whereas in Naples untreated patients were allowed per protocol. As a result, patients had a median of 2 lines of therapy (range: 0-6), had either untreated (35%), relapsed (22%) or refractory (43%) BMF condition. Among the 22 AA patients 12 were untreated, or had relapsed (N=4), or refractory disease (N=6), with concomitant PNH clone in 8/22 patients. LGL patients (N=18) treated with alemtuzumab were younger, had a median of 2 prior therapies, 50% were STAT3 mutants, with comparable degree of cytopenias but excess splenomegaly (60% vs. 38%, p=.012) at presentation, compared to the remainder LGL cohort. Amongst these patients, 18% had relapsed LGL while the rest had refractory disease. PRCA cases treated were either idiopathic (N=18, of whom 3 associated with thymoma) or LGL-associated (N=4); this group was very heterogeneous, including 9 untreated patients (in Naples) and a subgroup of heavily pretreated patients (5 with refractory disease) with a median of 5 prior therapies, with mean hemoglobin of 7.5 g/dL. Among the group of PWCA/IN, one case of PWCA was LGL-associated. The treatment was well tolerated in 92% of the patients, except in four patients who did not complete treatment course due to adverse events. The main adverse events include infectious complications with 7/65 developing CMV reactivation, 4/65 HSV reactivation, and more rarely other viral reactivation (VZV and HBV, 1/65 each). Two fatal infections were recorded: 1 fungemia (heavily pretreated with other therapies) and 1 JCV-related PML (in a patients also receiving chemotherapy for refractory thymoma). The overall response rate was 55%; by disease subtype 54% of AA, 44% of LGL, 59% of PRCA and all three cases of PWCA/IN responded. The median time to response in AA was 12 weeks (range: 6-24 weeks), and responses lasted a median of 6 months (range: 2-72 months). In AA, we observed responses in 72% of the cases treated with almetuzumab upfront and 45% of the relapsed/refractory disease. Similarly in PRCA cases, 77% of the alemtuzumab upfront and 46% of the relapsed/refractory disease responded. With a median follow up >4 years, no late treatment-related complication emerged; treatment failures were mostly due to relapses (sometimes refractory to further immunosuppressive treatment), with clonal evolution around 15% (mostly in non-responders). In summary, low-dose sc alemtuzumab is a reasonable alternative option for patients with BMF conditions, especially in relapsed/refractory cases; patients need to be monitored with a heightened vigilance for infectious complications, as well as for possible recurrence of their underlying disease. Disclosures Risitano: Alexion Pharmaceuticals: Other: lecture fees, Research Funding; Alnylam: Research Funding; Rapharma: Research Funding; Novartis: Research Funding

The medieval booklists of the southern Low Countries. 7: The surviving manuscripts and incunables from medieval Belgian libraries

Introduction: Tremor of the upper limbs is a disabling symptom that is present during several neurological disorders and is currently without treatment. Functional MRI (fMRI) is an essential tool to investigate the pathophysiology of tremor and aid the development of treatment options. However, no adequately or standardized protocols for fMRI exists at present. Here we present a novel, online available fMRI task that could be used to assess the in vivo pathology of tremor. Objective: This study aims to validate the tremor-evoking potential of the fMRI task in a small group of tremor patients outside the scanner and assess the reproducibility of the fMRI task related activation in healthy controls. Methods: Twelve HCs were scanned at two time points (baseline and after 6-weeks). There were two runs of multi-band fMRI and the tasks included a "brick-breaker" joystick game. The game consisted of three conditions designed to control for most of the activation related to performing the task by contrasting the conditions: WATCH (look at the game without moving joystick), MOVE (rhythmic left/right movement of joystick without game), and PLAY (playing the game). Task fMRI was analyzed using FSL FEAT to determine clusters of activation during the different conditions. Maximum activation within the clusters was used to assess the ability to control for task related activation and reproducibility. Four tremor patients have been included to test ecological and construct validity of the joystick task by assessing tremor frequencies captured by the joystick. Results: In HCs the game activated areas corresponding to motor, attention and visual areas. Most areas of activation by our game showed moderate to good reproducibility (intraclass correlation coefficient (ICC) 0.531-0.906) with only inferior parietal lobe activation showing poor reproducibility (ICC 0.446). Furthermore, the joystick captured significantly more tremulous movement in tremor patients compared to HCs (p = 0.01) during PLAY, but not during MOVE. Conclusion: Validation of our novel task confirmed tremor-evoking potential and reproducibility analyses yielded acceptable results to continue further investigations into the pathophysiology of tremor. The use of this technique in studies with tremor patient will no doubt provide significant insights into the treatment options

Patterns of subregional cerebellar atrophy across epilepsy syndromes: An ENIGMA-Epilepsy study.

OBJECTIVE: The intricate neuroanatomical structure of the cerebellum is of longstanding interest in epilepsy, but has been poorly characterized within the current cortico-centric models of this disease. We quantified cross-sectional regional cerebellar lobule volumes using structural MRI in 1,602 adults with epilepsy and 1,022 healthy controls across twenty-two sites from the global ENIGMA-Epilepsy working group. METHODS: A state-of-the-art deep learning-based approach was employed that parcellates the cerebellum into 28 neuroanatomical subregions. Linear mixed models compared total and regional cerebellar volume in i) all epilepsies; ii) temporal lobe epilepsy with hippocampal sclerosis (TLE-HS); iii) non-lesional temporal lobe epilepsy (TLE-NL); iv) genetic generalised epilepsy; and (v) extra-temporal focal epilepsy (ETLE). Relationships were examined for cerebellar volume versus age at seizure onset, duration of epilepsy, phenytoin treatment, and cerebral cortical thickness. RESULTS: Across all epilepsies, reduced total cerebellar volume was observed (d=0.42). Maximum volume loss was observed in the corpus medullare (dmax=0.49) and posterior lobe grey matter regions, including bilateral lobules VIIB (dmax= 0.47), Crus I/II (dmax= 0.39), VIIIA (dmax=0.45) and VIIIB (dmax=0.40). Earlier age at seizure onset (ηρ2max=0.05) and longer epilepsy duration (ηρ2max=0.06) correlated with reduced volume in these regions. Findings were most pronounced in TLE-HS and ETLE with distinct neuroanatomical profiles observed in the posterior lobe. Phenytoin treatment was associated with reduced posterior lobe volume. Cerebellum volume correlated with cerebral cortical thinning more strongly in the epilepsy cohort than in controls. SIGNIFICANCE: We provide robust evidence of deep cerebellar and posterior lobe subregional grey matter volume loss in patients with chronic epilepsy. Volume loss was maximal for posterior subregions implicated in non-motor functions, relative to motor regions of both the anterior and posterior lobe. Associations between cerebral and cerebellar changes, and variability of neuroanatomical profiles across epilepsy syndromes argue for more precise incorporation of cerebellum subregions into neurobiological models of epilepsy

Bridging big data: procedures for combining non-equivalent cognitive measures from the ENIGMA Consortium

Investigators in the cognitive neurosciences have turned to Big Data to address persistent replication and reliability issues by increasing sample sizes, statistical power, and representativeness of data. While there is tremendous potential to advance science through open data sharing, these efforts unveil a host of new questions about how to integrate data arising from distinct sources and instruments. We focus on the most frequently assessed area of cognition - memory testing - and demonstrate a process for reliable data harmonization across three common measures. We aggregated raw data from 53 studies from around the world which measured at least one of three distinct verbal learning tasks, totaling N = 10,505 healthy and brain-injured individuals. A mega analysis was conducted using empirical bayes harmonization to isolate and remove site effects, followed by linear models which adjusted for common covariates. After corrections, a continuous item response theory (IRT) model estimated each individual subject’s latent verbal learning ability while accounting for item difficulties. Harmonization significantly reduced inter-site variance by 37% while preserving covariate effects. The effects of age, sex, and education on scores were found to be highly consistent across memory tests. IRT methods for equating scores across AVLTs agreed with held-out data of dually-administered tests, and these tools are made available for free online. This work demonstrates that large-scale data sharing and harmonization initiatives can offer opportunities to address reproducibility and integration challenges across the behavioral sciences