Faculty Bibliography

Spinal cord lesions detected on MRI hold important diagnostic and prognostic value for multiple sclerosis. Previous attempts to correlate lesion burden with clinical status have had limited success, however, suggesting that lesion location may be a contributor. Our aim was to explore the spatial distribution of multiple sclerosis lesions in the cervical spinal cord, with respect to clinical status. We included 642 suspected or confirmed multiple sclerosis patients (31 clinically isolated syndrome, and 416 relapsing-remitting, 84 secondary progressive, and 73 primary progressive multiple sclerosis) from 13 clinical sites. Cervical spine lesions were manually delineated on T2- and T2*-weighted axial and sagittal MRI scans acquired at 3 or 7 T. With an automatic publicly-available analysis pipeline we produced voxelwise lesion frequency maps to identify predilection sites in various patient groups characterized by clinical subtype, Expanded Disability Status Scale score and disease duration. We also measured absolute and normalized lesion volumes in several regions of interest using an atlas-based approach, and evaluated differences within and between groups. The lateral funiculi were more frequently affected by lesions in progressive subtypes than in relapsing in voxelwise analysis (P < 0.001), which was further confirmed by absolute and normalized lesion volumes (P < 0.01). The central cord area was more often affected by lesions in primary progressive than relapse-remitting patients (P < 0.001). Between white and grey matter, the absolute lesion volume in the white matter was greater than in the grey matter in all phenotypes (P < 0.001); however when normalizing by each region, normalized lesion volumes were comparable between white and grey matter in primary progressive patients. Lesions appearing in the lateral funiculi and central cord area were significantly correlated with Expanded Disability Status Scale score (P < 0.001). High lesion frequencies were observed in patients with a more aggressive disease course, rather than long disease duration. Lesions located in the lateral funiculi and central cord area of the cervical spine may influence clinical status in multiple sclerosis. This work shows the added value of cervical spine lesions, and provides an avenue for evaluating the distribution of spinal cord lesions in various patient groups.

Objective/UNASSIGNED:Assessment of performance validity is a necessary component of any neuropsychological evaluation. Prior research has shown that cutoff scores of ≤6 or ≤7 on Reliable Digit Span (RDS) can detect suboptimal effort across numerous adult clinical populations; however, these scores have not been validated for that purpose in an adult epilepsy population. This investigation aims to determine whether these previously established RDS cutoff scores could detect suboptimal effort in adults with epilepsy. Method/UNASSIGNED:Sixty-three clinically referred adults with a diagnosis of epilepsy or suspected seizures were administered the Digit Span subtest of the Wechsler Adult Intelligence Scale (WAIS-III or WAIS-IV). Most participants (98%) passed Trial 2 of the Test of Memory Malingering (TOMM), achieving a score of ≥45. Results/UNASSIGNED:Previously established cutoff scores of ≤6 and ≤7 on RDS yielded a specificity rate of 85% and 77% respectively. Findings also revealed that RDS scores were positively related to attention and intellectual functioning. Given the less than ideal specificity rate associated with each of these cutoff scores, together with their strong association to cognitive factors, secondary analyses were conducted to identify more optimal cutoff scores. Preliminary results suggest that an RDS cutoff score of ≤4 may be more appropriate in a clinically referred adult epilepsy population with a low average IQ or lower. Conclusions/UNASSIGNED:Preliminary findings indicate that cutoff scores of ≤6 and ≤7 on RDS are not appropriate in adults with epilepsy, especially in individuals with low average IQ or below.

Mild traumatic brain injury (mTBI) affects about 42 million people worldwide. It is often associated with headache, cognitive deficits and balance difficulties but rarely shows any abnormalities on conventional CT or MR imaging. While in most mTBI patients the symptoms resolve within 3 months, 10-15% of patients continue to exhibit symptoms beyond a year. Also, it is known that there exists a vulnerable period post-injury, when a second injury may exacerbate clinical prognosis. Identifying this vulnerable period may be critical for patient outcome, but very little is known about the neural underpinnings of mTBI and its recovery. In this work, we used advanced functional neuroimaging to study longitudinal changes in functional organization of the brain during the 3-month recovery period post mTBI. Fractional amplitude of low frequency fluctuations (fALFF) measured from resting state functional MRI (rs-fMRI) was found to be associated with symptom severity score (SSS, r=-0.28, p=0.002). Decreased fALFF was observed in specific functional networks for patients with higher SSS, and fALFF returned to higher values when the patient recovered (lower SSS). In addition, functional connectivity of the same networks was found to be associated with concurrent SSS, and connectivity immediately after injury (<10 days) was capable of predicting SSS at a later time point (3 weeks to 3 months, p<0.05). Specific networks including motor, default-mode and visual networks were found to be associated with SSS (p<0.001) , and connectivity between these networks predicted 3-month clinical outcome (motor and visual: p<0.001, default-mode: p<0.006). Our results suggest that functional connectivity in these networks are potential biomarkers for predicting mTBI recovery profiles and clinical outcome.

BACKGROUND AND PURPOSE/OBJECTIVE:Impaired distal perfusion predicts neurological deterioration in large artery atherosclerosis. We aim to determine the optimal threshold of Tmax delay on perfusion imaging that is associated with neurological deterioration in patients with symptomatic proximal anterior circulation large artery stenosis. METHODS:Data were abstracted from a prospective ischemic stroke database of consecutively enrolled patients with symptomatic proximal intracranial stenosis (internal carotid artery or M1 segment of the middle cerebral artery) who underwent magnetic resonance perfusion imaging within 24 hours of symptom onset during a 15-month period. Tissue volumes of perfusion delay Tmax 0-4 seconds, Tmax > 4 seconds, Tmax > 6 seconds, and Tmax > 8 seconds were calculated using an automated approach. A target mismatch (penumbra-core) was defined as ≥15mL of brain tissue using each of the Tmax threshold categories. The outcome was neurological deterioration at 30 days defined as new or worsening neurological deficits that are not attributed to a nonvascular etiology. RESULTS:Among 52 patients with symptomatic intracranial stenosis, 26 patients met inclusion criteria. Neurological deterioration was associated with target mismatch profile defined according to Tmax > 6 seconds (66.7% [6/9] vs. 5.9% [1/17], P < .01) and Tmax >8 seconds (57.1% [4/7] vs. 15.8% [3/19], P = .05] but not according to Tmax > 4 seconds (27.3% [6/17] vs. 11.1% [1/9], P = .35]. CONCLUSIONS:A target mismatch profile using Tmax > 6 seconds may define tissue at risk in patients with acute symptomatic proximal anterior circulation intracranial stenosis. More studies are needed to confirm our findings.

OBJECTIVE:Patients with Lennox-Gastaut syndrome (LGS) who completed 1 of 2 randomized, double-blind, placebo-controlled trials of add-on cannabidiol (CBD) (GWPCARE3, NCT02224560 or GWPCARE4, NCT02224690) were invited to enroll in an open-label extension (OLE) study evaluating the long-term safety and efficacy of CBD (GWPCARE5, NCT02224573). Herein we present an interim analysis of the safety, efficacy, and patient-reported outcomes from this trial. METHODS:Patients received a pharmaceutical formulation of highly purified CBD oral solution (Epidiolex; 100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week titration period, in addition to their existing medications. Doses could be reduced if not tolerated or increased up to 30 mg/kg/d if thought to be of benefit. RESULTS:This interim analysis was based on a November 2016 data cut. Of 368 patients who completed treatment in GWPCARE3 and GWPCARE4, 366 (99.5%) enrolled in the OLE study (GWPCARE5). Median treatment duration was 38 weeks at a mean modal dose of 23 mg/kg/d. Most patients (92.1%) experienced adverse events (AEs), primarily of mild (32.5%) or moderate (43.4%) severity. The most common AEs were diarrhea (26.8%), somnolence (23.5%), and convulsion (21.3%). Thirty-five patients (9.6%) discontinued treatment due to AEs. Liver transaminase elevations were reported in 37 patients (10.1%), of whom 29 were receiving concomitant valproic acid; 34 cases resolved spontaneously or with dose modification of CBD or concomitant medication. Median reduction from baseline in drop seizure frequency (quantified monthly over 12-week periods) ranged from 48% to 60% through week 48. Median reduction in monthly total seizure frequency ranged from 48% to 57% across all 12-week periods through week 48. Eighty-eight percent of patients/caregivers reported an improvement in the patient's overall condition per the Subject/Caregiver Global Impression of Change scale. SIGNIFICANCE/CONCLUSIONS:In this study, long-term add-on CBD treatment had an acceptable safety profile in patients with LGS and led to sustained reductions in seizures.

INTRODUCTION/BACKGROUND:We explored regional brain atrophy patterns and their clinical correlates in dementia with Lewy bodies (DLB). METHODS:In this multicentre study, we included a total of 333 patients with DLB, 352 patients with Alzheimer's disease (AD), and 233 normal controls and used medial temporal lobe atrophy, posterior atrophy, and frontal atrophy (GCA-F) visual rating scales. Patients were classified according to four atrophy patterns. RESULTS:Patients with DLB had higher scores on all the three atrophy scales than healthy controls but had less medial temporal lobe atrophy than those with AD (all P-values < .001). A signature hippocampal-sparing pattern of regional atrophy was observed in DLB. The magnetic resonance imaging measures showed 65% ability to discriminate between DLB and AD and marginally contributed to the discrimination over and above the core clinical features. DISCUSSION/CONCLUSIONS:The most common pattern of atrophy of DLB was hippocampal-sparing. Future studies should explore whether comorbid AD pathology underlies the atrophy patterns seen in DLB.

INTRODUCTION/BACKGROUND:In this multicenter study on subjective cognitive decline (SCD) in community-based and memory clinic settings, we assessed the (1) incidence of Alzheimer's disease (AD) and non-AD dementia and (2) determinants of progression to dementia. METHODS:Eleven cohorts provided 2978 participants with SCD and 1391 controls. We estimated dementia incidence and identified risk factors using Cox proportional hazards models. RESULTS:In SCD, incidence of dementia was 17.7 (95% Poisson confidence interval 15.2-20.3)/1000 person-years (AD: 11.5 [9.6-13.7], non-AD: 6.1 [4.7-7.7]), compared with 14.2 (11.3-17.6) in controls (AD: 10.1 [7.7-13.0], non-AD: 4.1 [2.6-6.0]). The risk of dementia was strongly increased in SCD in a memory clinic setting but less so in a community-based setting. In addition, higher age (hazard ratio 1.1 [95% confidence interval 1.1-1.1]), lower Mini-Mental State Examination (0.7 [0.66-0.8]), and apolipoprotein E ε4 (1.8 [1.3-2.5]) increased the risk of dementia. DISCUSSION/CONCLUSIONS:SCD can precede both AD and non-AD dementia. Despite their younger age, individuals with SCD in a memory clinic setting have a higher risk of dementia than those in community-based cohorts.

BACKGROUND:It is largely unknown whether functional outcomes after mechanical thrombectomy for large vessel occlusion (LVO) ischemic strokes differ by sex in non-clinical trial populations. We investigated sex differences in 90-day outcomes among ischemic stroke patients receiving mechanical thrombectomy. METHODS:This was a prospective cohort of adults treated with mechanical thrombectomy for LVO at a single academic comprehensive stroke center from July 2015 to April 2017. Data on independence (mRS ≤2) at hospital discharge and 90 days were collected prospectively. Multiple logistic regression was used to determine the association between sex and 90-day independence, first adjusting for demographics, pre-stroke mRS, and NIHSS, then by co-morbidities and time to thrombectomy, and finally by vessel recanalization and use of intravenous thrombolysis. RESULTS:We included 279 patients, 52% of whom were female. Compared with males, females were older (median years (IQR) 81 (75-88) vs. 71.5 (60-81), P<0.001) and had higher baseline NIHSS (mean SD 18.2±7.5 vs . 16.0±7.1, P=0.02). Similar proportions of males and females had pre-stroke mRS ≤2 (73.3% vs.67.1%, P=0.27). In multivariate analyses, males and females had a similar likelihood of being independent at discharge (aOR 0.71 (95%CI 0.32 to 1.58)), but females were less likely to be independent at 90 days (aOR 0.37 95% CI 0.16 to 0.87). CONCLUSIONS:In patients treated with mechanical thrombectomy for LVOs at a large comprehensive stroke center, females were less likely to be independent at 90 days. Future research should investigate contributors to poor outcomes post-discharge in females with LVOs, along with potential interventions to improve outcomes.

Alzheimer's disease (AD) is the most common type of dementia in the elderly with no effective treatment currently. Recent studies of noninvasive neuroimaging, resting-state functional magnetic resonance imaging (rs-fMRI) with graph theoretical analysis have shown that patients with AD and mild cognitive impairment (MCI) exhibit disrupted topological organization in large-scale brain networks. In previous work, it is a common practice to threshold such networks. However, it is not only difficult to make a principled choice of threshold values, but also worse is the discard of potential important information. To address this issue, we propose a threshold-free feature by integrating a prior persistent homology-based topological feature (the zeroth Betti number) and a newly defined connected component aggregation cost feature to model brain networks over all possible scales. We show that the induced topological feature (Integrated Persistent Feature) follows a monotonically decreasing convergence function and further propose to use its slope as a concise and persistent brain network topological measure. We apply this measure to study rs-fMRI data from the Alzheimer's Disease Neuroimaging Initiative and compare our approach with five other widely used graph measures across five parcellation schemes ranging from 90 to 1,024 region-of-interests. The experimental results demonstrate that the proposed network measure shows more statistical power and stronger robustness in group difference studies in that the absolute values of the proposed measure of AD are lower than MCI and much lower than normal controls, providing empirical evidence for decreased functional integration in AD dementia and MCI.