Faculty Bibliography

Deep learning (DL) methods have in recent years yielded impressive results in medical imaging, with the potential to function as clinical aid to radiologists. However, DL models in medical imaging are often trained on public research cohorts with images acquired with a single scanner or with strict protocol harmonization, which is not representative of a clinical setting. The aim of this study was to investigate how well a DL model performs in unseen clinical datasets-collected with different scanners, protocols and disease populations-and whether more heterogeneous training data improves generalization. In total, 3117 MRI scans of brains from multiple dementia research cohorts and memory clinics, that had been visually rated by a neuroradiologist according to Scheltens' scale of medial temporal atrophy (MTA), were included in this study. By training multiple versions of a convolutional neural network on different subsets of this data to predict MTA ratings, we assessed the impact of including images from a wider distribution during training had on performance in external memory clinic data. Our results showed that our model generalized well to datasets acquired with similar protocols as the training data, but substantially worse in clinical cohorts with visibly different tissue contrasts in the images. This implies that future DL studies investigating performance in out-of-distribution (OOD) MRI data need to assess multiple external cohorts for reliable results. Further, by including data from a wider range of scanners and protocols the performance improved in OOD data, which suggests that more heterogeneous training data makes the model generalize better. To conclude, this is the most comprehensive study to date investigating the domain shift in deep learning on MRI data, and we advocate rigorous evaluation of DL models on clinical data prior to being certified for deployment.

OBJECTIVE:demonstrated superior efficacy and comparable safety of fingolimod versus interferon β-1a (IFN β-1a) in paediatric-onset multiple sclerosis (PoMS). This study aimed to report all predefined MRI outcomes from this study. METHODS:Patients with multiple sclerosis (MS) (aged 10-<18 years) were randomised to once-daily oral fingolimod (n=107) or once-weekly intramuscular IFN β-1a (n=108) in this flexible duration study. MRI was performed at baseline and every 6 months for up to 2 years or end of the study (EOS) in case of early treatment discontinuation/completion. Key MRI endpoints included the annualised rate of formation of new/newly enlarging T2 lesions, gadolinium-enhancing (Gd+) T1 lesions, new T1 hypointense lesions and combined unique active (CUA) lesions (6 months onward), changes in T2 and Gd+ T1 lesion volumes and annualised rate of brain atrophy (ARBA). RESULTS:Of the randomised patients, 107 each were treated with fingolimod and IFN β-1a for up to 2 years. Fingolimod reduced the annualised rate of formation of new/newly enlarging T2 lesions (52.6%, p<0.001), number of Gd+ T1 lesions per scan (66.0%, p<0.001), annualised rate of new T1 hypointense lesions (62.8%, p<0.001) and CUA lesions per scan (60.7%, p<0.001) versus IFN β-1a at EOS. The percent increases from baseline in T2 (18.4% vs 32.4%, p<0.001) and Gd+ T1 (-72.3% vs 4.9%, p=0.001) lesion volumes and ARBA (-0.48% vs -0.80%, p=0.014) were lower with fingolimod versus IFN β-1a, the latter partially due to accelerated atrophy in the IFN β-1a group. CONCLUSION/CONCLUSIONS:Fingolimod significantly reduced MRI activity and ARBA for up to 2 years versus IFN β-1a in PoMS.

Background/UNASSIGNED:Although the COVID-19 pandemic is affecting a relatively small proportion of the global population, its effects have already reached everyone. The pandemic has the potential to differentially disadvantage chronically ill patients, including those with Parkinson's disease (PD). The first health care reaction has been to limit access to clinics and neurology wards to preserve fragile patients with PD from being infected. In some regions, the shortage of medical staff has also forced movement disorders neurologists to provide care for patients with COVID-19. Objective/UNASSIGNED:To share the experience of various movement disorder neurologists operating in different world regions and provide a common approach to patients with PD, with a focus on those already on advanced therapies, which may serve as guidance in the current pandemic and for emergency situations that we may face in the future. Conclusion/UNASSIGNED:Most of us were unprepared to deal with this condition given that in many health care systems, telemedicine has been only marginally available or only limited to email or telephone contacts. In addition, to ensure sufficient access to intensive care unit beds, most elective procedures (including deep brain stimulation or the initiation of infusion therapies) have been postponed. We all hope there will soon be a time when we will return to more regular hospital schedules. However, we should consider this crisis as an opportunity to change our approach and encourage our hospitals and health care systems to facilitate the remote management of chronic neurological patients, including those with advanced PD.

Constipation is the most common adverse event (AE) of opioid therapy. This multicenter, phase 2 study evaluated the efficacy and safety of linaclotide in treating opioid-induced constipation (OIC) in patients with chronic noncancer pain syndromes (NCT02270983). Adults with OIC (<3 spontaneous bowel movements [SBMs]/week) related to chronic noncancer pain were randomized 1:1:1 to receive linaclotide 145 µg, linaclotide 290 µg, or placebo once daily for 8 weeks. The primary endpoint was change from baseline in 8-week SBM frequency rate (SBMs/week). Secondary efficacy endpoints included 6/8-week SBM 3 + 1 responders, time to first SBM, and changes from baseline in 8-week stool consistency, abdominal bloating, and straining. Additional endpoints included treatment satisfaction and adequate relief responders. In total, 254 patients were randomized: 87, 88, and 79 received linaclotide 145 µg, linaclotide 290 µg, and placebo, respectively. The mean changes from baseline in SBMs/week during the treatment period were 2.9 and 3.5 in the linaclotide 145 and 290 µg groups (P < 0.01 for both doses), respectively, vs 1.6 in the placebo group. Diarrhea, the most common AE, was generally mild, resulting in 1.1%, 5.7%, and 1.3% of patients discontinuing in the linaclotide 145 μg, linaclotide 290 μg, and placebo groups, respectively. No serious AEs related to diarrhea were reported in any treatment group. Compared with placebo, linaclotide-treated patients had significant improvements in stool consistency, straining, abdominal bloating, and treatment satisfaction scores (P < 0.05). Linaclotide significantly improved OIC symptoms and was well tolerated in patients with chronic noncancer pain.

Neck pain and headache are two of the most common complications of whiplash injury. Therefore, we performed a systematic literature search on PubMed and Embase for publications reporting on the prevalence of neck pain and headache following whiplash injury. The literature search identified 2,709 citations of which 44 contained relevant original data. Of these, 27 studies provided data for the quantitative analysis. For non-population-based studies, the present meta-analysis showed that a pooled relative frequency of neck pain was 84% CI (68-95%) and a pooled relative frequency of headache was 60% (46-73%), within 7 days following whiplash injury. At 12 months post-injury, 38% (32-45%) of patients with whiplash still experienced neck pain, while 38% (18-60%) of whiplash patients reported headache at the same time interval post-injury. However, we also found considerable heterogeneity among studies with I-values ranging from 89-98% for the aforementioned meta-analyses. We believe that the considerable heterogeneity among studies underscores the need for clear-cut definitions of whiplash injury and standardized reporting guidelines for post-whiplash sequelae such as neck pain and headache. Future studies should seek to optimize these aspects paving the way for a better understanding of the clinical characteristics and natural course of whiplash-associated sequelae.

Objectives: Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder that is characterized by selective degeneration of both upper and lower motor neurons, resulting in paralysis of skeletal muscle and respiratory failure, with death occurring within 2-5 years of diagnosis. 90% of cases are sporadic, and of the 10% that are familial more than 20 genes (>150 mutations) have been found to be associated with ALS, most notably copper/zinc superoxide dismutase (SOD1). SOD1 mutant proteins are believed to cause toxicities in degenerating neurons. Studies suggest that the neuronal and non-neuronal cell contributions to the onset and progression of ALS are complex. It was proposed that there are two phases of neuroinflammation in the spinal cord - the first being an early neuroprotective phase followed by a second late neurotoxic phase. One of the challenges in the study of neuroinflammation is that it is difficult to serially track the disease process, as there are no bona fide biomarkers for onset and progression in ALS. For this reason, we use PET with [¹¹C]PBR28 to track microglial neuroinflammation in the brain and spinal cord. We and others have shown that the receptor for advanced glycation end products (RAGE) is highly expressed in human ALS spinal cord, particularly in microglia, and to an increased degree compared to that of age-matched control subjects. Our previous studies with myeloid/microglia deletion of Ager and treatment with sRAGE (soluble RAGE) suggested that RAGE impairs survival and motor function in Sod1G93Amice. The ultimate goal is to test the hypothesis that RAGE inhibition in either initiation or progression phases of the ALS will prolong survival and maintain motor function in adult Sod1G93Amice.
Method(s): MicroPET/CT (Inveon, Siemens) with [¹¹C]PBR28 was used to track and compare microglial neuroinflammation in the brain and spinal cord of WT vs. ALS mice (110-120 day old), also after treatment with RAGE inhibitors (subject identity was blind to study investigator and data analyst). Using IRW (Inveon Research Workplace, Siemens), several ROIs in the thoracic and lumbar spinal cord (T13, L1, L2, L3) were drawn on the fused PET/CT images to obtain the regional SUVs. An automated atlasbased methodology using Firevoxel (https://urldefense.proofpoint.com/v2/url?u=https-3A__wp.nyu.edu_Firevoxel&d=DwIBAg&c=j5oPpO0eBH1iio48DtsedeElZfc04rx3ExJHeIIZuCs&r=CY_mkeBghQnUPnp2mckgsNSbUXISJaiBQUhM-Uz9W58&m=_uGsTvUTTD_GxqvwK245ZUiiSbzVraIboytFijFDOwU&s=RlC-AQtmqr84rzBwvDmgK_FCVdvbCfsFvuN-dVODTpM&e= ) that we previously developed was used for brain mapping and segmentation to derive regional timeactivity curves (TAC) and SUVs for 20 brain regions.
Result(s): Dynamic regional SUV [¹¹C]PBR28 binding data were obtained and averaged SUVs derived from the last 5 frames (with steady and less variable intensity levels) were compared. Results derived from both spinal cord and brain regions displayed a similar trend with two obvious clusters. Reduced binding was observed for ALS group as compared to WT. RAGE inhibitor-treated ALS mi ce showed increased binding (brain SUV avg. 0.402+/-0.0382 over 20 ROIs) as compared to vehicle-treated (0.157+/-0.0339), suggesting that RAGE inhibition may contribute to the restoration of homeostasis in ALS animals (i.e., their bindings after treatment were closer to those in WT (0.485+/-0.171)). Notably, hypothalamus, brain stem, and olfactory bulb consistently exhibited higher binding, suggesting their role in this regulation.
Conclusion(s): Inconsistent outcomes have been reported in the literature when comparing TSPO ligand binding for imaging neuroinflammation. Our data are consistent with findings from several recent studies; i.e., reduced PBR28 binding was associated with disease state (e.g., in patients with PTSD or alcoholism). A notion that the reduced binding might reflect competition from endogenous TSPO ligands such as cholesterol can't be excluded. The strategies described here will test the hypothesis that pharmacological antagonism of RAGE signal transduction in either initiation or progression phases of the ALS will prolong survival and maintain motor function in adult Sod1G93Amice

Huntington disease, a neurodegenerative disease characterized by progressive motor, behavioral, and cognitive decline, is caused by a CAG trinucleotide repeat expansion in the huntingtin gene on chromosome 4. Current treatments target symptom management because there are no disease-modifying therapies at this time. Investigation of RNA-based and DNA-based treatment strategies are emerging and hold promise of possible future disease-modifying therapy.

OBJECTIVE:To establish cytometry profiles associated with disease stages and immunotherapy in MS. METHODS:Demographic/clinical data and peripheral blood samples were collected from 227 patients with MS and 82 sex- and age-matched healthy controls (HCs) enrolled in a cross-sectional study at 4 European MS centers (Spain, Italy, Germany, and Norway). Flow cytometry of isolated peripheral blood mononuclear cells was performed in each center using specifically prepared antibody-cocktail Lyotubes; data analysis was centralized at the Genoa center. Differences in immune cell subsets were assessed between groups of untreated patients with relapsing-remitting or progressive MS (RRMS or PMS) and HCs and between groups of patients with RRMS taking 6 commonly used disease-modifying drugs. RESULTS:T-regulatory and B-regulatory cells. CONCLUSIONS:Our highly standardized, multisite cytomics data provide further understanding of treatment impact on MS immunophenotype and could pave the way toward monitoring immune cells to help clinical management of MS individuals.