Searched for: school:SOM
Department/Unit:Neurology
Longitudinal positron emission tomography of dopamine synthesis in subjects with GBA1 mutations
Lopez, Grisel; Eisenberg, Daniel P; Gregory, Michael D; Ianni, Angela M; Grogans, Shannon E; Masdeu, Joseph C; Kim, Jenny; Groden, Catherine; Sidransky, Ellen; Berman, Karen Faith
Mutations in GBA1, the gene mutated in Gaucher disease, are a common genetic risk factor for Parkinson disease, although the penetrance is low. We performed [18 F]-Fluorodopa PET studies of 57 homozygous and heterozygous GBA1 mutation carriers (15 with parkinsonism) and 98 controls looking for early indications of dopamine loss using voxel-wise analyses to identify group differences in striatal [18 F]-Fluorodopa uptake (Ki ). Forty-eight subjects were followed longitudinally. Cross-sectional and longitudinal comparisons of Ki and Ki -change found significant effects of Parkinson disease. However, at baseline and over time, striatal [18 F]-Fluorodopa uptake in mutation carriers without parkinsonism did not significantly differ from controls. This article is protected by copyright. All rights reserved.
PMID: 32030791
ISSN: 1531-8249
CID: 4300742
Deep brain stimulation for monogenic Parkinson's disease: a systematic review
Kuusimäki, Tomi; Korpela, Jaana; Pekkonen, Eero; Martikainen, Mika H; Antonini, Angelo; Kaasinen, Valtteri
Deep brain stimulation (DBS) is an effective treatment for Parkinson's disease (PD) patients with motor fluctuations and dyskinesias. The key DBS efficacy studies were performed in PD patients with unknown genotypes; however, given the estimated monogenic mutation prevalence of approximately 5-10%, most commonly LRRK2, PRKN, PINK1 and SNCA, and risk-increasing genetic factors such as GBA, proper characterization is becoming increasingly relevant. We performed a systematic review of 46 studies that reported DBS effects in 221 genetic PD patients. The results suggest that monogenic PD patients have variable DBS benefit depending on the mutated gene. Outcome appears excellent in patients with the most common LRRK2 mutation, p.G2019S, and good in patients with PRKN mutations but poor in patients with the more rare LRRK2 p.R1441G mutation. The overall benefit of DBS in SNCA, GBA and LRRK2 p.T2031S mutations may be compromised due to rapid progression of cognitive and neuropsychiatric symptoms. In the presence of other mutations, the motor changes in DBS-treated monogenic PD patients appear comparable to those of the general PD population.
PMID: 30659355
ISSN: 1432-1459
CID: 3682652
The role of affibody in aged mouse model of alzheimer's disease [Meeting Abstract]
Greenberg, J H; Lindberg, H; Orozco, J; Vama, B; Habbat, H; Loflom, J; Stahl, S; Mejouate, O; Wisniewski, T; Boutajangout, A
Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease that currently accounts for over 70% of cases of dementia in adults over 65 worldwide, and is the only cause of death among the top ten with no effective treatments. Clinically, AD is characterized by progressive deterioration in memory and other areas of cognitive function. Neuropathologically, the disease is characterized by extracellular aggregations of amyloid-B (AB) and intraneuronal neurofibrillary tangles (NFTS) composed of abnormally phosphorylated tau, causing progressive neuronal death. The aim of this study was to investigate whether the affibody ZSYM73-ABD (a portion of the active antibody molecule) can reverse AD pathology in an AD mouse model, without also causing significant neuroinflammation and/or microhemorrhage.
Method(s): APP/PS1 double transgenic mice were injected twice weekly with either ZSYM-ABD or a non-AB specific affibody, Ztaq2, as a control. Mice underwent behavioral testing and their brains were then sacrificed for immunohistochemistry.
Result(s): Semi-quantitative analysis of amyloid burden, performed using 6E10/4G8 antibodies, showed a statistically significant reduction in amyloid burden in the hippocampus, and a trend towards reduction in amyloid burden in the cortex. Inflammation was assessed using GFAP and Iba1(markers of gliosis) which showed a statistically significant reduction of GFAP in the cortex and in the hippocampus, and a slight reduction of microgliosis in ZSYM73-ABD affibody treated mice. Finally, mice treated with ZSYM73-ABD performed significantly better on a novel object recognition task than control mice, suggesting a correlation between the histological findings above and improvement in cognitive function.
Conclusion(s): In conclusion, this study demonstrates that passive immunization with an affibody molecule improves cognitive function and significantly decreases amyloid burden in the hippocampus of a transgenic mouse model of AD, without inducing inflammation. This has potential implications for treatment of AD in humans
EMBASE:633776658
ISSN: 1532-5415
CID: 4757572
Peri-procedural stroke or death in stenting of symptomatic severe intracranial stenosis
Yaghi, Shadi; Khatri, Pooja; de Havenon, Adam; Yeatts, Sharon; Chang, Andrew D; Cutting, Shawna; Mac Grory, Brian; Burton, Tina; Jayaraman, Mahesh V; McTaggart, Ryan A; Fiorella, David; Derdeyn, Colin; Zaidat, Sam; Dehkharghani, Seena; Amin-Hanjani, Sepideh; Furie, Karen; Prahbakaran, Shyam; Liebeskind, David
BACKGROUND AND PURPOSE/OBJECTIVE:There are limited data on predictors of 30-day stroke or death in patients with symptomatic intracranial atherosclerosis (sICAS) undergoing stenting. We aim to determine the factors associated with stroke or death at 30 days in the stenting arm of the SAMMPRIS trial. METHODS:This is a post-hoc analysis of the SAMMPRIS trial including patients who underwent angioplasty/stenting. We compared patient-specific variables, lesion-specific variables, procedure-specific variables, and FDA-approved indications between patients with and without the primary outcome (stroke or death at 30 days). Logistic regression analyses were performed to evaluate associations with the primary outcome. RESULTS:We identified 213 patients, 30 of whom (14.1%) met the primary outcome. Smoking status and lesion length were associated with the primary outcome: the odds of stroke or death for non-smokers versus smokers (adjusted OR 4.46, 95% CI 1.79 to 11.1, p=0.001) and for increasing lesion length in millimeters (adjusted OR 1.20, 95% CI 1.02 to 1.39, p=0.029). These had a modest predictive value: absence of smoking history (sensitivity 66.7%, specificity 65.4%) and lesion length (area under curve 0.606). Furthermore, event rates were not significantly different between patients with and without the FDA-approved indication for stenting (15.9% vs 12%, p=0.437). CONCLUSION/CONCLUSIONS:In SAMMPRIS patients who underwent angioplasty/stenting, neither clinical and neuroimaging variables nor the FDA indication for stenting reliably predicted the primary outcome. Further work in identifying reliable biomarkers of stroke/death in patients with sICAS is needed before considering new clinical trials of stenting. TRIAL REGISTRATION NUMBER/BACKGROUND:SAMMPRIS NCT00576693; Results.
PMID: 31484697
ISSN: 1759-8486
CID: 4067412
ADHD IN OLDER ADULTS: A CASE REPORT LITERATURE AND REVIEW OF THE [Meeting Abstract]
Ojo, K Y; Balasubramaniam, M; Gurin, L; Mitra, P
Introduction: The prevalence of attention deficit hyperactivity disorder (ADHD) in older adults is estimated to be between 1.5 - 3.3 % across studies (Kooji et al, 2016). Older adults constitute a group in which ADHD is frequently underdiagnosed, undertreated, and often overlooked in both clinical practice and research. It is believed that older adults may have experienced longitudinal impact and a lifelong consequences of ADHD symptoms, in the absence of support for their problems in child- or adulthood (Michielson et al, 2015). Nadeau reported that age related cognitive changes, worsening physical health, and the lack of structure that often comes with retirement frequently tend to perpetuate symptoms of inattention (Nadeau, 2018). We present the case of an elderly man with ADHD. This will be followed by a review of the literature on ADHD in older adults.
Method(s): Case of Mr. R: We present the case of Mr. R, a 75-year old man who presented for evaluation of cognitive complaints. He reported chronic difficulties with attention and concentration, with recent worsening of focus, attention, concentration, and memory. Assessment consisted of evaluation of the patient, collateral information from his wife, brain imaging, and neuropsychological testing. His presentation was felt to be consistent with chronic untreated ADHD, now superimposed with mild cognitive changes across other domains. A trial of low dose methylphenidate was associated with marked improvement in his ability to focus, to follow conversations, and his working memory. The subjective changes were corroborated on the Montreal cognitive assessment (MOCA) which showed improvement in his scores, especially in the area of attention. Electronic searches of The Cochrane Central Register of Controlled Trials and the standard bibliographic databases PubMed, MEDLINE, EMBASE, and PsycINFO will be performed for papers which focus on ADHD in older adults. Keywords include "late life," "elderly," "aged," "senior citizen," or "geriatric" combined with the keywords "ADHD" or "attention deficit," Original research, case reports, and reviews will be included.
Result(s): Preliminary search conducted yielded five papers. Data from the included papers will be extracted. The epidemiology of ADHD in older adults will be discussed. This will be followed by a description of diagnostic assessment and diagnostic issues specific to older adults. The impact of ADHD in older adults will be outlined, which emphasis on its difference from that in the younger population. This will be followed by treatment considerations unique to older adults. Finally, the relationship between ADHD and cognitive impairment will be explored.
Conclusion(s): ADHD is frequently underdiagnosed and undertreated in older adults. Timely and accurate diagnosis followed by treatment results in significant improvement in symptoms and functionality. This research was funded by: None
Copyright
EMBASE:2005202772
ISSN: 1545-7214
CID: 4387942
Pre-endovascular therapy change in blood pressure is associated with outcomes in patients with stroke [Letter]
Mistry, Eva A; Dakay, Katarina; Petersen, Nils H; Jayaraman, Mahesh; McTaggart, Ryan; Furie, Karen; Mistry, Akshitkumar; Mehta, Tapan; Arora, Niraj; De Los Rios La Rosa, Felipe; Starosciak, Amy Kathryn; Siegler, James E; Barnhill, Natasha; Patel, Kishan; Assad, Salman; Tarboosh, Amjad; Cruz, Aurora Seaton; Wagner, Jeffrey; Fortuny, Enzo; Bennett, Alicia; James, Robert F; Jagadeesan, Bharathi Dasan; Streib, Christopher; Kasner, Scott; Weber, Stuart; Chitale, Rohan V; Volpi, John; Mayer, Stephan A; Khatri, Pooja; Yaghi, Shadi
PMID: 32029540
ISSN: 1468-330x
CID: 4300642
Modafinil in Recovery after Stroke (MIRAS): A Retrospective Study
Cross, Danielle B; Tiu, Jonathan; Medicherla, Chaitanya; Ishida, Koto; Lord, Aaron; Czeisler, Barry; Wu, Christopher; Golub, Danielle; Karoub, Amabel; Hernandez, Christopher; Yaghi, Shadi; Torres, Jose
BACKGROUND AND PURPOSE/OBJECTIVE:Acute rehabilitation is known to enhance stroke recovery. However, poststroke lethargy and fatigue can hinder participation in rehabilitation therapies. We hypothesized that in patients with moderate to severe stroke complicated by poststroke fatigue and lethargy early stimulant therapy with modafinil increases favorable discharge disposition defined as transfer to acute inpatient rehabilitation or home. METHODS:We retrospectively reviewed a cohort of patients with acute stroke admitted to the stroke service over a 3-year period. All patients 18 years or older with confirmed ischemic or hemorrhagic stroke, an NIHSS greater than or equal to 5 and documentation of fatigue/lethargy in clinical documentation were included. We compared patients that were treated with modafinil 50-200 mg to those managed with standard care. The primary outcome measure was discharge disposition. Secondary outcome was 90 day modified Rankin score (mRS). Statistical significance was determined using chi-square test for association and logistic regression models. Logistic regression models were derived in 2 ways with both raw data and an adjusted model that accounted for age, sex, and NIHSS score to account for the lack of randomization. RESULTS:This study included 199 stroke patients (145 ischemic, 54 hemorrhagic). Seventy-two (36.2%) were treated with modafinil and 129 (64.8%) were discharged to acute inpatient rehabilitation, while none were recommended for discharge home. Median NIHSS for modafinil patients was 13.5 versus 11 for standard care patients (P = .059). In adjusted models, modafinil was associated with higher odds of favorable discharge disposition (OR 2.00, 95% CI 1.01-3.95). Favorable outcome at 90 days defined as mRS less than or equal to 2 occurred more frequently with modafinil (5.6% versus 3.3%) but this did not achieve statistical significance (P > .1). These results occurred despite the modafinil group requiring longer ICU stays and having more in-hospital complications such as infections and need for percutaneous gastrostomy tubes. The benefit of modafinil was seen across all subgroups except those with severe stroke (NIHSS ≥ 15). There were no significant adverse events associated with modafinil administration. CONCLUSIONS:Modafinil use in acute in-hospital stroke patients with moderate stroke complicated by lethargy and fatigue was associated with improved discharge disposition. Randomized controlled trials are needed to further study the safety, efficacy, and long-term effects of modafinil in this patient population.
PMID: 32147025
ISSN: 1532-8511
CID: 4348592
Independent functional outcomes after prolonged coma following cardiac arrest: a mechanistic hypothesis
Forgacs, Peter B; Devinsky, Orrin; Schiff, Nicholas D
OBJECTIVE:Survivors of prolonged (> 2 weeks) post-cardiac arrest (CA) coma are expected to remain permanently disabled. We aimed to investigate three outlier patients who ultimately achieved independent functional outcomes after prolonged post-CA coma to identify electroencephalographic (EEG) markers of their recovery potential. For validation purposes, we also aimed to evaluate these markers in an independent cohort of post-CA patients. METHODS:We identified three patients with late recovery from coma (17-37 days) following CA who recovered to functionally independent behavioral levels. We performed spectral power analyses of available EEGs during prominent burst suppression patterns (BSP) present in all three patients. Using identical methods, we also assessed the relationship of intra-burst spectral power and outcomes in a prospectively enrolled cohort of post-CA patients. We performed chart reviews of common clinical, imaging, EEG prognostic variables and clinical outcomes for all patients. RESULTS:All three patients with late recovery from coma lacked evidence of overwhelming cortical injury but demonstrated prominent BSP on EEG. Spectral analyses revealed a prominent theta (~4-7Hz) feature dominating the bursts during BSP in these patients. In the prospective cohort, similar intra-burst theta spectral features were evident in patients with favorable outcomes; patients with BSP and unfavorable outcomes showed either no features, transient burst features or decreasing intra-burst frequencies with time. INTERPRETATION/CONCLUSIONS:BSP with theta (~4-7Hz) peak intra-burst spectral power after CA may index a recovery potential. We discuss our results in the context of optimizing metabolic substrate availability and stimulating the cortico-thalamic system during recovery from prolonged post-CA coma. This article is protected by copyright. All rights reserved.
PMID: 31994749
ISSN: 1531-8249
CID: 4299152
Epilepsy: key experimental therapeutics in early clinical development
Steriade, Claude; French, Jacqueline; Devinsky, Orrin
Introduction: Antiseizure medications are the mainstay of epilepsy treatment. Currently therapies are not specific to epilepsy etiology, and control seizures in two thirds of cases. Drugs in clinical development aim to bridge that gap by targeting novel receptors and epileptogenesis. While currently approved antiseizure medications target focal or generalized epilepsies regardless of etiology, newly approved and investigational epilepsy drugs also target rare or orphan epilepsy syndrome indications, such as Lennox-Gastaut or Dravet syndrome. We identified investigational drugs through the Epilepsy Foundation pipeline tracker and conference proceedings of recent novel epilepsy drug conferences (XV AEDD, XIV EILAT).Areas Covered: We review antiseizure medications in clinical development and their targets (GABA, T-type calcium channels, 5-HT, potassium channels). We also discuss drugs with unknown or multiple mechanisms of action (cannabinoids, carisbamate, cenobamate). Therapies with potential disease-modifying effects in preclinical and clinical development are then outlined, ranging from gene-targeted treatments (antisense oligonucleotide, gene therapy, antisense transcript regulators) targeting specific genetic epilepsies, mTOR inhibitors, to inflammation-targeted treatments.Expert Opinion: Drugs to treat novel targets to control seizures as well as prevent epileptogenesis offer great promise. To assess disease modifying agents, we may need new clinical trial designs. Precision medicine therapies for genetic epilepsies may control seizures and restore brain health.
PMID: 32172604
ISSN: 1744-7658
CID: 4352342
Longitudinal ultra-high field MRI of brain lesions in neuromyelitis optica spectrum disorders
Chawla, Sanjeev; Ge, Yulin; Wuerfel, Jens; Asadollahi, Shadi; Mohan, Suyash; Paul, Friedemann; Sinnecker, Tim; Kister, Ilya
BACKGROUND:In neuromyelitis optica spectrum disorder (NMOSD), clinical disability in NMOSD patients is relapse-related and progressive phase is rare. This observation raises the question whether there is any radiographic disease activity. The aim of present study was to determine the longitudinal changes in cerebral lesion number, lesion size, lesion-to-venule relationship, and morphological patterns of lesions in NMOSD using multiparametric 7T MR imaging. We also aimed to assess brain volume changes in NMOSD. METHODS:A cohort of 22 patients with NMOSD underwent high-resolution 3D-susceptibility weighted imaging (SWI) and 2D-gradient-echo (GRE-T2*) weighted imaging on 7T MRI of brain at baseline and after ~2.8 years of follow-up. Morphologic imaging characteristics, and signal intensity patterns of lesions were recorded at both time points. Lesions were classified as "iron-laden" if they demonstrated hypointense signal on GRE-T2* images and/or SWI as well as hyperintense signal on quantitative susceptibility mapping (QSM). Lesions were considered "non-iron-laden" if they were hyperintense on GRE-T2*/SWI and isointense or hyperintense on QSM. Additionally, fractional brain parenchymal volume (fBPV) was computed at both time points. RESULTS:A total of 169 lesions were observed at baseline. At follow-up, 6 new lesions were found in 5 patients. In one patient, a single lesion could not be detected on the follow-up scan. No appreciable change in lesion size and vessel-lesion relationship was observed at follow up. All lesions demonstrated hyperintense signal intensity on GRE-T2* weighted images and isointense signal on QSM at both time points. Therefore, these lesions were considered as non-associated with iron pathology. Additionally, no significant change in brain volume was observed: fBPV 0.78 ± 0.06 at baseline vs. 0.77 ± 0.05 at follow up, p>0.05. CONCLUSION/CONCLUSIONS:Cerebral lesions in NMOSD patients remain 'inert' and do not show any substantial variations in morphological characteristics during a 2-3-year follow-up period.
PMID: 32272444
ISSN: 2211-0356
CID: 4374602