Faculty Bibliography
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school:SOM
Department/Unit:Neurology
Total Results:
23438
A New MRI Measure to Early Differentiate Progressive Supranuclear Palsy From De Novo Parkinson's Disease in Clinical Practice: An International Study
BACKGROUND:Enlargement of the third ventricle has been reported in atypical parkinsonism. We investigated whether the measurement of third ventricle width could distinguish Parkinson's disease (PD) from progressive supranuclear palsy (PSP). METHODS:We assessed a new MR T1-weighted measurement (third ventricle width/internal skull diameter) in a training cohort of 268 participants (98 PD, 73 PSP, 98 controls from our center) and in a testing cohort of 291 participants (82 de novo PD patients and 133 controls from the Parkinson's Progression Markers Initiative, 76 early-stage PSP from an international research group). PD diagnosis was confirmed after a 4-year follow-up. Diagnostic performance of the third ventricle/internal skull diameter was assessed using receiver operating characteristic curve with bootstrapping; the area under the curve of the training cohort was compared with the area under the curve of the testing cohort using the De Long test. RESULTS:In both cohorts, third ventricle/internal skull diameter values did not differ between PD and controls but were significantly lower in PD than in PSP patients (P < 0.0001). In PD, third ventricle/internal skull diameter values did not change significantly between baseline and follow-up evaluation. Receiver operating characteristic analysis accurately differentiated PD from PSP in the training cohort (area under the curve, 0.94; 95% CI, 91.1-97.6; cutoff, 5.72) and in the testing cohort (area under the curve, 0.91; 95% CI, 87.0-97.0; cutoff,: 5.88), validating the generalizability of the results. CONCLUSION/CONCLUSIONS:Our study provides a new reliable and validated MRI measurement for the early differentiation of PD and PSP. The simplicity and generalizability of this biomarker make it suitable for routine clinical practice and for selection of patients in clinical trials worldwide. © 2020 International Parkinson and Movement Disorder Society.
PMID: 33151015
ISSN: 1531-8257
CID: 4664302
Requests for somatic support after neurologic death determination: Canadian physician experiences
PURPOSE/OBJECTIVE:Neurologic determination of death (NDD) is legally accepted as death in Canada but remains susceptible to misunderstandings. In some cases, families request continued organ support after NDD. Conflicts can escalate to formal legal challenges, causing emotional, financial, and moral distress for all involved. We describe prevalence, characteristics, and common experiences with requests for continued organ support following NDD in Canada. METHODS:Mixed-methods design combining anonymous online survey with semi-structured interviews of Canadian critical care physicians (448 practitioners, adult and pediatric). RESULTS:One hundred and six physicians responded to the survey and 12 participated in an interview. Fifty-two percent (55/106) of respondents had encountered a request for continued organ support after NDD within two years, 47% (26/55) of which involved threat of legal action. Requests for continued support following NDD ranged from appeals for time for family to gather before ventilator removal to disagreement with the concept of NDD. Common responses to requests included: consultation with an additional physician (54%), consultation with spiritual services (41%), and delay of one to three days for NDD acceptance (49%). Respondents with prior experience were less likely to recommend ancillary tests (P = 0.004) or consultation with bioethics services (P = 0.004). Qualitative analysis revealed perceptions that requests for continued organ support were driven by mistrust, tensions surrounding decision-making, and cultural differences rather than a lack of specific information about NDD. CONCLUSIONS:Family requests for continued somatic support following NDD were encountered by half our sample of Canadian critical care physicians. Mitigation strategies require attention to the multifaceted social contexts surrounding these complex scenarios.
PMID: 33174163
ISSN: 1496-8975
CID: 5148132
Journal of clinical & experimental neuropsychology. 2021:43(2):213-223.DOI: 10.1080/13803395.2021.1914002
Establishing the base rate of performance invalidity in a clinical electrical injury sample: Implications for neuropsychological test performance
PMID: 33858295
ISSN: 1744-411x
CID: 5250022
Racemization in Post-Translational Modifications Relevance to Protein Aging, Aggregation and Neurodegeneration: Tip of the Iceberg
Homochirality of DNA and prevalent chirality of free and protein-bound amino acids in a living organism represents the challenge for modern biochemistry and neuroscience. The idea of an association between age-related disease, neurodegeneration, and racemization originated from the studies of fossils and cataract disease. Under the pressure of new results, this concept has a broader significance linking protein folding, aggregation, and disfunction to an organism's cognitive and behavioral functions. The integrity of cognitive function is provided by a delicate balance between the evolutionarily imposed molecular homo-chirality and the epigenetic/developmental impact of spontaneous and enzymatic racemization. The chirality of amino acids is the crucial player in the modulation the structure and function of proteins, lipids, and DNA. The collapse of homochirality by racemization is the result of the conformational phase transition. The racemization of protein-bound amino acids (spontaneous and enzymatic) occurs through thermal activation over the energy barrier or by the tunnel transfer effect under the energy barrier. The phase transition is achieved through the intermediate state, where the chirality of alpha carbon vanished. From a thermodynamic consideration, the system in the homo-chiral (single enantiomeric) state is characterized by a decreased level of entropy. The oscillating protein chirality is suggesting its distinct significance in the neurotransmission and flow of perceptual information, adaptive associative learning, and cognitive laterality. The common pathological hallmarks of neurodegenerative disorders include protein misfolding, aging, and the deposition of protease-resistant protein aggregates. Each of the landmarks is influenced by racemization. The brain region, cell type, and age-dependent racemization critically influence the functions of many intracellular, membrane-bound, and extracellular proteins including amyloid precursor protein (APP), TAU, PrP, Huntingtin, α-synuclein, myelin basic protein (MBP), and collagen. The amyloid cascade hypothesis in Alzheimer's disease (AD) coexists with the failure of amyloid beta (Aβ) targeting drug therapy. According to our view, racemization should be considered as a critical factor of protein conformation with the potential for inducing order, disorder, misfolding, aggregation, toxicity, and malfunctions.
PMCID:8330555
PMID: 34350031
ISSN: 2073-8994
CID: 5066712
New perspectives on brain death
Brain death, or death by neurological criteria (BD/DNC), has been accepted conceptually, medically and legally for decades. Nevertheless, some areas remain controversial or understudied, pointing to a need for focused research to advance the field. Multiple recent contributions have increased our understanding of BD/DNC, solidified our practice and provided guidance where previously lacking. There have also been important developments on a global scale, including in low-to-middle income countries such as in South America. Although variability in protocols and practice still exists, new efforts are underway to reduce inconsistencies and better train practitioners in accurate and sound BD/DNC determination. Various legal challenges have required formal responses from national societies, and the American Academy of Neurology has filled this void with much needed guidance. Questions remain regarding concepts such as 'whole brain' versus 'brainstem' death, and the intersection of BD/DNC and rubrics of medical futility. These concepts are the subject of this review.
PMID: 33219040
ISSN: 1468-330x
CID: 4702692
Rationale and design of the Kidney Precision Medicine Project [Editorial]
Chronic kidney disease (CKD) and acute kidney injury (AKI) are common, heterogeneous, and morbid diseases. Mechanistic characterization of CKD and AKI in patients may facilitate a precision-medicine approach to prevention, diagnosis, and treatment. The Kidney Precision Medicine Project aims to ethically and safely obtain kidney biopsies from participants with CKD or AKI, create a reference kidney atlas, and characterize disease subgroups to stratify patients based on molecular features of disease, clinical characteristics, and associated outcomes. An additional aim is to identify critical cells, pathways, and targets for novel therapies and preventive strategies. This project is a multicenter prospective cohort study of adults with CKD or AKI who undergo a protocol kidney biopsy for research purposes. This investigation focuses on kidney diseases that are most prevalent and therefore substantially burden the public health, including CKD attributed to diabetes or hypertension and AKI attributed to ischemic and toxic injuries. Reference kidney tissues (for example, living-donor kidney biopsies) will also be evaluated. Traditional and digital pathology will be combined with transcriptomic, proteomic, and metabolomic analysis of the kidney tissue as well as deep clinical phenotyping for supervised and unsupervised subgroup analysis and systems biology analysis. Participants will be followed prospectively for 10 years to ascertain clinical outcomes. Cell types, locations, and functions will be characterized in health and disease in an open, searchable, online kidney tissue atlas. All data from the Kidney Precision Medicine Project will be made readily available for broad use by scientists, clinicians, and patients.
PMID: 33637194
ISSN: 1523-1755
CID: 4807142
FDA safety warning on the cardiac effects of lamotrigine: An advisory from the Ad Hoc ILAE/AES Task Force
PMCID:7918301
PMID: 33681647
ISSN: 2470-9239
CID: 4808172
Journal of clinical & experimental neuropsychology. 2021:43(2):144-155.DOI: 10.1080/13803395.2021.1889989
The relationship between neuropsychological dispersion, processing speed and memory after electrical injury
PMID: 33648409
ISSN: 1744-411x
CID: 5592812
Brief potentially ictal rhythmic discharges and paroxysmal fast activity as scalp electroencephalographic biomarkers of seizure activity and seizure onset zone
OBJECTIVE:The electroencephalographic (EEG) terms "brief potentially ictal rhythmic discharges" (BIRDs) and "paroxysmal fast activity" (PFA) are considered distinct entities; however, their definitions overlap, and they may have similar clinical significance. We investigated their clinical significance and their association with seizures and the seizure onset zone (SOZ). METHODS:We retrospectively identified an adult cohort (July 2015 to March 2018) whose long-term (>12 h) EEGs in any setting reported BIRDs (>4 Hz, lasting .5-10 s) and/or PFA. Different frequency cutoffs for PFA (>13 Hz or ≥8 Hz) were tested to compare their clinical significance. Patient demographics, clinical history, and EEG features were recorded. RESULTS:We identified 94 patients with BIRDs/PFA out of 3520 patients (3%); 36 were critically ill (12 with epilepsy), and 58 were noncritically ill (all with epilepsy). The frequency of BIRDs/PFA was largely dependent on EEG background: it tended to be slower (theta) in the absence of a posterior dominant rhythm or in the presence of continuous focal slowing in the same region (p = .01). Sixty-two of 94 patients (66%; 32/36 [89%] critically ill, 30/58 [52%] noncritically ill) had electrographic seizures during the recording. The scalp EEG SOZ colocalized with BIRDs/PFA in all cases. BIRDs with faster frequency (also qualifying as PFA by definition) had similar seizure risk to that of slower BIRDs (62%-71%), regardless of frequency cutoff used to define PFA. In addition, 30 of 30 (100%) patients with evolving BIRDs/PFA (which lasted a median of 6 s, range = 2-9.5 s) had electrographic seizures (>10 s), compared to 32 of 64 (50%) with nonevolving BIRDs (median = 1 s, range = .5-3.5 s; p < .01). SIGNIFICANCE/CONCLUSIONS:A high proportion of patients with BIRDs/PFA had seizures on EEG, regardless of their frequency (i.e., whether they also qualified as PFA), and their location colocalized with scalp SOZ in all cases. BIRDs appear to be a scalp EEG biomarker of uncontrolled seizure activity and a reliable localizing sign of the SOZ.
PMID: 33576500
ISSN: 1528-1167
CID: 4780162
Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture
The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
PMCID:7946812
PMID: 33589841
ISSN: 1546-1718
CID: 4808032
