Faculty Bibliography
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person:kaufmh06 or norcll01 or palmaj02
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429
Views on Memory and Treatment of Cognitive Impairment in 17th-Century Spain: Juan Gutiérrez de Godoy's Work
Memory and its care were significant sociocultural and scientific topics in early modern Spain. While a major interest in memory was related to its rhetorical implications, medical treatises discussing memory, cognitive impairment, and its treatment began to appear in the 16th- and 17th-century. Among these treatises, Disputationes phylosophicæ ac medicæ super libros Aristotelis de memoria, et reminiscentia (Philosophical and medical arguments on Aristotle's "De memoria et reminiscentia"), published in 1629 by the physician Juan Gutiérrez de Godoy, is unique in that it is entirely devoted to the medical aspects of memory. While many of its concepts are now superseded, the treatise is valuable to understand the views on memory and cognitive impairment in 17th-century Spain and their sources, as Gutiérrez quoted many classical, medieval, and contemporary scholars and physicians. The book, written in Latin, is exclusively devoted to memory from a physiological and medical point of view, with chapters on the classification of memory loss, a description of its causes (including old age, something not widely recognized before), and several chapters on its prevention and treatment, with a fascinating emphasis on confectio anacardina, or anacardium, an intranasal concoction made with the "marking nut", the fruit of the Semecarpus anacardium tree (also known as Malacca bean), with alleged memory-enhancing properties. We review Gutiérrez's Disputationes phylosophicæ, putting it into the wider intellectual and social context in the Europe of its time, and discuss the relevance and purported neuropharmacological effects of anacardina.
PMID: 35794022
ISSN: 1526-632x
CID: 5280452
Movement disorder society criteria for the diagnosis of multiple system atrophy-what's new? [Editorial]
PMID: 35633428
ISSN: 1619-1560
CID: 5248112
The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy
BACKGROUND:The second consensus criteria for the diagnosis of multiple system atrophy (MSA) are widely recognized as the reference standard for clinical research, but lack sensitivity to diagnose the disease at early stages. OBJECTIVE:To develop novel Movement Disorder Society (MDS) criteria for MSA diagnosis using an evidence-based and consensus-based methodology. METHODS:We identified shortcomings of the second consensus criteria for MSA diagnosis and conducted a systematic literature review to answer predefined questions on clinical presentation and diagnostic tools relevant for MSA diagnosis. The criteria were developed and later optimized using two Delphi rounds within the MSA Criteria Revision Task Force, a survey for MDS membership, and a virtual Consensus Conference. RESULTS:The criteria for neuropathologically established MSA remain unchanged. For a clinical MSA diagnosis a new category of clinically established MSA is introduced, aiming for maximum specificity with acceptable sensitivity. A category of clinically probable MSA is defined to enhance sensitivity while maintaining specificity. A research category of possible prodromal MSA is designed to capture patients in the earliest stages when symptoms and signs are present, but do not meet the threshold for clinically established or clinically probable MSA. Brain magnetic resonance imaging markers suggestive of MSA are required for the diagnosis of clinically established MSA. The number of research biomarkers that support all clinical diagnostic categories will likely grow. CONCLUSIONS:This set of MDS MSA diagnostic criteria aims at improving the diagnostic accuracy, particularly in early disease stages. It requires validation in a prospective clinical and a clinicopathological study. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
PMID: 35445419
ISSN: 1531-8257
CID: 5206282
Stress and the baroreflex
The stress response to emotions elicits the release of glucocorticoids from the adrenal cortex, epinephrine from the adrenal medulla, and norepinephrine from the sympathetic nerves. The baroreflex adapts to buffer these responses to ensure that perfusion to the organs meets the demands while maintaining blood pressure within a within a narrow range. While stressor-evoked autonomic cardiovascular responses may be adaptive for the short-term, the recurrent exaggerated cardiovascular stress reactions can be maladaptive in the long-term. Prolonged stress or loss of the baroreflex's buffering capacity can predispose episodes of heightened sympathetic activity during stress leading to hypertension, tachycardia, and ventricular wall motion abnormalities. This review discusses 1) how the baroreflex responds to acute and chronic stressors, 2) how lesions in the neuronal pathways of the baroreflex alter the ability to respond or counteract the stress response, and 3) the techniques to assess baroreflex sensitivity and stress responses. Evidence suggests that loss of baroreflex sensitivity may predispose heightened autonomic responses to stress and at least in part explain the association between stress, mortality and cardiovascular diseases.
PMID: 35086020
ISSN: 1872-7484
CID: 5137072
mTOR Inhibition with Sirolimus in Multiple System Atrophy: A Randomized, Double-Blind, Placebo-Controlled Futility Trial and 1-Year Biomarker Longitudinal Analysis
BACKGROUND:Multiple system atrophy (MSA) is a fatal neurodegenerative disease characterized by the aggregation of α-synuclein in glia and neurons. Sirolimus (rapamycin) is an mTOR inhibitor that promotes α-synuclein autophagy and reduces its associated neurotoxicity in preclinical models. OBJECTIVE:To investigate the efficacy and safety of sirolimus in patients with MSA using a futility design. We also analyzed 1-year biomarker trajectories in the trial participants. METHODS:Randomized, double-blind, parallel group, placebo-controlled clinical trial at the New York University of patients with probable MSA randomly assigned (3:1) to sirolimus (2-6 mg daily) for 48 weeks or placebo. Primary endpoint was change in the Unified MSA Rating Scale (UMSARS) total score from baseline to 48 weeks. (ClinicalTrials.gov NCT03589976). RESULTS:The trial was stopped after a pre-planned interim analysis met futility criteria. Between August 15, 2018 and November 15, 2020, 54 participants were screened, and 47 enrolled and randomly assigned (35 sirolimus, 12 placebo). Of those randomized, 34 were included in the intention-to-treat analysis. There was no difference in change from baseline to week 48 between the sirolimus and placebo in UMSARS total score (mean difference, 2.66; 95% CI, -7.35-6.91; P = 0.648). There was no difference in UMSARS-1 and UMSARS-2 scores either. UMSARS scores changes were similar to those reported in natural history studies. Neuroimaging and blood biomarker results were similar in the sirolimus and placebo groups. Adverse events were more frequent with sirolimus. Analysis of 1-year biomarker trajectories in all participants showed that increases in blood neurofilament light chain (NfL) and reductions in whole brain volume correlated best with UMSARS progression. CONCLUSIONS:Sirolimus for 48 weeks was futile to slow the progression of MSA and had no effect on biomarkers compared to placebo. One-year change in blood NfL and whole brain atrophy are promising biomarkers of disease progression for future clinical trials. © 2022 International Parkinson and Movement Disorder Society.
PMID: 35040506
ISSN: 1531-8257
CID: 5131432
The Clinical Autonomic Research journal 2021 and onward [Editorial]
PMCID:8727978
PMID: 34985586
ISSN: 1619-1560
CID: 5107152
Glia Imaging Differentiates Multiple System Atrophy from Parkinson's Disease: A Positron Emission Tomography Study with [11 C]PBR28 and Machine Learning Analysis
BACKGROUND:The clinical diagnosis of multiple system atrophy (MSA) is challenged by overlapping features with Parkinson's disease (PD) and late-onset ataxias. Additional biomarkers are needed to confirm MSA and to advance the understanding of pathophysiology. Positron emission tomography (PET) imaging of the translocator protein (TSPO), expressed by glia cells, has shown elevations in MSA. OBJECTIVE:In this multicenter PET study, we assess the performance of TSPO imaging as a diagnostic marker for MSA. METHODS:C]PBR28 binding to TSPO using imaging data of 66 patients with MSA and 24 patients with PD. Group comparisons were based on regional analysis of parametric images. The diagnostic readout included visual reading of PET images against clinical diagnosis and machine learning analyses. Sensitivity, specificity, and receiver operating curves were used to discriminate MSA from PD and cerebellar from parkinsonian variant MSA. RESULTS:C]PBR28 binding to TSPO in MSA as compared with PD, with "hotspots" in the lentiform nucleus and cerebellar white matter. Visual reading discriminated MSA from PD with 100% specificity and 83% sensitivity. The machine learning approach improved sensitivity to 96%. We identified MSA subtype-specific TSPO binding patterns. CONCLUSIONS:We found a pattern of significantly increased regional glial TSPO binding in patients with MSA. Intriguingly, our data are in line with severe neuroinflammation in MSA. Glia imaging may have potential to support clinical MSA diagnosis and patient stratification in clinical trials on novel drug therapies for an α-synucleinopathy that remains strikingly incurable. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
PMID: 34609758
ISSN: 1531-8257
CID: 5067692
Pathogenic Huntingtin Repeat Expansions in Patients with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis
We examined the role of repeat expansions in the pathogenesis of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS) by analyzing whole-genome sequence data from 2,442 FTD/ALS patients, 2,599 Lewy body dementia (LBD) patients, and 3,158 neurologically healthy subjects. Pathogenic expansions (range, 40-64 CAG repeats) in the huntingtin (HTT) gene were found in three (0.12%) patients diagnosed with pure FTD/ALS syndromes but were not present in the LBD or healthy cohorts. We replicated our findings in an independent collection of 3,674 FTD/ALS patients. Postmortem evaluations of two patients revealed the classical TDP-43 pathology of FTD/ALS, as well as huntingtin-positive, ubiquitin-positive aggregates in the frontal cortex. The neostriatal atrophy that pathologically defines Huntington's disease was absent in both cases. Our findings reveal an etiological relationship between HTT repeat expansions and FTD/ALS syndromes and indicate that genetic screening of FTD/ALS patients for HTT repeat expansions should be considered.
PMID: 33242422
ISSN: 1097-4199
CID: 5429222
Three decades of Clinical Autonomic Research and beyond [Editorial]
PMCID:7797191
PMID: 33426613
ISSN: 1619-1560
CID: 5069352
Different phenoconversion pathways in pure autonomic failure with versus without Lewy bodies
Pure autonomic failure (PAF) is a rare disease in which chronic neurogenic orthostatic hypotension (nOH) dominates the clinical picture. Longitudinal studies have reported that PAF can phenoconvert to a central synucleinopathy with motor or cognitive involvement-i.e., to Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA). These studies have classified patients clinically as having PAF based on nOH without an identified secondary cause or clinical evidence of motor or cognitive impairment due to central neurodegeneration. This approach lumps together two nOH syndromes that are pathologically and neurochemically distinct. One is characterized by intraneuronal cytoplasmic alpha-synuclein aggregates (i.e., Lewy bodies) and degeneration of postganglionic sympathetic neurons, as in PD and DLB; the other is not, as in MSA. Clinical and postmortem data show that the form of PAF that involves sympathetic intraneuronal synucleinopathy and noradrenergic deficiency can phenoconvert to PD or DLB-but not to MSA. Conversely, PAF without these features leaves open the possibility of premotor MSA.
PMID: 34669076
ISSN: 1619-1560
CID: 5043312
