A case study in the history of neurology

We review the case of a young man who developed a constellation of symptoms and signs—bizarre behavior, seizures, abnormal movements, and autonomic instability—that evaded diagnosis at the time of presentation. We use this case to explore the way medical knowledge changes over time. Despite the dramatic advances in our understanding of neurological diseases in recent decades, physicians tend to approach diseases and diagnoses as if they were immutable. Our case reinforces how the diagnosis and treatment of disease are determined by an ever-changing historical context driven by the rapid expansion of medical knowledge. We discuss the implications of this realization and present strategies for navigating the boundaries of knowledge, both in practice and in principle

Deciphering the factors that influence participation in studies requiring serial lumbar punctures

Introduction: Cerebrospinal fluid biomarkers increasingly inform the causes of dementia and may provide objective markers of disease progression. There is a need to decipher participant and procedural factors that promote participation in studies incorporating longitudinal biomarker measures. Methods: Participant and procedural factors associated with participation in longitudinal biomarker studies were determined in individuals enrolled in studies of memory and aging at the Knight Alzheimer Disease Research Center (Saint Louis, MO, USA). Results: Complications were encountered following 331 of 1484 lumbar punctures (22.3%; LPs), affecting 280 of 929 participants (30.1%); in \u3e95% complications were minor. Three hundred fifteen of 679 eligible participants (46.4%) completed multiple LPs. Younger age (odds ratio [OR] 2.08 per decade [95% confidence interval (CI) 1.61-2.94]), normal cognition (OR 21.4 [2.85-160.1]), and the absence of heart disease (OR 2.0 [1.01-3.85]) or seizures at study entry identified participants with increased odds of completing three or more LPs. Discussion: Factors influencing participation may be leveraged to improve recruitment and retention within observational and therapeutic studies requiring serial LPs

Positive allosteric modulation as a potential therapeutic strategy in anti-NMDA receptor encephalitis

N-methyl-d-aspartate receptors (NMDARs) are ionotropic glutamate receptors important for synaptic plasticity, memory, and neuropsychiatric health. NMDAR hypofunction contributes to multiple disorders, including anti-NMDAR encephalitis (NMDARE), an autoimmune disease of the CNS associated with GluN1 antibody-mediated NMDAR internalization. Here we characterize the functional/pharmacological consequences of exposure to CSF from female human NMDARE patients on NMDAR function, and we characterize the effects of intervention with recently described positive allosteric modulators (PAMs) of NMDARs. Incubation (48 h) of rat hippocampal neurons of both sexes in confirmed NMDARE patient CSF, but not control CSF, attenuated NMDA-induced current. Residual NMDAR function was characterized by lack of change in channel open probability, indiscriminate loss of synaptic and extrasynaptic NMDARs, and indiscriminate loss of GluN2B-containing and GluN2B-lacking NMDARs. NMDARs tagged with N-terminal pHluorin fluorescence demonstrated loss of surface receptors. Thus, function of residual NMDARs following CSF exposure was indistinguishable from baseline, and deficits appear wholly accounted for by receptor loss. Coapplication of CSF and PAMs of NMDARs (SGE-301 or SGE-550, oxysterol-mimetic) for 24 h restored NMDAR function following 24 h incubation in patient CSF. Curiously, restoration of NMDAR function was observed despite washout of PAMs before electrophysiological recordings. Subsequent experiments suggested that residual allosteric potentiation of NMDAR function explained the persistent rescue. Further studies of the pathogenesis of NMDARE and intervention with PAMs may inform new treatments for NMDARE and other disorders associated with NMDAR hypofunction.SIGNIFICANCE STATEMENTAnti-N-methyl-d-aspartate receptor encephalitis (NMDARE) is increasingly recognized as an important cause of sudden-onset psychosis and other neuropsychiatric symptoms. Current treatment leaves unmet medical need. Here we demonstrate cellular evidence that newly identified positive allosteric modulators of NMDAR function may be a viable therapeutic strategy.</jats:p

Association of acquired and heritable factors with intergenerational differences in age at symptomatic onset of Alzheimer disease between offspring and parents with dementia

Importance: Acquired and heritable traits are associated with dementia risk; however, how these traits are associated with age at symptomatic onset (AAO) of Alzheimer disease (AD) is unknown. Identifying the associations of acquired and heritable factors with variability in intergenerational AAO of AD could facilitate diagnosis, assessment, and counseling of the offspring of parents with AD. Objective: To quantify the associations of acquired and heritable factors with intergenerational differences in AAO of AD. Design, Setting, and Participants: This nested cohort study used data from the Knight Alzheimer Disease Research Center that included community-dwelling participants with symptomatic AD, parental history of dementia, and available DNA data who were enrolled in prospective studies of memory and aging from September 1, 2005, to August 31, 2016. Clinical, biomarker, and genetic data were extracted on January 17, 2017, and data analyses were conducted from July 1, 2017, to August 20, 2019. Main Outcomes and Measures: The associations of acquired (ie, years of education; body mass index; history of cardiovascular disease, hypertension, hypercholesterolemia, diabetes, active depression within 2 years, traumatic brain injury, tobacco use, and unhealthy alcohol use; and retrospective determination of AAO) and heritable factors (ie, ethnicity/race, paternal or maternal inheritance, parental history of early-onset dementia, APOE ε4 allele status, and AD polygenic risk scores) to intergenerational difference in AAO of AD were quantified using stepwise forward multivariable regression. Missense or frameshift variants within genes associated with AD pathogenesis were screened using whole-exome sequencing. Results: There were 164 participants with symptomatic AD, known parental history of dementia, and available DNA data (mean [SD] age, 70.9 [8.3] years; 90 [54.9%] women) included in this study. Offspring were diagnosed with symptomatic AD a mean (SD) 6.1 (10.7) years earlier than their parents (P \u3c .001). The adjusted R2 for measured acquired and heritable factors for intergenerational difference in AAO of AD was 0.29 (F8,155 = 9.13; P \u3c .001). Paternal (β = -9.52 [95% CI, -13.79 to -5.25]) and maternal (β = -6.68 [95% CI, -11.61 to -1.75]) history of dementia, more years of education (β = -0.58 [95% CI -1.08 to -0.09]), and retrospective determination of AAO (β = -3.46 [95% CI, -6.40 to -0.52]) were associated with earlier-than-expected intergenerational difference in AAO of AD. Parental history of early-onset dementia (β = 21.30 [95% CI, 15.01 to 27.59]), presence of 1 APOE ε4 allele (β = 5.00 [95% CI, 2.11 to 7.88]), and history of hypertension (β = 3.81 [95% CI, 0.88 to 6.74]) were associated with later-than-expected intergenerational difference in AAO of AD. Missense or frameshift variants within genes associated with AD pathogenesis were more common in participants with the greatest unexplained variability in intergenerational AAO of AD (19 of 48 participants [39.6%] vs 26 of 116 participants [22.4%]; P = .03). Conclusions and Relevance: Acquired and heritable factors were associated with a substantial proportion of variability in intergenerational AAO of AD. Variants in genes associated with AD pathogenesis may contribute to unexplained variability, justifying further study

Prevalence of surgical procedures at symptomatic onset of prion disease

This case-control study examines the frequency of invasive procedures at the onset of prion disease symptoms to determine the scope of the risk of contamination to future patients

Flortaucipir (tau) PET in LGI1 antibody encephalitis

The contributors to persistent cognitive impairment and hippocampal atrophy in leucine-rich glioma-inactivated 1 antibody encephalitis (LGI1) patients are unknown. We evaluated whether tau neuropathology measured with

MAPT R406W increases tau T217 phosphorylation in absence of amyloid pathology

OBJECTIVE: Tau hyperphosphorylation at threonine 217 (pT217) in cerebrospinal fluid (CSF) has recently been linked to early amyloidosis and could serve as a highly sensitive biomarker for Alzheimer\u27s disease (AD). However, it remains unclear whether other tauopathies induce pT217 modifications. To determine if pT217 modification is specific to AD, CSF pT217 was measured in AD and other tauopathies. METHODS: Using immunoprecipitation and mass spectrometry methods, we compared CSF T217 phosphorylation occupancy (pT217/T217) and amyloid-beta (Aβ) 42/40 ratio in cognitively normal individuals and those with symptomatic AD, progressive supranuclear palsy, corticobasal syndrome, and sporadic and familial frontotemporal dementia. RESULTS: Individuals with AD had high CSF pT217/T217 and low Aβ42/40. In contrast, cognitively normal individuals and the majority of those with 4R tauopathies had low CSF pT217/T217 and normal Aβ 42/40. We identified a subgroup of individuals with increased CSF pT217/T217 and normal Aβ 42/40 ratio, most of whom were MAPT R406W mutation carriers. Diagnostic accuracies of CSF Aβ 42/40 and CSF pT217/T217, alone and in combination were compared. We show that CSF pT217/T217 × CSF Aβ 42/40 is a sensitive composite biomarker that can separate MAPT R406W carriers from cognitively normal individuals and those with other tauopathies. INTERPRETATION: MAPT R406W is a tau mutation that leads to 3R+4R tauopathy similar to AD, but without amyloid neuropathology. These findings suggest that change in CSF pT217/T217 ratio is not specific to AD and might reflect common downstream tau pathophysiology common to 3R+4R tauopathies

KVX-053, A Protein Tyrosine Phosphatase 4A3 Inhibitor, Ameliorates SARS-CoV-2 Spike Protein Subunit 1 - Induced Acute Lung Injury in Mice

The Acute Respiratory Distress Syndrome (ARDS), often preceded by acute lung injury (ALI), is characterized by the accumulation of inflammatory fluid in the lung alveoli, leaky alveolar epithelium and endothelium, and overexpression of pro-inflammatory cytokines. This progression from ALI to ARDS is a major contributor to the high mortality observed in COVID-19 patients. The Spike protein of SARS-CoV-2 binds to lung ACE2 and, in addition to facilitating viral cell entry, it plays an important role in the development of ALI and ARDS, especially in the later phases of COVID-19 as well as long COVID. Protein tyrosine phosphatase (PTP) 4A3 is a key mediator of ARDS pathology. This study tested the hypothesis that targeting PTP4A3 would prevent COVID-19 associated ALI. Intratracheal administration of SARS-CoV-2 Spike protein Subunit 1 to K18-hACE2 transgenic mice expressing human ACE2 elicited pulmonary and systemic inflammation, leaky alveoli, overexpression of cytokines, structural lung injury and lung dysfunction; all these symptoms were ameliorated by the selective, allosteric inhibitor of PTP4A3, KVX-053. These findings provide the first evidence supporting a role for PTP4A3 in the development of SARS-CoV-2- mediated ALI

Recurrent Evolution of Melanism in South American Felids

Morphological variation in natural populations is a genomic test bed for studying the interface between molecular evolution and population genetics, but some of the most interesting questions involve non-model organisms that lack well annotated reference genomes. Many felid species exhibit polymorphism for melanism but the relative roles played by genetic drift, natural selection, and interspecies hybridization remain uncertain. We identify mutations of Agouti signaling protein (ASIP) or the Melanocortin 1 receptor (MC1R) as independent causes of melanism in three closely related South American species: the pampas cat (Leopardus colocolo), the kodkod (Leopardus guigna), and Geoffroy’s cat (Leopardus geoffroyi). To assess population level variation in the regions surrounding the causative mutations we apply genomic resources from the domestic cat to carry out clone-based capture and targeted resequencing of 299 kb and 251 kb segments that contain ASIP and MC1R, respectively, from 54 individuals (13–21 per species), achieving enrichment of ~500–2500-fold and ~150x coverage. Our analysis points to unique evolutionary histories for each of the three species, with a strong selective sweep in the pampas cat, a distinctive but short melanism-specific haplotype in the Geoffroy’s cat, and reduced nucleotide diversity for both ancestral and melanism-bearing chromosomes in the kodkod. These results reveal an important role for natural selection in a trait of longstanding interest to ecologists, geneticists, and the lay community, and provide a platform for comparative studies of morphological variation in other natural populations