Abstract Parkinson's disease (PD) is a complex illness characterized by progressive dopaminergic neuronal loss. Several mechanisms associated with the iron-induced death of dopaminergic cells have ...been described. Ferroptosis is an iron-dependent, regulated cell death process that was recently described in cancer. Our present work show that ferroptosis is an important cell death pathway for dopaminergic neurons. Ferroptosis was characterized in Lund human mesencephalic cells and then confirmed ex vivo (in organotypic slice cultures) and in vivo (in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model). Some of the observed characteristics of ferroptosis differed from those reported previously. For example, ferroptosis may be initiated by PKCα activation, which then activates MEK in a RAS-independent manner. The present study is the first to emphasize the importance of ferroptosis dysregulation in PD. In neurodegenerative diseases like PD, iron chelators, Fer-1 derivatives and PKC inhibitors may be strong drug candidates to pharmacologically modulate the ferroptotic signaling cascade.
To determine whether higher neutrophil counts before IV recombinant tissue plasminogen activator (rtPA) administration in ischemic stroke (IS) patients are associated with symptomatic intracerebral ...hemorrhages (sICH) and worse outcomes at 3 months.
Blood samples for leukocyte, neutrophil, and lymphocyte counts were drawn before IV rtPA administration in IS patients included in the cohorts of Lille and Helsinki. The primary endpoint was sICH (European Cooperative Acute Stroke-II definition). Secondary endpoints were death and excellent (modified Rankin Scale mRS score 0-1 or equal to prestroke mRS) and good (mRS score 0-2 or equal to prestroke mRS) outcomes at 3 months.
We included 846 patients (median age 71 years; 50.8% men). The neutrophil count and neutrophil to lymphocyte ratio (NLR) were independently associated with the 4 endpoints: sICH (adjusted odds ratio adjOR for an increase of 1,000 neutrophils = 1.21 and adjOR 1.11, respectively), death (adjOR 1.16 and adjOR 1.08), and excellent (adjOR 0.87 and adjOR 0.85) and good (adjOR 0.86 and adjOR 0.91) outcomes. The total leukocyte count was not associated with any of the 4 endpoints. The best discriminating factor for sICH was NLR ≥4.80 (sensitivity 66.7%, specificity 71.3%, likelihood ratio 2.32). Patients with NLR ≥4.80 had a 3.71-fold increased risk for sICH (95% confidence interval adjOR: 1.97-6.98) compared to patients with NLR <4.80.
Higher neutrophil counts and NLR are independently associated with sICH and worse outcome at 3 months. The identification of mediators of this effect could provide new targets for neuroprotection in patients treated by rtPA.
Vascular cognitive impairment (VCI) is a complex spectrum encompassing post-stroke cognitive impairment (PSCI) and small vessel disease-related cognitive impairment. Despite the growing health, ...social, and economic burden of VCI, to date, no specific treatment is available, prompting the introduction of the concept of a disease modifier.
Within this clinical spectrum, VCI and PSCI remain advancing conditions as neurodegenerative diseases with progression of both vascular and degenerative lesions accounting for cognitive decline. Disease-modifying strategies should integrate both pharmacological and non-pharmacological multimodal approaches, with pleiotropic effects targeting (1) endothelial and brain-blood barrier dysfunction; (2) neuronal death and axonal loss; (3) cerebral plasticity and compensatory mechanisms; and (4) degenerative-related protein misfolding. Moreover, pharmacological and non-pharmacological treatment in PSCI or VCI requires valid study designs clearly stating the definition of basic methodological issues, such as the instruments that should be used to measure eventual changes, the biomarker-based stratification of participants to be investigated, and statistical tests, as well as the inclusion and exclusion criteria that should be applied.
A consensus emerged to propose the development of a disease-modifying strategy in VCI and PSCI based on pleiotropic pharmacological and non-pharmacological approaches.
The pathophysiological role of iron in Parkinson's disease (PD) was assessed by a chelation strategy aimed at reducing oxidative damage associated with regional iron deposition without affecting ...circulating metals. Translational cell and animal models provided concept proofs and a delayed-start (DS) treatment paradigm, the basis for preliminary clinical assessments.
For translational studies, we assessed the effect of oxidative insults in mice systemically prechelated with deferiprone (DFP) by following motor functions, striatal dopamine (HPLC and MRI-PET), and brain iron deposition (relaxation-R2*-MRI) aided by spectroscopic measurements of neuronal labile iron (with fluorescence-sensitive iron sensors) and oxidative damage by markers of protein, lipid, and DNA modification. DFP significantly reduced labile iron and biological damage in oxidation-stressed cells and animals, improving motor functions while raising striatal dopamine. For a pilot, double-blind, placebo-controlled randomized clinical trial, early-stage Parkinson's patients on stabilized dopamine regimens enrolled in a 12-month single-center study with DFP (30 mg/kg/day). Based on a 6-month DS paradigm, early-start patients (n=19) compared to DS patients (n=18) (37/40 completed) responded significantly earlier and sustainably to treatment in both substantia nigra iron deposits (R2* MRI) and Unified Parkinson's Disease Rating Scale motor indicators of disease progression (p<0.03 and p<0.04, respectively). Apart from three rapidly resolved neutropenia cases, safety was maintained throughout the trial.
A moderate iron chelation regimen that avoids changes in systemic iron levels may constitute a novel therapeutic modality for PD.
The therapeutic features of a chelation modality established in translational models and in pilot clinical trials warrant comprehensive evaluation of symptomatic and/or disease-modifying potential of chelation in PD.
Identifying modifiable risk factors for Alzheimer's disease (AD) is critical for research. Data mining may be a useful tool for finding new AD associated factors.
We included all patients over 49 ...years of age, hospitalized in France in 2008 (without dementia) and in 2014. Dependent variable was AD or AD dementia diagnosis in 2014. We recoded the diagnoses of hospital stays (in ICD-10) into 137 explanatory variables.To avoid overweighting the "age" variable, we divided the population into 7 sub-populations of 5 years.
We analyzed 1,390,307 patients in the PMSI in 2008 and 2014: 55,997 patients had coding for AD or AD dementia in 2014 (4.04%). We associated Alzheimer disease in 2014 with about 20 variables including male sex, stroke, diabetes mellitus, mental retardation, bipolar disorder, intoxication, Parkinson disease, depression, anxiety disorders, alcohol, undernutrition, fall and 3 less explored variables: intracranial hypertension (odd radio 95% confidence interval: 1.16 1.12-1.20 in 70-80 years group), psychotic disorder (OR: 1.09 1.07-1.11 in 70-75 years group) and epilepsy (OR: 1.06 1.05-1.07 after 70 years).
We analyzed 137 variables in the PMSI identified some well-known risk factors for AD, and highlighted a possible association with intracranial hypertension, which merits further investigation. Better knowledge of associations could lead to better targeting (identifying) at-risk patients, and better prevention of AD, in order to reduce its impact.
New antipsychotics continuously arrive on the market, which thereby influences the approved and off-label prescribing (OLP) schemes. We aimed to identify the recent trends in the OLP of ...antipsychotics. We conducted a literature review based on three different populations: adult, pediatric, and elderly patients.
A literature search was performed in the PubMed and ScienceDirect databases using the following keyword algorithm: "offlabel" AND ("antipsychotic*" OR "neuroleptic*"). The period investigated ranged from January 2000 to January 2015. Only Englishwritten pharmacoepidemiological studies were included.
Seventy-seven relevant results were identified. Among adults, OLP consisted of 40 to 75% of all antipsychotic prescriptions. The main indications were mood disorders, anxiety disorders, insomnia and agitation. Quetiapine was the most frequently prescribed offlabel antipsychotic, especially for anxiety and insomnia. Among children, OLP was estimated between 36 and 93.2% of all antipsychotic prescriptions. Risperidone and aripiprazole were primarily used and were most often prescribed for attention deficit hyperactivity disorder, anxiety, or mood disorders. Among elderly individuals, OLP consisted of 22 to 86% of all antipsychotic prescriptions. Antipsychotic OLP was particularly frequent for agitation; however, a recent decrease in this OLP was identified.
Antipsychotics have largely been prescribed off-label in recent years. The types of antipsychotic OLP practices differ according to the age category of patients. OLP is often used in cases of therapeutic dead-ends or for specific disorders with few or no currently approved medications. However, other OLP practices only reflect temporary prescription trends for mild symptoms, which may induce safety concerns.
To examine whether the Montreal Cognitive Assessment (MoCA) administered within 7 days after stroke predicts long-term cognitive impairment, functional impairment, and mortality.
MoCA was ...administered to 274 patients from 2 prospective hospital-based cohort studies in Germany (n = 125) and France (n = 149). Cognitive and functional outcomes were assessed at 6, 12, and 36 months after stroke by comprehensive neuropsychological testing, the Clinical Dementia Rating (CDR) scale, the modified Rankin Scale (mRS), and Instrumental Activities of Daily Living (IADL) and analyzed with generalized estimating equations. All-cause mortality was investigated by Cox proportional hazard models. Analyses were adjusted for demographic variables, education, vascular risk factors, premorbid cognitive status, and NIH Stroke Scale scores. The additive predictive value of MoCA was examined with receiver operating characteristic curves.
In pooled analyses, a baseline MoCA score <26 was associated with cognitive impairment, defined by neuropsychological testing (odds ratio OR 5.30, 95% confidence interval CI 2.75-10.22) and by CDR score ≥0.5 (OR 2.53, 95% CI 1.53-4.18); functional impairment, defined by mRS score >2 (OR 5.03, 95% CI 2.20-11.51) and by IADL score <8 (OR 2.48, 95% CI 1.40-4.38); and mortality (hazard ratio 7.24, 95% CI 1.99-26.35) across the 3-year follow-up. Patients with MoCA score <26 performed worse across all prespecified cognitive domains (executive function/attention, memory, language, visuospatial ability). MoCA increased the area under the curve for predicting cognitive impairment (neuropsychological testing 0.81 vs 0.72,
= 0.01) and functional impairment (mRS score >2, 0.88 vs 0.84,
= 0.047).
Early cognitive testing by MoCA predicts long-term cognitive outcome, functional outcome, and mortality after stroke. Our results support routine use of the MoCA in stroke patients.
Background
Cognitive and emotional disorders frequently persist after recovery from the acute symptoms of COVID-19; possible explanations include pneumonia-induced hypoxia, infection of the central ...nervous system, and microstrokes. The objective of the present study was to characterize the impact of hypoxia on the cognitive and psychological profile following COVID-19.
Methods
Sixty-two patients with COVID-19 were enrolled in a cross-sectional study and divided into two groups based on disease severity: outpatients with no pulmonary complications vs. inpatients with hypoxemic pneumonia having received oxygen therapy. All the participants underwent a comprehensive neuropsychological evaluation that included depression, anxiety, fatigue, sleepiness, attentional, memory and executive processes, and social cognition. For the inpatients, we also collected laboratory data (blood gas, blood glucose, fibrin, fibrinogen, D-dimer, and C-reactive protein).
Results
Cognitive disorders was found in patients with COVID-19: at least 18% had an impairment of memory and 11% had attentional dysfunctions. A high level of fatigue (90% of the patients), anxiety (52%), and depression (50%) was also observed. The impairments in attentional (
p
< 0.001 for omission and commission in CPT 3) and memory (
p
< 0.003 for Index Cue Efficiency from free and cue selected reminding test) functions were greater in COVID-19 inpatients that in COVID-19 outpatients. In contrast, levels of fatigue, depression, and anxiety were similarly high in both groups.
Conclusions
These findings might help to improve the management of COVID-19 patients as a function of the disease severity in particular for patients with hypoxia.
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