Prognostic Value of Serum Copper for Post-Stroke Clinical Recovery: A Pilot Study

Survivors don't the fuck care about prognostication, they want results. This research was not quite a complete waste of time. Now followup research will need to be done on reducing copper levels for better recovery.
Then there is this from Sept, 2015; I bet there was no followup.

Long sleep and high blood copper levels go hand in hand, inflammation problems

Prognostic Value of Serum Copper for Post-Stroke Clinical Recovery: A Pilot Study

Rosanna Squitti¹, Mariacristina Siotto², Giovanni Assenza³, Nadia M. Giannantoni^4,5, Mauro Rongioletti⁶, Filippo Zappasodi^7,8† and Franca Tecchio^5,9*^†

• ¹Molecular Markers Laboratory, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy
• ²IRCCS Fondazione Don Carlo Gnocchi, Milan, Italy
• ³Clinical Neurology, Campus Biomedico University of Rome, Rome, Italy
• ⁴Neurocenter of Southern Switzerland, Civic Hospital, Lugano, Switzerland
• ⁵Laboratory of Electrophysiology for Translational neuroScience (LET’S), ISTC–CNR, Rome, Italy
• ⁶Department of Biology Medicine, Research and Development Division, Fatebenefratelli Hospital, Isola Tiberina, Rome, Italy
• ⁷Department of Neuroscience, Imaging and Clinical Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy
• ⁸Institute for Advanced Biomedical Technologies, “G. d’Annunzio” University of Chieti-Pescara, Chieti, Italy
• ⁹Institute of Neurology, Catholic University of the Sacred Heart, Rome, Italy

The clinical course after ischemic stroke can vary considerably despite similar lesions and clinical status at the onset of symptoms, suggesting that individual factors modulate clinical recovery. Here, we sought to test the working hypothesis that elevated copper values provide prognostic information, and specifically predict worse clinical recovery. We further sought to support previous findings regarding metal metabolism in acute stroke. We assessed total antioxidant status, oxidative stress factors (peroxides) and metal metabolism markers (iron, copper, ceruloplasmin concentration and activity, ferritin, and transferrin) in the acute phase (2–10 days from symptom onset) in 30 patients affected by unilateral middle cerebral artery (MCA) stroke. A longitudinal assessment of clinical deficit was performed in the acute and stabilized phases (typically 6 months post-stroke) using the National Institutes of Health Stroke Scale (NIHSS). In identifying recovery-related factors, we considered effective recovery (ER), calculated as the ratio between actual NIHSS recovery and the total potential recovery. This allows an estimation of the actual recovery adjusted for the patient’s initial condition. In the acute phase, clinical severity was correlated with increased peroxide concentrations, and lower iron levels. Less successful clinical recovery was correlated with increased acute copper levels, which entered a multiple regression model that explained 24% of ER variance. These pilot data suggest that, in the acute phase of an ischemic stroke, copper may provide useful information about clinical recovery.

Introduction

Ischemic stroke is the rapid loss of brain function due to a reduction in the blood supply to the brain. It is among the prevalent causes of mortality and disability in adults and elderly people (1). In the weeks and months after the onset of symptoms, the clinical course of stroke patients can vary largely even in patients with similar clinical pictures and lesion characteristics (2). For this reason, exploring diverse biomarkers with recovery prognostic value can provide information about potential interventions, which can be adapted to personalize acute and subacute treatments.

Brain blood flow interruption during ischemic insult triggers multiple inflammatory, oxidative stress, and immune responses, for which trace metals and antioxidant systems are required. Free radicals production, disturbed metal homeostasis and glutamatergic excitotoxicity are among the processes activated during the reperfusion phase, with complex relationships with the vital mechanisms limiting the damage within the penumbra, the neighboring area to the ischemic core. Excessive concentrations of divalent metal ions, such as zinc, copper, iron along with the cation calcium, are known mediators of damage in acute ischemic stroke (3–5), through excitotoxicity leading to neuronal death (6, 7). Iron homeostasis is pivotal in maintaining normal brain functions because of the high oxygen requirement of this organ, which further increases during ischemic stroke, placing higher demands on iron transport and utilization within the preserved regions of the brain (8, 9). However, excess metals in the blood and their movement from the blood to the brain can concur with brain insult, when the blood–brain barrier (BBB) is damaged. Iron and transferrin (Tf) withdrawal in serum during the acute phase after ischemic stroke have been reported (10). Recent literature reports that more severe clinical states correlated with increased peroxide concentrations and lower iron levels (11, 12). Moreover, local acidosis may facilitate further metal release from the transporting proteins. In these conditions, iron and copper can produce neuronal injury by catalyzing the conversion of superoxide and hydrogen peroxide into highly reactive radicals. Three previous studies discovered significantly elevated contents of both total copper and “free” copper (generally understood as copper not bound to ceruloplasmin, nCp-Cu) in the serum of cerebral ischemic stroke patients (10, 13, 14), while others described the direct role of copper in learning and memory tied to plasticity mechanisms largely mediated by glutamate neurotransmission (7, 15–17). In both healthy people and Alzheimer’s disease patients, we observed a link between circulating copper and glutamate-mediated neural transmission (18, 19). Besides the phenomena impacting the clinical severity in the acute phase, largely uncoupled mechanisms sustain clinical recovery (20–22), also mediated by brain plasticity phenomena (23, 24). However, no study has yet explored serum early metal and oxidative stress biomarkers in relation to post-stroke clinical recovery. Here, we present a prospective study of a panel of metal and oxidative stress biomarkers in a group of patients after acute ischemic stroke. Our working hypothesis is that elevated copper values can provide prognostic information about a less successful clinical recovery. To resolve this question, we designed a prolonged 6-month clinical follow-up study. Our secondary aim was to confirm previous results about iron, copper, ceruloplasmin, ferritin, and Tf trends in the ischemic acute phase.

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