sabato, Luglio 13, 2024

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Sickle cell disease: how to see pain “stroking” the brain

Sickle Cell Disease (SCD) is rare but devastating. Due to a genetic mutation affecting hemoglobin, the component of the red blood cell that carries oxygen, a reduced amount of oxygen is supplied to vital tissues and organs. Blood cells also deform into a characteristic crescent shape and lodge into the smallest blood vessels, blocking blood flow and leading to excruciating pain. On top of these symptoms, patients face a high risk of ischemic stroke, one among the main leading causes of death in SCD patients. Specializing in the unique challenges facing SCD, physician and investigator John Wood, PhD of CHLA, studies how blood flow and oxygen delivery are affected by the disease. The compromised hemoglobin that is characteristic of SCD presents a serious danger to the brain. Just minutes without oxygen can kill brain cells. Scientists and doctors have learned a lot about how to prevent the large vessel strokes, those in clinical practice that have immediate, overt effects such as loss of speech, blindness or paralysis. But patients with SCD still suffer from silent strokes.

Silent strokes can have debilitating effects on executive function, the brain’s ability to execute complex tasks needed for things like maintaining a job or doing well in school. It may silently compromise memory and the ability to recall simple events. Dr. Wood is working to discover what causes these devastating silent strokes. On the surface, the cause seems clear: red blood cells are damaged in SCD, so the brain receives less oxygen. Less oxygen to the brain lead to ischemia, that is short supply for cellular energy. But Dr. Wood found that total oxygen to the brain is not actually reduced in SCD patients. His research shows that the body compensates for reduced oxygen content of the blood by increasing blood flow to the brain. This led him to wonder why these patients were continuing to suffer strokes. So he began to think that there could be a distribution problem. Total blood flow is fine, but this is the question: is it going where it needs to go? Using an advanced imaging technique called arterial spin labeling to measure blood flow, Dr. Wood’s team found a disparity among brain areas.

While brain total oxygen delivery was unchanged, oxygen delivery to the white matter was reduced by 35% in patients with SCD. Critically, the white matter is where the majority of silent strokes occur in these patients. Grey matter is composed of neurons, while white matter is the network of highways in the brain that neurons use to transmit this information. Dr. Wood’s finding demonstrates that the body differentiates between grey and white matter, clearly prioritizing neurons. This makes sense because keeping neurons alive is critical for our own survival. Strokes in grey matter are immediately catastrophic and cause major clinical outcomes, while strokes in white matter appear silent because they simply cause informational processing or traveling to slow down. Though they may not cause major clinical symptoms, effects of white matter silent strokes can greatly impede important aspects of a patient’s daily activities. Similarly, under the stress of low oxygen in SCD, blood flow is diverted to neurons in the grey matter to prevent their death.

Another striking result is that patients with SCD have a greater brain connectivity in a cerebral area called locus coeruleus, indicating that this region is critical for mediating communication between other brain regions. The LC is the primary brain region involved in the synthesis of noradrenaline and is the sole source of cortical noradrenaline to the neocortex. After exposure to a stressor (e.g. pain), noradrenaline is released as a messenger to various brain cells . Many projections from the  locus coeruleus are to regions that are responsible for regulating the autonomic response to stress, arousal, and homeostatic mechanisms (e.g. suppression of the baroreceptor reflex), all of which can be a risk factor for vaso-occlusive pain crises in patients with SCD who have greater pain sensitivity. Dr. Wood found that the oxygen delivery to the white matter was critically sensitive to the hemoglobin level – the more severe the anemia, the lower the oxygen delivery to the white matter. Dr. Wood’s study is the first to use arterial spin labeling to quantify oxygen delivery separately to the white and grey matter in the brain, correcting for patient’s anemia severity.

He commented: “These findings likely shed light on anemia in general, which is a growing concern in our aging population. I hope this technique will help the medical community assess how current and future SCD treatments, like novel gene therapy approaches, affect the brain”. Results of this study were published recently in the American Journal of Hematology.

  • Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.

Scientific references

Chai Y et al., Wood JC. Am J Hematol. 2019 Jan 29. 

Bhatt RR et al. Neuroimage Clin. 2019 Jan 22; 21:101686.

Václavů L et al., Biemond B. Haematologica 2018 Dec 6.

Bush AM et al. Magn Reson Med. 2018 Jul; 80(1):294-303.



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Dott. Gianfrancesco Cormaci
Dott. Gianfrancesco Cormaci
Laurea in Medicina e Chirurgia nel 1998, specialista in Biochimica Clinica dal 2002, ha conseguito dottorato in Neurobiologia nel 2006. Ex-ricercatore, ha trascorso 5 anni negli USA alle dipendenze dell' NIH/NIDA e poi della Johns Hopkins University. Guardia medica presso la casa di Cura Sant'Agata a Catania. In libera professione, si occupa di Medicina Preventiva personalizzata e intolleranze alimentari. Detentore di un brevetto per la fabbricazione di sfarinati gluten-free a partire da regolare farina di grano. Responsabile della sezione R&D della CoFood s.r.l. per la ricerca e sviluppo di nuovi prodotti alimentari, inclusi quelli a fini medici speciali.

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