Reperfusion Therapies in the Aged Brain: When Every Neuron Counts

International guidelines specify no upper age limit for reperfusion therapies in the acute ischemic stroke setting, however, an increased deployment of intravenous thrombolysis (IVT) and mechanical thrombectomy (MT) in old patients (i.e. ≥ 80 years old) raised uncertainties on the net clinical benefit in this population. Indeed, old patients have been underrepresented in randomized clinical trials on IVT and MT (especially the early ones), and the older age is one of the strongest independent predictors of poor clinical outcome.¹

The aged brain is likely to be a very fast progressor from penumbra to infarction, accordingly to different mechanisms. Age and brain frailty are known to be associated with both an increased vulnerability to brain ischemia and to a worse collateral vessel status, with evidence reporting an age-dependent increase in conversion of hypo-perfused tissue into brain infarction on non-invasive neuroimaging analysis.^2,3 However, a quick restoration of blood flow can prevent the evolution of a brain region with perfusion deficit to irreversibly infarcted tissue independently of a patient’s age.⁴ In fact, the salvage of hypo-perfused brain tissue likely relies on the efficacy and timing of reperfusion more than on the patient’s frailty and comorbidities, and the expected benefit of a prompt reperfusion may be even higher in patients with poor compared vs. good collateral vessel status.^4,5

Despite older subjects suffer from worse clinical outcomes compared to younger ones, clinical trials and observational cohort studies carried out in the last years did not suggest a reduced effect of IVT or MT in the elders.^6,7 Conversely, recent findings suggest that older patients might experience even higher relative benefit from reperfusion therapies compared to younger ones:¹ unlike younger patients, who can count on brain plasticity and adaptative mechanisms, we can suppose that – in the aged brain – stroke recovery mostly depends on the salvaged ischemic tissue.⁸ The best argument dwells in the findings of a recent study on subjects aged ≥ 90 years with stroke due to large vessel occlusion, where a remarkable rate of one in three patients achieved favorable outcome three months after mechanical thrombectomy.⁹

To conclude, IVT and MT improve clinical outcome even in the very old patients and there is no reason to withhold reperfusion treatments based merely on age. A prompt reperfusion counts even more in old patients: time could be even “more brain” in the acute phase and, in the aged brain, every spared neuron can make a big difference for stroke recovery. Lord of the Rings’ wise fictional hero Gandalf once said, “the long explanations needed by the young are wearying” and to date, many interesting physiopathological mechanisms of brain ischemia and recovery in the old brain are yet to be unveiled.

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References:

1. Groot AE, Treurniet KM, Jansen IGH, et al. Endovascular treatment in older adults with acute ischemic stroke in the MR CLEAN Registry. Neurology 2020; 95: E131–E139.
2. Ay H, Koroshetz WJ, Vangel M, et al. Conversion of ischemic brain tissue into infarction increases with age. Stroke 2005; 36: 2632–2636.
3. Menon BK, Smith EE, Coutts SB, et al. Leptomeningeal collaterals are associated with modifiable metabolic risk factors. Ann Neurol 2013; 74: 241–248.
4. Al-Ajlan FS, Goyal M, Demchuk AM, et al. Intra-Arterial Therapy and Post-Treatment Infarct Volumes: Insights From the ESCAPE Randomized Controlled Trial. Stroke 2016; 47: 777–781.
5. Renú A, Laredo C, Montejo C, et al. Greater infarct growth limiting effect of mechanical thrombectomy in stroke patients with poor collaterals. J Neurointerv Surg 2019; 11: 989–993.
6. Bluhmki E, Danays T, Biegert G, et al. Alteplase for Acute Ischemic Stroke in Patients Aged >80 Years: Pooled Analyses of Individual Patient Data. Stroke 2020; 51: 2322.
7. Jayaraman M V., McTaggart RA. Endovascular treatment of anterior circulation large vessel occlusion in the elderly. Front Neurol 2018; 8: 713.
8. Luijten SPR, Compagne KCJ, van Es ACGM, et al. Brain atrophy and endovascular treatment effect in acute ischemic stroke: a secondary analysis of the MR CLEAN trial. Int J Stroke 2022; 17: 881.
9. Fujita K, Tanaka K, Yamagami H, et al. Outcomes of Large Vessel Occlusion Stroke in Patients Aged ≥90 Years. Stroke 2021; 1561–1569.