Cognitive Outcomes Poststroke: A Need for Better Insights into Mechanisms.

Brain ConnectivityAhead of Print Free AccessCognitive Outcomes Poststroke: A Need for Better Insights into MechanismsNagaendran KandiahNagaendran KandiahAddress correspondence to: Nagaendran Kandiah, Dementia Research Centre (Singapore), Lee Kong Chian School of Medicine, 11 Mandalay Road, Singapore 308232, Singapore E-mail Address: [email protected]Associate Professor of Neuroscience and Mental Health, Nanyang Technological University, Singapore, Singapore.Director, Dementia Research Centre (Singapore), LKC-Imperial Medical School, Nanyang Technological University, Singapore, Singapore.Consultant Neurologist, National University Hospital, Singapore, Singapore.Clinician Scientist, National Medical Research Council, Singapore, Singapore.Search for more papers by this authorPublished Online:29 Sep 2023https://doi.org/10.1089/brain.2023.29054.editorialAboutSectionsPDF/EPUB Permissions & CitationsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail Poststroke cognitive impairment (PSCI) continues to be a major complication of strokes. 7–52% of stroke patients suffer from some degree of cognitive dysfunction (Pendlebury and Rothwell, 2009). The wide range in prevalence of PSCI stems from the nonuniform definition of PSCI as well as varying duration of follow-up poststroke (Melkas et al., 2014). It is also important to note that due to the heterogeneous nature of strokes in terms of lesion location, lesion size, burden of pre-existing small vessel disease and concomitant neurodegenerative pathology, the presentation and natural history of PSCI can be complex.Temporally, cognitive symptoms may emerge soon after a stroke (early PSCI) or many months later (late PSCI) (Levine et al., 2015; Lo et al., 2023). While early PSCI is more likely to be recognized and evaluated as cognitive symptoms begin while patients are still in the health care environment, late PSCI often goes undetected with patients having to live with cognitive difficulties for prolonged periods of time before eventually seeking treatment. Late PSCI typically starts 3–6 months poststroke although it can even manifest much later (Lo et al., 2022).Clinicians should also be mindful that intact cognition in the acute phase is not predictive of long-term cognitive performance, as there is likely to be changes in cerebral perfusion and brain connectivity over time, which could result in fluctuations in cognition later on (Ballard et al., 2003). In view of this natural history, there is a need to put systems in place to ensure that patients are reviewed and evaluated for cognitive symptoms periodically after a stroke. High-risk patients such as older patients and those with pre-existing cerebrovascular disease should be prioritized for periodic evaluation of cognitive function. Scales such as the CHANGE score may be useful in this regard as it allows for cognitive risk stratification of stroke patients at the point of their acute stroke event (Chander et al., 2017).Presenting symptoms can include cognitive and behavioral symptoms (Yatawara et al., 2018). Common cognitive symptoms include executive dysfunction and impaired processing speed (Sachdev et al., 2004). Patients often realize that they take longer to complete their tasks and have trouble with judgment and planning. Often, these symptoms become more evident when patients return to their occupation or become socially active again. In addition to these cognitive symptoms, a majority of patients may also develop isolated behavioral symptoms or behavioral symptoms concomitant to cognitive symptoms.Behavioral symptoms could include apathy, depression, and aggressive behavior among others. From a pathobiological perspective, early PSCI is likely related to disruption of the brain connectivity, whereas late PSCI has been associated with burden of cerebral small vessel disease and neurodegenerative pathology such as amyloid-β and tau pathology (Mok et al., 2017; Yatawara et al., 2020a). Specifically, white matter hyperintensities and microbleeds have been strongly correlated to incidence of PSCI (Wilson et al., 2019; Yatawara et al., 2020b).In this issue of the journal, Baogen Du et al. report their findings on cerebral perfusion in patients who suffered a nondisabling ischemic stroke having intracranial atherosclerotic disease (ICAS). They compared cerebral perfusion using magnetic resonance imaging pseudocontinuous arterial spin labeling (pCASL) as well as neuropsychological performance in 47 stroke patients having ICAS compared with controls. They specifically studied spatial coefficient of variation (sCoV) of pCASL-based blood flow (CBF) images to explore abnormal cerebral perfusion. All participants underwent global and individual neuropsychological assessments and magnetic resonance imaging scan.They report that CBF in the ipsilateral middle cerebral artery (MCA) territory of the lesion side decreased significantly, whereas it increased on the contralateral side. CBF value was also significantly correlated with the memory function in the right MCA lesion group. They demonstrate that the sCoV values increased in both gray matter (GM) and the ipsilateral MCA territory of the lesion and that these sCoV values were significantly correlated with global cognitive function, memory function, and executive function in patients with ICAS. They conclude that sCoV could be a better indicator of cognitive impairment than CBF and that interventions to relieve vascular stenosis or occlusion could potentially delay cognitive impairment.This study adds to the growing literature that cognitive symptoms poststroke are more directly correlated with cerebral perfusion in the poststroke phase and may be less dependent on the area of the infarction. The presence of steno-occlusive cerebrovascular disease has been associated with delays in arterial transit time (ATT) due to decreases in perfusion pressure as well as decreased CBF (Ibaraki et al., 2019).Preliminary studies quantifying sCoV show associations between increasing sCoV magnitude with worsening cognitive function (Morgan et al., 2021). In addition, increasing sCoV of GM is also strongly correlated with decreased CBF, further supporting delayed perfusion effects (Morgan et al., 2021). Thus, the sCoV of pCASL CBF imaging can be a reliable measure of hemodynamic status to predict prolonged ATT in stroke patients (Ibaraki et al., 2019; Mutsaerts et al., 2020; Mutsaerts et al., 2017).Previous work has also suggested that the burden of prestroke cerebral small vessel disease is a major factor that determines development of PSCI. High burdens of pre-existing cerebral small vessel disease could alter global cerebral perfusion, which becomes further compromised after an acute stenosis of intracranial vessels related to the stroke event.Although stroke is associated with lower perfusion throughout the GM, reduced CBF in regions involved in cognitive functioning as measured by Arterial Spin Labeling imaging has been consistently reported in studies on stroke survivors and poststroke dementia (Brumm et al., 2010; Firbank et al., 2011; Schuff et al., 2009). Deficits in CBF may occur either at baseline or as abnormally long transit delays, both of which may affect tissue viability and subsequently impact cognitive functioning (Brumm et al., 2010; Hillis, 2007).Indeed, such global hypoperfusion has been further associated with vascular cognitive decline (Schuff et al., 2009). In addition, individuals with poststroke dementia show greater burden of vascular pathology as determined by white matter hyperintensity volume and associated cortical hypoperfusion illustrating possible mechanisms underlying PSCI (Firbank et al., 2011). This combination of white matter hyperintensities, lower brain volume, and impaired cognitive ability poststroke strongly predict increased risk of future dementia due to collective vascular dysfunction (Firbank et al., 2011; Savva and Stephan, 2010).In addition, longitudinal parietal and global CBF deficits have also been shown to appear up to 6 years poststroke, indicating sustained vascular disruption (Firbank et al., 2011). Further studies examining cerebral perfusion with CBF measures, ATT measures, and sCOV in patients with lacunar strokes and large vessel strokes could shed light on the natural history of PSCI, allowing for better monitoring strategies and development of interventions that target cerebral perfusion poststroke.Another article in this issue by Erin L. Meier et al. examined connectivity changes and language impairment poststroke. This is timely research, given that aphasia remains a major neurological deficit poststroke, resulting in poor functional status and interferes with the rehabilitation process. This study used functional near-infrared spectroscopy (fNIRS) to study aphasia poststroke. Resting state functional connectivity changes were compared between patients with early poststroke aphasia and neurological healthy adults using the preprocessed oxyhemoglobin (Hbo) data derived from fNIRS.Using a 46-channel montage centered over bilateral perisylvian areas, the authors demonstrated that patients with aphasia had reduced global resting state connectivity across all Hbo-based connections compared with healthy controls. These findings are in keeping with the connectivity changes that occur after an acute stroke event. fNIRS may be relatively more accessible in clinical settings and thus could be integrated in the evaluation of patients with PSCI.PSCI remains a major complication of strokes with debilitating consequence on stroke survivors and their families. The fluctuations in cognitive symptoms over time related to changes in cerebral perfusion and brain connectivity are key mechanisms that require further longitudinal studies. A deeper understanding of the perfusion-connectivity changes poststroke will provide for better prediction models for PSCI, which will in turn allow for more accurate selection of stroke patients for close monitoring of cognition as well as those that may benefit from intensive vascular and cognitive enhancer therapies.ReferencesBallard C, Rowan E, Stephens S, et al. 2003. 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