Efficacy of remote ischemic conditioning on improving WMHs and cognition in very elderly patients with intracranial atherosclerotic stenosis

Introduction

White matter hyperintensities (WMHs), also known as leukoaraiosis, are not uncommon neuroimaging findings in elderly individuals, particularly in those with known vascular risk factors and associated cerebrovascular diseases [1, 2]. Anatomically, blood vessels supplying the white matter (WM) are mainly long, penetrating arterioles with few anatomic branches, and the WM receives less blood flow than that in the gray matter. These vascular features may render the WM more vulnerable to ischemic insult. In addition, a group of aging-related vascular changes, such as increased tortuous arterioles, thickened vascular walls due to collagen deposition, decreased vascular density and impaired cerebral blood flow (CBF) autoregulation could further exacerbate WM damage [3, 4]. Clinically, a high WMH burden is considered to be associated with progressive cognitive impairment, increased risk of stroke and dementia, gait disturbance, depression and even death [2, 5, 6].

Although the pathophysiological mechanisms underlying WMHs remain unclear, endotheial dysfunction and chronic hypoperfusion secondary to atherosclerosis appear to play a central role in the initiation and progression of WMHs [7, 8]. Recently, intracranial atherosclerotic stenosis (ICAS) has been suggested as a major cause of chronic cerebral ischemia (CCI) worldwide, notably in Asians [9, 10]. ICAS-induced CCI is the basis for vascular cognitive impairment and can promote the occurrence and recurrence of stroke. In addition, a growing body of evidence indicates a strong association between ICAS and WMHs in stroke patients as well as in an asymptomatic population [7, 8, 11, 12]. Severe stenosis or occlusion of intracranial arteries can cause diffuse cerebral hypoperfusion, and if this CBF reduction is continuous, WMHs may develop, followed by stroke and impaired cognition. Other possible explanations for a high prevalence of WMHs in ICAS patients include artery-to-artery embolism from atherosclerotic lesions and shared risk factors by ICAS and WMHs [7, 8].

To date, despite decades of exploration, effective treatment strategies for reversing or preventing WMHs are still lacking. Preclinical drugs with great efficacy in experimental models have frequently failed to yield encouraging outcomes, which raise doubts about the translational value of these initial findings. Additionally, the conclusions from clinical trials on whether risk factor management in elderly patients could prevent WMHs progression or ameliorate cognitive impairment are mixing and inconsistent [2, 13].

Limb remote ischemic conditioning (RIC) refers to an approach that brief, repetitive and sublethal ischemia-reperfusion applied to a limb or limbs can induce systemic endogenous tolerance, whereby preventing remote organs or tissues from subsequent (detrimental) ischemic injury [14]. Animal studies have demonstrated that daily limb RIC is effective in reducing WM damage, promoting angiogenesis and improving cognitive function after CCI [15–17]. In a proof-of-concept randomized controlled trial conducted by our study group, we found that chronic RIC was able to alleviate WMHs and slow down cognitive decline in patients with cerebral small-vessel disease (CSVD) [18]. Importantly, regarding the patients with ICAS either above or beneath 80 years of age, chronic RIC is safe and shown to decrease the incidence of stroke recurrence, possibly via enhancing cerebral perfusion and ameliorating plasma biomarkers of coagulation and inflammation [19, 20]. However, whether RIC can alter WMHs in octo- and nonagenarians with ICAS has not been reported yet. Herein, the aim of this study was to investigate whether long-term RIC could prevent the progression of WMHs and improve cognition in octo- and nonagenarians with ICAS.

Results

Discussion

The principal findings from the present randomized clinical trial exploring the effect of RIC on WMHs and cognition in octo- and nonagenarians with ICAS are that long-term twice-daily RIC combined with standard medical therapy is clinically effective in ameliorating WMHs and improving cognitive function when compared with standard medical therapy alone.

WMHs of presumed vascular origin are often found in elderly individuals, particularly those with vascular risk factors or vascular diseases. Recent studies have shown that intracranial large artery stenosis may result in WMHs, high loads of which are believed to be associated with increased risk of cognitive impairment, gait abnormalities, stroke, dementia and some unspecific symptoms such as headache, dizziness and sleep disturbance [6, 8, 10, 20]. Measuring the severity and progression of WMHs has been proposed as a useful surrogate marker for predicting therapeutic outcomes. Despite the lack of the optimal method of measuring WMHs, varied visual rating scales and volumetric measurements based on computerized techniques have been used in clinical and research settings. Unlike semi-automated volumetric methods, visual rating scales are relatively less time-consuming and much easier to perform on the MRI scans obtained from different devices. Moreover, there is ample evidence showing that volumetric and visual rating methods for the measurement of WMHs are moderately or highly correlated, and they may yield nearly equivalent estimations of WMHs burden [21, 22]. Hence, in this study, two widely used rating scales including the Fazekas scale and Scheltens scale were adopted to evaluate WMHs amongst elderly patients with ICAS. Importantly, we found that twice-daily RIC therapy for either 180-day or 300-day significantly reduced WMHs scores compared with controls, and longer-term use of RIC may be more effective than shorter-term treatment (lower Fazekas and Scheltens scores at 300-day than 180-day). In contrast, patients treated with medical therapy alone seemed to have more severe WMHs measured at 300-day follow-up relative to that at the baseline. Our results are consistent with previous studies examining the neuroprotective effects of RIC on experimental animal models, which demonstrated that chronic limb RIC could reverse or attenuate WM damage induced by bilateral carotid artery occlusion-related CCI [15, 17]. Additionally, a more recent pilot study enrolling patients with CSVD showed that daily RIC for 1-year was associated with a substantially lower mean WMHs volume than that in the control group [18]. Although we did not explore the detailed mechanisms underlying the RIC-mediated protective effect on WMHs in this study, such benefits may be largely attributable to improved CBF resulting from cerebral angiogenesis, collateral formation and vascular remodeling [14, 17, 19]. Furthermore, RIC has been shown to reduce inflammatory responses, downregulate microglial expression, inhibit the apoptosis of oligodendrocytes, and attenuate production of free radicals, all of which may facilitate the recovery of WMHs derived from ischemic injury [14–17]. Interestingly, our previous study using the same group of patients demonstrated that RIC administered for 180-day markedly reduced the incidence of stroke or TIA recurrence [27]. Given the association between WMHs and stroke or TIA recurrence, we may speculate that this clinical benefit is, at least partially, due to attenuation of WMHs.

Vascular cognitive impairment comprises a clinical spectrum ranging from mild cognitive decline (MCD) to vascular dementia, which poses a great threat to patients’ quality of life. Therefore, early and routine screening for cognitive deficits with sensitive instruments is required, knowing that it allows for timely initiation of interventions to prevent cognitive deterioration. While the MMSE is the most commonly used screening test for cognitive impairment in the world, the MoCA has been proven to be more sensitive than the MMSE for the detection of MCD and mild dementia [23–25]. In the present study, we also observed different percentages of patients with cognitive impairment at baseline depending on the type of screening test used: RIC group, MMSE (13%) vs. MoCA (25%); control group, MMSE (12%) vs. MoCA (25%). Compared with pretreatment, the post-treatment overall MMSE scores in the RIC group were significantly increased, whereas no such change was observed in the control group. Moreover, the overall MoCA scores measured at both 180-day and 300-day follow-ups were substantially increased in both groups, whereas the increases were more pronounced in the RIC group, implying that RIC may confer extra benefits over currently used medical therapies for improving cognition. This result may be supported by the evidence of experimental studies, which demonstrated that long-term RIC could improve cognition via enhancing spatial and working memory after CCI [15–17]. Notably, the result of MMSE and MoCA subitems showed that patients in the RIC group had significantly higher delayed recall, calculation, attention and orientation subscores. Compared with MMSE, MoCA is acknowledged as a potentially more sensitive method to evaluate cognitive domains including visuospatial and executive functions. In our study, although there was no significant difference in the visuospatial and executive subscores between groups, these domains were improved in the RIC group relative to the baseline levels.

Population-based studies have found an association between WMHs and cognition, knowing that increased WMHs burden can contribute to poorer cognitive function [6, 26]. We also noticed a significant negative correlation between WMHs (assessed by the Fazekas scale and Scheltens scale) and cognition (assessed by the MMSE and MoCA-BJ) at baseline, 180-day and 300-day. Therefore, it is reasonable to infer that improved cognition may be secondary to reduced WMHs and enhanced CBF.

Our study is of high clinical relevance due to the following reasons. First of all, to the best of our knowledge, this is the first randomized controlled clinical trial reporting the efficacy of RIC on WMHs reduction and cognition improvement amongst patients with ICAS-induced CCI. ICAS is considered as the most common cause of both stroke and CCI in Chinese and even whole Asian populations. At present, studies designed to explore approaches for slowing down or even reversing the progression of ICAS-associated WMHs are sparse. Second, given the overwhelming role of age on clinical outcomes, uncertainty exists regarding the benefits and risks related to current therapeutic recommendations applicable to elderly patients, particularly octo- and nonagenarians. Hence, clinicians should be intensely cautious in the prevention and treatment of adverse events at this advanced age with functional deterioration and multimorbidity. Unlike other clinical trials of RIC restricted to relatively younger patients, all participants in our study were in the very elderly age (older than 80 years) and showed good compliance within 300-day follow-up. Moreover, the RIC device used in the study provides many advantages, such as simplicity (can be performed automatically), low cost (can be performed repetitively) and mild or no adverse effect, all of which render it an optimal option for inpatients as well as home-care patients.

One of the major limitations of the present study was the small number of patients enrolled from a single center in China. Consequently, this study should be viewed as exploratory and cannot be generalized to the overall or other ethnic populations at this stage. Another limitation was that the follow-up period was not long enough, given the progressive feature of WMHs and cognitive function in the elderly patients. In addition, we only used two visual rating scales to assess the severity of WMHs and did not analyze the microstructural alterations within visible lesions as well as in the surrounding normal-appearing WM. The underlying mechanisms of RIC-mediated neuroprotection, such as WMHs reduction, and cognition or symptoms improvement were not fully investigated. Last but not least, we applied a previously reported RIC protocol in our patients, bur whether modifying RIC protocol in this clinical setting could achieve better outcomes remains unknown. A series of larger prospective clinical trials (Clinical Trials.gov: NCT03105141 and NCT02534545) is ongoing in our study group in an attempt to work out ways to tackle these challenges.

Materials and Methods

Conclusions

In summary, our current findings underline that RIC may prove to be an adjunctive to standard medical therapy for preventing the progression of WMHs and ameliorating cognitive impairment in very elderly patients with ICAS-induced CCI. The clinical implications of this pilot study need to be further explored in future multicenter randomized clinical trials powered for the clinical outcomes.

Supplementary Materials

Supplementary Figure and Tables