Brain Circulation

: 2015  |  Volume : 1  |  Issue : 2  |  Page : 133--139

Remote ischemic conditioning: A treatment for vascular cognitive impairment

David C Hess1, Mohammad B Khan1, John C Morgan1, Md Nasrul Hoda2,  
1 Department of Neurology, Medical College of Georgia, Georgia Regent's University, Augusta, Georgia, USA
2 Department of Medical Laboratory, Imaging and Radiologic Sciences, College of Allied Health Sciences, Georgia Regent's University, Augusta, Georgia, USA

Correspondence Address:
David C Hess
Department of Neurology, Medical College of Georgia, Georgia Regent«SQ»s University, Augusta - 30912, Georgia


There is a strong link between hypoperfusion and white matter (WM) damage in patients with leukoaraiosis and vascular cognitive impairment (VCI). Other than management of vascular risk factors, there is no treatment for WM damage and VCI that delays progression of the disease process to dementia. Observational studies suggest that exercise may prevent or slow down the progression of Alzheimer«SQ»s disease (AD) and VCI. However, getting patients to exercise is challenging, especially with advancing age and disability. Remote ischemic conditioning, an «DQ»exercise equivalent,«DQ» allows exercise to be given with a «DQ»device«DQ» at home for long periods of time. Since remote ischemic conditioning (RIC) increases cerebral blood flow (CBF) in preclinical studies and in humans, RIC may be an ideal therapy to treat VCI and WM disease and perhaps even sporadic AD. By using magnetic resonance imaging (MRI) imaging of WM progression, a sample size in the range of about 100 subjects per group could determine if RIC has activity in WM disease and VCI.

How to cite this article:
Hess DC, Khan MB, Morgan JC, Hoda M. Remote ischemic conditioning: A treatment for vascular cognitive impairment.Brain Circ 2015;1:133-139

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Hess DC, Khan MB, Morgan JC, Hoda M. Remote ischemic conditioning: A treatment for vascular cognitive impairment. Brain Circ [serial online] 2015 [cited 2021 Oct 25 ];1:133-139
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The prevalence of dementia is expected to triple by 2050, making it a major threat to world public health. [1] In the last few decades, there has been an "alzheimerization" of dementia with a tendency to attribute all cognitive decline to Alzheimer's disease (AD). [2] This view is now being challenged and revised with the pendulum swinging back to the recognition of the major contribution of vascular causes to dementia. [1],[3],[4],[5] Vascular dementia makes up to 20% of the cases of dementia. [4],[6] However, many more cases of dementia are of "mixed" etiology with the estimates of "mixed dementia" related to AD and vascular causes ranging up to 50% in the cases of dementia. Moreover, cerebral ischemia worsens AD and triggers its clinical expression. In the Nun study, among participants fulfilling neuropathological criteria for AD, those with brain infarcts had a much higher prevalence of dementia. [7] Participants with lacunar infarcts in the basal ganglia, thalamus, or deep white matter (WM) had an odds ratio for dementia of 20.7 compared to those without infarcts. [7]

The National Alzheimer's Project Act, signed into law in the United States in 2011, mandates a National Plan to address AD. In the plan, the term "Alzheimer's" includes not only Alzheimer's disease (AD) proper but also AD and related disorders. Vascular dementia and mixed dementia are among these related disorders. [8] Recognizing the vascular contributions to cognitive impairment and AD, in 2013 the Alzheimer's Association together with the National Institutes of Health convened a panel to outline steps to move the research field of vascular contributions to cognitive impairment forward. [9] The National Institute of Neurological Disease and Stroke (NINDS) Stroke Progress Review Group in 2012 cited "prevention of vascular cognitive impairment" as a major research priority.

 Alzheimer's Disease and Cerebral Blood Flow

Cerebral hypoperfusion is an early finding in AD and may play a role in the pathogenesis of AD. [10],[11],[12] In AD, low cerebral blood flow (CBF) is an early finding that precedes deposition of amyloid beta. Patients with autosomal dominant AD have early CBF changes that precede any cognitive symptom. [13] High amyloid beta deposition in specific brain regions is associated with lower CBF in those same regions. [14] In the Rotterdam study, subjects with higher middle cerebral artery velocity by transcranial Doppler had a lower risk of dementia and higher middle cerebral artery velocity predicted less cognitive impairment in nondemented subjects, suggesting that hypoperfusion preceded cognitive decline. [15] One theory "critically attained threshold of cerebral hypoperfusion" (CATCH) proposes that impaired perfusion in the brain microvasculature triggers neuronal degeneration and cognitive dysfunction. [16],[17],[18] It is debated whether the low CBF reflects lowered neuronal metabolism or if it is a primary cause of neuronal dysfunction and amyloid beta deposition. CBF has been proposed as a biomarker of AD similar to positron emission tomography (PET) imaging of amyloid beta.

A link between hypoperfusion, infarcts, and amyloid beta deposition may be explained by dysfunction of the glymphatic system in the brain. Amyloid beta accumulation is thought to be related to an imbalance between production and its clearance from the brain. Recent findings suggest that amyloid beta clearance is mediated by astrocyte-mediated interstitial fluid bulk flow, the glymphatic system (g for "glia"). The glymphatic system involves three components: a) transport from a para-arterial cerebrospinal fluid (CSF) influx route around penetrating arteries; b) a para-venous interstitial fluid (ISF) clearance route; and c) a transparenchymal pathway that is dependent on astroglial water transport via the astrocytic aquaporin-4 (AQP4) that is polarized in location being expressed on perivascular astrocytes. [19],[20],[21],[22] Microinfarcts with accompanying astrogliosis impair polarization of AQP-4. [23] Moreover, the loss of arterial pulsatility with aging and the inflammation and gliosis often found in the aging brain impair this glymphatic pathway and clearance of amyloid beta. [24] Defects in this glymphatic clearance system from ischemia and infarcts may be related to the deposition of amyloid beta and tau and may provide the link between brain vascular disease and sporadic AD.

 Vascular Cognitive Impairment

Vascular cognitive impairment (VCI) is the term that encompasses the clinical spectrum from mild cognitive dysfunction to vascular dementia. The pathological hallmark of VCI is WM damage from ischemia in the periventricular regions and centrum semiovale. [1],[5] The underlying pathology involves small vessel disease although hypertension only accounts for a small proportion of the risk. [25] The imaging correlate of this WM damage is "leukoaraiosis" best detected by magnetic resonance imaging (MRI) and almost always apparent by the age of 70 years. The degree and severity of leukoaraiosis is associated with cognitive impairment, depression, gait abnormalities, and disability. [26] WM changes are mediated by blood-brain barrier (BBB) leakage, microglial activation, and injury to oligodendrocytes and myelin. [1]

Hypoperfusion of WM appears to be an early finding and plays a pathophysiological role in the development of WM damage. Reduction of CBF is an early finding in areas of leukoaraiosis. [27] The hemispheric WM receives its blood supply through long, penetrating arteries originating from the pial network on the surface of the brain (rami medullaris) and the WM adjacent to the walls of the ventricles from penetrating vessels originating from the base of the brain (rami striati). [28] The location of WM damage in the periventricular area and deep WM is likely related to this area being an arterial border zone or "watershed" zone susceptible to injury from systemic blood pressure drops or local decreases in CBF related to disease in these vessels. Low blood flow by MRI perfusion or MRI arterial spin labeling (ASL) in normal appearing WM is predictive of these regions transitioning to WM lesions. [29],[30] A CSF penumbra exists around WM lesions that expands in relation to low CBF. [30]

 Exercise and Physical Activity and Risk of Dementia

There is a large body of evidence suggesting that physical exercise reduces the risk of cognitive decline and dementia (see review). [31] Moreover, physical activity reduces biomarkers of AD and dementia such as PET amyloid beta burden, and hippocampal volumes on MRI. On volumetric MRI, physical activity was independently associated with greater whole brain and regional brain volumes and reduced ventricular dilation. [32] A physically active lifestyle is associated with lower amyloid burden on PET and higher hippocampal volumes by MRI. [33]

The leukoaraiosis and disability (LADIS) study is a prospective multinational European cohort study that evaluates the impact of WM changes on the transition of independent elderly subjects to disability. In 3 years of follow-up, physical activity reduced the risk of cognitive decline and dementia. [34] Physical activity also prevented decline of executive function in nondemented and noncognitively impaired patients with "age-related white matter changes." [35]

These observational studies support the concept that exercise may be an effective treatment for VCI and patients with early WM damage. While exercise and physical activity appear to reduce cognitive impairment and the risk of dementia, observational studies are limited and often confounded. There is a lack of randomized trials that show exercise as reducing dementia or cognitive decline in AD or VCI. There may also be another explanation for the effect of exercise in observational studies. There is evidence that children and young adults with better cognitive function may select healthier lifestyles with more exercise, and so it is called "neuroselection." [36]

 Exercise and Age

While physical activity and exercise are associated with lower risk of cognitive decline, older patients are less likely to exercise than younger patients. A telephone survey of over 450,000 in the US conducted by the Centers for Disease Control found that only 20.6% of Americans met the aerobic and muscle-strengthening guidelines in the 2008 Physical Activity Guidelines for Americans. [37] While 30.7% of persons aged 18-24 years met the guidelines, this fell to 15.9% in those over the age of 65 years. Both age and educational status were significantly associated with exercise as older age and less education were associated with less exercise and physical activity. Therefore, as patients age they are less willing or less able to exercise. Since exercise is difficult to enforce and many patients are unwilling or unable to exercise, an alternative is to develop therapies that are equivalent to "exercise in a pill" or "exercise in a device."

 Ischemic Preconditioning and Remote Ischemic Conditioning

Ischemic preconditioning is one of the most potent cardioprotectants and neuroprotectants known. Ischemic preconditioning like other forms of preconditioning triggers endogenous protective pathways and allows the brain to "self-protect." First described in 1986 by Murry in the canine heart, [38] it was soon learned that ischemic conditioning could be applied regionally and then remotely in other organs and finally with a blood pressure cuff on the limbs, making it highly translatable.

Remote ischemic conditioning (RIC) involves repeated (blood pressure) cuff inflations on the arm or leg to reduce ischemic damage in a distant organ such as the heart, kidney, or brain. RIC can be applied before ischemia (pre-), during ischemia (per-) or after ischemia, and during reperfusion (post-). There are a large number of randomized clinical trials of remote limb preconditioning to protect the heart suggestive of benefit. [39] RLIC effectively reduces MI when used in the prehospital setting before percutaneous coronary interventions. [40]

A large number of preclinical studies indicate that RIC is effective at reducing injury in focal cerebral ischemia models (see review). [41] RIC improves CBF, reduces ischemic damage, and also attenuates adverse effects of late IV-tissue plasminogen activator (tPA) in a mouse embolic stroke model. [42] Moreover, the effects are sex-independent as ovariectomized female mice also benefit. [43] A recent clinical trial of RIC in the prehospital setting in acute stroke did not show efficacy in its primary endpoint but most patients did not receive the full regimen and a post hoc "tissue analysis" demonstrated an overall significantly reduced risk of infarction in patients randomized to RIC. [44] A consistent finding is that RIC increases CBF in multiple brain injury models, making it an attractive therapy for VCI. [42],[43],[45]

 Chronic Remote Ischemic Conditioning

In an insidious progressing disease such as VCI or vascular dementia, a therapy will need to be administered early in the course and chronically, perhaps for months or even years. There is evidence demonstrating that RIC can be applied chronically and daily at home. Two small randomized clinical trials of chronic RIC in patients with intracranial stenosis showed safety, tolerability, and efficacy with a reduction in stroke or stroke and transient ischemic attack (TIA). [46],[47] RIC was safe and well-tolerated as patients were treated for 6 months and 300 days, indicating long-term feasibility. RIC increased CBF as measured by single-photon emission computed tomography (SPECT). [46] Similarly, chronic RIC daily at home could be adapted for VCI as an "exercise equivalent," a therapy easier to adopt for aged individuals.

 Remote Ischemic Conditioning: An Exercise Equivalent?

Preconditioning and exercise may share common mechanisms and protective pathways. Brief, intense exercise "preconditions" dog hearts and is similar to classical ischemic preconditioning with an early phase and a late phase. [48] Similarly, RIC and exercise may share common mechanisms of protection. Dialysates prepared from plasma from human subjects undergoing vigorous exercise or remote limb conditioning were both protective in an isolated rabbit Langendorff heart preparation. [49] The opioid antagonist, naloxone blocked the effects of dialysates from both exercisers and those undergoing RIC suggesting that common humoral mediators are shared by exercise and RIC. [49] Exercise acts as a form of "remote" conditioning. Alternatively, RIC can be viewed as an "exercise equivalent" and may confer the benefits of exercise to patients unable to unwilling to exercise.

 Animal Models of Vascular Cognitive Impairment

There are a number of proposed animal models for VCI. In a recent review of all mouse models for VCI and vascular dementia, Bink determined the mouse bilateral carotid artery stenosis (BCAS) model to be the most valid. [50] Microcoils are placed around the extracranial carotid arteries with reduction of CBF [Figure 1]. This model reproduces the WM damage, cerebral hypoperfusion, inflammation, BBB damage, and cognitive deficits of the human condition. [51],[52] There are also fibrinoid changes in the small vessels of the brain with gliosis and disruption of aquaporin polarization. [53] With these small vessel changes, the BCAS model may be useful to test interventions to treat small vessel disease of the brain. [53]{Figure 1}

RIC was tested daily for 2 weeks in C57/B6 male mice (10-week-old) and subjected to BCAS using microcoils to induce cerebral chronic hypoperfusion [45] [Figure 2]. The mice were randomized into three groups: A sham-operated group, BCAS with daily sham RIC, and BCAS with daily RIC. CBF was measured using high-resolution laser speckle contrast imager. There was no significant difference between baseline CBF of BCAS with sham RIC and BCAS with RIC (before and immediately after BCAS). RIC or sham RIC was started 7 days after BCAS surgery. After 7 days of RIC treatment, there was a significant increase in CBF compared to sham RIC. RIC therapy was continued for 1 more week up to day 21 post-BCAS and then discontinued for the next 1 week. When measured on day 28, the RIC significantly increased CBF even after the RIC therapy was discontinued for 1 week. This demonstrated a sustained effect on CBF even after the cessation of RIC. {Figure 2}

At 28 days, BCAS significantly triggered the accumulation of Aβ42 (fourfold) and increased inflammation as measured by intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), and microglial activation, gliosis, demyelination, and subsequent cell death. RIC therapy for 2 weeks attenuated upregulation of ICAM and VCAM, microglial activation, and decreased the Aβ42 (2 fold) accumulation in RIC as compared to sham RIC, leading to attenuation of WM degeneration. RIC also improved cognition as measured by the novel object recogntion test. These results indicate that RIC improves CBF, improves cognition, reduces inflammation and WM damage, and reduces amyloid accumulation in a BCAS model. [45]

 Mechanism of Action of Remote Ischemic Conditioning

The mechanism of action of RIC in neuroprotection is not precisely known but it likely involves humoral factors and neural loops, especially type C afferents and the autonomic nervous system. [41] Chronic RIC also has anti-inflammatory effects and stimulates autophagy. [54],[55] Humoral mediators associated with the cardioprotective effect of RIC include stromal derived factor 1, [56] interleukin (IL)-10, [57] micro-RNA-144, [58] and nitrite. [59] Moreover, opioids appear to play a role in the protective effect of both exercise and RIC. [49]

 The Endothelial Nitric Oxide Synthase/Nitric Oxide/Nitrite System

The endothelial nitric oxide synthase/nitric oxide (eNOS/NO) system plays a key role in regulating CBF in the brain and in the processing of amyloid-beta and may serve as the link between vascular dysfunction and impaired cognition in AD. [60],[61] Inhibition of "vascular nitric oxide (NO)" after chronic cerebral hypoperfusion in the rat causes immunocytochemical changes in the brain leading to loss in learning and spatial memory function. [62] Plasma nitrite reflects endothelial NO production and improved endothelial function. [63] Endothelial NO produced remotely can be delivered via plasma nitrite to protect a distant ischemic organ such as the brain, an "endocrine effect" of NO. [64] Rassaf et al. recently showed that circulating nitrite mediates the cardioprotective effect of RIC in a myocardial infarction model. [59] Mice undergoing BCAS have lower plasma nitrite and RIC increases plasma nitrite in the mouse BCAS model. [65],[66] Plasma nitrite mediates hypoxic vasodilation via reduction to NO by hemoglobin and other heme moieties. [67],[68],[69],[70],[71],[72],[73],[74] This suggests that plasma nitrite may be the mediator of the increased CBF observed after RIC and may serve as a blood biomarker of the conditioning response. The eNOS/NO system may also underlie the beneficial effects of exercise in cerebral ischemia. In a mouse model of acute ischemic stroke, the beneficial effects of exercise-improving recovery and increased CBF are abrogated in eNOS knockout mice. [75] Thus, the mechanism of both exercise and RIC may be eNOS dependent. While the effects of RIC are pleotropic and likely involve multiple mechanisms, enhancement of the eNOS/NO/nitrite system may underlie the beneficial effects of RIC in the BCAS model and may be important in VCI patients.

 Future Perspectives

RIC may be an effective treatment for VCI and in patients with WM and small vessel disease. RIC appears to increase CBF and in a mouse, the BCAS model improves cognition and reduces inflammation. Clinical trials already show that RIC can be applied chronically for up to 300 at home with safety and tolerability. An ongoing clinical trial is evaluating the safety, feasibility, and effect of RIC on WM damage on MRI in patients with recent lacunar infarct and WM disease. (REM-PROTECT clinical NCT0218992) Using participant and MRI data from the LADIS study, WM progression would only require a sample size of 58 to 70 subjects per treatment arm. [76] Similarly, data from the prospective St. George's Cognition and Neuroimaging in Stroke (SCANS) study suggest that MRI of WM and diffusion tensor imaging (DTI) measurements would allow sample sizes in the 100s. [77] The time has arrived to evaluate RIC in patients with VCI. A clinical trial with a sample size as small as about 100 per group using WM progression of DTI as a biomarker would determine if RIC has "activity" in VCI and WM disease.


We would like to acknowledge Colby Polonsky, Medical Illustrator, Georgia Regent's University.

Financial support and sponsorship

NIH/NINDS R21NS090609-01A1.

Conflicts of interest

The authors have no conflicts of interest to declare.


1Iadecola C. The pathobiology of vascular dementia. Neuron 2013;80:844-66.
2Libon DJ, Price CC, Heilman KM, Grossman M. Alzheimer's "other dementia". Cogn Behav Neurol 2006;19:112-6.
3Jellinger KA. Pathology and pathogenesis of vascular cognitive impairment - A critical update. Front Aging Neurosci 2013;5:17.
4Gorelick PB, Scuteri A, Black SE, Decarli C, Greenberg SM, Iadecola C, et al.; American Heart Association Stroke Council, Council on Epidemiology and Prevention, Council on Cardiovascular Nursing, Council on Cardiovascular Radiology and Intervention, and Council on Cardiovascular Surgery and Anesthesia. Vascular contributions to cognitive impairment and dementia: A statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2011;42:2672-713.
5Iadecola C. The overlap between neurodegenerative and vascular factors in the pathogenesis of dementia. Acta Neuropathol 2010;120:287-96.
6Pantoni L, Gorelick P. Advances in vascular cognitive impairment 2010. Stroke 2011;42:291-3.
7Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 1997;277:813-7.
8Montine TJ, Koroshetz WJ, Babcock D, Dickson DW, Galpern WR, Glymour MM, et al.; ADRD 2013 Conference Organizing Committee. Recommendations of the Alzheimer's disease-related dementias conference. Neurology 2014;83:851-60.
9Snyder HM, Corriveau RA, Craft S, Faber JE, Greenberg SM, Knopman D, et al. Vascular contributions to cognitive impairment and dementia including Alzheimer's disease. Alzheimers Dement 2015;11:710-7.
10Wang Z. Characterizing early Alzheimer's disease and disease progression using hippocampal volume and arterial spin labeling perfusion MRI. J Alzheimers Dis 2014;42(Suppl 4): S495-502.
11Wang Z, Das SR, Xie SX, Arnold SE, Detre JA, Wolk DA; Alzheimer's Disease Neuroimaging Initiative. Arterial spin labeled MRI in prodromal Alzheimer's disease: A multi-site study. Neuroimage Clin 2013;2:630-6.
12Wierenga CE, Hays CC, Zlatar ZZ. Cerebral blood flow measured by arterial spin labeling MRI as a preclinical marker of Alzheimer's disease. J Alzheimers Dis 2014;42(Suppl 4): S411-9.
13McDade E, Kim A, James J, Sheu LK, Kuan DC, Minhas D, et al. Cerebral perfusion alterations and cerebral amyloid in autosomal dominant Alzheimer disease. Neurology 2014;83:710-7.
14Mattsson N, Tosun D, Insel PS, Simonson A, Jack CR Jr, Beckett LA, et al.; Alzheimer's Disease Neuroimaging Initiative. Association of brain amyloid-β with cerebral perfusion and structure in Alzheimer's disease and mild cognitive impairment. Brain 2014;137:1550-61.
15Ruitenberg A, den Heijer T, Bakker SL, van Swieten JC, Koudstaal PJ, Hofman A, et al. Cerebral hypoperfusion and clinical onset of dementia: The Rotterdam Study. Ann Neurol 2005;57:789-94.
16de la Torre JC. Critical threshold cerebral hypoperfusion causes Alzheimer's disease? Acta Neuropathol 1999;98:1-8.
17de la Torre JC. Cerebral hemodynamics and vascular risk factors: Setting the stage for Alzheimer's disease. J Alzheimers Dis 2012;32:553-67.
18de la Torre JC, Stefano GB. Evidence that Alzheimer's disease is a microvascular disorder: The role of constitutive nitric oxide. Brain Res Brain Res Rev 2000;34:119-36.
19Iliff JJ, Lee H, Yu M, Feng T, Logan J, Nedergaard M, et al. Brain-wide pathway for waste clearance captured by contrast-enhanced MRI. J Clin Invest 2013;123:1299-309.
20Iliff JJ, Nedergaard M. Is there a cerebral lymphatic system? Stroke 2013;44(Suppl 1):S93-5.
21Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med 2012;4:147ra111.
22Tarasoff-Conway JM, Carare RO, Osorio RS, Glodzik L, Butler T, Fieremans E, et al. Clearance systems in the brain-implications for Alzheimer disease. Nat Rev Neurol 2015;11:457-70.
23Wang M, Iliff JJ, Liao Y, Chen MJ, Shinseki MS, Venkataraman A, et al. Cognitive deficits and delayed neuronal loss in a mouse model of multiple microinfarcts. J Neurosci 2012;32:17948-60.
24Kress BT, Iliff JJ, Xia M, Wang M, Wei HS, Zeppenfeld D, et al. Impairment of paravascular clearance pathways in the aging brain. Ann Neurol 2014;76:845-61.
25Wardlaw JM, Allerhand M, Doubal FN, Valdes Hernandez M, Morris Z, Gow AJ, et al. Vascular risk factors, large-artery atheroma, and brain white matter hyperintensities. Neurology 2014;82:1331-8.
26Poggesi A, Pantoni L, Inzitari D, Fazekas F, Ferro J, O'Brien J, et al.; The LADIS Study Group 2001-2011: A decade of the LADIS (Leukoaraiosis And DISability) Study: What have we learned about white matter changes and small-vessel disease? Cerebrovasc Dis 2011;32:577-88.
27O'Sullivan M, Lythgoe DJ, Pereira AC, Summers PE, Jarosz JM, Williams SC, et al. Patterns of cerebral blood flow reduction in patients with ischemic leukoaraiosis. Neurology 2002;59:321-6.
28Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis: A review. Stroke 1997;28:652-9.
29Bernbaum M, Menon BK, Fick G, Smith EE, Goyal M, Frayne R, et al. Reduced blood flow in normal white matter predicts development of leukoaraiosis. J Cereb Blood Flow Metab 2015;35:1610-5.
30Promjunyakul N, Lahna D, Kaye JA, Dodge HH, Erten-Lyons D, Rooney WD, et al. Characterizing the white matter hyperintensity penumbra with cerebral blood flow measures. Neuroimage Clin 2015;8:224-9.
31Barnes JN. Exercise, cognitive function, and aging. Adv Physiol Educ 2015;39:55-62.
32Boyle CP, Raji CA, Erickson KI, Lopez OL, Becker JT, Gach HM, et al. Physical activity, body mass index, and brain atrophy in Alzheimer's disease. Neurobiol Aging 2015;36(Suppl 1):S194-202.
33Okonkwo OC, Schultz SA, Oh JM, Larson J, Edwards D, Cook D, et al. Physical activity attenuates age-related biomarker alterations in preclinical AD. Neurology 2014;83:1753-60.
34Verdelho A, Madureira S, Ferro JM, Baezner H, Blahak C, Poggesi A, et al. Physical activity prevents progression for cognitive impairment and vascular dementia: Results from the LADIS (Leukoaraiosis and Disability) study. Stroke 2012;43: 3331-5.
35Frederiksen KS, Verdelho A, Madureira S, Bäzner H, O'Brien JT, Fazekas F, et al. Physical activity in the elderly is associated with improved executive function and processing speed: The LADIS Study. Int J Geriatr Psychiatry 2015;30:744-50.
36Belsky DW, Caspi A, Israel S, Blumenthal JA, Poulton R, Moffitt TE. Cardiorespiratory fitness and cognitive function in midlife: Neuroprotection or neuroselection? Ann Neurol 2015;77:607-17.
37Centers for Disease Control and Prevention (CDC). Adult participation in aerobic and muscle-strenghening physical activites--United States, 2011. MMWR Morb Mortal Wkly Rep 2013;62:326-30.
38Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: A delay of lethal cell injury in ischemic myocardium. Circulation 1986;74:1124-36.
39Brevoord D, Kranke P, Kuijpers M, Weber N, Hollmann M, Preckel B. Remote ischemic conditioning to protect against ischemia-reperfusion injury: A systematic review and meta-analysis. PLoS One 2012;7:e42179.
40Botker HE, Kharbanda R, Schmidt MR, Bøttcher M, Kaltoft AK, Terkelsen CJ, et al. Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: A randomised trial. Lancet 2010;375:727-34.
41Hess DC, Hoda MN, Bhatia K. Remote limb perconditioning [corrected] and postconditioning: Will it translate into a promising treatment for acute stroke? Stroke 2013;44:1191-7.
42Hoda MN, Siddiqui S, Herberg S, Periyasamy-Thandavan S, Bhatia K, Hafez SS, et al. Remote ischemic perconditioning is effective alone and in combination with intravenous tissue-type plasminogen activator in murine model of embolic stroke. Stroke 2012;43:2794-9.
43Hoda MN, Bhatia K, Hafez SS, Johnson MH, Siddiqui S, Ergul A, et al. Remote ischemic perconditioning is effective after embolic stroke in ovariectomized female mice. Transl Stroke Res 2014;5:484-90.
44Hougaard KD, Hjort N, Zeidler D, Sørensen L, Nørgaard A, Hansen TM, et al. Remote ischemic perconditioning as an adjunct therapy to thrombolysis in patients with acute ischemic stroke: A randomized trial. Stroke 2014;45:159-67.
45Khan MB, Hoda MN, Vaibhav K, Giri S, Wang P, Waller JL, et al. Remote ischemic postconditioning: Harnessing endogenous protection in a murine model of vascular cognitive impairment. Transl Stroke Res 2015;6:69-77.
46Meng R, Asmaro K, Meng L, Liu Y, Ma C, Xi C, et al. Upper limb ischemic preconditioning prevents recurrent stroke in intracranial arterial stenosis. Neurology 2012;79:1853-61.
47Meng R, Ding Y, Asmaro K, Brogan D, Meng L, Sui M, et al. Ischemic conditioning is safe and effective for octo- and nonagenarians in stroke prevention and treatment. Neurotherapeutics 2015;12: 667-77.
48Domenech R, Macho P, Schwarze H, Sánchez G. Exercise induces early and late myocardial preconditioning in dogs. Cardiovasc Res 2002;55:561-6.
49Michelsen MM, Støttrup NB, Schmidt MR, Løfgren B, Jensen RV, Tropak M, et al. Exercise-induced cardioprotection is mediated by a bloodborne, transferable factor. Basic Res Cardiol 2012;107:260.
50Bink DI, Ritz K, Aronica E, van der Weerd L, Daemen MJ. Mouse models to study the effect of cardiovascular risk factors on brain structure and cognition. J Cereb Blood Flow Metab 2013;33: 1666-84.
51Shibata M, Ohtani R, Ihara M, Tomimoto H. White matter lesions and glial activation in a novel mouse model of chronic cerebral hypoperfusion. Stroke 2004;35:2598-603.
52Shibata M, Yamasaki N, Miyakawa T, Kalaria RN, Fujita Y, Ohtani R, et al. Selective impairment of working memory in a mouse model of chronic cerebral hypoperfusion. Stroke 2007;38:2826-32.
53Holland PR, Searcy JL, Salvadores N, Scullion G, Chen G, Lawson G, et al. Gliovascular disruption and cognitive deficits in a mouse model with features of small vessel disease. J Cereb Blood Flow Metab 2015;35:1005-14.
54Rohailla S, Clarizia N, Sourour M, Sourour W, Gelber N, Wei C, et al. Acute, delayed and chronic remote ischemic conditioning is associated with downregulation of mTOR and enhanced autophagy signaling. PLoS One 2014;9:e111291.
55Wei D, Ren C, Chen X, Zhao H. The chronic protective effects of limb remote preconditioning and the underlying mechanisms involved in inflammatory factors in rat stroke. PLoS One 2012;7:e30892.
56Davidson SM, Selvaraj P, He D, Boi-Doku C, Yellon RL, Vicencio JM, et al. Remote ischaemic preconditioning involves signalling through the SDF-1α/CXCR4 signalling axis. Basic Res Cardiol 2013;108:377.
57Cai ZP, Parajuli N, Zheng X, Becker L. Remote ischemic preconditioning confers late protection against myocardial ischemia-reperfusion injury in mice by upregulating interleukin-10. Basic Res Cardiol 2012;107:277.
58Li J, Rohailla S, Gelber N, Rutka J, Sabah N, Gladstone RA, et al. MicroRNA-144 is a circulating effector of remote ischemic preconditioning. Basic Res Cardiol 2014;109:423.
59Rassaf T, Totzeck M, Hendgen-Cotta UB, Shiva S, Heusch G, Kelm M. Circulating nitrite contributes to cardioprotection by remote ischemic preconditioning. Circ Res 2014;114:1601-10.
60Austin SA, d'Uscio LV, Katusic ZS. Supplementation of nitric oxide attenuates AβPP and BACE1 protein in cerebral microcirculation of eNOS-deficient mice. J Alzheimers Dis 2013;33:29-33.
61Katusic ZS, Austin SA. Endothelial nitric oxide: Protector of a healthy mind. Eur Heart J 2014;35:888-94.
62de la Torre JC, Aliev G. Inhibition of vascular nitric oxide after rat chronic brain hypoperfusion: Spatial memory and immunocytochemical changes. J Cereb Blood Flow Metab 2005;25:663-72.
63Nagababu E, Rifkind JM. Measurement of plasma nitrite by chemiluminescence. Methods Mol Biol 2010;610:41-9.
64Elrod JW, Calvert JW, Gundewar S, Bryan NS, Lefer DJ. Nitric oxide promotes distant organ protection: Evidence for an endocrine role of nitric oxide. Proc Natl Acad Sci U S A 2008;105:11430-5.
65Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature 1999;399:597-601.
66Hess DC, Hoda MN, Khan MB. Humoral mediators of remote ischemic conditioning: Important role of eNOS/NO/nitrite. Acta Neurochir Suppl 2015;121:45-8.
67Alef MJ, Vallabhaneni R, Carchman E, Morris SM Jr, Shiva S, Wang Y, et al. Nitrite-generated NO circumvents dysregulated arginine/NOS signaling to protect against intimal hyperplasia in Sprague-Dawley rats. J Clin Invest 2011;121:1646-56.
68Grubina R, Basu S, Tiso M, Kim-Shapiro DB, Gladwin MT. Nitrite reductase activity of hemoglobin S (sickle) provides insight into contributions of heme redox potential versus ligand affinity. J Biol Chem 2008;283:3628-38.
69Hendgen-Cotta UB, Merx MW, Shiva S, Schmitz J, Becher S, Klare JP, et al. Nitrite reductase activity of myoglobin regulates respiration and cellular viability in myocardial ischemia-reperfusion injury. Proc Natl Acad Sci U S A 2008;105:10256-61.
70Lundberg JO, Weitzberg E, Gladwin MT. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat Rev Drug Discov 2008;7:156-67.
71Mack AK, McGowan Ii VR, Tremonti CK, Ackah D, Barnett C, Machado RF, et al. Sodium nitrite promotes regional blood flow in patients with sickle cell disease: A phase I/II study. Br J Haematol 2008;142:971-8.
72Shiva S, Gladwin MT. Nitrite mediates cytoprotection after ischemia/reperfusion by modulating mitochondrial function. Basic Res Cardiol 2009;104:113-9.
73Shiva S, Sack MN, Greer JJ, Duranski M, Ringwood LA, Burwell L, et al. Nitrite augments tolerance to ischemia/reperfusion injury via the modulation of mitochondrial electron transfer. J Exp Med 2007;204:2089-102.
74Totzeck M, Hendgen-Cotta UB, Luedike P, Berenbrink M, Klare JP, Steinhoff HJ, et al. Nitrite regulates hypoxic vasodilation via myoglobin-dependent nitric oxide generation. Circulation 2012;126:325-34.
75Gertz K, Priller J, Kronenberg G, Fink KB, Winter B, Schröck H, et al. Physical activity improves long-term stroke outcome via endothelial nitric oxide synthase-dependent augmentation of neovascularization and cerebral blood flow. Circ Res 2006;99: 1132-40.
76Schmidt R, Berghold A, Jokinen H, Gouw AA, van der Flier WM, Barkhof F, et al. White matter lesion progression in LADIS: Frequency, clinical effects, and sample size calculations. Stroke 2012;43:2643-7.
77Benjamin P, Zeestraten E, Lambert C, Ster IC, Williams OA, Lawrence AJ, et al. Progression of MRI markers in cerebral small vessel disease: Sample size considerations for clinical trials. J Cereb Blood Flow Metab 2015. [Epub ahead of print].