Life Extension Magazine®

Pair of doctors examining brain scan for signs of Leukoaraiosis

Leukoaraiosis: A Hidden Cause Of Brain Aging

According to a study conducted at the Mayo Clinic, a surprising number of aging people suffer from a condition in which tiny areas of their brain become oxygen deprived. This vascular deficit sharply increases risk of stroke, dementia, and cognitive impairment. Healthy lifestyle choices can prevent and may help reverse it.

Scientifically reviewed by: Dr. Scott Fogle, ND, Physician, in August 2023. Written by: Clyde Eberley.

Leukoaraiosis: A Hidden Cause Of Brain Aging  

According to a study conducted at the Mayo Clinic, a surprising number of aging people suffer a condition in which tiny areas of their brain become oxygen deprived. This cerebral vascular deficit sharply increases risk of stroke, dementia, and cognitive impairment. Healthy lifestyle choices can prevent and may help reverse it.1

As imaging techniques evolve, we are able to understand more about the workings of our brain. One of the most alarming discoveries has been the existence of ominous changes found in the brains of more than 60% of people in late middle age and beyond2—changes that were once thought to be simply “age spots” on the brain, but have now taken center stage in the battle against age-related cognitive decline. 

Officially known as “leukoaraiosis,” or “white matter hyperintensities,” these tiny spots appear bright white on magnetic resonance imaging (MRI) scans. Scientists are only now coming to grips with the fact that these innocent-appearing spots carry grave implications for cognition, memory, personality, and even gait and balance changes as we age.3,4

Fortunately, as we learn more about leukoaraiosis, we’re finding clues to its causes and, therefore, intriguing hints about how we might slow its progress or even prevent it entirely, thereby preserving our cherished brain function well into advanced age.

What you need to know

  • Your brain is under attack by “unidentified bright structures,” known to physicians and scientists as leukoaraiosis.
  • Undetectable until the advent of modern imaging technology, leukoaraiosis is now closely associated with most symptoms of brain aging, including cognitive decline, gait and balance abnormalities, and dementia.
  • The cause of leukoaraiosis is not entirely clear, though it is clear that it represents disease of the brain’s tiniest blood vessels.
  • Risk factors for leukoaraiosis include hypertension, platelet dysfunction, excessive homocysteine levels, and most causes of endothelial dysfunction such as diabetes, obesity, and the metabolic syndrome.
  • There’s not a known cure for leukoaraiosis, but we have an abundance of nutraceutical weapons at hand for fighting the risk factors that seem to produce it.
  • You can protect yourself against leukoaraiosis and the brain aging it produces by getting regular exercise and choosing nutritional supplements that work against any known risk factors you might have.

What Is Leukoaraiosis?

What Is Leukoaraiosis?  

Leukoaraiosis, a small vessel disease, refers to the appearance on CT or MRI scans of damage in the white matter regions of the brain.5

Leukoaraiosis is a common finding in stroke patients. Leukoaraiosis appears to be an independent predictor of stroke outcomes. Evidence from neuroimaging indicates that some leukoaraiosis is caused by white matter infarcts, which may be particularly frequent in patients with aggressive small vessel disease.

Much of the brain’s total volume is composed of white matter, which runs like tracts of communications cables throughout the brain, connecting different regions so that they can coordinate and optimize the essential exchange of information.

Damage to white matter, then, is likely to result in impairment of brain functions that require complex interactions between regions. Such interactions include the so-called “executive functions” such as memory processing, decision-making, and priority-setting, as well as more basic functions like motor coordination, balance, and maintaining a normal gait.5,6

The damage that produces leukoaraiosis appears to result from poor blood flow through the smallest arteries and capillaries in the brain (as opposed to “large vessel disease” involving bigger arteries). Small vessel disease caused by insufficient blood flow (hypoperfusion) usually produces few specific symptoms.5

But that does not mean that leukoaraiosis is benign, as was originally thought. It represents regions of the brain that are not getting enough blood—and hence, not enough oxygen and nutrients.5,6

It was not until powerful imaging techniques such as MRI were developed that we had any way of detecting small vessel disease as it formed and progressed.4 Thanks to MRI and other advanced technology, however, we can now watch as leukoaraiosis forms, the hallmark of small vessel disease. On such scans, leukoaraiosis shows up as bright white regions (“unidentified bright objects”) scattered through white matter areas of the brain.1,5 Each region of leukoaraiosis represents real brain damage, even though it is often undetected by victims or health care providers.

And even though early and limited leukoaraiosis typically produces no specific symptoms, the more leukoaraiosis you have, the poorer your function on tests of memory, cognition, gait, and balance—reflecting the damage to those white matter communications channels.6,7 Over time, leukoaraiosis may produce slowed thinking, forgetfulness, disorientation, perseveration (inability to get off of one subject), depression, and many other problems.5

The white matter hyperintensities characteristic of leukoaraiosis have now been found in at least 40 to 50% of apparently healthy adults over age 50, and some reports estimate as high as 95%.5,6 Though several different possible explanations for the cause of leukoaraiosis exist, we still don’t know exactly what causes the lesions seen in leukoaraiosis, in part because the symptoms of the condition are so non-specific.6,8,9

What Causes Leukoaraiosis?

Like so many age-related, chronic conditions, leukoaraiosis appears to have multiple causes, but these differ somewhat from the typical risk factors for larger-vessel diseases of the kinds that cause stroke and heart attacks.6,8-10

Hypertension is a leading risk factor for leukoaraiosis, and the small vessel disease it represents.6,11,12 People who have hypertension are up to 14 times as likely to develop leukoaraiosis than those who do not.13,14 That differs from large vessel disease of the kind that typically causes overt strokes, in which atherosclerosis is the greatest risk factor.9

Research shows that having high blood pressure, particularly ongoing hypertension occurring over time, is a strong predictor of having more severe leukoaraiosis, and of its progression over time; people with the highest cumulative blood pressure across 5 visits had twice the risk of leukoaraiosis progression, compared to those with lower blood pressures.15

Reduced cerebral blood flow is increasingly being recognized as a cause of leukoaraiosis. People with leukoaraiosis were found to have just 39.7% of the volume of blood flow in affected regions of their brains compared with those having normal appearing white matter.16 And the ability of the brain’s smaller blood vessels to react to changes in blood flow is also reduced to about 53% of normal in leukoaraiosis patients.2 Some of this loss of blood flow may be related to the age-related twisting of smaller arteries, which creates increased resistance and hence lower flow.17 Finally, arterial stiffening of larger arteries, a consequence of long-term endothelial dysfunction, creates increased pulse waves in smaller arteries that feed the brain, again resulting in periods of very low blood flow.18

Homocystelne, a byproduct of protein metabolism, is known to be involved in dysfunction of the endothelium, the ultra-thin lining layer of small blood vessels and capillaries, and endothelial dysfunction in turn is related to poor blood flow in small vessels, leading to leukoaraiosis.19-23 High homocysteine levels increase the risk of developing leukoaraiosis, with changes detectable as early as middle age.24-28

Platelets are the tiny blood components responsible for forming clots; treatments aimed at keeping platelets in check have been successful at preventing large vessel diseases including strokes and heart attacks.29 But platelet characteristics also affect risk factors for developing leukoaraiosis; those with larger, “stickier” platelets have at least a 60% increase in the risk of developing the brain abnormality.30

Sleep-disordered breathing , which includes the common malady known as obstructive sleep apnea, increases your risk for high blood pressure (the more severe the breathing problem, the higher the risk of hypertension), and hence, the risk of leukoaraiosis.31 Fortunately, various non-invasive interventions, such as continuous positive airway pressure (CPAP), have been shown to correct sleep-disordered breathing and lower blood pressure, thereby probably reducing your risk for leukoaraiosis.31 Anyone with high blood pressure should, therefore, be evaluated for a sleep-related breathing disorder.

Other risk factors for leukoaraiosis are being discovered; some of the most prominent of these are diabetes (types I or II),32,33 high levels of inflammation,34 the metabolic syndrome35-38, mitochondrial dysfunction39, and smoking.40 Note that all of these factors are known contributors to endothelial dysfunction. Table 1 shows the main risk factors for the small blood vessel disease that produces leukoaraiosis as cited in a recent review.5

Table 1
Main Risk Factors For Small Vessel Disease5



Coronary artery disease

Obesity (body mass index 30 or higher)

Elevated homocysteine

Inactive lifestyle

Age over 45 in men and over 55 in women

What Are The Consequences Of Leukoaraiosis?

The white matter damage that shows up as leukoaraiosis produces no symptoms until it is relatively widespread, and even then symptoms emerge only very slowly over time, and are often confused with “just getting older.”6 But studies show that, even in non-disabled older adults, leukoaraiosis on MRI scans is significantly associated with subtle neurological changes that can be detected on a simple physical exam: gait and stance abnormalities, abnormal reflexes, and slowing of small precise movements like finger-tapping.41


And, when symptoms do arise, leukoaraiosis produces a number of concerning findings.6,42

Cognitive decline across many different kinds of function is one of the most widely recognized consequences of leukoaraiosis.6,43,44 As one would expect, based on the involvement of white matter communications channels, leukoaraiosis mainly affects executive functioning (planning, prioritizing, risk assessment, etc.), processing speed, and attention, all of which depend on rapid and accurate exchange of information throughout the brain.6

A telling study was conducted at the Mayo Clinic and published late in 2012.7 Researchers studied a group of apparently cognitively healthy elderly people with and without significant areas of leukoaraiosis, comparing specific regions of brain activation using a functional MRI scanner. Such scans “light up” in brain regions that are activated by specific tasks. The participants with leukoaraiosis had reduced brain activation in all areas associated with certain forms of decision-making.7

These changes in cognition and executive function appear to produce some very worrisome outcomes, since they occur in people who typically continue to function and operate independently in society. Leukoaraiosis has been found to be associated, for example, with the risk of being involved in serious traffic crashes. People with large or multiple areas of leukoaraiosis have a two-to-three-fold increase in having crashes, especially deadly crossroad crashes.45

Finally, leukoaraiosis has been associated with a greater risk of dementia, and even of death.6 In one study, leukoaraiosis was independently associated with a 46% increase in the risk of dying early; another study found that the risk of dying early was nearly 3-fold higher in those with severe leukoaraiosis than in those without.46,47

Gait and balance disturbances are another hallmark of leukoaraiosis, again the result of white matter damage that prevents quick and reliable communication between various brain centers.6,44 Studies show an association between the amount of leukoaraiosis and deficiencies in gait, balance, and walking speed.48,49 These disturbances more than double the risk of falling, which is itself a leading cause of disability and premature death in older people.49 People with larger areas of leukoaraiosis perform more poorly in daily activities than matched, same-aged controls with no damage to their white matter pathways.6,50

Table 2
Impact Of Severe Leukoaraiosis On Health Outcome

Impact Of Severe Leukoaraiosis On Health Outcomes47


Increased Risk Compared
With No Leukoaraiosis


2.9 times


5.1 times

Death from Pneumonia

8.3 times


6.8 times


Depression is increasingly common as people age; now there is solid evidence to suggest that growing areas of leukoaraiosis may be involved.6,44 Studies show that people with more progression of leukoaraiosis over a 3-year period have higher rates of depression than those with slower or no progression.51,52

Stroke risk is clearly affected by the presence of leukoaraiosis, at least for certain stroke types, particularly those that also affect smaller brain blood vessels in white matter areas of the brain.53-56 In people who have had a “minor” warning, such as a transient ischemic attack (TIA) or a non-disabling stroke, the presence of leukoaraiosis significantly increases their chances of having a stroke—one study found that 37% of people with widespread leukoaraiosis had a stroke within 3 years, compared with just 20% of those without leukoaraiosis.57 Another study found the risk of stroke to increase nearly five-fold for people with higher-level leukoaraiosis, compared with those having low-grade leukoaraiosis.58

Leukoaraiosis is also associated with an increased risk of a type of “silent stroke” called cerebral microbleeds by more than five-fold in patients with a prior stroke history.59 And in people who have just had a serious stroke and have been treated with modern “clot busting” drugs, having leukoaraiosis raised the risk of having dangerous bleeding into the brain (intra cerebral hemorrhage) by nearly three-fold, and doubled the risk of any bad outcome within 90 days of the treatment.11,60

Other consequences of leukoaraiosis are rapidly becoming evident, as shown in Table 2, driving home the point that we all need to do everything we can to prevent this insidious form of brain damage.

How Can I Prevent Leukoaraiosis?

Currently there is no reliable treatment for leukoaraiosis, partly because its fundamental causes remain unknown.5,6 But our knowledge of its risk factors can be used to our advantage in preventing leukoaraiosis, and at the very least in slowing its progression.

Not surprisingly, lifestyle and dietary interventions have proven the most effective approaches, especially those that help lower blood pressure, lower blood sugar, reduce obesity, and contribute to improvement in endothelial function.

A few specific interventions have already been shown to directly address leukoaraiosis and its related cognitive deficits:

Physical activity reduces leukoaraiosis-related limitations in mobility.48 In one study of people with leukoaraiosis, greater physical activity was associated with a 36% reduction in the risk of cognitive impairment, a 39% reduction in risk of dementia, and a 58% reduction in risk of vascular dementia.61

Homocysteine-lowering therapy using B vitamins has been shown to improve executive function, which is so strongly affected by leukoaraiosis.62

Correcting platelet function, specifically, the tendency of platelets to be too “sticky,” slows the progression of leukoaraiosis.63

Table 3 provides a partial listing of some nutraceutical supplements that can be helpful in reducing risk factors, thereby potentially slowing the progression of leukoaraiosis. Those with blood pressure readings above 115/75 that do not respond to nutraceuticals may consider pharmaceutical intervention, though those with severe leukoaraiosis sometimes require higher blood pressure to squeeze blood into deformed cerebral arterial and capillary beds.

Table 3
Nutraceuticals To Prevent Leukoaraiosis

Nutraceuticals To Prevent Leukoaraiosis

Risk Factor

Suggested Nutraceuticals


Aged garlic extract




Decreased Brain Blood Flow65-71


(Gastrodia orchid extract)


Homocysteine Elevation72-75

B vitamins


N-acetylcysteine (NAC)

Endothelial Dysfunction76-82


Lipoic acid



Metabolic Syndrome83-87



Green tea extract

Omega-3 fatty acids



Mitochondrial Dysfunction88-94


Lipoic acid



Platelet Dysfunction81,95-99


Omega-3 fatty acids (fish oil)





Unidentified bright objects, formally known as leukoaraiosis, or white matter hyperintensities, are early warning signs of ongoing chronic brain damage.5 It’s almost like having a stroke in ultra-slow motion.

No one even knew of the existence of leukoaraiosis until modern scanning technology detected it. Now we recognize that leukoaraiosis is both widespread and dangerous, signaling the presence of insidious disease in the brain’s smallest blood vessels. Small vessel disease deprives local areas of the brain of sufficient blood supply to carry out normal activities, and eventually leads to formation of leukoaraiosis that can be seen on scans.

The causes of leukoaraiosis are not entirely understood, but evidence points to hypertension, endothelial dysfunction, platelet aggregation problems, and homocysteine elevations as major risk factors. And the consequences of leukoaraiosis are increasingly apparent: the larger the volume of brain involved in leukoaraiosis, the worse a person’s cognitive function is—even before they become aware of it.

Leukoaraiosis also increases risk for stroke, cognitive decline, and dementia, while interfering with normal gait and balance, eventually leading to greater risks of falling. Indeed, leukoaraiosis seems to correlate with most of the changes we’ve always associated with brain aging—except that it appears to be preventable and even reversible. Perhaps that’s the message those “unidentified bright objects” are trying to send us.

Life Extension members should find comfort that their nutrients and healthy lifestyle choices confer significant protection against leukoaraiosis.

If you have any questions on the scientific content of this article, please call a Life Extension® Health Advisor at 1-866-864-3027.


  1. Available at: Accessed January 10, 2014.
  2. Sheline YI, Price JL, Vaishnavi SN, et al. Regional white matter hyperintensity burden in automated segmentation distinguishes late-life depressed subjects from comparison subjects matched for vascular risk factors. Am J Psychiatry. 2008 Apr;165(4):524-32.
  3. Helenius J, Tatlisumak T. Treatment of leukoaraiosis: a futuristic view. Curr Drug Targets. 2007 Jul;8(7):839-45.
  4. Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ. 2010;341:c3666.
  5. Schenk C, Wuerz T, Lerner AJ. Small vessel disease and memory loss: what the clinician needs to know to preserve patients’ brain health. Curr Cardiol Rep. 2013 Dec;15(12):427.
  6. Grueter BE, Schulz UG. Age-related cerebral white matter disease (leukoaraiosis): a review. Postgrad Med J. 2012 Feb;88(1036):79-87.
  7. Welker KM, De Jesus RO, Watson RE, Machulda MM, Jack CR. Altered functional MR imaging language activation in elderly individuals with cerebral leukoaraiosis. Radiology. 2012 Oct;265(1):222-32.
  8. Khan U, Porteous L, Hassan A, Markus HS. Risk factor profile of cerebral small vessel disease and its subtypes. J Neurol Neurosurg Psychiatry. 2007 Jul;78(7):702-6.
  9. Pantoni L, Garcia JH. Pathogenesis of leukoaraiosis: a review. Stroke. 1997 Mar;28(3):652-9.
  10. Criqui MH, Browner D, Fronek A, et al. Peripheral arterial disease in large vessels is epidemiologically distinct from small vessel disease. An analysis of risk factors. Am J Epidemiol. 1989 Jun;129(6):1110-9.
  11. Choi JH, Bae HJ, Cha JK. Leukoaraiosis on magnetic resonance imaging is related to long-term poor functional outcome after thrombolysis in acute ischemic stroke. J Korean Neurosurg Soc. 2011 Aug;50(2):75-80.
  12. Schwartz GL, Bailey KR, Mosley T, et al. Association of ambulatory blood pressure with ischemic brain injury. Hypertension. 2007 Jun;49(6):1228-34.
  13. Thein SS, Hamidon BB, Teh HS, Raymond AA. Leukoaraiosis as a predictor for mortality and morbidity after an acute ischaemic stroke. Singapore Med J. 2007 May;48(5):396-9.
  14. Li H, Xu G, Xiong Y, et al. Relationship between Cerebral Atherosclerosis and Leukoaraiosis in Aged Patients: Results from DSA. J Neuroimaging. 2013 Sep 3.
  15. Gottesman RF, Coresh J, Catellier DJ, et al. Blood pressure and white-matter disease progression in a biethnic cohort: Atherosclerosis Risk in Communities (ARIC) study. Stroke. 2010 Jan;41(1):3-8.
  16. Uh J, Yezhuvath U, Cheng Y, Lu H. In vivo vascular hallmarksof diffuse leukoaraiosis. J Magn Reson Imaging. 2010 Jul;32(1):184-90.
  17. Brown WR, Thore CR. Review: cerebral microvascular pathology in ageing and neurodegeneration. Neuropathol Appl Neurobiol. 2011 Feb;37(1):56-74.
  18. Webb AJ, Simoni M, Mazzucco S, Kuker W, Schulz U, Rothwell PM. Increased cerebral arterial pulsatility in patients with leukoaraiosis: arterial stiffness enhances transmission of aortic pulsatility. Stroke. 2012 Oct;43(10):2631-6.
  19. Calabro RS, Gervasi G, Baglieri A, Furnari A, Marino S, Bramanti P. Is high oral dose L-arginine intake effective in leukoaraiosis? Preliminary data, study protocol and expert’s opinion. Curr Aging Sci. 2013 Jul;6(2):170-7.
  20. Hogervorst E, Ribeiro HM, Molyneux A, Budge M, Smith AD. Plasma homocysteine levels, cerebrovascular risk factors, and cerebral white matter changes (leukoaraiosis) in patients with Alzheimer disease. Arch Neurol. 2002 May;59(5):787-93.
  21. Deplanque D, Lavallee PC, Labreuche J, et al. Cerebral and extracerebral vasoreactivity in symptomatic lacunar stroke patients: a case-control study. Int J Stroke. 2013 Aug;8(6):413-21.
  22. Giwa MO, Williams J, Elderfield K, et al. Neuropathologic evidence of endothelial changes in cerebral small vessel disease. Neurology. 2012 Jan 17;78(3):167-74.
  23. Szolnoki Z. Genetic variant-associated endothelial dysfunction behind small-vessel cerebral circulatory disorders: a new pathomechanism behind common cerebral phenotypes. Mini Rev Med Chem. 2007 May;7(5):527-30.
  24. Khan U, Crossley C, Kalra L, et al. Homocysteine and its relationship to stroke subtypes in a UK black population: the south London ethnicity and stroke study. Stroke. 2008 Nov;39(11):2943-9.
  25. Hassan A, Hunt BJ, O’Sullivan M, et al. Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction. Brain. 2004 Jan;127(Pt 1):212-9.
  26. Censori B, Partziguian T, Manara O, Poloni M. Plasma homocysteine and severe white matter disease. Neurol Sci. 2007 Oct;28(5):259-63.
  27. Sachdev P, Parslow R, Salonikas C, et al. Homocysteine and the brain in midadult life: evidence for an increased risk of leukoaraiosis in men. Arch Neurol. 2004 Sep;61(9):1369-76.
  28. Naka H, Nomura E, Takahashi T, et al. Plasma total homocysteine levels are associated with advanced leukoaraiosis but not with asymptomatic microbleeds on T2*-weighted MRI in patients with stroke. Eur J Neurol. 2006 Mar;13(3):261-5.
  29. Harrington RA, Hodgson PK, Larsen RL. Cardiology patient page. Antiplatelet therapy. Circulation. 2003 Aug 19;108(7):e45-7.
  30. Kang SJ, Park BJ, Shim JY, Lee HR, Hong JM, Lee YJ. Mean platelet volume (MPV) is associated with leukoaraiosis in the apparently healthy elderly. Arch Gerontol Geriatr. 2012 Mar-Apr;54(2):e118-21.
  31. Culebras A. Cerebrovascular disease and sleep. Curr Neurol Neurosci Rep. 2004 Mar;4(2):164-9.
  32. Park JH, Ryoo S, Kim SJ, et al. Differential risk factors for lacunar stroke depending on the MRI (white and red) subtypes of microangiopathy. PLoS One. 2012;7(9):e44865.
  33. Putaala J, Kurkinen M, Tarvos V, Salonen O, Kaste M, Tatlisumak T. Silent brain infarcts and leukoaraiosis in young adults with first-ever ischemic stroke. Neurology. 2009 May 26;72(21):1823-9.
  34. Wright CB, Moon Y, Paik MC, et al. Inflammatory biomarkers of vascular risk as correlates of leukoariosis. Stroke. 2009 Nov;40(11):3466-71.
  35. Zeevi N, Pachter J, McCullough LD, Wolfson L, Kuchel GA. The blood-brain barrier: geriatric relevance of a critical brain-body interface. J Am Geriatr Soc. 2010 Sep;58(9):1749-57.
  36. Bokura H, Yamaguchi S, Iijima K, Nagai A, Oguro H. Metabolic syndrome is associated with silent ischemic brain lesions. Stroke. 2008 May;39(5):1607-9.
  37. Park K, Yasuda N, Toyonaga S, et al. Significant association between leukoaraiosis and metabolic syndrome in healthy subjects. Neurology. 2007 Sep 4;69(10):974-8.
  38. Seo SK, Jung I, Lee SM, et al. Relationship between leukoaraiosis and menopause in healthy middle-aged women. Fertil Steril. 2013 Aug;100(2):500-4.
  39. Szolnoki Z. Pathomechanism of leukoaraiosis: a molecular bridge between the genetic, biochemical, and clinical processes (a mitochondrial hypothesis). Neuromolecular Med. 2007;9(1):21-33.
  40. Pu Y, Liu L, Zou X, et al. Relationship between leukoaraiosis and cerebral large artery stenosis. Neurol Res. 2009 May;31(4):376-80.
  41. Poggesi A, Gouw A, van der Flier W, et al. Cerebral white matter changes are associated with abnormalities on neurological examination in non-disabled elderly: the LADIS study. J Neurol. 2013 Apr;260(4):1014-21.
  42. Miki Y, Sakamoto S. Age-related white matter lesions (leukoaraiosis): an update. Brain Nerve. 2013 Jul;65(7):789-99.
  43. Macfarlane MD, Looi JC, Walterfang M, et al. Executive dysfunction correlates with caudate nucleus atrophy in patients with white matter changes on MRI: a subset of LADIS. Psychiatry Res. 2013 Oct 30;214(1):16-23.
  44. Schmidt R, Berghold A, Jokinen H, et al. White matter lesion progression in LADIS: frequency, clinical effects, and sample size calculations. Stroke. 2012 Oct;43(10):2643-7.
  45. Park K, Nakagawa Y, Kumagai Y, Nagahara M. Leukoaraiosis, a common brain magnetic resonance imaging finding, as a predictor of traffic crashes. PLoS One. 2013;8(2):e57255.
  46. Simoni M, Li L, Paul NL, et al. Age- and sex-specific rates of leukoaraiosis in TIA and stroke patients: population-based study. Neurology. 2012 Sep 18;79(12):1215-22.
  47. Briley DP, Haroon S, Sergent SM, Thomas S. Does leukoaraiosis predict morbidity and mortality? Neurology. 2000 Jan 11;54(1):90-4.
  48. Baezner H, Blahak C, Poggesi A, et al. Association of gait and balance disorders with age-related white matter changes: the LADIS study. Neurology. 2008 Mar 18;70(12):935-42.
  49. Srikanth V, Beare R, Blizzard L, et al. Cerebral white matter lesions, gait, and the risk of incident falls: a prospective population-based study. Stroke. 2009 Jan;40(1):175-80.
  50. Berger K, Roesler A, Kretzschmar K. The association between white matter lesions, stroke and activities of daily living--the MEMO study on the KORA platform Augsburg. Gesundheitswesen. 2005 Aug;67 Suppl 1:S172-5.
  51. Teodorczuk A, Firbank MJ, Pantoni L, et al. Relationship between baseline white-matter changes and development of late-life depressive symptoms: 3-year results from the LADIS study. Psychol Med. 2010 Apr;40(4):603-10.
  52. Firbank MJ, Teodorczuk A, van der Flier WM, et al. Relationship between progression of brain white matter changes and late-life depression: 3-year results from the LADIS study. Br J Psychiatry. 2012 Jul;201(1):40-5.
  53. Arsava EM, Bayrlee A, Vangel M, et al. Severity of leukoaraiosis determines clinical phenotype after brain infarction. Neurology. 2011 Jul 5;77(1):55-61.
  54. Inzitari D. Leukoaraiosis: an independent risk factor for stroke? Stroke. 2003 Aug;34(8):2067-71.
  55. Jeerakathil T, Wolf PA, Beiser A, et al. Stroke risk profile predicts white matter hyperintensity volume: the Framingham Study. Stroke. 2004 Aug;35(8):1857-61.
  56. Fu JH, Lu CZ, Hong Z, Dong Q, Luo Y, Wong KS. Extent of white matter lesions is related to acute subcortical infarcts and predicts further stroke risk in patients with first ever ischaemic stroke. J Neurol Neurosurg Psychiatry. 2005 Jun;76(6):793-6.
  57. Streifler JY, Eliasziw M, Benavente OR, et al. Prognostic importance of leukoaraiosis in patients with symptomatic internal carotid artery stenosis. Stroke. 2002 Jun;33(6):1651-5.
  58. Kuller LH, Longstreth WT, Jr., Arnold AM, Bernick C, Bryan RN, Beauchamp NJ, Jr. White matter hyperintensity on cranial magnetic resonance imaging: a predictor of stroke. Stroke. 2004 Aug;35(8):1821-5.
  59. Naka H, Nomura E, Wakabayashi S, et al. Frequency of asymptomatic microbleeds on T2*-weighted MR images of patients with recurrent stroke: association with combination of stroke subtypes and leukoaraiosis. AJNR Am J Neuroradiol. 2004 May;25(5):714-9.
  60. Neumann-Haefelin T, Hoelig S, Berkefeld J, et al. Leukoaraiosis is a risk factor for symptomatic intracerebral hemorrhage after thrombolysis for acute stroke. Stroke. 2006 Oct;37(10):2463-6.
  61. Verdelho A, Madureira S, Ferro JM, et al. Physical activity prevents progression for cognitive impairment and vascular dementia: results from the LADIS (Leukoaraiosis and Disability) study. Stroke. 2012 Dec;43(12):3331-5.
  62. Boxer AL, Kramer JH, Johnston K, Goldman J, Finley R, Miller BL. Executive dysfunction in hyperhomocystinemia responds to homocysteine-lowering treatment. Neurology. 2005 Apr 26;64(8):1431-4.
  63. Fujita S, Kawaguchi T, Uehara T, Fukushima K. Progress of leukoaraiosis is inhibited by correction of platelet hyper-aggregability. Int Psychogeriatr. 2005 Dec;17(4):689-98.
  64. Cicero AF, Borghi C. Evidence of clinically relevant efficacy for dietary supplements and nutraceuticals. Curr Hypertens Rep. 2013 Jun;15(3):260-7.
  65. Bagoly E, Feher G, Szapary L. The role of vinpocetine in the treatment of cerebrovascular diseases based in human studies. Orv Hetil. 2007 Jul 22;148(29):1353-8.
  66. Diamond BJ, Bailey MR. Ginkgo biloba: indications, mechanisms, and safety. Psychiatr Clin North Am. 2013 Mar;36(1):73-83.
  67. Mashayekh A, Pham DL, Yousem DM, Dizon M, Barker PB, Lin DD. Effects of Ginkgo biloba on cerebral blood flow assessed by quantitative MR perfusion imaging: a pilot study. Neuroradiology. 2011 Mar;53(3):185-91.
  68. Patyar S, Prakash A, Modi M, Medhi B. Role of vinpocetine in cerebrovascular diseases. Pharmacol Rep. 2011;63(3):618-28.
  69. Valikovics A. Investigation of the effect of vinpocetine on cerebral blood flow and cognitive functions. Ideggyogy Sz. 2007 Jul 30;60(7-8):301-10.
  70. Zhang SJ, Xue ZY. Effect of Western medicine therapy assisted by Ginkgo biloba tablet on vascular cognitive impairment of none dementia. Asian Pac J Trop Med. 2012 Aug;5(8):661-4.
  71. Wei J-j, Zhou Y-l. Treatment of posterior circulation ischemia with gastrodin and betahistine. Practical Clinical Medicine. 2012;13(4).
  72. Baek JH, Bernstein EE, Nierenberg AA. One-carbon metabolism and bipolar disorder. Aust N Z J Psychiatry. 2013 Nov;47(11):1013-8.
  73. Cacciapuoti F. Lowering homocysteine levels may prevent cardiovascular impairments? Possible therapeutic behaviors. Blood Coagul Fibrinolysis. 2012 Dec;23(8):677-9.
  74. Hankey GJ, Ford AH, Yi Q, et al. Effect of B vitamins and lowering homocysteine on cognitive impairment in patients with previous stroke or transient ischemic attack: a prespecified secondary analysis of a randomized, placebo-controlled trial and meta-analysis. Stroke. 2013 Aug;44(8):2232-9.
  75. Ji Y, Tan S, Xu Y, et al. Vitamin B supplementation, homocysteine levels, and the risk of cerebrovascular disease: A meta-analysis. Neurology. 2013 Oct 8;81(15):1298-307.
  76. Davinelli S, Sapere N, Visentin M, Zella D, Scapagnini G. Enhancement of mitochondrial biogenesis with polyphenols: combined effects of resveratrol and equol in human endothelial cells. Immun Ageing. 2013;10(1):28.
  77. de la Rosa AP, Montoya AB, Martinez-Cuevas P, et al. Tryptic amaranth glutelin digests induce endothelial nitric oxide production through inhibition of ACE: antihypertensive role of amaranth peptides. Nitric Oxide. 2010 Sep 15;23(2):106-11.
  78. Heinisch BB, Francesconi M, Mittermayer F, et al. Alpha-lipoic acid improves vascular endothelial function in patients with type 2 diabetes: a placebo-controlled randomized trial. Eur J Clin Invest. 2010 Feb;40(2):148-54.
  79. Tome-Carneiro J, Larrosa M, Gonzalez-Sarrias A, Tomas-Barberan FA, Garcia-Conesa MT, Espin JC. Resveratrol and clinical trials: the crossroad from in vitro studies to human evidence. Curr Pharm Des. 2013;19(34):6064-93.
  80. Trombetta D, Cimino F, Cristani M, et al. In vitro protective effects of two extracts from bergamot peels on human endothelial cells exposed to tumor necrosis factor-alpha (TNF-alpha). J Agric Food Chem. 2010 Jul 28;58(14):8430-6.
  81. Voloshyna I, Hussaini SM, Reiss AB. Resveratrol in cholesterol metabolism and atherosclerosis. J Med Food. 2012 Sep;15(9):763-73.
  82. Wongpradabchai S, Chularojmontri L, Phornchirasilp S, Wattanapitayakul SK. Protective effect of Phyllanthus emblica fruit extract against hydrogen peroxide-induced endothelial cell death. J Med Assoc Thai. 2013 Jan;96 Suppl 1:S40-8.
  83. Cicero AF, Tartagni E, Ertek S. Nutraceuticals for metabolic syndrome management: From laboratory to benchside. Curr Vasc Pharmacol. 2013 Apr 25.
  84. Huang HY, Korivi M, Tsai CH, Yang JH, Tsai YC. Supplementation of Lactobacillus plantarum K68 and fruit-vegetable ferment along with high fat-fructose diet attenuates metabolic syndrome in rats with insulin resistance. Evid Based Complement Alternat Med. 2013;2013:943020.
  85. Jung MH, Seong PN, Kim MH, Myong NH, Chang MJ. Effect of green tea extract microencapsulation on hypertriglyceridemia and cardiovascular tissues in high fructose-fed rats. Nutr Res Pract. 2013 Oct;7(5):366-72.
  86. Kaur G, C M. Amelioration of obesity, glucose intolerance, and oxidative stress in high-fat diet and low-dose streptozotocin-induced diabetic rats by combination consisting of “curcumin with piperine and quercetin”. ISRN Pharmacol. 2012;2012:957283.
  87. Villalba JM, de Cabo R, Alcain FJ. A patent review of sirtuin activators: an update. Expert Opin Ther Pat. 2012 Apr;22(4):355-67.
  88. Arivazhagan P, Ramanathan K, Panneerselvam C. Effect of DL-alpha-lipoic acid on mitochondrial enzymes in aged rats. Chem Biol Interact. 2001 Nov 28;138(2):189-98.
  89. Bauerly K, Harris C, Chowanadisai W, et al. Altering pyrroloquinoline quinone nutritional status modulates mitochondrial, lipid, and energy metabolism in rats. PLoS One. 2011;6(7):e21779.
  90. Binukumar BK, Gupta N, Sunkaria A, et al. Protective efficacy of coenzyme Q10 against DDVP-induced cognitive impairments and neurodegeneration in rats. Neurotox Res. 2012 May;21(4):345-57.
  91. Chowanadisai W, Bauerly KA, Tchaparian E, Wong A, Cortopassi GA, Rucker RB. Pyrroloquinoline quinone stimulates mitochondrial biogenesis through cAMP response element-binding protein phosphorylation and increased PGC-1alpha expression. J Biol Chem. 2010 Jan 1;285(1):142-52.
  92. Gomez LA, Heath SH, Hagen TM. Acetyl-L-carnitine supplementation reverses the age-related decline in carnitine palmitoyltransferase 1 (CPT1) activity in interfibrillar mitochondria without changing the L-carnitine content in the rat heart. Mech Ageing Dev. 2012 Feb-Mar;133(2-3):99-106.
  93. Jun DW, Cho WK, Jun JH, et al. Prevention of free fatty acid-induced hepatic lipotoxicity by carnitine via reversal of mitochondrial dysfunction. Liver Int. 2011 Oct;31(9):1315-24.
  94. Valdecantos MP, Perez-Matute P, Gonzalez-Muniesa P, Prieto-Hontoria PL, Moreno-Aliaga MJ, Martinez JA. Lipoic acid administration prevents nonalcoholic steatosis linked to long-term high-fat feeding by modulating mitochondrial function. J Nutr Biochem. 2012 Dec;23(12):1676-84.
  95. Phang M, Lincz LF, Garg ML. Eicosapentaenoic and docosahexaenoic acid supplementations reduce platelet aggregation and hemostatic markers differentially in men and women. J Nutr. 2013 Apr;143(4):457-63.
  96. Ramprasath VR, Jones PJ. Anti-atherogenic effects of resveratrol. Eur J Clin Nutr. 2010 Jul;64(7):660-8.
  97. Yang Y, Shi Z, Reheman A, et al. Plant food delphinidin-3-glucoside significantly inhibits platelet activation and thrombosis: novel protective roles against cardiovascular diseases. PLoS One. 2012;7(5):e37323.
  98. Lauver DA, Driscoll EM, Lucchesi BR. Disodium disuccinate astaxanthin prevents carotid artery rethrombosis and ex vivo platelet activation. Pharmacology. 2008;82(1):67-73.
  99. Schrör K. Aspirin and platelets: the antiplatelet action of aspirin and its role in thrombosis treatment and prophylaxis. Semin Thromb Hemost. 1997;23(4):349-56.