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Reverse Mild Cognitive Impairment

March 2015

By Eric Braverman, MD, and Bruce Scali

Eventually, it happens to almost everyone. You enter a room and can’t remember why. You misplace your keys, fumble for a word, or can’t put a name to a familiar face. You might even experience a noticeable, albeit very slight, delay between deciding to do something and doing it—when changing lanes on a highway, for example. Any of these could be explained away by the fast pace and high stress of the lives we lead.

Or they could be the first signs of a medical condition fraught with complications known as mild cognitive impairment.

A major consequence of the intensive focus on Alzheimer’s disease has been the identification of its early stage, otherwise known as mild cognitive impairment (MCI).

Experts are increasingly viewing MCI as the “gray area” between normal cognitive decline attributed to aging and the onset of dementia.1 Interest in classifying, predicting, diagnosing, and treating MCI has been building since the turn of the century, and is heating up as alarming statistics are being published and confirmed. Estimates on the prevalence of mild cognitive impairment worldwide are as high as 29% with an annual risk of progression to dementia in affected individuals as high as 15%, compared to 2.5% in cognitively healthy adults.2

The progression from MCI to full-blown Alzheimer’s and other forms of dementia is a steady, but slow process that may extend over decades.3 The good news is that total loss of cognitive faculties isn’t a certainty for all of those who have MCI; the bad news is that, on average, approximately 34% will end up that way.4 The worst news of all applies to those who are diagnosed with MCI at 70 years of age or older: These individuals have a 126% increased risk of dying compared to those without MCI.5

Why does all of this matter? Because a lot of people have MCI or will experience it down the road; because the vast majority of us will have to watch or care for someone who loses any semblance of quality of life, and because everyone will have to bear the societal cost of dementia. Dementia has been growing steadily for years, and the 2010 figure for dementia was pegged between $157 and $215 billion.6 Whatever the number is today, it’s about to explode because the Baby Boomers are entering their sunset years.

Sooner or later, one way or another, MCI will likely come your way. No worries, however. There are some things you can do about MCI now—such as determine if you have it, discover why you have it, and decide what you will do about it.

What you kneed to know
Recognize And Reverse MCI

Recognize And Reverse MCI

  • Sooner or later, it’s bound to happen—you misplace your car keys or forget why you entered the room. It may simply be stress, or it could be the first signs of mild cognitive impairment, or MCI.
  • There are 12 domains of MCI—ranging from delayed recall to a drifting mind to unclear communication—and recognition of symptoms is key.
  • There are a variety of neuropsychometric tests that will provide your physician with a wealth of information that can help determine the nature and severity of MCI.
  • If diagnosed at an early stage, MCI can be treated with lifestyle and dietary changes, as well as numerous natural supplements.
  • Medical intervention from doctors with extensive experience with hormone therapy may be necessary to treat advanced stages of MCI.

Got MCI?

The first course of action item is differentiating between the harmless “senior moments” that can be laughed off and something much more serious that demands attention. Table 1 presents the 12 domains of MCI—the ways in which the brain misfires—and a simple Yes/No self-assessment. If you check “Yes” fewer than three times, MCI probably isn’t an issue for you right now. (But saving the quiz and repeating it annually is a good idea.) Three or more checks in the “Yes” column doesn’t mean you should hit the panic button, but it does mean you should enlist the help of medical professionals to investigate your cognitive status further.

Neurologists, neuropsychologists, neuropsychiatrists, gerontologists, and some primary care physicians qualify cognitive issues using the noninvasive neuropsychometric assessments named in Table 2, which are administered via booklets or digital screens. Your history and symptoms determine which ones are appropriate in your case.

Neuropsychometric assessments provide a wealth of information about the nature and severity of MCI. If the condition is at the earliest stages, it can be treated with lifestyle and dietary changes, plus natural supplements. In advanced cases of MCI, those that have progressed to intermediary stages or have butted up against the boundary of dementia, doctors will want to know more about its nature, so more powerful interventions can be prescribed.

That’s where the 3.0 Tesla MRI (3T MRI) scanner, a diagnostic tool, comes in.

The 3.0 Tesla MRI has two times the field strength of the 1.5T scanner, and 10 to 15 times the field strength of low field or open MRI scanners that are used in hospitals and medical offices.7 The 3.0 Tesla MRI produces high-resolution images.8 That means doctors get more detailed and much clearer pictures of brain anatomy and vascular status. (The pictures are so good in the latter case, they often eliminate the need for more invasive, and therefore more risky, catheter insertions.)

Mild cognitive impairment means your brain is short-circuiting. Electrical messages aren’t getting through fast enough, or at all. For a treatment plan to be effective, the cause of MCI must be explored.

Table 1: MCI Symptom Assessment
MCI Symptom Assessment

Symptom

Yes

No

1. ATTENTION

Do you often miss stop signs or jump the gun? Does your mind drift all of a sudden during tasks or conversations?

2. REACTION TIME

Do you respond slowly to thoughts or directions, or alternate between fast and slow responses?

3. JUDGMENT

Are your decisions less than satisfactory recently? Are you often confused about what you should do?

4. LEARNING ABILITY

Do you have unusual difficulty understanding concepts, instructions, or directions?

5. DELAYED RECALL

Do you struggle with words or facts that are “on the tip of your tongue” more than usual? Do you hesitate when asked to repeat something you just learned?

6. LINGUISTIC FUNCTION

Is your verbal communication becoming unclear to others?

7. VERBAL IQ

Do you have difficulty with language-based problems, coming up with
analogies, or comparing different words?

Symptom

Yes

No

8. VISUAL IQ

Have you noticed a change in any of these abilities: following maps, understanding diagrams, putting picture or board puzzles together, or building a structure out of blocks?

9. ABSTRACT IQ

Is problem solving using theories, complex analogies, and metaphors more difficult than it used to be? Is it harder now to form ideas about the nature of objects,
concepts, and processes?

10. PROCESSING SPEED

Is it taking longer for you to think things through or to learn something new?

11. IMMEDIATE MEMORY

Do you stumble or draw a blank
reciting the details of a recent event or when asked to repeat a short list of items?

12. GENERAL COGNITIVE
FUNCTIONING

Do you have unusual difficulty assembling the “big picture” using multiple facts and observations?

Why MCI?

A 3T MRI reveals four conditions that result in a diagnosis of MCI:

  1. Atrophy, or shrinkage, resulting from the loss of cells in the brain,9,10
  2. Demyelination, the loss of the sheathing that surrounds neurons, which protects them as insulation does copper wiring. Myelination, or the development of the sheath around neurons, continues until age 30; thereafter, demyelination, or deterioration of the sheathing occurs,11
  3. Ischemia, the restriction of blood flow,12 and
  4. Calcification, the hardening of tissue resulting from calcium deposits.13

The PATH Foundation NY, with support from the Life Extension Foundation®, conducted a review of 3T MRIs administered to 116 PATH Medical patients, aged 30 to 80, whose domain assessments pointed toward cognitive impairment. Its findings are summarized in Table 3.

In addition to the definitive anatomical explanations for MCI, several contributing factors have been associated with cognitive decline. Aging alone is sufficient cause, which likely doesn’t come as a surprise to anyone. Without direct interventions, there’s no getting around that we burn up, swell up, dry up, and turn to stone—in the brain and everywhere else.

A family history of Alzheimer’s14 or the presence of the ApoE4 gene15,16 that has been linked to it, concussions and other trauma, and drug abuse all play a role in MCI, as do numerous health issues.17-20

Research is also linking vitamin deficiencies with MCI, which will be discussed in Table 4.21,22

No matter which path MCI has taken to your door, there are approaches that can halt it in its tracks, and even turn it around.

Table 2: Neuropsychometric Tests to Detect Mild Cognitive Impairment
Neuropsychometric Tests to Detect Mild Cognitive Impairment

MCI
Symptoms

Assessment(s)

1

Tests of Variables of Attention (TOVA)

2

Central Nervous System Vital Signs (CNSVS), TOVA

3

CNSVS, TOVA

4

Wechsler Memory Scale (WMS), CNSVS, Wechsler Adult
Memory Scale (WAIS)

5

WMS, CNSVS

6

Mini-Mental State Examination (MMSE)

7

WAIS

8

Wechsler Memory Scale II (WMS II)

9

General Ability Measure For Adults (GAMA)

10

CNSVS, P300—Brainwave that reveals brain speed and brain voltage (power)

11

WMS, MMSE, RANDT (Memory test designed by CT Randt, MD, and ER Brown, PhD)

12

CNSVS

What You Can Do About MCI

The prevention and treatment of MCI is a multipronged approach that includes behavior modification, aggressive management of medical conditions, and, when cognitive loss is in its advanced stages, enlisting the support of doctors who are up to speed.

Change Your Life, Change Your Mind

If there is one characteristic of health and wellness (or the lack thereof) that is universal, it’s lifestyle. The choices we make every day about what we eat, whether we exercise, and how we support our brains and bodies have a direct bearing on how long we live and on our quality of life.

The best way to handle any health complaint, including MCI, is to avoid it in the first place. A diet rich in foods that represent every color of the rainbow, regular exercise, and nutritional supplements are the first line of defense that can forestall breakdowns. Healthy living can also reduce the severity of medical issues, and it can be instrumental in reversing them too.

Table 3: PATH Foundation 3T MRI Study
PATH Foundation 3T MRI Study

Conditions
Contributing
to MCI

Number of Patients Affected (n=116)

Percentage of Patients Affected

Calcification

1

0.8

Small Vessel
Ischemia

55

47

Demyelination

47

40

Empty Sella

(Pituitary Gland Atrophy)

11

9.5

Hippocampal
Atrophy

30

26

Temporal Atrophy

56

48

Central Atrophy

58

50

Bilateral Atrophy

5

4.3


Diet

Research on the impact of diet on neurogenesis, or the formation of new brain cells, is one breakthrough that will allow treatment and reversal of MCI. Neurogenesis in the hippocampus, a small seahorse-shaped structure in the middle of the brain that plays a crucial role in memory, is the most studied in this regard.

It probably also comes as no surprise that fish is brain food.38 Specifically, fin fish, such as salmon, sardines, and mackerel that are chockfull of omega-3 fatty acids.39 Other excellent food sources of fatty acids are walnuts,40 pecans,41 Brazil nuts,42 and sunflower seeds.43

Nature is also an abundant supplier of flavonoids, which have been shown to effectively support brain function.44 You can find flavonoids in berries, especially dark ones, fruits and vegetables, dark beans,45 and spices, including dill, parsley, and thyme.46,47 You can even get some flavonoids from a glass of red wine.

While we’re on beverages, one to three cups of coffee improves brain power.48 Caffeine binds to adenosine receptors and in doing so, enhances neuron function, synaptic transmission, and neurotransmitter release in the hippocampus.49

Last but not least, there have been numerous studies on the anti-aging benefits of calorie restriction.50-52 Putting down your utensils and avoiding empty calories also helps those electrical messages get through.53

Common Medical Problems That Accelerate Development Of MCI23-37
Common Medical Problems That Accelerate Development Of MCI
  • Obesity
  • Excessive alcohol consumption
  • Diabetes
  • Elevated homocysteine
  • Sleep disorders
  • Hypertension
  • Renal failure
  • Stroke
  • High cortisol
  • Depression
  • Vascular constriction
  • Low testosterone
  • Hypothyroidism
  • Low estrogen
  • Prescription drugs
  • Osteoporosis
  • Toxins
  • Psychological stress

Exercise

You also do not need yet another reminder about the salutary effects of getting off the couch, walking instead of driving, taking the stairs instead of the elevator, and resistance training. We’re giving it to you anyway.

Working out your body also gives your brain a workout.54,55 Aerobic exercise fires up primary neurotransmitters—dopamine,56 GABA,57 and serotonin55—and anaerobic exercise builds brainpower as it builds muscle.58

Get going to keep going. Medical schools used to say that we cannot replace neurons once they are lost. We know now that is not the case, as recent studies are showing that exercise boosts brain-derived neurotrophic factor (BDNF), which is critical for neurogenesis.59-62

Nutritional Supplements

When it comes to brain function, the good news about dietary supplements is running neck-and-neck with that related to exercise.63-66 In Table 4, you’ll note how vital fish consumption is, as fish oil (EPA/DHA) impacts at least three categories, starting with brain power.67 Vitamin D is also critical. According to a recent major study, low levels of vitamin D result in a 53% increased risk for dementia, and those with a serious deficiency have a 125% higher risk.68

The most recent research reveals how these natural supplements are revolutionizing brain health support:

  • Acetyl-l-carnitine arginate is a patented form of carnitine, an amino acid, which improves brain power and contributes to neurogenesis,69,70
  • Gastrodin, extracted from the root of an exotic orchid, plays a role in neurogenesis,71,72 rhythm,73,74 blood circulation,75 and neural plasticity,72
  • Uridine-5’-monophosphate, a nucleotide (organic molecule) or sub-unit of RNA, also contributes to neurogenesis,76
  • Alpha-glyceryl phosphoryl choline, a natural B-vitamin, improves brain speed,77,78 as do magnesium L-threonate (a magnesium salt)79 and methylcobalamin (a form of B12),80
  • Ashwagandha (a plant in the nightshade family, known as Indian ginseng, gooseberry, or winter cherry) contributes to a stable brain rhythm,81
  • Pregnenolone, a steroid hormone manufactured in the body via conversion of cholesterol, has positive effects on mood,82
  • Vinpocetine, derived from the Vinca minor (or lesser periwinkle) plant, increases blood circulation to the brain,83
  • Blueberry extract 84 and magnesium L-threonate85,86 have a positive effect on the brain’s plasticity.

Electrical Therapy

Noninvasive cranial electrical stimulation (CES), which administers gentle current via electrodes attached to the forehead and left wrist, has been studied for decades. It accelerates the conversion of amino acids into neurotransmitters, increasing the impact of nutrients and nutritional supplements, and it is proving efficacious in reducing anxiety, depression, and insomnia, and for increasing blood flow to the brain and improving attention span.104-107

Relationships

If you want to nurture your brain, nurture your social interaction skills. Research is proving that connection to others can generate new brain cells, can improve cognition, and can help in the avoidance of harmful addictions.108-110

Table 4: Brain Support Nutrients84,87-103
Brain Support Nutrients

Brain
Mechanism

Cognitive
Impact

Supplement
Therapies

Power

Fatigue/Addiction

L-Tyrosine, Folic Acid, Acetyl-L-Carnitine Arginate, EPA/DHA

Neurogenesis

Atrophy

Phosphatidylserine, Resveratrol, Tea Polyphenols, Berry Extracts, Quercetin, Curcumin, Gastrodin, Uridine-5’-Monophosphate

Speed

Demyelination/ Memory Loss

Alpha-Glyceryl Phosphoryl Choline, Huperzine A, EPA/DHA, Tocotrienols (vitamin E), Magnesium L-Threonate, Methylcobalamin

Rhythm

Anxiety/Stress

GABA, B-Vitamins, Inositol, Gastrodin, Ashwagandha

Mood

Depression/Insomnia

Tryptophan, 5-Hydroxytryptophan (5-HTP), Melatonin, Pregnenolone

Blood
Circulation

Ischemia

EPA/DHA, Acetyl-L-Carnitine, CoQ10, Gastrodin, Vinpocetine

Plasticity

Calcification

Vitamin K, Tocotrienols, Magnesium L-Threonate, Blueberry Extract


Manage Your Recovery

It stands to reason that if you overcome medical conditions, or reduce their negative effects, you break their connection to cognitive decline. Although we cannot address all of the conditions that accelerate MCI within the scope of this article, there are some conditions that stand out when it comes to aggressive self-management.

Caloric restriction can have a major impact on obesity and diabetes, and blood sugar level can be brought under control with fiber111 and other supplements, especially chromium,112 DHEA,113,114 lipoic acid,115 EPA/DHA,116 bilberry,117 and liberal use of cinnamon.118,119 Stress and other psychological issues, osteoporosis, and insomnia respond to the supplements listed in Table 4. Toxins can be removed from the body via chelation.

The last point to be made concerns prescription drugs. They are powerful and can be wonderful treatments, but they also have a downside—side effects, which include MCI. If you are taking any, do your homework and discuss each and every one with your doctor with an eye toward reducing a dosage or eliminating one entirely. After all, nature provides a substitute for just about every pharmaceutical.

Get Professional Help

Get Professional Help  

If MCI is more advanced, enlist the support of doctors who have extensive experience with hormone therapies that improve cognitive function. Growth hormone, testosterone, pregnenolone, and thyroid hormone all support neurogenesis; bioidentical estrogen improves brain speed in menopausal women; pregnenolone and progesterone can reduce anxiety, depression, and insomnia; parathyroid hormone impacts osteoporosis; and we now know that the hormone leptin plays a key role in obesity.120-126

Prescription drugs, such as donepezil (Aricept®), can have impacts similar to that of the above hormones, and are indeed effective in the battle against cognitive decline. However, with all of the other weapons at your disposal, they should be your last line of defense.

Summary

Mild cognitive impairment is an ever-growing concern that affects many individuals and all of society. It can be recognized, and it can be prevented. MCI can be reversed in its earliest stages by using proactive lifestyle measures, and its advanced affects can be reduced with effective medical treatment.

Our lives can be extended, and we can take our brains along for the ride. Going forward, clinical experience and brain research reveal the path that should be taken: A comprehensive brain health checkup assessing anatomy and function is critical for total health and it should be implemented in primary care. Growing older can mean growing smarter.

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

Eric R. Braverman, MD, is the Founder and Medical Director of The Place for Achieving Total Health (PATH Medical) in New York City and of the PATH Foundation, a nonprofit research organization dedicated to brain science. Dr. Braverman is the author of more than a dozen books, including The Edge Effect and Younger Brain, Sharper Mind, which present his brain-based medicine. He has published over 90 research papers presented to the medical community and is a recipient of the American Medical Association’s Physician’s Recognition Award. Bruce Scali has made several contributions to Life Extension magazine and has written or edited numerous books across multiple genres. He has broad expertise with cutting-edge healthcare topics, transforming complex subject matter in a manner that makes it accessible to every reader.

More information about Dr. Braverman is available at www.pathmed.com and www.pathfoundationny.org.

References

  1. Morris JC , Storandt M, Miller JP, et al. Mild cognitive impairment represents early-stage Alzheimer disease. Arch Neurol. 2001 Mar; 58(3):397-405.
  2. Plassman BL, Langa KM, Fisher GG, et al. Prevalence of cognitive impairment without dementia in the United States. Ann Intern Med. 2008; 148(6):427-34 (ISSN: 1539-3704)
  3. Howe E. Initial screening of patients for Alzheimer’s disease and minimal cognitive impairment. Psychiatry . 2007 Jul;4(7):24-7.
  4. Zhang S , Smailagic N, Hyde C, et al. (11)C-PIB-PET for the early diagnosis of Alzheimer’s disease dementia and other dementias in people with mild cognitive impairment (MCI). Cochrane Database Syst Rev. 2014 Jul 23;7:CD010386
  5. Available at: https://www.aan.com/PressRoom/home/GetDigitalAsset/11222. Accessed November 20, 2014.
  6. Hurd M, Martorell P, Delavande A, et al. Monetary costs of dementia in the United States. N Engl J Med. 2013;368:1326-34.
  7. Available at: http://www.3timaging.com/why-3-tesla-mri-ct-xray-mri-imaging-center-morton-grove-riverside-chicago-illinois.htm . Accessed November 20, 2014.
  8. Luccichenti G, Giugni E, Péran P, et al. 3 Tesla is twice as sensitive as 1.5 Tesla magnetic resonance imaging in the assessment of diffuse axonal injury in traumatic brain injury patients. Funct Neurol . 2010 Apr-Jun;25(2):109-14.
  9. Zhang N, Song X, Zhang Y, et al. Alzheimer’s disease neuroimaging initiative— an MRI brain atrophy and lesion index to assess the progression of structural changes in Alzheimer’s disease, mild cognitive impairment, and normal aging: a follow-up study. J Alzheimers Dis . 2011;26 Suppl 3:359-67.
  10. Cherubini A, Péran P, Spoletini I, et al. Combined volumetry and DTI in subcortical structures of mild cognitive impairment and Alzheimer’s disease patients. J Alzheimers Dis . 2010;19(4):1273-82.
  11. Van Dinteren R, Arns M, Jongsma M. et al. P300 development across the lifespan: a systematic review and meta-analysis. PLoS One. 2014 Feb. 9(2):e87347.
  12. Haeusler KG , Koch L, Herm J, et al. 3 Tesla MRI-detected brain lesions after pulmonary vein isolation for atrial fibrillation: results of the MACPAF study. J Cardiovasc Electrophysiol. 2013 Jan;24(1):14-21.
  13. Wu Z , Mittal S,Kish K,Yu Y,Hu J, Haacke EM. Identification of calcification with MRI using susceptibility-weighted imaging: a case study. J Magn Reson Imaging. 2009 Jan;29(1):177-82.
  14. Available at: http://www.alz.org/dementia/mild-cognitive-impairment-mci.asp. Accessed November 20, 2014.
  15. Risacher SL, Kim S, Shen L, et al.The role of apolipoprotein E (APOE) genotype in early mild cognitive impairment (E-MCI). Front Aging Neurosci. 2013 Apr 1;5:11.
  16. Xu WL, Caracciolo B, Wang HX, Santoni G, Winblad B, Fratiglioni L.Accelerated progression from mild cognitive impairment to dementia among APOE ε4ε4 carriers. J Alzheimers Dis. 2013;33(2):507-15.
  17. Etgen T , Bickel H, Förstl H. Metabolic and endocrine factors in mild cognitive impairment. Ageing Res Rev. 2010 Jul;9(3):280-8.
  18. Etgen T , Sander D,Bickel H, Förstl H. Mild cognitive impairment and dementia: the importance of modifiable risk factors. Dtsch Arztebl Int. 2011 Nov;108(44):743-50.
  19. Kim J , Park MH,Kim E,Han C,Jo SA, Jo I. Plasma homocysteine is associated with the risk of mild cognitive impairment in an elderly Korean population. J Nutr. 2007 Sep;137(9):2093-7.
  20. Lui LY, Stone K, Cauley JA, Hillier T, Yaffe K. Bone loss predicts subsequent cognitive decline in older women: the study of osteoporotic fractures. J Am Geriatr Soc. 2003;51:38-43.
  21. Clarke R , Birks J, Nexo E, et al. Low vitamin B-12 status and risk of cognitive decline in older adults. Am J Clin Nutr. 2007 Nov;86(5):1384-91.
  22. Siuda J , Gorzkowska A, Patalong-Ogiewa M, et al . From mild cognitive impairment to Alzheimer’s disease - influence of homocysteine, vitamin B12 and folate on cognition over time: results from one-year follow-up. Neurol Neurochir Pol. 2009 Jul-Aug;43(4):321-9.
  23. Ganguli M, Fu B, Snitz BE, Hughes TF, Chang CC. Mild cognitive impairment: incidence and vascular risk factors in a population-based cohort. Neurology . 2013 Jun 4;80(23):2112-20.
  24. Anttila T, Helkala EL, Viitanen M, et al. Alcohol drinking in middle age and subsequent risk of mild cognitive impairment and dementia in old age: a prospective population based study. BMJ . 2004 Sep 4;329(7465):539.
  25. Luchsinger JA, Reitz C, Patel B, Tang MX, Manly JJ, Mayeux R. Relation of diabetes to mild cognitive impairment. Arch Neurol. 2007 Apr;64(4):570-5.
  26. Quadri P, Fragiacomo C, Pezzati R, Zanda E, Tettamanti M, Lucca U. Homocysteine and B vitamins in mild cognitive impairment and dementia. Clin Chem Lab Med . 2005;43(10):1096-100.
  27. Boot BP, Boeve BF, Roberts RO, et al. Probable rapid eye movement sleep behavior disorder increases risk for mild cognitive impairment and Parkinson disease: a population-based study. Ann Neurol . 2012 Jan;71(1):49-56.
  28. Reitz C, Tang MX, Manly J, Mayeux R, Luchsinger JA. Hypertension and the risk of mild cognitive impairment. Arch Neurol. 2007 Dec;64(12):1734-40.
  29. Post JB, Jegede AB, Morin K, Spungen AM, Langhoff E, Sano M.Cognitive profile of chronic kidney disease and hemodialysis patients without dementia. Nephron Clin Pract. 2010;116(3):247-55.
  30. Steenland K, Karnes C, Seals R, Carnevale C, Hermida A, Levey A. Late-life depression as a risk factor for mild cognitive impairment or Alzheimer’s disease in 30 US Alzheimer’s disease centers. J Alzheimers Dis . 2012;31(2):265-75.
  31. Glodzik L, Randall C, Rusinek H, de Leon MJ. Cerebrovascular reactivity to carbon dioxide in Alzheimer’s disease. J Alzheimers Dis. 2013;35(3):427-40.
  32. Chu LW, Tam S, Lee PW, et al. Bioavailable testosterone is associated with a reduced risk of amnestic mild cognitive impairment in older men. Clin Endocrinol (Oxf). 2008;68:589-98.
  33. Muangpaisan W, Petcharat C, Srinonprasert V. Prevalence of potentially reversible conditions in dementia and mild cognitive impairment in a geriatric clinic. Geriatr Gerontol Int. 2012 Jan;12(1):59-64.
  34. Bittner DM, Bittner V, Riepe MW. Verbal episodic memory and endogenous estradiol: an association in patients with mild cognitive impairment and Alzheimer’s disease. Curr Gerontol Geriatr Res . 2011;2011:673012.
  35. Tannenbaum C, Paquette A, Hilmer S, Holroyd-Leduc J, Carnahan R. A systematic review of amnestic and non-amnestic mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid drugs. Drugs Aging . 2012 Aug 1;29(8):639-58.
  36. Lee DY, Na DL, Seo SW, et al.Association between cognitive impairment and bone mineral density in postmenopausal women. Menopause. 2012 Jun;19(6):636-41.
  37. Brewer GJ. The risks of copper toxicity contributing to cognitive decline in the aging population and to Alzheimer’s disease. J Am Coll Nutr . 2009 Jun;28(3):238-42.
  38. Solfrizzi V , Frisardi V, Capurso C, et al. Dietary fatty acids in dementia and predementia syndromes: epidemiological evidence and possible underlying mechanisms. Ageing Res Rev. 2010 Apr;9(2):184-99.
  39. Available at: http://www.seafoodhealthfacts.org/seafood_nutrition/practitioners/omega3_content.php. Accessed November 20, 2014.
  40. Maguire LS, O’Sullivan SM, Galvin K, O’Connor TP, O’Brien NM. Fatty acid profile, tocopherol, squalene and phytosterol content of walnuts, almonds, peanuts, hazelnuts, and the macadamia nut. Int J Food Sci Nutr . 2004 May;55(3):171-8.
  41. Rajaram S, Burke K, Connell B, Myint T, Sabaté J. A monounsaturated fatty acid-rich pecan-enriched diet favorably alters the serum lipid profile of healthy men and women. J Nutr . 2001 Sep;131(9):2275-9.
  42. Ros E. Health benefits of nut consumption. Nutrients. 2010 Jul;2(7):652-82.
  43. Skorić D, Jocić S, Sakac Z, Lecić N.Genetic possibilities for altering sunflower oil quality to obtain novel oils. Can J Physiol Pharmacol. 2008 Apr;86(4):215-21.
  44. Stangl D, Thuret S. Impact of diet on adult hippocampal neurogenesis. Genes Nutr. 2009; 4:271-282
  45. Available at: http://www.whfoods.com/genpage.php?tname=george&dbid=72. Accessed November 20,2014.
  46. Available at: http://www.lpi.oregonstate.edu/infocenter/phytochemicals/flavonoids/. Accessed November 20, 2014.
  47. Teuber H , Herrmann K. Flavonol glycosides of leaves and fruits of dill (Anethum graveolens L.). Z Lebensm Unters Forsch. 1978 Aug 30;167(2):101-4.
  48. Abreu RV, Silva-Oliveira EM, Moraes MF, Pereira GS, Moraes-Santos T. Chronic coffee and caffeine ingestion effects on the cognitive function and antioxidant system of rat brains. Pharmacol Biochem Behav . 2011 Oct;99(4):659-64.
  49. Yoshimura H. The potential of caffeine for functional modification from cortical synapses to neuron networks in the brain. Curr Neuropharmacol. 2005 Oct;3(4):309-16.
  50. Mirzaei H , Suarez JA, Longo VD. Protein and amino acid restriction, aging and disease: from yeast to humans. Trends Endocrinol Metab. 2014 Aug 18. pii: S1043-2760(14)00127-1.
  51. Grymula K , Piotrowska K, Słuczanowska-Głąbowska S , et al. Positive effects of prolonged caloric restriction on the population of very small embryonic-like stem cells - hematopoietic and ovarian implications. J Ovarian Res. 2014 Jun 21;7:68.
  52. Brown JE . Can restricting calories help you to live longer? Post Reprod Health. 2014 Mar 13;20(1):16-8.
  53. Witte AV, Fobker M, Gellner R, Knecht S, Flöel A. Caloric restriction improves memory in elderly humans. Proc Natl Acad Scie USA. 2009 Jan 27;106(4):1255-60.
  54. Spindler C , Cechinel LR, Basso C, et al. Treadmill exercise alters histone acetyltransferases and histone deacetylases activities in frontal cortices from wistar rats. Cell Mol Neurobiol. 2014 Aug 24.
  55. Melancon MO , Lorrain D, Dionne IJ. Exercise and sleep in aging: emphasis on serotonin. Pathol Biol. 2014 Aug 4.
  56. Sutoo D, Akiyama K. Regulation of brain function by exercise. Neurobiol Dis . 2003 Jun;13(1):1-14.
  57. Schoenfeld TJ, Rada P, Pieruzzini PR, Hsueh B, Gould E. Physical exercise prevents stress-induced activation of granule neurons and enhances local inhibitory mechanisms in the dentate gyrus. J Neurosci . 2013 May 1;33(18):7770-7.
  58. Ten Brinke LF, Bolandzadeh N, Nagamatsu LS, et al. Aerobic exercise increases hippocampal volume in older women with probable mild cognitive impairment: A 6 month randomised controlled trial. Br J Sports Med. 2014 Apr 7.
  59. Skriver K , Roig M, Lundbye-Jensen J, et al. Acute exercise improves motor memory: Exploring potential biomarkers. Neurobiol Learn Mem. 2014 Aug 14.
  60. Rojas Vega S , Knicker A,Hollmann W,Bloch W, Strüder HK. Effect of resistance exercise on serum levels of growth factors in humans. Horm Metab Res. 2010 Dec;42(13):982-6.
  61. Lee J, Duan W, Mattson MP. Evidence that brain-derived neurotrophic factor is required for basal neurogenesis and mediates, in part, the enhancement of neurogenesis by dietary restriction in the hippocampus of adult mice. J Neurochem . 2002 Sep;82(6):1367-75.
  62. Scharfman H, Goodman J, Macleod A, Phani S, Antonelli C, Croll S. Increased neurogenesis and the ectopic granule cells after intrahippocampal BDNF infusion in adult rats. Exp Neurol . 2005 Apr;192(2):348-56.
  63. Pirotta S , Kidgell DJ, Daly RM. Effects of vitamin D supplementation on neuroplasticity in older adults: a double-blinded, placebo-controlled randomised trial. Osteoporos Int. 2014 Aug 20.
  64. Sen CK , Khanna S, Roy S. Tocotrienol: the natural vitamin E to defend the nervous system? Ann N Y Acad Sci. 2004 Dec;1031:127-42.
  65. Engelborghs S , Gilles C,Ivanoiu A, Vandewoude M. Rationale and clinical data supporting nutritional intervention in Alzheimer’s disease. Acta Clin Belg. 2014 Jan-Feb;69(1):17-24.
  66. Kamphuis PJ , Scheltens P. Can nutrients prevent or delay onset of Alzheimer’s disease? J Alzheimers Dis. 2010;20(3):765-75.
  67. Heinrichs SC. Dietary omega-3 fatty acid supplementation for optimizing neuronal structure and function. Mol Nutr Food Res. 2010 Apr;54(4):447-56.
  68. Littlejohns TJ , Henley WE, Lang IA, et al. Vitamin D and the risk of dementia and Alzheimer disease. Neurology. 2014 Sep 2;83(10):920-8.
  69. Athanassakis I, Zarifi I, Evangeliou A, Vassiliadis S. L-carnitine accelerates the in vitro regeneration of neural network from adult murine brain cells. Brain Res . 2002 Apr 5;932(1-2):70-8.
  70. Malaguarnera M, Cammalleri L, Gargante MP, Vacante M, Colonna V, Motta M. L-carnitine treatment reduces severity of physical and mental fatigue and increases cognitive functions in centenarians: a randomized and controlled clinical trial. Am J Clin Nutr. 2007 Dec;86(6):1738-44.
  71. Ramachandran U, Manavalan A, Sundaramurthi H, et al. Tianma modulates proteins with various neuro-regenerative modalities in differentiated human neuronal SH-SY5Y cells. Neurochem Int. 2012 Jun;60(8):827-36.
  72. Manavalan A, Ramachandran U, Sundaramurthi H, et al. Gastrodia elata Blume (tianma) mobilizes neuro-protective capacities. Int J Biochem Mol Biol. 2012;3(2):219-41.
  73. Zhang CY, Du GY, Wang W, et al. Effects of tianma gouteng fang on transmitter amino acids in the hippocampus extracellular liquids in freely moving rats subjected to brain ischemia. Zhongguo Zhong Yao Za Zhi. 2004 Nov;29(11):1061-5.
  74. An SJ, Park SK, Hwang IK, et al. Gastrodin decreases immunoreactivities of gamma-aminobutyric acid shunt enzymes in the hippocampus of seizure-sensitive gerbils. J Neurosci Res. 2003 Feb 15;71(4):534-43.
  75. Wei J, Zhou Y. Treatment of posterior circulation ischemia with gastrodin and betahistine. Practical Clinical Medicine. 2012;13(4).
  76. Wang L, Pooler AM, Albrecht MA, Wurtman RJ. Dietary uridine-5’-monophosphate supplementation increases potassium-evoked dopamine release and promotes neurite outgrowth in aged rats. J Mol Neurosci. 2005;27(1):137-45.
  77. Amenta F, Tayebati SK. Association with the cholinergic precursor choline alphoscerate and the cholinesterase inhibitor rivastigmine: an approach for enhancing cholinergic neurotransmission. Mech Ageing Dev. 2005 Nov 14.
  78. Parnetti L, Amenta F, Gallai V. Choline alphoscerate in cognitive decline and in acute cerebrovascular disease: an analysis of published clinical data. Mech Ageing Dev. 2001 Nov;122(16):2041-55.
  79. Slutsky I. Enhancement of learning and memory by elevating brain magnesium. Neuron. 65(2):2010;165-77.
  80. Liao WC, Chen JR, Wang YJ, Tseng GF. Methylcobalamin, but not methylprednisolone or pleiotrophin, accelerates the recovery of rat biceps after ulnar to musculocutaneous nerve transfer. Neuroscience. 2010 Dec 15;171(3):934-49.
  81. Jain S, Shukla SD, Sharma K, Bhatnagar M. Neuroprotective effects of Withania somnifera Dunn. in hippocampal sub-regions of female albino rat. Phytother Res. 2001 Sep;15(6):544-8.
  82. Osuji IJ, Vera-Bolaños E, Carmody TJ, Brown ES. Pregnenolone for cognition and mood in dual diagnosis patients. Psychiatry Res. 2010 Jul 30;178(2):309-12.
  83. Kidd PM. A review of nutrients and botanicals in the integrative management of cognitive dysfunction. Altern Med Rev. 1999 Jun;4(3):144-61.
  84. Casadesus G. Modulation of hippocampal plasticity and cognitive behavior by short-term blueberry supplementation in aged rats. Nutr Neurosci. 2004 Oct-Dec;7(5-6):309-16.
  85. Slutsky I, Sadeghpour S, Li B, Liu G. Enhancement of synaptic plasticity through chronically reduced Ca2+ flux during uncorrelated activity. Neuron. 2004 Dec 2;44(5):835-49.
  86. Slutsky I, Abumaria N, Wu LJ, et al. Enhancement of learning and memory by elevating brain magnesium. Neuron. 2010 Jan 28;65(2):165-77.
  87. Deijen JB , Orlebeke JF. Effect of tyrosine on cognitive function and blood pressure under stress. Brain Res Bull. 1994;33(3): 319-23.
  88. Ramos MI , Allen LH, Mungas DM, et al. Low folate status is associated with impaired cognitive function and dementia in the Sacramento Area Latino Study on Aging. Am J Clin Nutr. 2005 Dec;82(6):1346-52.
  89. Bertrand PC, O’Kusky JR, Innis SM. Maternal dietary (n-3) fatty acid deficiency alters neurogenesis in the embryonic rat brain. J. Nutr. 2006 Jun 136(6):1570-5.
  90. Moriya J , Chen R,Yamakawa J,Sasaki K,Ishigaki Y, Takahashi T. Resveratrol improves hippocampal atrophy in chronic fatigue mice by enhancing neurogenesis and inhibiting apoptosis of granular cells. Biol Pharm Bull. 2011;34(3):354-9.
  91. Dias GP , Cavegn N, Nix A, et al. The role of dietary polyphenols on adult hippocampal neurogenesis: molecular mechanisms and behavioural effects on depression and anxiety. Oxid Med Cell Longev. 2012;2012:541971.
  92. Tchantchou F , Lacor PN,Cao Z,Lao L,Hou Y,Cui C,Klein WL, Luo Y. Stimulation of neurogenesis and synaptogenesis by bilobalide and quercetin via common final pathway in hippocampal neurons. J Alzheimers Dis. 2009;18(4):787-98.
  93. Zhang SQ , Wang G,Luo GJ,Zhan H, Chen HW. Effects of huperzine A on cognitive function of rats recovering from general anesthesia. Nan Fang Yi Ke Da Xue Xue Bao. 2008 Feb;28(2):225-7.
  94. Nagapan G , Meng Goh Y, Shameha Abdul Razak I , Nesaretnam K, Ebrahimi M. The effects of prenatal and early postnatal tocotrienolrich fraction supplementation on cognitive function development in male offspring rats. BMC Neurosci. 2013 Jul 31;14:77.
  95. Abubakari AR , Naderali MM, Naderali EK. Omega-3 fatty acid supplementation and cognitive function: are smaller dosages more beneficial? Int J Gen Med. 2014 Sep 19;7:463-73.
  96. Cardinali DP , Golombek DA. The rhythmic GABAergic system. Neurochem Res. 1998 May;23(5):607-14.
  97. Lehmann M , Regland B,Blennow K, Gottfries CG. Vitamin B12-B6-folate treatment improves blood-brain barrier function in patients with hyperhomocysteinaemia and mild cognitive impairment. Dement Geriatr Cogn Disord. 2003;16(3):145-50.
  98. Young SN. The effect of raising and lowering tryptophan levels on human mood and social behavior. Philos Trans R Soc Lond B Biol Sci . 2013 Feb 25;368.
  99. Boyce P , Hopwood M. Manipulating melatonin in managing mood. Acta Psychiatr Scand Suppl. 2013;(444):16-23.
  100. Haast RA , Kiliaan AJ. Impact of fatty acids on brain circulation, structure and function. Prostaglandins Leukot Essent Fatty Acids. 2014 Jan 15.
  101. Rosadini G , Marenco S,Nobili F,Novellone G, Rodriguez G. Acute effects of acetyl-L-carnitine on regional cerebral blood flow in patients with brain ischaemia. Int J Clin Pharmacol Res. 1990;10(1-2):123-8.
  102. Kalayci M , Unal M, Gul S, et al. Effect of coenzyme Q10 on ischemia and neuronal damage in an experimental traumatic brain-injury model in rats. BMC Neurosci. 2011 Jul 29;12:75.
  103. Nagap G , Meng Goh Y, Shameha Abdul Razak I , Nesaretnam K, Ebrahimi M. The effects of prenatal and early postnatal tocotrienolrich fraction supplementation on cognitive function development in male offspring rats. BMC Neurosci. 2013 Jul 31;14:77.
  104. Rose KM , Taylor AG,Bourguignon C,Utz SW, Goehler LE. Cranial electrical stimulation: potential use in reducing sleep and mood disturbances in persons with dementia and their family caregivers. Fam Community Health. 2008 Jul-Sep;31(3):240-6.
  105. Rose KM , Taylor AG, Bourguignon C. Effects of cranial electrical stimulation on sleep disturbances, depressive symptoms, and caregiving appraisal in spousal caregivers of persons with Alzheimer’s disease. Appl Nurs Res. 2009 May;22(2):119-25.
  106. Gense de Beaufort D , Sesay M,Stinus L,Thiebaut R,Auriacombe M, Dousset V. Cerebral blood flow modulation by transcutaneous cranial electrical stimulation with Limoge’s current. J Neuroradiol. 2012 Jul;39(3):167-75.
  107. Southworth S . A study of the effects of cranial electrical stimulation on attention and concentration. Integr Physiol Behav Sci. 1999 Jan-Mar;34(1):43-53.
  108. Venna VR , Xu Y,Doran SJ,Patrizz A, McCullough LD. Social interaction plays a critical role in neurogenesis and recovery after stroke. Transl Psychiatry. 2014 Jan 28;4.
  109. Doulames V , Lee S, Shea TB. Environmental enrichment and social interaction improve cognitive function and decrease reactive oxidative species in normal adult mice. Int J Neurosci. 2014 May;124(5):369-76.
  110. El Rawas R , Klement S, Kummer KK, et al. Brain regions associated with the acquisition of conditioned place preference for cocaine vs. social interaction. Front Behav Neurosci. 2012 Sep 24;6:63.
  111. Nader N, Weaver A, Eckert S, Lteif A. Effects of fiber supplementation on glycemic excursions and incidence of hypoglycemia in children with type 1 diabetes. Int J Pediatr Endocrinol. 2014;2014(1):13.
  112. Clausen J. Chromium induced clinical improvement in symptomatic hypoglycemia. Biol Trace Elem Res. 1988 Sep-Dec;17:229-36.
  113. Sato K, Iemitsu M, Aizawa K, Mesaki N, Ajisaka R, Fujita S.DHEA administration and exercise training improves insulin resistance in obese rats. Nutr Metab (Lond). 2012 May 30;9:47.
  114. Kanazawa I, Yamaguchi T, Sugimoto T. Effects of intensive glycemic control on serum levels of insulin-like growth factor-I and dehydroepiandrosterone sulfate in Type 2 diabetes mellitus. J Endocrinol Invest . 2012 May;35(5):469-72.
  115. Khamaisi M, Rudich A, Potashnik R, Tritschler HJ, Gutman A, Bashan N.Lipoic acid acutely induces hypoglycemia in fasting nondiabetic and diabetic rats. Metabolism. 1999 Apr;48(4):504-10.
  116. Shida T, Kamei N, Takeda-Morishita M, Isowa K, Takayama K. Colonic delivery of docosahexaenoic acid improves impaired glucose tolerance via GLP-1 secretion and suppresses pancreatic islet hyperplasia in diabetic KK-A(y) mice. Int J Pharm . 2013 Jun 25;450(1-2):63-9.
  117. Available at: http://www.ncbi.nlm.nih.gov/books/NBK92770/. Accessed November 17, 2014.
  118. Available at: http://www.lef.org/magazine/2005/7/report_diabetes/Page-03. Accessed Aug. 26 , 2014
  119. Khan A, Safdar M, Ali Khan MM, Khattak KN, Anderson RA. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care. 2003 Dec;26(12):3215-8.
  120. Devesa P , Agasse F, Xapelli S, et al. Growth hormone pathways signaling for cell proliferation and survival in hippocampal neural precursors from postnatal mice. BMC Neurosci. 2014 Aug 26;15(1):100.
  121. Fanaei H , Karimian SM, Sadeghipour HR, et al. Testosterone enhances functional recovery after stroke through promotion of antioxidant defenses, BDNF levels and neurogenesis in male rats. Brain Res. 2014 Apr 16;1558:74-83.
  122. Shilling V , Jenkins V,Fallowfield L, Howell T. The effects of hormone therapy on cognition in breast cancer. J Steroid Biochem Mol Biol. 2003 Sep;86(3-5):405-12.
  123. Bowen MT , Hari Dass SA,Booth J,Suraev A, Vyas A, McGregor IS . Active coping towards predatory stress is associated with lower corticosterone and progesterone plasma levels and decreased methylation in the medial amygdala vasopressin system. Horm Behav. 2014 Aug 12.
  124. Winarno AS , Kyvernitakis I, Hadji P. Successful treatment of 1-34 parathyroid hormone (PTH) after failure of bisphosphonate therapy in a complex case of pregnancy associated osteoporosis and multiple fractures. Z Geburtshilfe Neonatol. 2014 Aug;218(4): 171-3.
  125. Van Swieten MM,Pandit R,Adan RA, van der Plasse G. The neuroanatomical function of leptin in the hypothalamus. J Chem Neuroanat. 2014 Jul 4.
  126. O’Rahilly S . 20 years of leptin: What we know and what the future holds. J Endocrinol. 2014 Aug 20.