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           AGinG BRAin

        How preventive
          medicine can                   Alzheimer’s dementia prevalence in-       motrypsin, il-6, c-reactive protein. inflam-
             help fight                  creases with age and the total number
                                         of people affected is expected to rise
                                                                                   mation leads to:
                                                                                    a) Proinflammatory cytokines (im-
     neurodegenerative                   as time passes. The main reasons that      mune system mediators)
                                         the brain is affected by aging are         b) Reactive microglia
            diseases of                  largely attributable to:                   c) Activation of complement path-
                                         1. inflammation                            way (immune system activation)
              the brain                  2. Free radical damage to neurons          d) can be protected by anti-inflam-
                                         and mitochondria. 1                        matory drugs.2,3,4
                By: Dr Craige Golding,                                              Reactive microglia express comple-
             American board-certified,   INFLAMMATION                               ment receptors and compliment
                   antiaging physician   The higher the inflammatory markers        activation leads to beta-amyloid dep-
         mBcHB (cum laude), FcP(SA),     the higher the incidence of Alzheimer’s    osition (the hallmark of Alzheimer’s
                       ABAARm, FAAFm     disease. These inflammatory markers        disease).5,6 Anti-inflammatories and
          (Fellowship in antiaging and   can be measured in the blood and           aspirin have been proven to reduce
                  functional medicine)   include for example: alpha1-antichy-       the incidence of Alzheimer’s.7,8

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    HOw INFLAMMATION INCREASES                   damage include:20,21                        oxygen species formation.
               inFLAmmATiOn                      2. ANTI-INFLAMMATORIES / COX-2              EXCITOTOXICITY OF THE BRAIN
                      |                          INHIBITORS/ ASPIRIN                         The excitotoxicity theory whereby the
          ReAcTiVe OXYGen SPecieS                                                            brain is damaged can be summarised
                      |                          3. RESVERATROL                              as follows:
         ReAcTiVe niTROGen SPecieS                a) induces phase 2 detoxification                  mitochondrial dysfunction
                      |                           enzymes in the liver                                             |
      indUcTiOn OF TOXic GeneS (inOS,             b) inhibits cox-2 enzyme induction              decreased energy production
                   cOX-2)                         (inflammation)22                                        (decreased ATP)
                      |                           c) inhibits leukotrines (inflammatory                            |
        neUROdeGeneRATiVe diSeASe                 mediators)                                     Partial depolarisation of neurons
                                                  d) Suppresses nitric oxide synthetase                            |
    RISK FACTORS FOR ALzHEIMER’S                  e) inhibits mitochondrial reactive               Persistant nmdA activation by
      1. Genetic (family history)                 oxygen species formation                                    glutamate
      2. Head trauma                              f) Red wine contains resveratrol and                             |
      3. Transient ischemia                                                                                 calcium influx
      4. microvascular defects                                                               Consequences of raised intracellular
      5. diabetes mellitus 10,11,12,13,               DHEA pROVIDES                          calcium: 24 - 32
                                                                                               a) mitochondrial accumulation of
      6. chronic infections
                                                         MARkEDLy                              calcium leads to reactive oxygen
    These factors lead to increased brain               pROTEcTIVE                             species production
                                                                                               b) cleavage of amyloid precursor
    inflammation and subsequent degen-
    erative change. Activators of microglia           EFFEcTS OF THE                           protein to form beta amyloids
    include sugar/glucose, reactive oxygen            HIppOcAMpUS.                             c) cox-2 upregulation (inflammation)
                                                                                               d) memantine (namenda) blocks
    species and fat.
    The diabetic brain is at increased risk            DHEA LEVELS                             nmdA activation and protects
    due to:                                          HAVE AN INVERSE                           the brain.33
       1. Glycosylation14
       2. cox-2 upregulation                           RELATIONSHIp                          CONCLUSION
       3. Hippocampal atrophy (memory                wITH ALzHEIMER’S                        due to flawed methods and small
                                                                                             clinical benefits, the scientific basis for
       area of the brain)
       4. nmdA receptor modulation                       DEMENTIA                            recommendations of cholinesterase in-
       5. Hypothalamic pituitary adrenal                                                     hibitors for the treatment of Alzheimer’s
       axis activation                                                                       is questionable.
       6. inflammation and cytokine (im-          accounts for protection and the            The study concludes:34
       mune system factors) activation.           French paradox of lower cardiovascu-          1. Recommendations for the use of
                                                  lar disease in red wine drinkers.23           cholinesterase inhibitors do not seem
    Glycosylation causes advanced glyca-         4. DHA OMEGA 3 - Hugely protective             to be evidence-based
    tion end products (AGe).                     of the brain.                                  2. Benefits measured on rating scales
    The AGEs cause the following effects:15                                                     were minimal
       a) Reactive oxygen species                disturbances in homeostasis of cytos-          3. The methodological quality of the
       b) Activation of nFkB                     tolic free calcium may present a final         available trials was poor.
       c) Activation of microglia                common pathway in the multifactorial
       d) increased production of superox-       pathogenesis of neurological com-           NMDA-glutamate stimulation leads to:
       ide radicals and nitric oxide             plications of diabetes, which involve       ACUte          CHrOniC
       e) increased free radical production.     vascular changes, oxidative stress, and
                                                 non-enzymatic protein glycation.            Hypoxia             Alzheimer’s
    Free radical damage and glycosylation        Resveratrol inhibits transduction for cox   Hypoglycaemia       Parkinson’s
    can be protected from by the use of nat-     2 at multiple levels. This lowers PGe2.     Seizures            Huntington’s
    ural antioxidants and anti-inflammatories.   cox 2 upregulation is seen in many          ischaemia           motor neuron disease
          The most important protector is:       cancers and is a target for anticancer
    1. N-ACETYL-CYSTEINE (NAC) 18,19             therapies. Resveratrol induces phase 2      Diabetes increases the risk of
    nAc elevates glutathione levels.             detoxification enzymes. it also inhibits    Alzheimer’s disease due to:
    Glutathione is the most important            cox 2 enzyme induction and lipoxyge-          a) Vascular disease
    protective antioxidant in the human          nase (decreased arachidonic acid to           b) Glycation of proteins
    body. Other brain protectors from            leukotrienes). Suppresses nO syn-             c) Amyloid
    inflammation and free radical                thetase. inhibits mitochondrial reactive      d) increased inflammation (cox-2)35

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        e) Hippocampus and amygdala                Overactivation of the adrenal glands         it is produced in astrocytes, carried by
        damage                                     /cortisol hypersecretion leads to:           LdL receptor into neurons and has the
        f) diabetic retinopathy associated           1. immune suppression                      highest affinity for B-amyloid increasing
        with cognitive decline, decline in abil-     2. muscle atrophy                          deposition of fibrillar B-amyloids.38,39,40
        ity to process information, attention        3. Osteoporosis                            • Homozygotes have an onset of
        and concentration                            4. Arteriosclerosis                        Alzheimer’s 10-20 years earlier.
        g) elevated glucose leads to                 5. diabetes mellitus                       • Heterozygotes have an onset 5-10
        increased neuronal apoptosis,                                                           years earlier
        decreased insulin-like-growth factor,                                                   •ApoE4 allele accounts for 13-20% of
        increased long-term depression and                                                      causes of dementia 41,42,43
        ultimately cognitive failure. These ef-                                                 • Modulates effects of other risk factors
        fects are attenuated by dHeA, which                                                     Diabetes-ApoE4 synergy:
        provides marked protective effects of                                                       5-fold increase in Alzheimer’s
        the hippocampus. dHeA levels have                                                           Apoe4 allele associated with
        an inverse relationship with Alzheimer’s                                                decreased antioxidant and neuronal
        dementia and increase Rem sleep.                                                        repair
                                                                                                    Associated with advanced glycation
      THE HIPPOCAMPUS                                                                           endproducts in senile plaques
      The hippocampus mediates the glu-                                                             e4 stabilises B-amyloid.
      cocorticoid negative feedback. With                                                       Antioxidant protection protects from          solal
      aging or damage like with elevated                                                        genetic predisposition. For example,          ad to
      blood sugar hypersecretion of gluco-                                                      trials have shown an 89% reduction in
                                                                                                                                              go on
      corticoids occurs. decrease in function                                                   memory decline in heterozygous Apoe4
      leads to memory loss.                                                                     people with high beta-carotene levels.
      The following functions are inhibited
      by glucocorticoids:                                                                       PROTECTION AGAINST CORTISOL
        immune interferon                                                                       DAMAGE TO HIPPOCAMPUS
        natural killer cells                                                                    The latest studies confirm that human
        Prostaglandin synthesis                                                                 brain cells retain the potential for self-
        insulin secretion                                                                       renewal throughout life.44
        B-endorphin production                       pARkINSONS AND                               1. melatonin protects the hippocam-
        Growth hormone secretion                                                                  pus by decreasing gluococoticoid
        Glucose transport and glycogen              DEMENTIA pATIENTS                             secretion (cortisol) and increased
         calcium transport into bone
                                                     HAVE LOw LEVELS                              sensitivity to cortisol feedback
                                                                                                  2. Lithium increases human grey
        insulin like growth factor secretion         OF GLUTATHIONE                               matter and is both neuroprotective
        Protein synthesis.
                                                    IN THE SUbSTANTIA                             and neurotrophic and also upregu-
                                                                                                  lates cytoprotective Bcl-2. Lithium also
                                                          NEGRA                                   significantly protects against beta-
                                                                                                  amyloid-induced neurodegeneration.
                                                                                                  Studies have showed decreased
     The Apo e4 allele combined with                                                              neuronal death in rat neurons incu-
     any of the following risk factors               6. Loss of hippocampal corticosteroid        bated with beta amyloid
     greatly increases one’s risk for                receptors and neurotoxicity leading to       3. Hippocampus sensitive to the
     Alzheimer’s:                                    cognitive dysfunction and memory loss        effects of anti-depressants and elec-
       1. Genetic predisposition                     7. enhances glutamine synthetase             troconvulsive seizures
       2. Head traumas                               increasing glutamate activity                4. Hippocampal atrophy is observed
       3. transient ischemias                        8. increases calcium influx                  in depression, electroconvulsive
       4. Microvascular deficits                     9. disrupts neuronal energetics              therapy induces cellular growth in
       5. environmental insults                      10. Worsens oxidative damage                 the hippocampus
       6. infectious agents                          11. Binds to specific hippocampal            5. Running induces neurogenesis,
       7. Atherosclerosis                            neuronal receptors.                          and increased learning
       8. peripheral vascular disease              APO E4 ALLELE                                  6. Positive emotions are associated
       9. Diabetes mellitus                        • Individuals positive for the gene            with improved cognitive functioning.
       10. elevated cortisol                       Apoe4 allele have a greater risk for hip-
       11. Decreased reM sleep                     pocampal atrophy and an increased            ALzHEIMER’S RISK FACTORS
       12. increased inflammatory markers          risk for Alzheimer’s.36,37 Apoe4 is one of   Age, obesity, dietary fat, head trauma,
                                                   3 genetic varients of apolipoprotein e.      homocysteine, Apoe4 allele, diabetes.

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                                                                                                    have protective effects against these
     Drugs that deplete             Drugs that deplete              Drugs that deplete
                                                                                                    vascular changes, oxidative stress, and
     vitamin B12 and increase       vitamin B6                      folic acid:
                                                                                                    protein glycation. Alpha lipoic acid is a
     homocysteine:                  Aminoglycosides, Chlo-          Aspirin, barbiturates,
                                                                                                    fine example for defence.
     Aminoglycosdies, Ce-           rtetracycline, Doxycycline,     carbamazepine, celec
     phalosporines, Chlortet-       Fluoroquinolones, Hy-           oxib, cholestyramine,
     racycline, Cimetidine,         drochlorthiazide, mino-         cimetidine, colestipol,
                                                                                                    Body fat acts as a reservoir for lipid-
     Co-trimoxazole, Doxycy-        cycline, penicillamine,         corticosteroids, etho-
                                                                                                    soluble neurotoxins that selectively
     cline, Famotidine, Fluoro-     raloxifene, theophyline,        suximide, famotidine,
                                                                                                    damage dopamine-producing neurons
     quinolones, Lansoprazole,      Bumetanide, deme-               fosphenitoin, hydrochlo-
                                                                                                    in the substantia nigra. midlife obesity
     Macrolides, Metfornin,         clocycline, estrogens,          rthiazide, indomethacin,
                                                                                                    is associated with an increased risk for
     Minocycline, neomycine,        furosemide, isoniazid, oral     methotraxate, meth-
                                                                                                    Alzheimer’s disease.
     nizatidine, Omeprazole,        contraceptives, penicillins,    suxemide, nSAiDs, oral
     Oral contraceptives, Ox-       sulfonamides, torseimide,       contraceptives, phenytoin,
                                                                                                    MEDITERRANEAN DIET IS
     ytetracyclines, penicillins,   cephalosporins, diethyl-        primidone, ranitidine,
     phenytoin, ranitidine, Sul-    stilbestrol, ethacrynic acid,   salsalate, triamterene,
                                                                                                    High consumption of fruit, vegetables,
     fonamides, tetracyclines,      hydralazine, macrolides,        trimethoprim, valproic
                                                                                                    legumes, cereal and fish. Low con-
     trimethoprim.                  oxytetracycline, quinestrol,    acid.
                                                                                                    sumption of meat and dairy. mono-
                                    tetracyclines, trimethoprim.
                                                                                                    unsaturated:saturated fat ratio is high.
                                                                                                    Low alcohol consumption.

                                                                                                    DIABETES AND THE BRAIN
                                                                                                      • Glycation
                                                       from rise in intracellular calcium             • Cytokines
        HOMOCYSTEINE                                   6. neuroprotective - inhibits molecular        • Cox-2 upregulation
        High levels are caused by B vitamin            cascades from a rise in intracellular          • Hypothalamicpituitary upregulation
        deficiencies. Homocysteine promotes            calcium                                        • NMDA receptor upregulation.
        dementia by:45,46,47,48                        7. increases glucose transport in the
          a) cerebral microangiopathy                  whole brain, through blood-brain bar-        Mitochondrial oxidative damage
          b) Oxidative stress                          rier, and in ischaemic penumbra                 • Inactivation of electron transport chain
          c) Apoptosis                                 8. improves memory, learning, cogni-            • Inhibition of energy production
          d) enhancement of b-amyloid                  tive performance, aphasia, dysar-               • Peroxidation of lipids
          neurotoxicity                                thria, agnosia, muscle strength and             • Oxidation of DNA
          e) nmdA mediated excitotoxicity.             coordination.                                   • Enhanced reactive oxygen species
        Treatment of elevated homocysteine           THE DIABETES AND MULTIPLE                      Antioxidants like vitamins e and c have
        with vascular damage:                        SCLEROSIS LINK                                 been proven to reduce the prevalence
          a) Folic acid: 800ug daily                   • Both autoimmune disorders                  of Alzheimer’s disease.56,57 Because
          b) Vit B6: 100 mg daily                      • More common in northern latitudes          of flawed methods and small clinical
          c) Vit B12: 1000ug twice daily or            • Related to cow’s milk intake               benefits, the scientific basis for recom-
          oral or sublingual B12                       in childhood                                 mendations of choline esterase inhibi-
          d) Trimethyglycine (TmG):                    • Essential fatty acid deficiency            tors for the treatment of Alzheimer’s is
          1000mg daily                                 • Vit D deficiency                           questionable.
          e) dHA: 300mg daily                          • Hippocampal damage and gluco-
          f) coQ10: 100mg daily                        corticoid hypersecretion (cortisol)
          g) nAc: 1000mg daily                         • Hypothalamic pituitary axis
        VINPOCETINE                                                                                 Drugs that deplete CoQ10:
        From the periwinkle plant.                   elevation of cortisol results in sleep frag-   Amitryptiline, beta-blockers,
        Mechanism of action: 49-55                   mentation, reduction of Rem sleep and          chlorpromazine, clonidine, desipramine,
          1. enhances brain circulation and          memory deficits. There is a link between       doxepin, fluphenazine, fluvastatin, glipizide,
          oxygenation                                sleep loss and diabetes mellitus. Sleep        glyburide, haloperidol, hydralazine,
          2. increases brain tolerance of            loss leads to behavioural, synaptic,           hydrochlothiazide, imipramine, lovastatin,
          hypoxia and ischaemia                      and membrane excitability alterations          nortryptaline, pravastatin, protryptline,
          3. inhibits phosphodiesterase              in hippocampal neurons. Obstructive            simvastatin, tolazemide, trimipramine
          4. Anticonvulsant                          sleep apnoea for example leads to
          5. improves rheological properties of      fragmented sleep and cognitive deficits
          blood, inhibits molecular cascades         and hippocampal atrophy. Antioxidants

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    CO-ENzYME Q10
    Low coQ10 leads to low activities of mi-
    tochondrial complexes i and iii and in-
    creased reactive oxygen species.58,59
    So mitochondrial dysfunction can be
    repaired by coQ10. This is a safe treat-
    ment and well tolerated.

    Parkinson’s and dementia patients
    have low levels of glutathione in the
    substantia negra. Glutathione dis-
    places Glutamate from the binding site,
    regulates calcium influx, and regulates
    the release of dopamine.
    Enhancing glutathione:
      Lipoic acid
      nAc, L-glutathione, L-cysteine, L-
      methionine, L-glutamine
      Reduces xenobiotic challenge
      Reduces drug challenge (P450 inducers)
      complementary antioxidants
      Silymarin, which increases retention.      learning. enhances memory, synaptic              3. drinking unfiltered water and
                                                 function and dendrite formation. im-             spraying insecticides or deodorants,
    DIETARY FATS                                 proved by dHA, caloric restriction, physi-       shampoos all expose the brain to
      • Hydrogenated fats increase the           cal and mental exercise, and a low               toxins that age the brain faster
      Alzheimer’s risk                           saturated fat diet. Low in Alzheimer’s,          4. Stress exposes the brain to hormones
      • Unhydrogenated fats reduce the           stroke, trauma and mS patients.64                that can destroy the memory centre.
      Alzheimer’s risk                                                                        That’s the bad news.The good news is
      • High Omega 6 reduces risk by 70%         CONCLUSION:                                  that brain degeneration is not inevitable.
      • Obesity increases the Alzheimer’s risk   The deterioration of brain function is       it can be stopped and reversed.The brain
      • Meat, eggs, high fat and alcohol in-     promoted by the following:                   has regenerative powers – all it requires is
      crease prostaglandin 2 series, which         1. OTc medications, commonly used          the right raw materials. Free radical dam-
      enhances inflammation                        drugs, antacids, non-aspirin pain          age can be restricted with antioxidants
      • A vegetarian diet and high levels          relievers, and cholesterol-lowering        from fruit and vegetables or supplements.
      of omega 3 and 6 increase prostag-           medications can starve the brain of        Keeping glutathione levels high is very
      landin 1 and 3 series, which reduce          important nutrients that keep it func-     brain-protective (eg nAc). Other impor-
      inflammation                                 tioning at an optimal level                tant brain-protective antioxidants include
      • Inhibitors of inflammation and             2. certain types of food (canned,          coQ10, curcumin and vitamins e and c.
      cox2/arachidonic acid/inflammation           smoked and pickled food, saturated         Omega 3 fish oil is also hugely beneficial.
      include: dHA Omega 3, ginger, tur-           fats) and alcohol
      meric, nSAidS and cOX 2 inhibitors.

    DHA OMEGA 3                                      NEuROLOGIST, DR DAVID ANDERSON, COMMENTS:
    Breast milk is the richest source. Others
    are fish and microalgae. dHA improves            The concepts of neurodegeneration and neuroprotection have
    mitochondrial and neuronal fluidity, as          expanded rapidly over the last few years with our understanding
    well as signal transduction. it assists          of the pathophysiology of diseases like Alzheimer’s, Parkinson’s,
    with neurogenesis, gliogenesis and syn-          Huntington’s and motor neuron disease.
    aptogeneis. Low levels are associated              Laboratory models have shown great promise for preventing
    with cognitive decline. dHA also helps           progression of these diseases by modulating inflammation and
    with cox-2 inhibition.60 - 63                    neuronal metabolism but, unfortunately, clinical trials have yet
                                                     to bear fruit that change clinical practice beyond the use of
    NEUROTROPHIC FACTORS                             cholinesterase inhibitors and vitamin e.65 This is likely to change
    nerve growth factor (nGF)                        as more phase three trials become available.
    Brain derived neurotrophic factor (BdnF)           This concise review allows doctors treating the ever-aging
    Basic fibroblast growth factor (bFGF)            population insight into the advances in this field. But more
    BDNF: neurotrophin important to neu-             importantly it gives hope for our patients.
    ronal integrity, neuronal plasticity and

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     References:                                          adults, aged 55-81. iV saline or insulin and         neJm 345(6), Aug 9, 2001:433
     1. evan, et al, JAmA, 1989; 262.                     dextrose to maintain euglycemia, “moderate           23. Resveratrol inhibits cox 2 transcription in
     2. Risk of Alzheimer’s disease and duration          hyperinsulinemia can increase inflammatory           human mammary epithelial cells, cancer
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     years: RR nSAid 0.4, Aspirin 0.74,                   14. Alzheimer’s dementia-synergistic effects of      Journal of Pharmacology 447(2-3).201-209;
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     6. increased density of glial cells express-         end products or a specific RAGe ligand sig-          et al, diabetes, 51 :1256-1262; April 2002 [2
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     per 3 quartiles had a 3-fold increased risk for      neurodegeneration offer new treatment op-            disease”]
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     10. number of Americans diagnosed with               duction.”]                                           the temporal lobe cortex of Alzheimer’s brains.
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     ease control and Prevention, neJm, 354:545;          by nAc (n-acetyl cysteine). Scnmugam, n. et          June 2000
     Feb 9, 2006                                          al. Jnl. of Biological chemistry 278(37): 34834-     30. Reduced risk of Alzheimer’s dementia
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     Hippocampal dendrites and Synaptic Reor-             19. controlled trial of nAc for patients with                  .P
                                                                                                               Zandi, P et al, Archives of neurology, 61:82-88,
     ganization and increased Glucocorticoid              probable Alzheimer’s, Adair, d. et al, neurol,       Jan 2004 [4 750 patients 65 or older assessed,
     reactivity to Stress. magarainos, PnAS, USA 97:      57:1515-1517; Oct 2001 [“comparison of inter-        1995-1997ànd 1998-2000 use of vitamins (mVT,
     11056:11601; Sept 26, 2000. [9 days of uncon-        val change favoured nAc treatment of nearly          e, c showed a decrease in the prevalence of
     trolled streptozotocin-induced diabetes in           every outcome measure”]                              Alzheimer’s by 78%)]
     rats produces retraction and simplification of       20. circulating levels of soluble receptor           31. Long term donepezil treatment in 565
     hippocampal dendrites and morphological              for advanced glycation end products of               patients with Alzheimer’s disease: randomized
     changes in the presynaptic terminal.]                Alzheimer’s disease and vascular dementia,           double blind trial, Alzheimer’s disease collabo-
     12. diabetes mellitus and the risk of dementia       emanuelle, e. et al, Arch neurol 62:1734-36,         rative group. Lancet 363: 2105-15; June 26,
     Rotterdam study, Ott, A. et al, neurology            nov 2005 [152 patients with Alzheimer’s, 91          2004 [565 patients, donepezil (aricept) 5, 10,
     53:1937-42, dec 1999 [6 337 patients with            with vascular dementia and 161 controls.             or placebo, 120 weeks, end points: institution-
     diabetes -1.9x RR of Alzheimer’s, RR of demen-       measurement of secreted isoform of RAGe]             alization, loss of AdLs, side effects. There was
     tia if using insulin 4.3 x]                          21. euronal cycloxegenase 2 expression in the        no reduction in the rate of institutionalization
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|                                                  |||                                                       | preventive medicine |

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