Nonconventional Treatments of Dementia/Mild Cognitive Impairment

If current population trends continue and treatments thatarrest or reverse Alzheimer disease (AD) are not found,the number of patients with AD in the United States isprojected to increase to more than 13 million by the year2050.¹ Numbers of persons afflicted with severe cognitiveimpairment caused by traumatic brain injury and stroke alsocontinue to increase. Developing effective and cost-effectivetreatment approaches for AD and the other dementias is clearlyan urgent priority.

In addition to conventional pharmacologictreatments of dementia andmilder forms of cognitive impairment,promising research findings are beingreported for many nonconventionaltreatments. “Nonconventional” treatmentsare those biologic, somatic,mind-body, and energy-informationapproaches not currently accepted inWestern biomedical psychiatry. Thiscolumn provides a brief overview ofthe evidence for selected nonconventionalapproaches used to treat dementiaand mild cognitive impairment inthe United States and other Westerncountries. A review of more substantiatedapproaches in this issue will befollowed in the next installment by highlightsof approaches for which there islimited evidence at present.

DIETARY MODIFICATION

Epidemiologic studies, case controlstudies, and prospective trials suggestthat persons who consume a high-fat,high-calorie diet are at significantlygreater risk for AD than are persons whohave moderate fat intake and restricttotal calories. A meta-analysis of findingsfrom 18 community-wide studiesconcluded that the risk of AD increasedlinearly at a rate of 0.3% with every100-calorie increase in daily intake.²However, a systematic review of 6 casecontrol studies and 3 cohort studies thatexamined dietary preferences in dementiaconcluded that there is no compellingevidence for causal relationshipsbetween specific dietary factors and therisk of becoming demented.³ Consistentrelationships between dietary protein,vitamins, and minerals and the risk ofdementia were not identified.

Evidence from epidemiologic studiessuggests that regular intake of foodsrich in omega-3 fatty acids may beinversely related to cognitive impairmentor the rate of overall cognitive declinein nondemented elderly persons. However,findings to date are inconclusive.A large epidemiologic study concludedthat consuming fish 2 to 3 times weekly significantly reduces the risk of cognitivedecline in elderly populations.⁴Cognitive impairment scores wereanalyzed for 2 groups of elderly men(aged 69 to 89) with different dietarypreferences. High fish consumption wasinversely correlated with cognitive impairment.Findings from a prospectivecohort study suggest thatpersons who consume fishat least weekly have a 60%lower risk of AD than dopersons who seldom eat fish.⁵ However,another study failed to show a correlationbetween fish consumption andthe risk of AD.⁶

Moderate but not heavy consumptionof wine (2 to 4 glasses per day) isalso associated with a reduced risk ofAD.⁷ In a large 2-year follow-up study,moderate alcohol consumption wasfound to be associated with a significantreduction in risk for both AD andvascular dementia.⁸

MEDICINAL HERBS ANDSUPPLEMENTS

Ginkgo Biloba
Standardized preparations of Ginkgobiloba are widely used in Europe totreat dementia and other neurodegenerativediseases. More recently, use ofG biloba has become widespread inNorth America. Systematic reviewsand early meta-analyses of double-blindcontrolled studies show that standardizedpreparations of G biloba in dosagesbetween 120 and 600 mg/d taken forseveral weeks to 1 year result in consistentmodest improvements. These improvementsinvolve memory, generalcognitive functioning, and activities ofdaily living in mild to moderate casesof both AD and multi-infarct dementiaand are equivalent to improvementsseen with donepezil (Aricept), a conventionalcholinesterase inhibitor.^3,9-13

However, a more recent meta-analysisrevealed inconsistent findings of 3trials based on more rigorous researchprotocols and commented on researchdesign problems in both recent and early impairtrials,including the absence of standardizedginkgo preparations and theuse of different dementia rating scalesacross studies.¹⁴ Although most controlledstudies fail to support the claimthat ginkgo significantly improvesmemory in severely demented patients,the findings of one double-blind studysuggest that the rate of overall cognitivedecline is moderately slowed inthis population.¹⁵ A systematic review of40 controlled and observational studiessuggests that ginkgo improves cognitivesymptoms associated with cerebralvascular insufficiency, including impairedconcentration and memory loss.¹⁶

To date, there is uneven evidencefor beneficial effects of G biloba in dementia.However, a review of researchfindings suggests that G biloba extractshould be regarded as aprovisional approach forthe prevention or treatmentof mild cognitive impairment.A meta-analysis of 11 clinicaltrials of G biloba extract in elderly personswho reported cognitive difficultiesbut did not meet full diagnostic criteriafor dementia confirmed consistentcognitive-enhancing effects.¹⁷ However,more recent large studies on ginkgo inmild cognitive impairment have yieldednegative findings.¹⁸ Long-term use ofG biloba extract in nonimpaired elderlypersons may improve the efficiency andspeed of information processing anddelay onset of mild cognitive impairment.^19,20 However, a recent, largecontrolled trial failed to confirm aconsistent preventive effect.²¹

Because of its strong anti–plateletaggregation factor profile, G bilobaextract increases the risk of bleedingand should not be used by patients takingaspirin, warfarin, heparin, or other medicationsthat interfere with platelet activityand increase bleeding time. G bilobapreparations should be discontinued atleast 2 weeks before surgery.

Huperzine-A

This alkaloid derivative of the herbHuperzia serrata is an important ingredientof many compound herbal formulasused in Chinese medicine to treatmild cognitive impairment that occurswith normal aging. Huperzine-Areversibly inhibits acetylcholinesteraseand may also slow production of nitricoxide in the brain, possibly reducing agerelatedneurotoxicity.²² Controlled trialsshow consistent beneficial effects in bothage-related memory loss and AD atdosages between 200 and 400 g/d.^23,24 Infrequent adverseeffects include transientdizziness, nausea,and diarrhea.

Phosphatidylserine

This compound isone of the most importantphospholipids in the brain andis an essential component of nerve cellmembranes. The mechanism of actionis believed to be enhanced fluidity ofnerve cell membranes, indirectly resultingin increased brain levels of manyimportant neurotransmitters.²⁵ Brainderivedphosphatidylserine is probablymore effective than the soy-derivedproduct,²⁶ possibly because of its highercontent of docosahexaenoic acid, anomega-3 fatty acid, but recent concernshave been raised over the risk of slowviruses in infected bovine tissue. Thefindings of large, double-blind, placebocontrolledstudies confirm improvedglobal functioning and memory in ADand age-related cognitive decline attypical dosages of 300 mg/d.^27-31

CDP-choline

Cytidinediphosphocholine (CDPcholine)increases mitochondrial energyproduction and is used in many parts ofthe world to treat cognitive impairmentsthat result from neurodegenerative diseases.CDP-choline, 500 to 1000 mg/d,improves overall energy metabolism inthe brain, increases brain levels of dopamineand norepinephrine,³² and enhancesshort-term memory in patientswith AD.³³ Two Cochrane systematicreviews concluded that CDP-cholinehas consistent positive effects on the rateof recovery in post-stroke patients andin elderly persons who are cognitivelyimpaired because of cerebrovasculardisease.^34,35 There is preliminary butpromising evidence of a beneficial effectfollowing traumatic brain injury.³⁶The findings of one small study suggesta possible effect of CDP-choline, 1000mg/d, in the early stages of AD.³⁷

Idebenone

This is a substance that is related toubiquinone (coenzyme Q10), and likethat compound, it also increases intracellularenergy production in mitochondria.Animal and human studieshave shown that idebenone, 360 mg/d,may be more effective than tacrine(Cognex)³⁸ and possibly other conventionaltreatments of cognitive impairtment in mild to moderate cases of AD.³⁹However, in a large multicenter, doubleblind,placebo-controlled randomizedtrial, patients with probable early AD whoreceived varying dosages of idebenoneup to 300 mg tid did not experience slowingin the rate of cognitive decline comparedwith a control group.⁴⁰

SOMATIC AND MIND-BODYAPPROACHES
Physical exercise

Exercise increases levels of brainderivedneurotrophic factors, probablyenhancing neural plasticity and newsynapse formation.⁴¹ Regular exerciseis associated with increases in the relativesize of the frontotemporal and parietallobes, which are important centersfor learning, memory, and executivefunctioning.42 Long-term regular physicalactivity is associated with a reducedrisk of all categories of dementia inelderly men and women.

More than 2000 physically nonimpairedmen aged 71 to 93 years weremonitored with routine neurologic assessmentsat 2-year intervals starting in1991.⁴³ At the end of the study period,men who walked less than a quarter ofa mile daily had an almost 2-fold greaterprobability of having any category ofdementia compared with men whowalked at least 2 miles each day. Factorsother than the level of physical activitywere accounted for, including the possibilitythat limited activity could be a resultof early but undiagnosed dementia.

Findings of the Nurses' Health Study,based on biannual mailed surveys over10 years, showed that elderly womenaged 70 to 81 years who engaged inregular vigorous physical activity weresignificantly less likely to have dementiathan were women with more sedentarylifestyles.⁸ Although regular exerciseis an important preventive strategy, itis probably not an effective interventiononce dementia has begun. Arandomized controlled trial showed thatregular daily exercise in moderatelydemented individuals receiving in-homecare reduces depressed mood but doesnot improve cognitive functioning.⁴⁴

References:

References

1.

Hebert LE, Scherr PA, Bienias JL, et al.Alzheimer disease in the US population: prevalenceestimates using the 2000 census. Arch Neurol.2003;60:1119-1122.

2.

Grant W. Dietary links to Alzheimer's disease.Alzheimer's Dis Rev. 1997;2:42-55.

3.

Ernst E. Diet and dementia, is there a link? A systematicreview. Nutr Neurosci. 1999;2:1-6.

4.

Kalmijn S, Feskens EJ, Launer LJ, Kromhout D.Polyunsaturated fatty acids, antioxidants, and cognitivefunction in very old men. Am J Epidemiol.1997;145:33-41.

5.

Morris MC, Evans DA, Bienias JL, et al.Consumption of fish and n-3 fatty acids and risk ofincident Alzheimer disease. Arch Neurol.2003;60:940-946.

6.

Engelhart M, Geerlings M, Ruitenberg A, et al.Dietary intake of antioxidants and risk of Alzheimer'sdisease. JAMA. 2002;287:3223-3229.

7.

Orgogozo JM, Dartigues JF, Lafont S, et al. Wineconsumption and dementia in the elderly: a prospectivecommunity study in the Bordeaux area. RevNeurol (Paris). 1997;153:185-192.

8.

Deng J, Zhou DH, Li J, et al. A 2-year follow-upstudy of alcohol consumption and risk of dementia.Clin Neurol Neurosurg. 2006;108:378-383.

9.

Wong AH, Smith M, Boon HS. Herbal remediesin psychiatric practice. Arch Gen Psychiatry.1998;55:1033-1044.

10.

Kanowski S, Herrmann WM, Stephan K, et al.Proof of efficacy of the Ginkgo biloba special extractEGb 761 in outpatients suffering from mild to moderateprimary degenerative dementia of the Alzheimertype or multi-infarct dementia. Pharmacopsychiatry.1996;29:47-56.

11.

Oken BS, Storzbach DM, Kaye JA. The efficacyof Ginkgo biloba on cognitive function in Alzheimerdisease. Arch Neurol. 1998;55:1409-1415.

12.

Le Bars PL, Katz MM, Berman N, et al. A placebocontrolled,double-blind, randomized trial of onextract of Ginkgo biloba for dementia. North AmericanEGb Study Group. JAMA. 1997;278:1327-1332.

13.

Itil TM, Eralp E, Ahmed I, et al. The pharmacologicaleffects of Ginkgo biloba, a plant extract, onthe brain of dementia patients in comparison withtacrine. Psychopharmacol Bull. 1998;34:391-397.

14.

Birks J, Grimley E. Ginkgo biloba for cognitiveimpairment and dementia (Cochrane Review). In: TheCochrane Library. Issue 2. Chichester, UK: John Wiley& Sons; 2004.

15.

Le Bars PL, Velasco FM, Ferguson JM, et al.Influence of the severity of cognitive impairment onthe effect of the Ginkgo biloba extract EGb 761 inAlzheimer's disease. Neuropsychobiology.2002;45:19-26.

16.

Kleijnen J, Knipschild P. Ginkgo biloba. Lancet.1992;340:1136-1139.

17.

Hopfenmuller W. Evidence for a therapeuticeffect of Ginkgo biloba special extract. Meta-analysisof 11 clinical studies in patients with cerebrovascularinsufficiency in old age [in German].Arzneimittelforschung. 1994;44:1005-1013.

18.

van Dongen M, van Rossum E, Kessels A, et al.Ginkgo for elderly people with dementia and ageassociatedmemory impairment: a randomized clinicaltrial. J Clin Epidemiol. 2003;56:367-376.

19.

Allain H, Raoul P, Lieury A, et al. Effect of two dosesof ginkgo biloba extract (EGb 761) on the dual-codingtest in elderly subjects. Clin Ther. 1993;15:549-558.

20.

Semlitsch HV, Anderer P, Saletu B, et al. Cognitivepsychophysiology in nootropic drug research: effectsof Ginkgo biloba on event-related potentials (P300)in age-associated memory impairment.Pharmacopsychiatry. 1995;28:134-142.

21.

Cheuvront SN, Carter R III. Ginkgo and memory.JAMA. 2003;289:547-548.

22.

Zhao HW, Li XY. Ginkgolide A, B, and huperzineA inhibit nitric oxide-induced neurotoxicity. IntImmunopharmacol. 2002;2:1551-1556.

23.

Wang Z, Ren Q, Shen Y. A double-blind controlledstudy of huperzine A and piracetam in patients withage-associated memory impairment and dementia.In: Kanba S, Richelson E, eds. Herbal Medicinesfor Nonpsychiatric Diseases. Tokyo: Seiwa SholenPublishers; 1999:39-50.

24.

Zucker M. Huperzine-A: the newest brain nutrient.Let's Live. 1999:47-48.

25.

Pepeu G, Pepeu IM, Amaducci L. A review ofphosphatidylserine pharmacological and clinicaleffects. Is phosphatidylserine a drug for the ageingbrain? Pharmacol Res. 1996;33:73-80.

26.

Hibbeln JR, Salem N Jr. Dietary polyunsaturatedfatty acids and depression: when cholesterol doesnot satisfy. Am J Clin Nutr. 1995;62:1-9.

27.

Cenacchi T, Bertoldin T, Farina C, et al. Cognitivedecline in the elderly: a double-blind placebocontrolledmulticenter study on efficacy of phosphatidylserineadministration. Aging (Milano).1993;5:123-133.

28.

Crook TH, Tinklenberg J, Yesavage J, et al. Effectsof phosphatidylserine in age-associated memoryimpairment. Neurology. 1991;41:644-649.

29.

Villardita C, Grioli S, Salmeri G, et al. Multicentreclinical trial of brain phosphatidylserine in elderlypatients with intellectual deterioration. Clin Trials J.1987;24:84-93.

30.

Palmieri G, Palmieri R, Inzoli M, et al. Doubleblindcontrolled trial of phosphatidylserine in patientswith senile mental deterioration. Clin Trials J.1987;24:73-83.

31.

Amaducci L. Phosphatidylserine in the treatmentof Alzheimer's disease: results of a multicenter study.Psychopharmacol Bull. 1988:24;130-134.

32.

Secades JJ, Frontera G. CDP-choline: pharmacologicaland clinical review. Methods Find Exp ClinPharmacol. 1995;17(suppl B):1-54.

33.

Alvarez XA, Laredo M, Corzo D, et al. Citicolineimproves memory performance in elderly subjects.Methods Find Exp Clin Pharmacol. 1997;19:201-210.

34.

Mitka M. News about neuroprotectants for thetreatment of stroke. JAMA. 2002;287:1253-1254.

35.

Fioravanti M, Yanagi M. Cytidinediphosphocholine(CDP Choline) for cognitive and behavioraldisturbances associated with chronic cerebral disordersin the elderly (Cochrane Review). In: TheCochrane Library. Issue 2. Chichester, UK: John Wiley& Sons; 2004.

36.

Spiers PA, Hochanadel G. Citicoline for traumaticbrain injury: report of two cases, including my own.J Int Neuropsychol Soc. 1999;5:260-264.

37.

Alvarez XA, Mouzo R, Pichel V, et al. Doubleblindplacebo-controlled study with citicoline in APOEgenotyped Alzheimer's disease patients. Effects oncognitive performance, brain bioelectrical activity andcerebral perfusion. Methods Find Exp Clin Pharmacol.1999;21:633-644.

38.

Gutzmann H, Kuhl KP, Hadler D, Rapp MA. Safetyand efficacy of idebenone versus tacrine in patientswith Alzheimer's disease: results of a randomized,double-blind, parallel-group multicenter study.Pharmacopsychiatry. 2002;35:12-18.

39.

Gutzmann H, Hadler D. Sustained efficacy andsafety of idebenone in the treatment of Alzheimer'sdisease: update on a 2-year double-blind multicentrestudy. J Neural Transm Suppl. 1998;54:301-310.

40.

Thal LJ, Grundman M, Berg J, et al. Idebenonetreatment fails to slow cognitive decline in Alzheimer'sdisease. Neurology. 2003;61:1498-1502.

41.

Cotman CW, Berchtold NC. Exercise: a behavioralintervention to enhance brain health and plasticity.Trends Neurosci. 2002;25:295-301.

42.

Haier RJ. Cerebral glucose metabolism and intelligence.In: Vernon PA, ed. Biological Approaches tothe Study of Human Intelligence. Norwood, NJ:Ablex Publishing; 1993:318-332.

43.

Abbott RD, White LR, Ross GW, et al. Walkingand dementia in physically capable elderly men. JAMA.2004;292:1447-1453.

44.

Teri L, Gibbons LE, McCurry SM, et al. Exerciseplus behavioral management in patients withAlzheimer's disease: a randomized controlled trial.JAMA. 2003;290:2015-2022.