NEW THERAPEUTICAL ALTERNATIVES AND OUTCOME IN MILD COGNITIVE IMPAIRMENT

ORIGINAL ARTICLES NEW THERAPEUTICAL ALTERNATIVES AND OUTCOME IN MILD COGNITIVE IMPAIRMENT 1 2 Camelia Mila, Delia M. Podea Abstract: Background: Mild cognitive impairment (MCI) is an etiological heterogeneous condition characterized by cognitive decline greater than expected for an individual's age and education level but does not interfere notably with daily activities. At this time there is no standard treatment for this condition. Objective: The aim of this study is to determine comparatively the outcome of patients diagnosed with mild cognitive impairment and treated with different therapies. Method: The study evaluated a number of 250 elderly patients diagnosed with mild cognitive impairment and treated with different therapies. The patients were identified by screening, and evaluated with Mini Mental State Examination (MMSE); clock test and Raven Test at the inclusion in the study, after 1 month, after 6 months and after 1 year of treatment. The patients were divided in five groups: - group A, 50 elderly patients treated with piracetamum (1600mg/day); - group B, 50 patients treated with Rhodiola-rosea ( Rhodiolin 2 capsules/day); - group C, 50 patients diagnosed with mild cognitive impairment treated with Vitamin E (400mg/day); - group D comprises 50 patients treated with piracetamum (1600 mg/day) associated with 2 capsules/day of rhodiola rosea and vitamin E ( 400 ui/day); - group E, 50 elderly patients with mild cognitive impairment without treatment. In this group we have studied the natural evolution without treatment. Results: At the inclusion in study we have have similar groups having into account MMSE score and clock test score. After 1 month we have observed an improvement in group A, B, C and D and an little impairment in Group E. The third (after 6 months) and fourth evaluation (after 1 year of treatment) show improvement in groups treated compared with non-treated group. Conclusions: Different type of treatment determine improvement of cognitive function in elderly and absence of treatment is a risk factor for progression to dementia. Keywords: mild cognitive impairment syndrome, anti- BACKGROUND Mild cognitive impairment (MCI) is an etiological heterogeneous condition characterized by cognitive decline greater than expected for an individual's age and Rezumat: Introducere: Deficitul cognitiv u?or este o condiþie etiologicã heterogenã caracterizatã prin declin cognitiv mai mare decât declinul cognitiv asociat vârstei, dar care nu afecteazã activitãþile zilnice ale individului. La ora actualã nu existã tratament standardizat al acestei afecþiuni. Obiectiv: Obiectivul acestui studiu a fost de a determina comparativ evoluþia pacienþilor diagnosticaþi cu deficit cognitiv uºor ºi care au primit diferite tipuri de tratament. Metoda: Studiul evalueazã un numãr de 250 de pacienþi diagnosticaþi cu deficit cognitiv uºor?i trataþi cu diferite clase medicamentoase. Pacienþii au fost identificaþi prin screening ºi evaluaþi cu testul MMSE; testul ceasului?i testul Raven la includerea în studiu, dupã o lunã, dupã 6 luni?i dupã un an de tratament. Pacienþii au fost împãrþiþi în 5 grupuri: - grup A 50 de pacienþi vârstnici trataþi cu Piracetamum (1600mg/zi); - grup B 50 de pacienþi trataþi cu rhodiola- rosea (Rhodiolin 2 capsule/zi); - grup C 50de pacienti tratati cu Vitamina E (400mg/zi); - grup D cuprinde 50de pacienti tratati cu piracetamum (1600mg/zi) asociat cu 2capsule/zi de Rhodiola-rosea?i vitamina E (400mg/zi); -grup E, 50 de pacienþi vârstnici diagnosticaþi cu deficit cognitiv uºor care nu au primit tratament, acestora urmãrindu-li-se evolu?ia naturalã. Rezultate: Rezulatele la testul MMSE ºi testul ceasului au fost similare în grupurile studiate la momentul includerii în studiu. Dupã o lunã de tratament am observat o îmbunãtãþire a funcþiei cognitive la pacienþii din grupurile A, B, C?i D?i un usor declin în grupul E. Cea de-a treia (dupa 6luni)?i a patra evaluare ( dupa 1an) demonstreazã ameliorare ( îmbunãtãþire a funcþiei cognitive la pacienþii care urmeazã tratament pentru deficitul cognitiv uºor comparativ cu cei din grupul E, a cãror evoluþie este caracterizatã de progresia deficitului cognitiv. Concluzii: Administrarea tratamentului în deficitul cognitiv uºor conduce la îmbunãtãþirea funcþiei cognitive, în contrast lipsa tratamentului este urmatã de progresia deficitului cognitiv ºi instalarea demenþei. Cuvinte cheie: sindrom de deficit cognitiv u?or, terapie anti-îmbãtrânire, tratament alternativ,antioxidanþi education level but that does not interfere notably with activities of daily life, subjects perform more poorly on a variety of cognitive, functional and behavioral measures than normal person of the same age, but the cognitive decline is not enough severe to characterize dementia (1). 1 MD, Psychiatrist, PhD student West Vasile Goldis University of Arad, Department of Psychiatry, Arad, 17, Octavian Goga street, tel. 0040357407216, fax 004025725001, mobil: 0040747258478, email: grcami@yahoo.com. 2 Professor Dr., West Vasile Goldis University of Arad, Department of Psychiatry, Arad, 17, Octavian Goga street, tel. 0040357407216, fax 004025725001, mobil: 0040722583757, email: deliapodea@yahoo.com Received January 20, 2012, Revised March 02, 2012, Accepted April 13, 2012 65

Camelia Mila, Delia M. Podea : New Therapeutical Alternatives And Outcome In Mild Cognitive Impairment Currently this condition is considered to be a transitional stage between normal age and dementia. According to many studies mild cognitive impairment is an indicator for Alzheimer's disease in the next years and in the last time there are new theories that MCI is a prodromal stage of dementia. The cognitive changes in mild cognitive impairment are pathological and does not appear with aging and affect memory, attention, thought, ability of abstraction and sequencing of actions and solving problems (2, 3, 4). MCI is a relatively common entity, affect 10-17% of elderly people, the prevalence is 3-5% over 60 years, 15% over 75 and after 85 is 25% (5). For diagnosis of mild cognitive impairment are used the Peterson criteria (2001): 1.- memory complaint, preferably corroborated by informant 2.- impairment is 1.5 standard deviations(sd) below peer norms 3.- impaired memory function for age and education 4.- preserved general cognitive function 5.- intact activities of daily living 6.- not demented (6) MCI is a syndrome with one or more underlying causes. The etiology includes different factors, between these are food, smoking, stress and other medical disorders. Stress is the underlying cause for depression and untreated depression is a major risk factor for cognitive impairment and for dementia. Another risk factors for mild cognitive impairment are: cardiovascular disease, abnormal blood pressure, either too high or too low, metabolic disorders, low levels of physical, social and mental activity, fewer years of education. People who have higher levels of social, mental and physical activity seem to have less risk of MCI and dementia. A recent study done at Mayo Clinic revealed that the prevalence of mild cognitive impairment is higher in men and is increased with age and also to subjects who never married (7). The same study revealed that MCI prevalence decreased with increasing number of years of education (7). In present there is no specific treatment for mild cognitive impairment, the treatment for Alzheimer's disease could be extrapolated and used for patients diagnosed with mild cognitive impairment but many trials of treatments for MCI over the past few years have had negative results. Most of these trials involved Alzheimer's drugs MCI patients taking the drugs did no better on cognitive tests than those taking placebos. Researchers still face significant challenges before the goal of early diagnosis and treatment can be met. Third age involve, generally a differentiated psychotropic treatment because the older has a higher susceptibility than younger and require low doses. The adequate treatment for MCI includes non-pharmacological and pharmacological treatment. Pharmacological treatment shared the risk factors treatment and the pharmacological treatment for cognitive symptoms. Non-pharmacological treatment includes physical activity, diet and cognitive intervention (psychotherapy, verbal and behavioral targeting, cognitive and memory training and art therapy) (8). MCI can be improved by anti-aging products like: omega- 3 acids, herbal natural products (vinpocetinum, Rhodiolarosea, gingko-biloba), nootropics (Piracetam), antioxidants (Vitamin E, Vitamin C, Vitamin A, alphalipoic acid, Co-enzyme Q10). There is a reduce number of studies to sustain the validity, the secure and the effectiveness of this type of treatment for the psychiatric disorders, therefore the acceptance of alternative therapies is still low. Rhodiola-rosea is a herbal alternative treatment for mild cognitive impairment, this plant grows in the mountains of eastern Europe, Siberia and the Far East at 3000 meters. Its beneficial effects on the body have been mentioned 1,200 years ago in the writings of Tibetans. Its extract (bioactive alkaloids, polyphenols and phenylpropanoids including tyrosol, rosavin, rosin and rosarin) have complex effects on brain function: cognitive stimulation with emotional calming. The extracts of the roots of this plant have been found to favorably affect a number of physiological functions including neurotransmitter levels, central nervous system activity, and cardiovascular function. It is being used to decrease depression, enhance work performance, enhance learning and memory, increase accuracy in mental performance for prolonged periods of time, eliminate fatigue and prevent high-altitude sickness. The effects of Rhodiola Rosea are augmented in combination with Piracetam or ginseng. In clinical practice, the authors have found Rhodiola rosea to beneficial in a wide range of disorders of memory, cognition and fatigue. Increased clinical use and research will be highly beneficial (10). Antioxidants (vitamin E, Vitamin C, Vitamin A, alfalipoic acid, Co-enzyme Q10) are substances which may protect brain cells from the oxidative stress (1). The oxidative stress plays a role in Alzheimer's, but there's little evidence that either is effective in preventing MCI from progressing to dementia. In this study we have used for the third group vitamin E. Vitamin E has antioxidant properties involved in scavenging free radicals, laboratory and animal studies have pointed towards a possible role for Vitamin E in the prevention and management of cognitive impairment. OBJECTIVE The aim of this study is to determine, comparatively, the outcome of the patients diagnosed with mild cognitive impairment treated with nootropics (Piracetam piracetamum), alternative herbal agents (Rhodiolin - contain Rhodiola Rosea powder extract (100 mg) and zinc (5 mg) and antioxidant agents ( Vitamin E 400U.I./day). MATERIAL AND METHODS The patients with mild cognitive were identified by screening and before any procedure specific for our study has been performed subjects were asked to sign the informed consent to participate in this study. We have explained to subjects and their families the objective of our research, all the procedures that will be done in the study and the possible adverse events that can appear. The subjects were informed that they can withdraw from the study any time and these will not affect the relationship between them and doctor. After inclusion in the study, at the first visit, we have evaluated anamnestic the subjects included. We tried to identify the medical history and the possible risk factors for mild cognitive impairment like: arterial hypertension, cerebrovascular diseases, metabolic diseases 66

Romanian Journal of Psychiatry, vol. XIV, No.2, 2012 (hypercholesterolemia, diabetes mellitus), lifestyle, smoking, diet, alcohol consumption, education and history of dementia in their families. The subjects were evaluated with neuropsychological scales (MMSE; Clock test and Raven test). Patients who were selected in this study had a MMSE score between 21-28 points; this MMSE score is considered mild cognitive impairment. The study comprises a number of 250 elderly patients diagnosed with MCI. Patients with MCI were assigned to four groups of different treatment based on nootropics, herbal natural products and antioxidants and a group of 50 patients did not received treatment. Using MMSE scale, Clock test and Raven test, the four groups were evaluated at the screening, after 1 month, after 6 months and after one year of treatment. The study followed which from the four regimen were more efficacy for the improvement of MCI. -group A that comprises 50 elderly patients diagnosed with MCI that were treated with piracetamum 4 tablets/day (daily dose:1600 mg); -group B that comprises 50 elderly patients diagnosed with MCI that were treated with rhodiola rosea, 2 capsules/day; -group C that comprises 50 elderly patients which were treated with antioxidant agents ( vitamin E 400ui/day, 1 capsule/day); -group D that comprises 50 elderly subjects (over 65 years) with MCI treated with piracetamum (1600mg/day) associated with 2capsules/day of rhodiola rosea and vitamin E ( 400ui/day); -group E 50 elderly patients with MCI without treatment. In this group we have studied the natural evolution without treatment. The inclusion criteria were: -patients with 65 years of age and older than 65 -patients diagnosed with MCI: The exclusion criteria were: -patients younger than 65 years. -patients with mild cognitive impairment due to major depressive disorder and schizophrenia. -patients with moderate and severe cognitive impairment Statistical analysis The statistical analysis was performed using SPSS software for Windows, version 8.0 to determine the statistical significance of the data obtained. RESULTS In our study we have identified and included subjects with MCI using MMSE; clock test and Raven test. We tried to have similar groups having into account subject's age (as illustrated in fig. 1), sex (fig. 2) and MMSE score at the inclusion (fig. 3). Fig. 1. The analysis for groups function of age Fig. 2. The analysis for groups function of gender Fig. 3. MMSE scores at inclusion The average of MMSE scores at the inclusion into the study was 23, 96 points for group A, 24,16 points for group B, 24,34 points for group C, 23,92 points for group D and 24,5 points for group E. As shown in Table no. 1, the mean of the MMSE scale was 24.17 (SD=2.47) points (the maximum being 30 points). MEAN Table 1. MMSE mean and standard deviation In all study groups we have noticed a bigger number of men comparing with women, which show us that the prevalence of mild cognitive impairment is higher in men. As illustrated in the next chart (fig. 4) the score obtained for "Clock Test" is reduced by an average of 1.08 points out of the maximum 4 points. Fig. 4. Clock test average SD 24,17 2,47 Comparing Clock t est av erage wit h clock test maximum 4 values 4 3,5 3 2,5 2 1,5 1 0,5 0 2,92 average max imum c lock test resu lts 67

Camelia Mila, Delia M. Podea : New Therapeutical Alternatives And Outcome In Mild Cognitive Impairment Most of the subjects included in the study had cortical atrophy (165 patients, respectively 66%), 33 patients had hippocampal atrophy (13,2%) and 52 patients had leukoaraiosis, respectively 20,8%. C om p a rin g MMS E res u lt s at in c lu s io n an d a f te r 1 m o nt h MMSE 2 5 24,8 24,6 24,4 24,2 2 4 23,8 23,6 23,4 A B C D E inclus io n a f ter 1 mo nth Grou ps Fig. 5. MMSE scores at inclusion and after one month of treatments After 1 month of treatment, cognitive performance improves with 0,62 points for group A with 0,6 points for group B, 0,3 points for group C, 0,48 points in group D and in group E we observed an impairment of 0,2 points (fig. 5). Evaluation of patients after 6 months of treatment proves the efficacy of treatment to all four treated groups comparing to control group. In group E the patients present an impairment of cognitive performance. The statistically differences are between group E and all other study groups, using One-way ANOVA method we obtain F (4, 245)= 10,803; p=.000 ( p <.05) ( as shown in table no.2). After 1 year of treatment we have observed an improvement in groups A, B, C and D and an impairment in group E, 20% of the patients were diagnosed with dementia. This impairment confirmed us that without treatment patients with MCI progress to dementia. Using the same method, One-way Anova we obtain F (4,245)= 71,161 and p=.000 statistically significant ( p<0.05) ( table no. 3). Mean D ifference (I- J) Std. Error Sig. 95% Confidence Interval (I) GROUP (J) GROUP Lower Bo und Upper Bound group A group E 1,9000,403,000,6505 3,1495 group B group E 2,0800,403,000,8305 3,3295 group C group E 1,9800,403,000,7305 3,2295 group D group E 2,300,403,000 1,0505 3,5495 group E group A -1,900,403,000-3,1495 -,65 05 group E group B -2,0800,403,000-3,3295 -,83 05 group E group C -1,9800,403,000-3,2295 -,73 05 group E group D -2,3000,403,000-3,5495-1,0 505 Table 2. Statistical results after 6 months of treatment M e an D if fe renc e (I- J) S td. Err or S ig. 95% C onfidenc e Inte rval (I ) GR OUP ( J) GRO UP Lowe r Bo und Upper B ound group A gr oup C - 1,2800,377,024-2,4515 -,10 85 gr oup E 4,2600,377,000 3,0885 5,4315 group B gr oup E 4,3800,377,000-3,2085 5,5515 group C gr oup A 1,2800,377,024,1085 2,4515 gr oup E 5,5400,377,000 4,3685 6,7115 group D gr up E 5,3200,377,000 4,1485 6,4915 group E gr oup A - 4,2600,377,000-5,4315-3,0 885 gr oup B - 4,3800,377,000-5,5515-3,2 085 gr oup C - 5,5400,377,000-6,7115-4,3 685 gr oup D - 5,3200,377,000-6,4915-4,1 485 Table 3. Statistical results at the end of the study 68

Romanian Journal of Psychiatry, vol. XIV, No.2, 2012 DISCUSSIONS MCI is a term that is used to describe the decline of cognitive performance of a person who does not meet the diagnostic criteria for dementia, a border area characterized by cognitive decline, a prodromal stage of Alzheimer's dementia. The rate of transition from mild cognitive impairment to dementia has been estimated to be 10-15% per year and grow every year until 50% after 5 years. Patients who present diagnostic criteria for MCI should be monitored closely because of the increased risk of developing dementia. Currently there is no standard by which to monitor patients with MCI; in most cases, the practitioner's position is to wait and retest the cognitive functions, in order to detect any worsening or to establish a diagnosis of dementia. CONCLUSIONS In our study, we tried to show that alternative therapies are usefull for patients with MCI. Following the improvement of the cognitive impairment (using cognitive scales at the screening after 1 month, after 6 months and afer 1 year of treatment) at the four groups of patients treated with different regimens (group A - nootropics, group B herbal natural products, group C antioxidants and group D a combined treatment) and comparing with a group of patients which doesn't received any treatment, the study revealed a better improvement for group A and B, those treated with piracetamum and Rhodiola-rosea after 1 month of treatment, but the results for group C showed a better improvement after a longer period of treatment. After 1 year of treatment we observed statistically difference between group A treated with nootropics and group C treated with antioxidants (p=0.024) and another statistically difference is between the groups which received treatment and group E. We took into consideration the alternative therapies because we refer mainly to primary prevention, which can be applied also by general physicians, without the need for health professionals. The results being favorable, the therapy can be instituted with confidence and at lower costs compared with anti-dementia products. Alternative therapies along with lifestyle changes (exercises, Mediterranean diet) may contribute to primary prevention of dementia. We hope that our results will help to increase the use rates of the alternative therapies, to enlarge the spectrum of therapies in mild cognitive impairment. REFERENCES 1.Agronin ME. Alzheimer Disease and Related Dementias: A Practical Guide. 2nd ed. Baltimore, MD: Lippincott Williams and Wilkins, 2007. 2.Winblad B, Palmer K, Kivipelto M et al. Mild cognitive impairment beyond controversies, towards a consensus: report of the International Working Group on Mild cognitive impairment. J Int Med 2004; 256:240-246. 3.Dubois B, Albert LM. Amnestic MCI or prodromal Alzheimer's disease? The Lancet Neurology 2004; 3:246-248. 4.Dubois B, Feldman HH, Jacova C et al. Revising the definition of Alzheimer's disease: a new lexicon. The Lancet Neurology 2010;9: 1118-1127. 5.Edwards KR. Alzheimer's Disease and Dementia. Medscape Neurology, 2007. 6.International Psychogeriatrics. Special Issue focus on Mild Cognitive Impairment. Cambridge University Press 2008; 20: 1-16. 7.Petersen RC, Roberts RO, Knopman DS et al. Prevalence of mild cognitive impairment is higher in men. The Mayo Clinic Study of Aging Neurology 2010 ;75(10): 889-897. 8.Moniz-Cook E, Manthorpe J. Early psychosocial Intervention in Dementia, Evidence -Based Practice. London, Philadelphia: Jessica Kingsley publishers, 2009, 81-92. 9.Burns JM, Morris JC. Mild Cognitive Impairment and Early Alzheimer's Disease detection and diagnosis. Wiley, 2008. 10.Tassman A, Kay J, Lieberman JA. Psychiatry, Second Edition. Wiley, 2008, 2161-2180. 11.DeCarli Ch. Mild cognitive impairment: prevalance, prognosis, aetiology and treatment. Lancet Neurology 2003;2: 15-21. 12.Petersen RC, Smith GE, Waring SC et al. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol 1999;56: 303-8. ABBREVIATIONS Mild cognitive impairment -MCI Mini mental state examination -MMSE *** 69