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Hindawi Publishing Corporation Journal of Neurodegenerative Diseases Volume 2013, Article ID 454253, 7 pages http://dx.doi.org/10.1155/2013/454253 Clinical Study The Effect of Lipoic Acid Therapy on Cognitive Functioning in Patients with Alzheimer’s Disease 1 2 2 Antonietta Fava, Domenico Pirritano, Massimiliano Plastino, 2 2 3 4 Dario Cristiano, Giovanna Puccio, Carmen Colica, Caterina Ermio, 5 6 2 Matteo De Bartolo, Gaetano Mauro, and Domenico Bosco Department of Clinical and Experimental Medicine, University of Catanzaro, 88100 Catanzaro, Italy Department of Neuroscience, “S. Giovanni di Dio” Hospital, 88900 Crotone, Italy Institute of Neurological Science, National Research Council, Roccelletta di Borgia, 88021 Catanzaro, Italy Department of Neuroscience, “S. Giovanni Paolo II” Hospital, 88046 Lamezia Terme, Catanzaro, Italy Neurophysiology Unit, General Hospital, 87067 Rossano, Cosenza, Italy General Medicine Unit, General Hospital, 87055 San Giovanni in Fiore, Cosenza, Italy Correspondence should be addressed to Domenico Bosco; nico email@example.com Received 24 December 2012; Revised 27 February 2013; Accepted 13 March 2013 Academic Editor: Seishi Terada Copyright © 2013 Antonietta Fava et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Diabetes mellitus (DM) is an important risk factor for Alzheimer’s disease (AD). Most diabetic patients have insulin resistance (IR) that is associated with compensatory hyperinsulinemia, one of the mechanisms suggested for increased AD risk in patients with DM. Alpha-lipoic acid (ALA) is a disulfide molecule with antioxidant properties that has positive effects on glucose metabolism and IR. This study evaluated the effect of ALA treatment (600 mg/day) on cognitive performances in AD patients with and without DM. One hundred and twenty-six patients with AD were divided into two groups, according to DM presence (group A) or absence (group B). Cognitive functions were assessed by MMSE, Alzheimer’s Disease Assessment Scale-cognitive (ADAS-Cog), Clinician’s Interview-Based Impression of Severity (CIBIC), Clinical Dementia Rating (CDR), and Alzheimer’s Disease Functional and Change Scale (ADFACS). IR was assessed by HOMA index. At the end of the study, MMSE scores showed a significant improvement in 43% patients of group A (26 subjects) and 23% of group B (15 subjects), compared to baseline (𝑃=.001 ). Also ADAS-Cog, CIBIC, and ADFACS scores showed a significant improvement in group A versus group B. IR was higher in group A. Our study suggests that ALA therapy could be eeff ctive in slowing cognitive decline in patients with AD and IR. 1. Introduction insulin may also have important outcome on brain functions. A recent commentary offers two models on the relationship Alzheimer’s disease (AD) is a neurological disorder charac- between T2-DM and AD: “central insulin resistance” and terized by profound memory loss and progressive dementia. inflammation. Both mechanisms influence insulin sensitivity The cause of sporadic AD remains poorly understood. In in the brain, na fi lly leading to 𝛽 -amyloid accumulation and, addition to genetic susceptibility genes, such as ApoE4 allele, consequently, to AD . Moreover, most diabetic patients a number of risk factors has been identified including many have insulin resistance (IR) that is associated with compen- lifestyle and dietary choices . Type 2 diabetes mellitus satory hyperinsulinemia, one of the mechanisms suggested (T2-DM2) is an important risk factor for AD and vascular to explain the increased AD risk in diabetic patients [8, 9]. dementia [2, 3]. Recent longitudinal studies have shown Alpha-lipoic acid (ALA) is a naturally occurring disulfide that AD is related to glucose metabolism disorders [4, 5]. molecule with antioxidant and anti-inflammatory properties. An explanation seems to be that vascular complications of It has positive eeff cts on glucose metabolism and/or IR diabetes may cause neurodegenerative disease . On the  and should exert positive eeff cts in patients with AD. other hand, in addition to its peripheral metabolic effects, ALA plays many different roles in pathogenic pathways of 2 Journal of Neurodegenerative Diseases dementia, acting as a neuroprotective agent. It increases and hypertension) and smoking habit were defined by self- acetylcholine production, inhibits hydroxyl radical produc- reports. History of T2-DM was ascertained by patient self- tion, and increases the process of getting rid of reactive oxy- reports or antidiabetic medication use. IR was calculated by gen species. By the same ways, ALA promotes downregula- homeostasis model assessment (HOMA) formula . We tion of redox-sensitive inflammatory processes [ 11]. A decade defined DM as documented insulin or oral hypoglycaemic of small epidemiological studies provides evidence about the drug use or fasting plasma glucose level above 200 mg/dL role that ALA plays in patients with AD and related dementias (11.1 mmol/dL) . [11, 12]. In these studies, the authors presented patients with mild AD showing an unusually slow progression of cognitive 2.3. Neuropsychological Assessment. All patients underwent a impairment or a stabilization of cognitive function during general cognitive screening with Mini-Mental State Examina- ALA therapy. tion (MMSE) . We considered as significant an improve- eTh aimofthisstudy wastoevaluatethe eeff ctofALA ment/worsening of two points or more at the MMSE; a (600 mg/day) on cognitive functions in AD patients with or variation of one point or less was considered as not sig- without T2-DM, respectively. nificant. Depression was assessed with Montgomery Asberg Depression Rating Scale (MADRS) . Patient evaluation included Alzheimer’s Disease Assessment Scale, cognitive 2. Methods subscale (ADAS-Cog) , and the Clinician’s Interview- Based Impression of Change-Plus version (CIBIC-plus) . 2.1. Study Subjects. Between November 2009 and November Moreover, we used global Clinical Dementia Rating (CDR), 2011, we recruited 126 patients (75 women and 51 men) with the CDR sum of boxes (the sum of individual CDR domain AD according to Diagnostic and Statistical Manual of Mental scores) , andAlzheimer’s DiseaseFunctionaland Change Disorders, Fourth Edition (DSM-IV) criteria, associated with Scale (ADFACS) . ADFACS provides a measure of instru- or/without T2-DM . We enrolled patients with a MMSE mental and basic activities of daily living. Patients score’s score raging between 12 and 26. In accordance with the were compared with normal values according to age and official standards of the 1964 declaration of Helsinki, local educational level. laws and regulations, for each patient, informed consent was obtained by care givers. Differential diagnoses have been made according to the National Institute of Neurological and 2.4. Study Design. This is a prospective, open label, parallel- Communicative Disorders and Stroke—Alzheimer’s disease group study, performed from November 2009 to November and Related Disorders Association Internationale pour la 2011, in an outpatient setting, in two towns of south Italy Recherche´ et l’Enseignement en Neurosciences criteria for (Crotone and Lamezia Terme, Calabria). All patients were vascular dementia . We excluded subjects with (a) his- assigned to receive ALA (600 mg/day) in combination with tory of psychiatric disease (depression and/or antidepres- antidementia treatment. Study duration was 16 months and sant intake) and/or behaviour disorders; (b) tumour and/or consisted of three consecutive periods. At study entry (V1), vascular disease; (c) toxic or pharmacological exposure, all patients’ care givers gave an informed consent, and each alcohol overuse, and coexisting medical conditions associ- patient underwent neurological, endocrinological, and neu- ated with cognitive impairment (i.e., dysthyroidism, human ropsychological evaluation. Clinical and neuropsychological immunodeficiency virus); (d) abnormal results on blood assessments were also performed at month 8 (V2) and at tests, including electrolytes, renal and hepatic function, B12 the end of the study (V3; month 16). eTh neuropsychological and folic levels, serum protein electrophoresis with serum assessments were performed by trained neuropsychologists immunofixation, and autoimmune and infective screening; blind to group stratification. Fasting serum glucose, insulin (e) hydrocephalus; and (f) extrapyramidal disorders. andtriglycerides values,lipid profile,smoking habits,and Enrolled patients were divided into two groups as follows, antidiabetic and antipsychotic medications were also assessed according to the presence of T2-DM: at V1 and V3. For the entire study duration, dementia treat- ments (cholinesterase inhibitors (ChE) (donepezil, rivastig- group A—AD patients with T2-DM (61 patients); mine, and galantamine) and the N-methyl-D-aspartate (NMDA) receptor antagonist memantine) were kept xfi ed for group B—AD patients without T2-DM (65 patients). each patient (donepezil between 5 and 10 mg/day, rivastig- mine between 6 and 12 mg/day, galantamine between 8 and 16 mg/day, and memantine between 10 and 20 mg/day). ALA 2.2. Clinical Evaluation. Aeft r a rfi st-level checkup, carried therapy began about 3 months aer ft antidementia treatment. out by a neurologist and/or a geriatrician expert in neu- Care givers were responsible for all drug intake and for rodegenerative disease and by an endocrinologist, patients patients’ adherence to therapy. underwent neuroimaging studies (CT scan or MRI of the brain) and neuropsychological assessment. Recorded medi- cal data included anamnestic (health and behaviour status, 2.5. Data Analysis. Data were expressed as mean ± stan- disease duration, antipsychotic use) and demographic data dard deviation (SD). In the Intention-to-Treat (ITT) pop- (age, gender), body mass index (BMI), waist circumference ulation, all patients who received at least one dose of (WC), glucose and insulin fasting values, triglycerides, and ALA (600 mg/day) were included. No confirmatory statisti- blood lipid profile. Cardiovascular disease (heart disease cal testing was performed. Results were summarized using Journal of Neurodegenerative Diseases 3 Table 1: Demographic and clinical features of 128 patients with 128 patients screened Alzheimer’s disease with/or without diabetes mellitus (T2-DM). AD with AD without T2-DM T2-DM (group A) (group B) AD with DM AD 𝑛 =61 𝑛 =65 (𝑛=64 ) (𝑛=64 ) Age; years, M (SD) 72 (6.8) 74.2 (5.7) .32 Sex (M/F) 22/39 29/36 .05 MMSE score; M (SD) 20.7 (4.4) 21.8 (4.9) .32 56 completed 8 discontinued 56 completed 8 discontinued (13%) (13%) (87%) (87%) MADRS score 15.8 16.3 .42 Smokers;𝑛 ,% 12;20 18; 28 .09 4 DM worsening 2 poor compliance Educational level; years, M 1 poor compliance 1 SAE 10.6 (4.5) 11.7 (5.4) .21 (SD) 2 SAE 1 unknown cause Disease duration; years, M 1 death (SD): Figure 1: Patients flow-chart. Sixteen patients dropped out of trial: 11 (a) Alzheimer disease 5.3 (2.1) 4.9 (2.8) .12 (15%) in groupAand5(7%) in groupBformarkeddiabetesmellitus (b) Diabetes Mellitus 7.8 (3.7) // // (DM) worsening in 6 (all in group A); poor compliance in 3 (1 in Anti-Alzheimer drugs: n;% group A and 2 in group B); severe adverse events (SAEs) in 3 (2 in group A and 1 in group B); unknown cause in 2 (in group B), and 1 (a) Donezepil 21; 34 19; 29 .23 death (a stroke, in group A). (b) Rivastigmine 28; 46 26; 40 .18 (c) Galantamine 3; 4 3; 4.6 .24 descriptive statistic. Baseline and demographic characteris- (d) Memantine 4; 6 3; 4.6 .43 tics were summarized for all enrolled patients. An ANOVA Antipsychotic use: n;% test for independent samples was performed to compare (a) Total 21 27 .09 mean values. A𝜒 test was performed to compare prevalence (b) Atypical antipsychotic 10; 16 15; 23 .06 data. Finally, logistic regression was used to assess and allow (c) Typical antipsychotic 11; 12 11; 18 .12 for discrepancies among clinical characteristics in the group Concomitant diseases comparisons and to assess relative significance of potential aetiology variables. Besides, we included variables that are (a) Total pathologies 56 30 .001 usually associated with higher risk of dementia (i.e., age, sex, (b) Past 25 13 .03 glycaemia, education level, disease duration, smoking habit, (c) Current 31 17 .02 etc.). Current Pathologies MMSE, ADAS-Cog, CDR, and ADFACS scores were (a) Hypertension 20 10 .02 summarized using means for patients’ scores at V1, V2, and V3. CGI-C and MMSE scores were assessed in terms of (b) Hypercholesterolemia 11 7 .08 proportions of patients showing improvement, worsening, or Regresses pathologies no change from previous visit. In all cases,𝑃 value of .05 (a) Ischemic heart disease 13 9 .05 was considered statistically significant. Statistical analysis was (b) Others pathologies 12 4 .02 performed using SPSS 12.0. MMSE: Mini-Mental State Examination; MADRS: Montgomery Asberg Depression Rating Scale. Values are expressed as mean (SD) unless otherwise 3. Results indicated. P value of 0.05 was considered statistically significant. 3.1. Outcome and Adverse Events. Onehundred andtwenty- six patients (88,7% of the ITT/population) completed the to be related to donezepil treatment. u Th s, only 126 patients study: 61 in groupAand65ingroup B. Sixteenpatients (61 group A and 65 group B) were included in the analysis dropped out prematurely (11 in group A and 5 in group (Figure 1). B): marked T2-DM worsening in 6 (all in group A); poor compliance in 4 (2 in group A and 2 in group B); severe adverse events (SAEs) in 3 (2 in group A and 1 in group B); 3.2. Demographics. Table 1 summarizes demographic and unknown cause in 2 (in group B); and one death (a stroke, clinical characteristics of patients. Mean age was 72± 6.8 in group A) occurred during the study and judged unrelated years in group A and 74.2 ± 5.7 years in group B. eTh to treatment. ALA was well tolerated in all patients. Forty- percentage of maningroup Awas signicfi antly higher than four percent (27/61) of patients in group A and 41% (27/65) in group B (36% versus 44.6%;𝑃 = .05 ). Consequently, any group B showed adverse events (AEs). AEs included muscle statistical comparison between the groups took gender into cramps, gastrointestinal symptoms, and sleep disturbances in account. Mean AD duration was similar in both groups. both groups. Among dropped out patients, two had severe Educational level was 10.6± 4.5 years in group A and 11.7± 5.4 sleepiness and one profuse diarrhoea. All SAEs were judged years in group B, respectively. During the study, all patients 4 Journal of Neurodegenerative Diseases received medications for dementia. Smoking use was higher hypothesize that ALA therapy, in combination with antide- in group B, but aer ft adjusting for sex the difference was mentia drugs, may have an eeff ct on cognitive functions and not significant ( 𝑃 = .09 ). Sixty-eight percent (𝑛=86 )of could slow the progression of dementia in AD patients. The patients had one or more concomitant pathologies, 56 (44%) results of our study in a real life, naturalist clinical setting in group A and 30 (24%) in group B: 38 were past and 48 indicate that a large percentage of AD patients with T2- current pathologies. Hypertension, ischemic heart disease, DM (group A) could benefit from ALA therapy; in fact, we and hypercholesterolemia were among the most frequent documented a significant slowing in cognitive decline, at 8- concomitant pathologies. and16-monthfollowupinthisgroup of patients.Among AD patients with T2-DM around 43% improved over 16 months on MMSE-scores; moreover, daily living items showed a 3.3. Metabolic and Clinical Features. At presentation (V1), significant improvement in most of patients in group A mean BMI, WC, serum lipid, and triglycerides were similar in versus group B. Besides, 47% of patients in group A showed groups A and B. Mean HOMA value was 10.2± 4.2 in group significant improvement on the CIBIC-plus rating aeft r 16 Aand 1.6± 0.8 in group B, respectively (𝑃 = .001 ). At visit months (𝑃=.001 ). V3: HOMA index value between groups was lower compared We didnot observeasignicfi ant benetfi on CDR-SB. to baseline, but remained significantly higher in group A This may be due to some intrinsic limitations of this scale, (𝑃 = .03 ); the other metabolic parameters (serum lipid and including the relative insensitivity as a measure of change triglycerides) did not show significant differences between in pharmacological studies . Complex molecular mecha- thetwo groups.Besides,atthe beginning of thestudy,9 nisms, referring to insulin and/or insulin-like growth factor-1 patients in group A were taking insulin therapy alone or in (IGF-1) signalling, could link DM to AD . In fact, there combination with oral antidiabetic agents, the other patients is evidence that altered insulin and/or IGF-1 signalling to were taking only oral antidiabetic drugs. At the end of the brain cells may be responsible for beta-amyloid accumulation study, 5 patients required the administration of insulin, while in AD . Moreover, most diabetic patients have IR that the 12 patients increased oral antidiabetic dosage (Table 2). is associated with compensatory hyperinsulinemia, one of the mechanisms suggested to explain the increased AD 3.4. Neuropsychological Findings. Neuropsychological as- risk in diabetic patients [8, 26]. Subsequent investigations sessments were performed at times V1, V2, and V3. Patients demonstrated reduced blood glucose levels and increased from ITT population were included in neuropsychological insulin levels in patients with late onset AD compared to analysis if they had completed the study and had a n fi al aged controls or to patients with vascular dementia. Although assessment within 7 days after 16 months. Comparison of theauthors concludedthatthese nfi dingsdid notsupport neuropsychological differences between the groups is sum- an association between diabetes and AD , the same marized in Table 3. MMSE score demonstrated that overall data were reinterpreted as an increased prevalence of IR in dementia levels improved in group A compared with group AD. Further studies demonstrated that the administration of B at any evaluation time, reaching a statistical signicfi ance at insulin significantly improved memory performance in AD V2 (𝑃=.001 )and V3 (𝑃=.003 ). For the primary outcome, patients [9, 28]. patients in ITT population had a significant improvement ALA, a biological antioxidant and natural cofactor of in MMSE scores from the baseline at the end of the study mitochondrial dehydrogenase complexes, is considered to be (V3) in 43%ingroup Aand 23%ingroup B(𝑃 = .003 ). safe and ecffi acious for treatment of diabetic polyneuropathy Thirty-three percent of patients in group A and 40% in . ALA, which is synthesized by liver, exists as two different group B showed significant worsening from baseline (𝑃= enantiomers: the biologically active- (R-) isomer, and the .05). Besides, patients in group A demonstrated significant (S)-isomer, that is found in biological tissue in very small improvements versus group B on ADAS-cog, at all evaluation amounts. In vitro studies have provided evidence that R-(+)- times. Global function improvement, assessed by CIBIC- ALA can specifically activate two important molecules of the plus, was observed in a greater proportion of group A patients insulin signalling pathway-insulin receptor substrate-1 (IRS- compared to group B, at V3 (𝑃 = .001 ). Significant benefits 1) protein and phosphatidylinositol 3-kinase, with subsequent were not observed on CDR-SB. After an initial improvement, enhancement of glucose uptake, via the glucose transporter group A declined below baseline on CDR-SB at the end system in skeletal muscle and adipocytes . ALA has of the study (𝑃 = .39 ). Analysis of ADFACS total scores been shown to improve insulin sensitivity in cell cultures of demonstrated significant functional benefits in group A. skeletal muscles  and in animal model of T2-DM . The ADFACS scores remained close to the baseline values in effect of ALA therapy on cognitive decline is controversial group A, whereas group B declined. Separate analysis of [10, 33]. A longitudinal study in dogs showed that a diet ADFACS instrumental ADL (IADL) items also demonstrated enriched with a broad spectrum of antioxidants, along with significant differences between groups. ALA, induced rapid improvements in landmark performance and prevent age-related cognitive decline in old dogs . Conversely, Christie et al. reported no effects of short- 4. Discussion term supplementation with ALA and acetyl-L-carnitine on In this prospective study, we evaluated the effects of alpha- cognition in aged dogs . In one small open-label study, ALA (600 mg/daily) was given to nine patients with probable lipoic acid (600 mg/day) in 126 patients with mild-to- moderate AD with or without T2-DM, respectively. We AD. Treatment with ALA led to a stabilization of cognitive Journal of Neurodegenerative Diseases 5 Table 2: Changes from baseline in clinical and metabolic features in patients of groups A and B at baseline (V1) and aer ft 16 months of followup (V3) both groups. Baseline (0 month) V3 (16 months) 𝑃 𝑃 Group A Group A Group B Group B M (SD) M (SD) Adjusted for sex, hypercholesterolemia, ischemic heart disease, and hypertension Fasting glycaemia (mg/dL) 66 (9.3) 70 (8.6) .02 129 (10) .001 126 (11.4) Fasting insulinemia (UI/mL) 33 (8.7) 7.2 (2.2) .001 15 (3.3) 6.1 (1.9) .02 HOMA index 1.6 (0.8) 1.1 (0.6) .03 10.2 (4.2) .001 4.8 (2.3) Triglycerides (mg/dL) 157 (33) 155 (34) .18 166 (35.8) .23 159 (36) Serum lipid (mg/dL) 132.7 (32) 135.6 (33) .23 138.7 (24) .18 134.7 (25.9) BMI 24.1 (2.6) 22.7 (3.1) .09 24 (2.8) 23.8 (2.7) .58 Waist circumference (cm) 80.7 (2.1) 81.4 (2.9) .22 81.5 (1.7) .21 82 (2.1) Anti diabetic medication; n (a) Hypoglicemic drugs // // // 50 // 46 (b) Insuline + hypoglicemic drugs (c) Insulin 2 2 Body mass index: BMI [Weight (kg)/height (h )]; Insulin resistance (IR) was calculated by the homeostasis model assessment (HOMA) formula. HOMA index: basal glucose plasma (mg/dL)× basal insulin plasma (UI/mL)/405; differences between the proportions with insulin resistance ≥ 2.7 on the HOMA formula. Values are expressed as mean (SD) unless otherwise indicated. P value of 0.05 was considered statistically significant, aer ft adjusting for confounding variables (sex, serum lipid, triglycerides, BMI, WC, ischemic heart disease, and hypertension). Table 3: Changes from baseline in neuropsychological measures aft er 8 months (V2) and 16 months of followup (V3) in patients of groups Aand B. Change in Score from Baseline 8 months 16 months AD with T2-DM AD without T2-DM AD with T2-DM AD without T2-DM P 𝑃 Group A Group B Group A Group B 𝑛=61 𝑛=65 𝑛=61 𝑛=65 MMSE −031±1.2 0.64±1.19 .002 −0.85±1.4 −1.42±1.9 .001 MMSE (𝑛 ;%) (i) Improvement 26; 43 13; 20 .001 26; 43 15; 23 .003 (ii) Unchanged 12; 38 22; 34 .003 15; 24 24; 37 .001 (iii) Worsening 12; 20 30; 46 .001 20; 33 26; 40 .05 ADAS-Cog original; M 0.17 (3.4) 0.95 (3.8) .001 2.2 (4.9) 2.9 (5.4) .05 (SD) ADAS-Cog modified; M −0.59 (4.7) 0.27 (4.9) .001 1.9 (5.7) 2.5 (6.9) .002 (SD) CIBIC-Plus Category (𝑛 ;%) (i) Improvement 24; 39 20; 31 .05 29; 47 21; 32 .001 (ii) Unchanged 16; 26 21; 32 .05 11; 18 15; 23 .09 (iii) Worsening 21; 34 24; 37 .22 21; 34 29; 45 .08 CDR sum; M (SD) 0.50 (1.2) 0.75 (1.46) .09 1.5 (1.7) 1.67 (2.2) .39 ADFACS; M (SD) 0.53 (0.38) 1.56 (0.42) .002 0.37 (0.4) 1.6 (0.4) .002 IADL; M (SD) 0.87 (0.32) 0.13 (0.27) .002 0.9 (0.37) 0.03 (0.3) .001 ADAS-Cog: Alzheimer’s Disease Assessment Scale, cognitive subscale; CIBIS: Clinician’s Interview-Based Impression of Severity; CDR: Clinical Dementia rating; ADFACS: Alzheimer’s Disease Functional and Change Scale; ADL: Activities of Daily Living. Values are expressed as mean standard deviation (SD) unless otherwise indicated. 𝑃 Value of 0.05 was considered statistically significant, aer ft adjusting for confounding variables (sex, serum lipid, triglycerides, BMI, WC, HOMA va lue, ischemic heart disease, and hypertension). 6 Journal of Neurodegenerative Diseases functions, demonstrated by constant scores in two neuropsy- with stroke in a multiethnic cohort,” American Journal of Epidemiology,vol.154,no. 7, pp.635–641,2001. chological tests for a period of 12 months . These authors have subsequently extended the analysis to 43 patients with  J. A. Luchsinger, M. X. Tang, S. Shea, and R. Mayeux, “Hyper- insulinemia and risk of Alzheimer disease,” Neurology,vol.63, an observation period of 48 months. Cognitive progression no.7,pp. 1187–1192, 2004. appeared dramatically slower compared to untreated patients or patients on choline-esterase inhibitors, in the second year  J.Janson, T. Laedtke, J. E. Parisi,P.O’Brien,R.C.Petersen, and P. C. Butler, “Increased risk of type 2 diabetes in Alzheimer of long-term studies . Moreover, Siedlak et al., in a recent disease,” Diabetes,vol.53, no.2,pp. 474–481, 2004. work, suggest that supplementation with ALA is insucffi ient  R.A.Whitmer,S.Sidney,J.Selby,S.Claiborne Johnston,and K. toimprovecognitiveperformanceinagedorADmodels. Yaeff , “Midlife cardiovascular risk factors and risk of dementia In the present study, we showed no signicfi ant dieff rence in late life,” Neurology,vol.64, no.2,pp. 277–281, 2005. in BMI, WC, serum lipids, triglyceridemia, and smoking  W. Han and C. Li, “Linking type 2 diabetes and Alzheimer’s use between groups. Nevertheless, hypertension, ischemic disease,” Proceedings of the National Academy of Sciences of the heartdisease,and HOMA valueweresignicfi antlyhigher United States of America, vol. 107, pp. 6557–6558, 2010. in AD with T2-DM group; however, in our study, aer ft  W. Q. Qiu and M. F. Folstein, “Insulin, insulin-degrading adjustment for these factors, the improvement of cognitive enzyme and amyloid-𝛽 peptide in Alzheimer’s disease: review performances remained signica fi ntly greater in the group and hypothesis,” Neurobiology of Aging,vol.27, no.2,pp. 190– of patients with concomitant DM at the end of the study 198, 2006. (16-months). We suppose that ALA supplementation could  M. Plastino, A. Fava, D. Pirritano et al., “Eeff cts of insulinic have an independent eeff ct on cognitive performance. This therapy on cognitive impairment in patients with Alzheimer association could be explained through several mechanisms: disease and Diabetes Mellitus type-2,” Journal of the Neurologi- (i) increased acetylcholine (Ach) production by activation cal Sciences, vol. 288, no. 1-2, pp. 112–116, 2010. of choline-acetyltransferase; (ii) increased glucose uptake,  M. A. Kandeil, K. A. Amin, K. A. Hassanin, K. M. Ali, and E. supplying more acetyl-CoA for the production of Ach; (iii) T. Mohammed, “Role of lipoic acid on insulin resistance and inhibiting the formation of hydroxyl radicals; (iv) scavenging leptin in experimentally diabetic rats,” Journal of Diabetes and reactive oxygen species (ROS), downregulating inflamma- its Complications,vol.25, no.1,pp. 31–38, 2011. tory processes; (v) scavenging lipid peroxidation products;  L. Holmquist, G. Stuchbury, K. Berbaum et al., “Lipoic acid as a and (vi) inducing enzymes of glutathione synthesis [37, novel treatment for Alzheimer’s disease and related dementias,” 38]. We assumed an additional pathogenetic mechanism, Pharmacology and eTh rapeutics ,vol.113,no.1,pp.154–164,2007. suggesting that the benefit on cognitive function in our  K. Hager, A. Marahrens, M. Kenklies, P. Riederer, and G. patients could be related to IR improvement due to ALA. This Munc ¨ h, “Alpha-lipoic acid as a new treatment option for is confirmed by a marked IR value reduction at the end of the Alzheimer type dementia,” Archives of Gerontology and Geri- atrics,vol.51, no.1,p.110,2010. study (IR: T0–T16; 10.2± 4.2–4.8± 2.3). Our study has some limitations: diagnosis of AD was  American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, American Psychiatric Association, performed only by clinical criteria; nevertheless, the clinical Washington, DC, USA, 4th edition, 1994. evaluation was accurate and complete . We did not check our patients for biochemical markers that relate to amyloid  G. C. Roman, T. K. Tatemichi, T. Erkinjuntti et al., “Vascular dementia: diagnostic criteria for research studies: report of the or oxidative stress. Besides, the effect of concomitant insulin NINDS-AIREN International Workshop,” Neurology,vol.43, therapy on cognitive performance was not quantified [ 9]; no. 2, pp. 250–260, 1993. however, the number of patients taking insulin (𝑛=14 )  D.R.Matthews, J. P. Hosker,and A. S. Rudenski,“Homeostasis was small compared to the number of all examined patients. model assessment: insulin resistance and𝛽 -cell function from Finally, our data support a causal link between IR and AD fasting plasma glucose and insulin concentrations in man,” pathogenesis. Moreover, it is important to point that this is Diabetologia, vol. 28, no. 7, pp. 412–419, 1985. an observational study, and definitive conclusions about the  J. B. Meigs, L. A. Cupples, and P. W. F. Wilson, “Parental real efficacy of ALA therapy in AD cannot be made at this transmission of type 2 diabetes: the Framingham Offspring time. Further studies on larger samples should be warranted. Study,” Diabetes, vol. 49, no. 12, pp. 2201–2207, 2000.  M. F. Folstein, S. E. Folstein, and P. R. McHugh, “‘Mini mental References state’. A practical method for grading the cognitive state of patients for the clinician,” Journal of Psychiatric Research,vol.  W. J. Strittmatter, A. M. Saunders, D. Schmechel et al., 12, no. 3, pp. 189–198, 1975. “Apolipoprotein E: high-avidity binding to 𝛽 -amyloid and  S. A. Montgomery and M. Asberg, “A new depression scale increased frequency of type 4 allele in late-onset familial designed to be sensitive to change,” British Journal of Psychiatry, Alzheimer disease,” Proceedings of the National Academy of vol. 134, no. 4, pp. 382–389, 1979. Sciences of the United States of America,vol.90, no.5,pp. 1977– 1981, 1993.  W. G. Rosen, R. C. Mohs, and K. L. Davis, “A new rating scale for Alzheimer’s disease,” American Journal of Psychiatry,vol.141,  A.Ott,R.P.Stolk,F.Van Harskamp,H.A.P.Pols, A. Hofman, no. 11, pp. 1356–1364, 1984. andM.M.B.Breteler, “Diabetesmellitusand theriskof dementia: the Rotterdam Study,” Neurology,vol.53, no.9,pp.  L. S. Schneider, J. T. Olin, R. S. Doody et al., “Validity and 1937–1942, 1999. reliability of the Alzheimer’s disease cooperative study-clinical  J.A.Luchsinger, M. X. Tang,Y.Stern,S.Shea, andR.Mayeux, global impression of change,” Alzheimer Disease and Associated “Diabetes mellitus and risk of Alzheimer’s disease and dementia Disorders, vol. 11, no. 2, pp. S22–S32, 1997. Journal of Neurodegenerative Diseases 7  L. Berg, “Clinical Dementia Rating (CDR),” Psychopharmacol-  L. Packer, E. H. Witt, and H. J. Tritschler, “Alpha-lipoic acid as a ogy Bulletin, vol. 24, no. 4, pp. 637–639, 1988. biological antioxidant,” Free RadicalBiology andMedicine,vol. 19, no. 2, pp. 227–250, 1995.  R. C. Mohs, R. S. Doody, J. C. Morris et al., “A 1-year, placebo-  A. R. Smith, S. V. Shenvi,M.Widlansky,J.H.Suh,and T. M. controlled preservation of function survival study of donepezil Hagen, “Lipoic acid as a potential therapy for chronic diseases in AD patients,” Neurology,vol.57, no.3,pp. 481–488, 2001. associated with oxidative stress,” Current Medicinal Chemistry,  W. S. Lim, M. S. Chong, and S. Sahadevan, “Utility of the clinical vol. 11, no. 9, pp. 1135–1146, 2004. dementia rating in Asian populations,” Clinical Medicine and  L. Fratiglioni, M. Grut, Y. Forsell, M. Viitanen, and B. Winblad, Research,vol.5,no. 1, pp.61–70,2007. “Clinical diagnosis of Alzheimer’s disease and other dementias  S. Freude,K.Schilbach,and M. Schubert,“eTh role of IGF-1 in a population survey: agreement and causes of disagreement receptor and insulin receptor signaling for the pathogenesis of in applyingDiagnosticand StatisticalManualofMentalDisor- Alzheimer’s disease: from model organisms to human disease,” ders, Revised Third Edition, criteria,” Archives of Neurology,vol. Current Alzheimer Research,vol.6,no. 3, pp.213–223,2009. 49,no. 9, pp.927–932,1992.  E. Carro and I. Torres-Aleman, “eTh role of insulin and insulin- like growth factor I in the molecular and cellular mechanisms underlying the pathology of Alzheimer’s disease,” European Journal of Pharmacology,vol.490,no. 1–3, pp.127–133,2004.  M. Fisman, B. Gordon, V. Feleki, E. Helmes, T. McDonald, and J. Dupre, “Metabolic changes in Alzheimer’s disease,” Journal of the American Geriatrics Society, vol. 36, no. 4, pp. 298–300, 1988.  S. Craft,S.Asthana,J.W.Newcomeretal.,“Enhancementof memory in Alzheimer disease with insulin and somatostatin, but not glucose,” Archives of General Psychiatry,vol.56, no.12, pp. 1135–1140, 1999.  M. A. Roger, G. S. Watson, P. S. Green et al., “Intranasal insulin improves cognition and modulates beta-amyloid in early Alzheimer disease,” Neurology, vol. 70, no. 6, pp. 440–448,  D. Ziegler, H. Nowak, P. Kempler, P. Vargha, and P. A. Low, “Treatment of symptomatic diabetic polyneuropathy with the antioxidant𝛼 -lipoic acid: a meta-analysis,” Diabetic Medicine, vol. 21, no. 2, pp. 114–121, 2004.  D. E. Estrada, H. S. Ewart, T. Tsakiridis et al., “Stimulation of glucose uptake by the natural coenzyme𝛼 -lipoic acid/thioctic acid: participation of elements of the insulin signaling pathway,” Diabetes,vol.45, no.12, pp.1798–1804,1996.  S. Jacob, R. S. Streeper, D. L. Fogt et al., “The antioxidant 𝛼 - lipoic acid enhances insulin-stimulated glucose metabolism in insulin-resistant rat skeletal muscle,” Diabetes,vol.45, no.8,pp. 1024–1029, 1996.  S. Jacob, P. Ruus, R. Hermann et al., “Oral administration of rac- 𝛼 -lipoic acid modulates insulin sensitivity in patients with type- 2 diabetes mellitus: a placebo-controlled pilot trial,” Free Radical Biology and Medicine,vol.27, no.3-4,pp. 309–314, 1999.  L. A. Christie, W. O. Opii, E. Head et al., “Short-term supple- mentation with acetyl-l-carnitine and lipoic acid alters plasma protein carbonyl levels but does not improve cognition in aged beagles,” Experimental Gerontology,vol.44, no.12, pp.752–759,  N. W. Milgram, E. Head, B. Muggenburg et al., “Landmark discrimination learning in the dog: effects of age, an antioxidant fortified food, and cognitive strategy,” Neuroscience and Biobe- havioral Reviews, vol. 26, no. 6, pp. 679–695, 2002.  K. Hager, M. Kenklies, J. McAfoose, J. Engel, and G. Munc ¨ h, “𝛼 - Lipoic acid as a new treatment option for Alzheimer’s disease— a 48 months follow-up analysis,”JournalofNeuralTransmission, Supplementa,no. 72,pp. 189–193, 2007.  S. L. Siedlak, G. Casadesus, K. M. Webber et al., “Chronic antioxidant therapy reduces oxidative stress in a mouse model of Alzheimer’s disease,” Free Radical Research,vol.43, no.2,pp. 156–164, 2009. 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