NINCDS-ADRDA Criteria Research Articles

Decreased Serum Lipids in Patients with Probable Alzheimer´s Disease

Alzheimer;s disease (AD) is a multifactorial disease but its aetiology and pathophisiology are still not fully understood. Epidemiologic studies examining the association between lipids and dementia have reported conflicting results. High total cholesterol has been associated with both an increased, and decreased, risk of AD and/or vascular dementia (VAD), whereas other studies found no association. The aim of this study was to investigate the serum lipids concentration in patients with probable AD, as well as possible correlation between serum lipids concentrations and cognitive impairment. Our cross-sectional study included 30 patients with probable AD and 30 age and sex matched control subjects. The probable AD was clinically diagnosed by NINCDS-ADRDA criteria. Serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels were determined at the initial assessment using standard enzymatic colorimetric techniques. Low-density lipoprotein cholesterol (LDL-C) and very low density lipoprotein cholesterol (VLDL-C) levels were calculated. Subjects with probable AD had significantly lower serum TG (p<0,01), TC (p<0,05), LDL-C (p<0,05) and VLDL-C (p<0,01) compared to the control group. We did not observe significant difference in HDL-C level between patients with probable AD and control subjects. Negative, although not significant correlation between TG, TC and VLDL-C and MMSE in patients with AD was observed. In the control group of subjects there was a negative correlation between TC and MMSE but it was not statistically significant (r = -0,28). Further studies are required to explore the possibility for serum lipids to serve as diagnostic and therapeutic markers of AD.

Variation in RTN3 and PPIL2 Genes Does not Influence Platelet Membrane β-Secretase Activity or Susceptibility to Alzheimer’s Disease in the Northern Irish Population

Beta-site amyloid precursor protein cleaving enzyme (BACE1) is the rate-limiting enzyme for production of beta-amyloid peptides (Abeta), which are proposed to drive the pathological changes found in Alzheimer's disease (AD). Reticulon 3 (RTN3) is a negative modulator of BACE1 (beta-secretase) proteolytic activity, while peptidylprolyl isomerase (cyclophilin)-like 2 (PPIL2) positively regulates BACE1 expression. The present study investigated whether there was any association between genetic variation in RTN3 and PPIL2, and either risk for AD, or levels of platelet beta-secretase activity, in a large Northern Irish case-control sample. Four hundred and sixty-nine patients with a diagnosis of probable AD (NINCDS-ADRDA criteria) and 347 control individuals (MMSE > 28/30) were genotyped. SNPs in both genes were selected by downloading genotype data from the International HapMap Project (Phase II) and tags selected using multimarker approach in Haploview, where r (2) > 0.8 and LOD > 3.0. Non-synonymous SNPs of interest were also included. Genotyping was performed by Sequenom iPLEX and TaqMan technologies. Alleles, genotypes and multi-marker haplotypes were tested for association with AD, and platelet beta-secretase activities were measured for a subset of individuals (n = 231). Eight SNPs in RTN3 and 7 in PPIL2 were genotyped. We found no significant associations between allele, genotype or haplotype frequencies and risk of AD. Further, there was no effect of genotype on platelet membrane beta-secretase activity. We conclude that common or potentially functional genetic variation in these BACE1 interacting proteins does not affect platelet membrane beta-secretase activity or contribute to risk of AD in this population.

Leptin and adiponectin in plasma and CSF from Alzheimer's patients and normal controls

Life style related diseases such as hypertension, diabetes, and dyslipidemia are reported to be a great risk for dementia (1). Adipocytokines released from fat tissue are supposed to be related to the etiology of Alzheimer's disease (AD). We here analyzed leptin and adiponectin in cerebrospinal fluid (CSF), serum and plasma from AD patients and normal controls (NC) and discussed how these adipocytokines could contribute to the pathomechanism of AD. AD patients and NCs were recruited in Tohoku University Hospital. The diagnosis of AD was based on NINCDS-ADRDA criteria. Cognitive functions were examined using MMSE and ADAS-Cog. All the samples were obtained from each fasted patient or NC. Leptin in serum, plasma and CSF was assayed using a sandwich ELISA system (R&D) and adiponectin was assayed in three multimer forms, high molecular weight (HMW), middle molecular weight (MMW), and low molecular weigh (LMW) using a sandwich ELISA system (Daiichi Pure Chemicals Co) (2). We succeeded in quantification of leptin and HMW, MMW and LMW of adiponectin in both human plasma and serum. The levels of leptin and each form of adiponectin were comparable between in plasma and in serum. However, it was difficult to analyze three forms of adiponecin in CSF because of their concentrations looked too low. The levels of Leptin and three forms of adiponectin in CSF are highly correlated to those in plasma in both ADs and NCs. It was suggested that the levels of leptin and total adiponectin in serum or plasma reflect the levels of these adipocytokines in CSF from AD and NCs. Therefore the levels in serum or plasma could estimate the intracerebral concentrations of these molecules. Comparison of the levels of leptin and adiponectin between ADs and NCs are now underway.

Clinical and neuropsychological risk factors to conversion from mild cognitive impairment to Alzheimer disease

Mild Cognitive Impairment defines a transitional stage between normal ageing and dementia, and reflects the clinical situation where a person has memory complaints and objective evidence of cognitive impairment but no evidence of dementia. Forty two subjects consecutively recruited who met the operational criteria for MCI. They underwent multidimensional clinical assessment and a neuropsychological battery at baseline and at follow-up, after 6, 12 and 36 months. Diagnosis for Alzheimer Dementia was based on NINCDS-ADRDA criteria. Demented MCI were older (mean age 73.5_8.5 vs. 69.2_7.0; p<0.006) when compared to Stable and their global cognitive performances, at baseline, were more compromised when assessed by CAMCOG and by MMSE. Approximately 50% of MCI cases with memory impairment progressed to dementia. Demented were similarly compromised in basic activities of daily living but more compromised on instrumental daily functions. No effects of lifestyle, internal diseases or education were confirmed. The most importants neuropsychological risk factors were results in Global CAMCOG test and subtests Orientation, Perception and Memory. In subjects with MCI poor global cognitive performance at baseline, the worsening on executive functions and on functional status but not the worsening on memory functions are independently associated with the conversion to dementia of Alzheimer type at 2 years, follow-up.

The Structured Clinical Impression of Progressivity scale: Can we improve the success rate of Alzheimer's clinical trials by confirming progressivity?

Lack of cognitive impairment progressivity is likely a key reason for confirmatory trial failure (trials > 6-months) where the placebo arm did not cognitively deteriorate at the study end (phenserine, tramiprosate, MEM103). Three important abuses of NINCDS-ADRDA criteria have been observed during the source data verification process: absence of neuropsychological tests which confirm dementia, absence of neuroimaging to rule out other possible causes, lack of progressivity of cognitive impairment prior to baseline. Such pseudo-placebo effect has been observed in rosiglitazone clinical trials, where 40% of patients did not have evidence of a progressive course prior to baseline. Additional effort should be made to rule out patients with MCI or dementia with argyrophylic grains where cognitive deterioration is very slow and the difference will be difficult to capture in short trials (6-12 months duration). Described here is a potential screening tool that could confirm progressivity for subject inclusion in clinical trials. 1) Literature search for studies requiring evidence of progression as an inclusion criterion. 2) Design of the Structured Clinical Impression of Progressivity (SCIP) scale that captures evidence of progressivity with a weighted scoring scheme for each domain and total cut-off score. There are three domains: Diagnosis (how many years ago the AD diagnosis was made), Longitudinal Data (cognitive, functional, global scales), Caregiver (global impression of 6-month change in cognitive and functional activities). There appears to be only one confirmatory protocol that specifically requested evidence of cognitive deterioration prior to baseline as an inclusion criterion. This protocol successfully avoided pseudo-placebo effect in both primary (ADAS-Cog) and secondary (DAD) outcome measures after 6 months of drug exposure. We are convinced that lack of progressivity of cognitive impairment is a critical factor in failed AD clinical trials and we describe the development of a screening tool that would enable sites to exclude subjects who don't have confirmation of progressivity.

Plasma Levels of Amyloid β1-42 Are Independent of Neuronal Function in Alzheimer's Disease

The aggregation of amyloid-beta42 (Abeta42) constitutes one of the major pathogenic events in Alzheimer's disease (AD), and the study of regional cerebral blood flow (rCBF), using single photon emission computed tomography (SPECT), aids the diagnosis of AD. In this study, we evaluated whether there was a correlation between rCBF in brain regions and plasma levels of Abeta1-42 in AD. 29 patients (mean age 71 +/- 9) with a diagnosis of AD who fulfilled NINCDS-ADRDA criteria with a mean Mini-Mental Status Examination score of 15 +/- 9 and 16 normal controls (mean age 64 +/- 8) underwent SPECT brain imaging with hexamethylpropylene amine oxime, and semiquantitative analysis of rCBF was performed. Plasma samples were collected the same day of the SPECT and plasma Abeta1-42 measured by ELISA. A significant reduction of rCBF was observed in most regions in AD compared to controls, whereas mean plasma Abeta42 did not differ between the two groups. There was no correlation between rCBF in any region and plasma Abeta42 nor any correlations between gender, age, and severity with plasma levels of Abeta42. Since rCBF is coupled to neuronal activity, we conclude that plasma Abeta1-42 concentration is independent of neuronal function in every single region of the brain.

A novel presenilin 1 mutation (L282F) in familial Alzheimer’s disease

Sirs, Mutations in the genes of b-amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) have been identified as causative in familial Alzheimer’s disease (FAD) [9]. Mutations in PSEN1 are most common in FAD, and 168 pathogenic PSEN1 mutations have been reported to date [3]. We report a novel mutation of PSEN1 (L282F) in a patient with FAD. A 57-year-old woman consulted our hospital because of progressive memory loss. She had noticed forgetfulness since age 53 and had been treated with donepezil at a local clinic since age 55. She presented with impairment of recent memory and orientation for date and scored 24/30 on the mini-mental state examination without any other neurological deficits. Findings of routine blood tests were normal. Serum apolipoprotein E phenotype was E3/E4. Mild medial temporal atrophy was demonstrated on brain magnetic resonance imaging. Fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) revealed glucose hypometabolism in the bilateral parietal cortices and posterior cingulate gyri. Her family history suggested FAD, but we could not determine the hereditary pattern of FAD (Fig. 1). After written consent was obtained from the patient and her family, all exons of APP, PSEN1 and PSEN2 were analyzed by direct cycle sequencing as described previously [5, 10]. The analysis of PSEN1 demonstrated a C ? T transversion at the first position of codon 282 in exon 8 (genomic accession number: g. 50029C[T), which predicted a L282F substitution (Fig. 2). There were no other mutations detected in the analyzed genes. We also searched for this mutation in 192 Japanese patients with Alzheimer’s disease (AD) or other forms of dementia, and none demonstrated this PSEN1 mutation. We diagnosed this patient as having probable AD according to the NINCDS-ADRDA criteria [6]. The pattern of brain hypometabolism on FDG-PET supported the diagnosis [2, 7]. Although this L282F mutation has not been described previously, two other mutations at the same

Serum androgen levels and their association to depression and Alzheimer dementia in a cohort of 75-year-old men over 5 years: results of the VITA study

The role of androgens on cognitive function and mood is not well documented yet. We therefore evaluated all male participants (n=247, mean age 75.7 years) of a population-based study regarding testosterone, dehydroepiandrosterone sulfate (DHEAS), depression and Alzheimer Dementia (AD) for 5 years using the DSM-IV and NINCDS-ADRDA criteria. At study entry, low serum testosterone levels (<350 ng per 100 ml) were present in 45 (30.8%), low DHEAS (<50 microg per 100 ml) in 44 (30.1%), depression in 11 (7.5%) and AD in 7 (4.7%) men. After 5 years, the number of men with low testosterone levels increased to 52 (+15.5%), for low DHEAS to 57 (+29.5%) for depression to 34 (+219%) and for AD to 43 (+515%). Testosterone levels were not associated to prevalence or incidence of depression or dementia. Mean testosterone was 398.1 ng per 100 ml in depressive men and 431.7 ng per 100 ml in those without depression (P=0.57) and 406.3 ng per 100 ml in those with AD versus 429.5 ng per 100 ml without AD (P=0.66).

The short-term effect of acetylcholinesterase inhibitor on the regional cerebral blood flow of Alzheimer's disease

This study is to investigate changes in regional cerebral blood flow (rCBF) of Alzheimer's disease (AD) in short-term treatment with acetylcholinesterase inhibitor (ChEI). rCBF was measured by single photon emission computed tomography (SPECT). CBF measurements were performed in 13 AD patients before treatment and 4 months later, while the control group with syncope or headache consisted of 17 patients. The clinical diagnosis of AD was based on the NINCDS-ADRDA criteria. Significant increases in rCBF were noted in the left angular, the right superior frontal gyrus, the right occipital, the left temporal lobe and the left orbital gyrus at the end of short-term therapy. Reduction in the rCBF before treatment is more profound in the left superior temporal, the right precentral and the both inferior frontal gyri compared with the control group. It achieved increase of rCBF after ChEI treatment. Also it overall increased in global cognitive functions including Korean Version Mini Mental State Examination (K-MMSE) and Clinical Dementia Rating (CDR). Treatment with ChEI for 4 months could increase rCBF and improve cognitive function of patients with AD.

The memory alteration test (M@T) discriminates between subjective memory complaints, mild cognitive impairment and Alzheimer's disease

This work aimed at establishing the memory alteration test (M@T), which is a memory screening test, capable for discriminating between subjects with subjective memory complaints (SMC) (without objective memory impairment) and patients with amnestic mild cognitive impairment (A-MCI) and with mild Alzheimer's disease (AD). The discriminative validity was assessed in a sample of 37 subjects with SMC, 50 patients with A-MCI according to the Petersen-criteria, and 66 patients with mild AD (global deterioration scale: 4 stage) according to the NINCDS-ADRDA criteria. M@T mean scores were significantly different among groups: 39.7 ± 5.1 (±S.D.) in the SMC group, 31.5 ± 3.9 in the A-MCI group, and 21.8 ± 4.9 in mild AD. A cut-off score of 37 points had a sensitivity of 96% and a specificity of 70% to differentiate A-MCI from SMC (ABC = 0.88). A cut-off score of 33 points had a sensitivity of 100% and a specificity of 86% to differentiate mild AD from SMC sample (AUC = 0.99). We conclude that the M@T provides efficient and valid discrimination between SMC subjects and A-MCI, and between SMC subjects and mild AD.

The UPDRS scale as a means of identifying extrapyramidal signs in patients suffering from dementia with Lewy bodies.

The study aimed to evaluate the merits of the Unified Parkinson's Disease Rating Scale (UPDRS) in the assessment of parkinsonism in patients suffering from Dementia with Lewy Bodies (DLB). Parkinsonian symptoms were assessed in 73 dementia patients using the UPDRS and staged using the Hoehn & Yahr system. A staging of 1 or greater was taken to indicate significant parkinsonism. DLB (n=42) was diagnosed using the McKeith et al. criteria, Alzheimer's disease (n=30) was diagnosed using the NINCDS ADRDA criteria. The inability of some patients to comply with some of the more complicated tasks meant that the full UPDRS assessment could only be completed in 35 (83%) of the DLB patients, 23 (66%) of whom had significant parkinsonism. Patients with parkinsonism were significantly younger than those without. A Principal Components Analysis derived a sub-scale including the items tremor at rest, action tremor, bradykinesia, facial expression and rigidity. These items had a specificity of 100% and a sensitivity of 85% for significant parkinsonism using a cut-off of 7/8. The brief scale had several advantages over the complete UPDRS. Unlike the full scale it was independent of the severity of cognitive impairment and the 5 key items could be assessed in 41 (98%) of the DLB patients. Autopsies have been completed on 31 patients, with a specificity of greater than 90% for the operationalized clinical diagnosis of DLB. It is suggested that a 5 item subscale of the UPDRS provides a reliable and generally applicable instrument for the assessment of parkinsonism in DLB patients.

P01-95 Interferon gamma +874 T/A gene polymorphism is not a risk factor in the pathogenesis of Alzheimer’s disease

Inflammatory processes seem to play a role in neurodegenerative diseases such as Alzheimer's disease (AD). Local inflammatory mechanisms can affect to neurotoxicity, interfere with beta amyloid expression and metabolism. The increased production of amyloid precursor protein eventually leads to the deposition of amyloid beta. Interferon (INF) gamma plays a pivotal role in the inflammatory processes.The aim of this study was to evaluate the putative role of INF gamma +874 T/A polymorphism and its association with apolipoprotein E (ApoE) 4 allele in AD.One hundred and eighty nine healthy controls (HC) and 191 patients with AD were involved in this study. The probable AD patients were diagnosed by NINCDS-ADRDA criteria. The DNA was extracted from whole peripheral blood. INF gamma +874 T/A and ApoE polymorphisms were assessed by the PCR based method.ApoE 4 allele occurrence in AD was 27% compared to 9% in HC. There were no statistically significant differences in the distribution of INF gamma genotypes (AD: A/A:30.9%, T/A:46.1%, T/T:23.0%; HC: A/A:21.7%, T/A:54.5%, T/T:23.8%, p=0.110) or alleles. The INF gamma A/A genotype was more frequent in the presence of ApoE 4 allele in AD (13.6%) than in the HC (4.8%).Our results confirm the role of ApoE 4 allele in AD. However, no association was found between the INF gamma +874 T /A polymorphism and AD. The simultaneous occurrence of ApoE 4 allele and one of the INF gamma genotypes presumably can not modify the risk for AD. (ETT 198/04/2006 and OTKA K 60589/2006).

Donepecilo bucodispersable: ¿están los cuidadores principales del paciente con enfermedad de Alzheimer más satisfechos que con la formulación tradicional de donepecilo?

To know whether caregivers of Alzheimer's disease (AD) patients on donepezil treatment are more satisfied with the orally disintegrating tablet (ODT) formulation than with the film-coated tablets. Multicenter, cross-sectional study of patients with probably AD by DSM-IV or NINCDS-ADRDA criteria, on monotherapy with donepezil, ODT or film-coated tablets. Satisfaction with treatment was assessed by the caregiver self-administered generic Treatment Satisfaction with Medicines Questionnaire (SATMED-Q) -range: 0, no satisfaction, to 100, maximal satisfaction-, total and in six dimensions: undesirable effects, efficacy, medical care, medication ease and convenience, medication impact on daily activities, and overall satisfaction. 546 patients were enrolled (9,6% institutionalized); 64,8% women; 78,2 +/- 6,5 years of age; disease evolution of 22.5 +/- 24.6 months, Minimental State Examination (MMSE) mean score: 18,5 +/- 5; 67.9% on film-coated tablets and 32.1% on ODT. After adjusting by MMSE and time of treatment, caregivers of patients on ODT showed significantly higher SATMED-Q total score (74.5 +/- 11.8 vs. 70.4 +/- 12.3; p lower than 0.0004) and medication ease and convenience (84.9 +/- 16.4 vs. 79.8 +/- 17.6; p = 0.0059), impact of medication on daily activities (50.2 +/- 22.8 vs. 43.7 +/- 25.5; p = 0.0006) and satisfaction with medical care (79.4 +/- 19.5 vs. 75.6 +/- 21.8; p = 0.04894) scores. 91.6% of caregivers of patients on ODT (versus 82.9% of those on film-coated tablets; p = 0.023) stated that taking the medication was easy for their relatives. Results show that caregivers of AD patients on donepezil treatment are more satisfied with ODT versus film-coated tablets, especially due to its better ease of use.

Prevalence of Dementia and Alzheimer’s Disease in a Havana Municipality: A Community-Based Study among Elderly Residents

Introduction Approximately 24.2 million persons throughout the world suffer dementia with 4.6 million new cases reported annually. Only 10% of dementia and Alzheimer's disease studies are conducted in developing countries where 66% of sufferers live. Cuba, a developing country, exhibits health indicators similar to those of developed nations. Its population of 11.6 million is aging rapidly: by the year 2020 it is estimated that persons aged ≥65 years will comprise 25% of the population, making Cuban society the oldest in Latin America. Objectives Ascertain and characterize behavior of dementia, its etiologies and risk factors in persons aged ≥65 years in the Havana City municipality of Playa. Methods A two-phase, cross-sectional, door-to-door study was conducted in the municipality targeting all persons aged ≥65 years, achieving a 96.4% response rate (n=18,351). Folstein Mini Mental State Examination (MMSE), Hughes Clinical Dementia Rating (CDR) and a structured interview on risk factors were applied. DSM-IV, NINCDS-ADRDA and NINDS-AIREN criteria were used to determine dementia diagnosis, as well as other criteria for diagnosing Alzheimer's and other specific forms of dementia. Results Dementia prevalence was 8.2% of adults aged ≥65 years, with a slight predominance in males. The most frequent cause of dementia was Alzheimer's disease, followed by mixed dementias. Dementia-associated risk factors were: history of stroke, hypertension, depression, skull-brain trauma, family history of dementia, low educational level and advanced age. Conclusions This study corroborates that dementia and Alzheimer's disease constitute an important and growing health problem for our country due to the accelerated aging of the Cuban population. It also underlines the importance of early diagnosis and proper treatment of hypertension and other vascular risk factors, as well as the need for a national public health program for the prevention and early diagnosis of dementia and Alzheimer's disease, targeting elderly and at-risk populations.

Estado nutricional na doença de Alzheimer

To describe the nutritional status of elderly subjects with mild to moderate Alzheimer's disease. Subjects of both genders (n=40) diagnosed with mild to moderate Alzheimer's disease according to NINCDS-ADRDA criteria, participated in the study. Socioeconomic status, activities of daily life, anthropometric, clinical and dietary profiles were surveyed. Of the total, 65% were female. More than 70% were capable of accomplishing daily activities by themselves. Subjects were eutrophic with a statistically significant difference of the arm circumference between the mild and moderate groups. As for illnesses secondary to Alzheimer's, 52% of the elderly presented hypertension, followed by arthrosis type alterations (17%). The mean consumption of energy and macronutrients in the elderly classified as mild dementia was of 1645 kcal, distributed in 53.7% of carbohydrate, 17.5% of proteins or 0.9 g/kg and 28.8% of lipids. For those classified as moderate dementia it was of 1482 kcal, distributed in 59.3% of carbohydrate, 16.1% of proteins and 24.6% of lipids. In this descriptive study of elderly outpatients with mild and moderate Alzheimer's disease, most presented a nutritional status of eutrophy, with adequate dietary intake of carbohydrates, proteins, lipids and vitamin C, but with low dietary intake of vitamin E.

The Effect of Sleep on Quality of Life in Cognitively Impaired Elder

Backgraound: The prevalence of sleep disturbance in patients with Alzheimer’s disease (AD) is common. The purpose of this study is whether quality of sleep (QoS) has effect on quality of life (QoL) in Alzheimer’s disease (AD) patients and amnestic mild cognitive impairment (aMCI) patients or not. Method: The participants were included 44 AD patients and 54 aMCI patients in this study. AD patients met NINCDS-ADRDA criteria for “probable” or “possible” AD and K-MMSE score was more than 16, single or multi domain aMCI patients met Peterson’s Criteria. The QoS was assessed by Pittsburgh Sleep Quality Index (PSQI) and the QoL by Medical Outcome Study Short From-36 (SF-36). Result: Poor sleep was defined by PSQI score more than 6. Therefore, in AD group 23 patients were good sleepers and 21 patients were poor sleepers and in aMCI group 28 patents were good sleepers and 26 patents were poor sleepers. There was no significant difference in the demographic variables demographic factor and global cognitive function which was assessed by K-MMSE and CDR between good sleeper group and poorer sleep group. The poor sleeper group in AD and aMCI had significantly higher depression score and poorer QoL than good sleeper group. The depression played a role as a mediator between QoS and QoL. Conclusion: QoS was also associated QoL in AD and aMCI and depression seemed to play a role as a mediating variable between QoS and QoL. Therefore, QoS had an effect on QoL indirectly rather than directly. In conclusion, sleep has a great effect on cognitively impaired elder, even in very early stage.

The factorial structure of the mini mental state examination (MMSE) in Alzheimer's disease

Our aim was to evaluate the factorial structure of the mini mental state examination (MMSE) in Alzheimer's disease (AD). Five hundred and twenty-four consecutive outpatients at their first diagnostic work-up (age 78.02 ± 6.07 years, education 6.62 ± 3.48 years, mean MMSE score 20.23 ± 4.89) (±S.D.) with probable AD (based on DSM-IV and NINCDS-ADRDA criteria) were enrolled in a multicenter, cross-sectional, regional-based study. For the purpose of the present study, the 11 subtests composing the MMSE and the global MMSE score (ranging from 10 to 29, included) were considered. Factor analysis with Varimax rotation method identified two factors that explained about the 85% of total variance. The first factor explained the 65% of variance and mainly included temporal orientation, delayed recall, attention/concentration, and constructional praxia. The second factor explained the 20% of variance and included reading a sentence, writing a sentence, naming, verbal repetition and immediate memory. The first factor was a reliable index of cognitive deterioration along the MMSE score interval between 29 and 10, whereas the second factor was not a suitable marker in this range. The two-factor structure of the MMSE in AD is shown in a large series of patients. The first factor expresses the ability to use new information and is related with working memory. The second factor is related with a more consolidated knowledge, namely verbal abilities, and is essentially useless in mild to moderate AD.

Anatomically-distinct genetic associations of APOE ɛ4 allele load with regional cortical atrophy in Alzheimer's disease

APOE ɛ4 is the best-established genetic risk factor for sporadic Alzheimer's disease (AD). However, while homozygotes show greater disease susceptibility and earlier age of onset than heterozygotes, they may not show faster rates of clinical progression. We hypothesize that there are differential APOE ɛ4 allele-load dependent influences on neuropathology across the brain. Our aim was to define the relationship between APOE ɛ4 allele load and regionally-specific brain cortical atrophy in Alzheimer's Disease (AD). For this reason voxel-based morphometry (VBM) was performed using T1-weighted MR images from 83 AD patients, contrasting regional cortical grey matter by APOE ɛ4 load according to either dominant or genotypic models. Patients fulfilled NINCDS-ADRDA criteria and were genotyped for APOE ɛ4 (15 ɛ4/ɛ4, 39 ɛ4/− and 29−/−). We observed that grey matter volume (GMV) decreased additively with increasing allele load in the medial (MTL) and anterior temporal lobes bilaterally. By contrast, a 2 degree-of-freedom genotypic model suggested a dominant effect of the APOE ɛ4 allele in the left temporal lobe. Brain regions showing a significant APOE ɛ4 allele load effect on GMV in AD included only some of those typically described as having greatest amyloid plaque deposition and atrophy. Temporal regions appeared to show a dominant effect of APOE ɛ4 allele load instead of the additive effect previously strongly associated with age of onset. Regional variations with allele load may be related to different mechanisms for effects of APOE ɛ4 load on susceptibility and disease progression.

Cytokine IL‐1 beta but not IL‐1 alpha promoter polymorphism is associated with Alzheimer disease in a population from the Canary Islands, Spain

Previous studies have reported the presence of low-grade inflammation in Alzheimer disease (AD). Based on these data, our work attempts to investigate the effects of some promoter polymorphisms of pro-inflammatory cytokines [interleukin (IL)-1 alpha and IL-1 beta] on AD. A PCR-RFLP technique was used to analyze the promoter polymorphisms of both IL-1 alpha (-889 C/T) and IL-1 beta (-511 C/T) and the APOE genotype from the DNA samples of 282 patients (according to NINCDS-ADRDA criteria) and 312 control subjects. (i) The risk of developing AD in our population was associated with the IL-1 beta (-511 C/T) promoter polymorphism; (ii) such risk was independent of the risk factor allele in the APOE gene (APOE4); and (iii) the IL-1 alpha promoter polymorphism (-889 C/T) was not associated with the disease. In our population, IL-1 beta promoter polymorphism (-511 C/T) is an independent risk factor for AD.

GuidAge Study: A 5-Year Double Blind, Randomised Trial of EGb 761 for the Prevention of Alzheimers Disease in Elderly Subjects with Memory Complaints. I. Rationale, Design and Baseline Data

Primary and secondary prevention strategies for Alzheimer's disease (AD) are urgently needed. We have initiated a five-year prospective prevention study involving patients spontaneously reporting memory complaints. The primary objective is to determine the effect of treatment with EGb 76 on the rate of conversion from memory complaints to AD using survival analysis. Ambulatory patients aged at least 70 years who spontaneously reported a memory complaint during a GP or memory centre consultation were eligible for inclusion. Patients with major objective memory impairment or clinically relevant symptoms of anxiety and depression were excluded. Subjects were randomised to receive either EGb 761 120mg bid or matching placebo. Participants undergo an annual visit at a memory centre, where a series of neuropsychological tests are administered to assess cognitive function (Grober and Buschke, Trail-Making and controlled oral word association tests) and cognitive status (MMS and CDR). Functional status is evaluated with the Instrumental Activities of Daily Living questionnaire. The primary outcome is the transition to a diagnosis of AD (DSM-IV and NINCDS-ADRDA criteria), determined at the annual memory centre visit. A total of 4066 patients were screened for participation, of whom 2854 fulfilled the eligibility criteria and were entered into the study. Their mean age was 76.8+/-4.4 years and 66.7% were female. The mean MMSE score was 27.8+/-1.7 and 55.5% presented a CDR score of 0.5. This study will enable us to evaluate the efficacy of EGb761 in the prevention of AD, and to assess the usefulness of various baseline characteristics as predictors of conversion to AD in this population.