European Projects for Patients with Dementia and Their Caregivers.

As we all know there is no treatment that can stop or delay the progression of dementia. The treatment we use is only symptomatic. EFNS (European Federation of Neurological Societies) recommendations for dementia prevention by Sorbi et al. (2012) concluded that there is no treatment, no lifestyle, which could have an effect on prevention or delay of onset of different forms of dementia until today. The future studies in prevention must recruit younger people, larger sample, and for longer period. The last 10 years we have run, in collaboration with organizations in different European countries, many projects in order to support patients with neurodegenerative diseases, mainly patients with dementia and their caregivers. The first project was a 2-year prospective cohort study of antidementia drug non-persistency in mild-to-moderate Alzheimer's disease (AD) in Europe: predictors of discontinuation and switch in the ICTUS (Impact of Cholinergic Treatment USe) study, an FP5 project with 1380 patients. Five studies were published. The second project was DESCRIPA study, an FP5 project to DEvelopment of Screening guidelines and clinical CRIteria for Predementia Alzheimer's disease, with 881 patients with mild cognitive impairment (MCI). LLM (Long Lasting Memories) and VRADA (A virtual reality application for the exercise of dementia and Alzheimer patients) are two projects that include body and cognitive exercise for health for the elderly and patients with mild cognitive impairment. The next is the RECAGE (REspectful Caring for the AGitated Elderly) project (Horizon 2020), a prospective cohort study for coping with behavioral and psychological symptoms of dementia. With six European universities we finished a very interesting FP6 project, the AddNeuroMed one, which gives even now information about the progression of normal elderly MCI and AD patients, in collaboration with other consortia. A very interesting Innovative Medicines Initiative (IMI) project about digital biomarkers was entitled Remote Assessment of Disease and Relapse-Alzheimer's Disease (RADAR project). The main goal of this project was the development and validation of technology-enabled, quantitative and sensitive measures of functional decline in people with early-stage AD. A running project is an Erasmus+ one in the higher education field, "Genetic counseling in European universities: The case of neurodegenerative diseases" (GECONEU project). The target of this study is to develop an online course for university students focusing on genetic counseling, and support people and society to better understand the aims of genetic testing and the usefulness of genetic counseling by involving students in an innovative learning and teaching setting. AD-gaming, BRIDGE, iCONNECT (Intergenerational CONtact between studeNts and people with dEmentia through CreaTive education), E.L.So.M.C.I (English Lessons with the Use of Songs for People with Mild Cognitive Impairment), Games4CoSkills, and De-Sign are all Erasmus+ projects that aim to improve the quality of life of patients with MCI or dementia. Story2remember, Dementia right, ASPAD (Augmentation of the Support of Patients suffering from Alzheimer's Disease and their caregivers), INFOCARE (Supporting Informal Caregivers of People with Dementia), S.IN.CA.L.A (Supporting Informal Carers: A Whole-Family and Life course Approach), and PIA (Peer support workers as an Innovative force in Advocacy in dementia care) are all Erasmus+ projects for training and supporting caregivers of patients with dementia.

A Novel Method of Teaching English to People with Mild Cognitive Impairment Using Songs: A Randomized Controlled Trial Protocol.

BACKGROUND: People with mild cognitive impairment (MCI) need to prevent the further decline of their cognitive functions, and one way to do so is by learning a foreign language. OBJECTIVE: This study describes the development of a protocol for a novel, non-pharmacological intervention for people with MCI that seeks to prevent or reduce cognitive decline by teaching English through songs. METHODS: The development of this protocol follows a mixed-methodology approach, consisting of three stages: 1) development of the protocol of the intervention, 2) a randomized controlled trial study with two arms over six months that includes an intervention group and a control group, and 3) the evaluation of the protocol by trainers. In the second stage, we recruited a total of 128 people with MCI from the five participating countries of this study (Greece, Spain, Croatia, Slovenia, and Italy). This educational program will assess three main outcomes after 6 months of the English Lessons with the Use of Songs for People with Mild Cognitive Impairment (E.L.So.M.C.I.) workshops. RESULTS: Our primary outcome will hopefully be an improvement in general cognition in the intervention group compared to the control group from baseline to 6 months follow-up. Secondary outcomes include a decrease in participants' anxiety and depression and an improvement in their quality of life. Development of English language skills is the last outcome.

Analyzing social cognition and understanding of social inferences in patients with multiple sclerosis. A comparative study.

OBJECTIVE: The aim of the present study was to investigate the process of understanding social inferences and metaphors and the pragmatic use of language through emotion recognition and social inference tests in patients diagnosed with Primary Progressive Multiple Sclerosis (PPMS) mainly characterized by neurodegeneration. Additionally, we tried to identify a cerebrospinal fluid (CSF) biomarker correlated with the degree and rate of cognitive decline in progressive MS patients. METHOD: For the purpose of the present study 25 patients, aged 20 up to 55 years, with PPMS were evaluated. All patients were admitted in the First Department of Neurology, AHEPA Hospital of Thessaloniki. The control group was 30 healthy individuals which participated in the study voluntarily. The groups were matched for age, gender, years of education and intelligence. INSTRUMENTS: Social inference was examined with the Awareness of Social Inference Test (TASIT). The TASIT consists of two different parts. The "Tasit Part I: Emotion Evaluation Task (EET - FORM A). The EET is the first part of a broader audiovisual tool designed for the clinical assessment of social perception that is called "The Awareness of Social Inference Test (TASIT)". The second Part of the test TASIT - Social Inference examines the viewer's ability to determine the speaker's meaning and intentions based upon the dialogue, emotional expression, and paralinguistic cues. RESULTS: The findings indicate that patients with PPMS show decline in emotion recognition and social inference abilities, as compared with the control group. More specifically, PPMS patients have problems to understand the affective state of the others mirroring a specific problem in ToM. CONCLUSION: The level of Theory of Mind in the form of sarcasm understanding decreases significantly in MS patients compared with healthy group potentially mirroring impairment in ToM in general. The results indicate that MS group is not resilient to understand metaphoric speech. More specifically, their pathology seems to be able to affect complex ToM abilities.

Elders and mental capacity: Using a qualitative approach to examine views on independence and protection across the Balkans.

OBJECTIVE: How do people in contemporary Balkans think about elders and mental capacity, a particular medical and legal concept? SUBJECTS AND METHODS: Different interpretations and applications regarding elders' mental capacity are explored through in-depth semi-structured interviews and field notes of 28 Greeks, 27 Bulgarians and 10 Romanians of varying ages, all living in Northern Greece. This study attempts to shed some light on the perceptions of ageing, mental disease, civil capacities, family and state involvement across three nearby nations. Interpretative phenomenological analysis (IPA), an approach to psychological qualitative research that aims to offer insights into how a given person, in a given context, makes sense of a given phenomenon was used for the first time applied to this topic. RESULTS: Four areas for focus were formed, each relating to the elders and the aging process and presenting the associated themes drawn from the participants' accounts: 1) Discovering the altered-self of the elder, family and society, 2) General experience with old age and capacities in everyday life, 3) Ways of thinking and acting towards old age and capacity issues, and 4) Feelings and comparison thoughts towards old age and capacity issues. Education, occupation, life experience, and especially religious beliefs were all found to be involved in the ways that people from three cultural groups understand the concept of mental capacity and incapacity of elders in their everyday life. A main finding is that the more educated Bulgarians and Romanians tend to speak more easily and to be more positive towards the social construct of aging, while Greeks regardless of their gender, education, religious beliefs, and financial status, tend to consider in their narratives old age as equal to loss of mental capacity, which equals to loss of autonomy and total dependency on others. The process of old age for the group of Greeks begins with retirement which is perceived to reflect withdrawal from social life. This is primarily related to behaviors from individuals and society that result to deprivation of freedom. CONCLUSION: The similarities and differences among these three ethnic groups are discussed, which according to the interviewees discourse reveal peculiar cultural understandings about subordinate themes such as power and its relationship to the self and superordinate themes on emotional control, choice, and individualism.

Administration of the extra virgin olive oil (EVOO) in mild cognitive impairment (MCI) patients as a therapy for preventing the progress to AD.

OBJECTIVE: Although Mediterranean diet is connected with longevity and lower rate of many disorders including Alzheimer's disease (AD), the effect of olive oil, which is the principal component of the Mediterranean diet, on fibrinolytic system related to AD and especially on plasminogen activator inhibitor-1 (PAI-1) and a2-antiplasmin in aged participants are not yet examined. This study was performed on 108 aged participants allocated into 5 groups: Mild Cognitive Impairment (MCI) (36) patients subjected to 1-year therapy with extra virgin olive oil (EVOO), MCI without therapy patients (26), MCI without therapy 1-year later patients (11), AD patients (30) and healthy individuals (16). Hypothesis/Purpose: To examine the effect of EVOO therapy on the fibrinolytic factors PAI-1 and a2-antiplasmin, on hallmarks of AD, tau and Aß amyloid fragments and on an oxidative stress biomarker, MDA in the serum of MCI patients aiming to be exploited as a future preventive therapy. RESULTS: Using ELISA method, the levels of both fibrinolytic factors PAI-1 and a2- antiplasmin in the serum of MCI patients were reduced notably in the EVOO treated patients versus the control group and were lower than those of all other groups. For better determination of AD from other pathological conditions the ratio Aß1-42/Aß1-40 was measured in serum of all participants. The more lessened the ratio is, the more cognitive impairment is observed in patients. The MCI group with one-year EVOO therapy displayed a ratio similar to this of healthy individuals. Moreover, patients with EVOO therapy showed decreased tau protein levels in comparison with all the other groups. The levels of the oxidative stress's biomarker, malondialdehyde (MDA) showed a significant decrease in MCI patients subjected to EVOO therapy revealing the involvement of the beneficial antioxidative properties of EVOO in the progression of AD. CONCLUSION: We demonstrated that EVOO therapy may prevent the risk of patients with MCI to progress to AD via decreasing fibrinolytic factors PAI-1 and a2 antiplasmin that reflecting in the diminution of the hallmarks proteins of AD, tau and Aß amyloid as well and in a biomarker of oxidative stress, MDA.

Depression and financial capacity assessment in Parkinson's disease with dementia: Overlooking an important factor?

Depression affects cognitive abilities, such as thinking, concentration and making decisions in both young adults and elders. However, financial capacity (which consists of multiple cognitive domains and specific skills) and depression in Parkinson's disease with dementia (PDD) are little investigated. Sixty participants divided into four groups (PDD with and without depressive symptoms, non-demented elders with and without depression) were examined with the Mini-Mental State Examination (MMSE), the Geriatric Depression Scale (GDS-15) and the Legal Capacity for Property Law Transactions Assessment Scale (LCPLTAS) - full and short form. Results indicated that PDD patients' performance in cognitive functioning and financial capacity is severely impaired, while there is a statistically significant difference between depressed and non-depressed PDD patients. Differences in financial capacity performance indicate that depression should not be disregarded. Further studies on larger PDD population are necessary in order to investigate the decisive role of depression on financial capacity impairment.

Callosal Angle and Evans Index predict beta amyloid and tau protein in patients with dementia.

INTRODUCTION: Aß and tau protein have been widely investigated for the diagnosis of dementia entities, most commonly Alzheimer's disease (AD). However, their measurement is an interventional, time-consuming procedure, while it requires specialized personnel, unlike the evaluation of radiological markers, such as Evans index (EI) and Callosal angle (CA). This study aims to investigate the correlation between EI, CA, Aß and total tau in order to outline a basis of diagnostic evaluation for the patient's CSF biomarker profile. METHODS: Sixty-two (62) patients who presented with dementia symptoms participated in this study. Aß and total tau levels in their CSF as well as CA and EI values from their MRIs were measured. Multiple regression was employed to predict Aß and total tau values from EI and CA. From the Durbin-Watson analysis (d1=2.057, d2=1.881) we can assume that there is no first order linear auto-correlation in our multiple linear regression data. RESULTS: The variables statistically significantly predicted both Aß and total tau (F1=8.720, R1=0.484, p1=0.001 and F2=4.110, R2=0.355, p2=0.022). Out of all the variables, it was shown that CA, EI (p<0.05) and CA (p<0.05) added statistically significantly to the prediction of Aß and total tau. CONCLUSION: Collectively, these results support a significant correlation between EI and Aß and CA, Aß and total tau. This highlights the potential role of radiological markers as rough estimates of biomarker levels in everyday clinical practice, assisting to a robust and inexpensive diagnosis.

Non-pharmacological interventions for agitation/aggressive behaviour in patients with dementia: a randomized controlled crossover trial.

Agitation/aggressive behaviour is a common behavioural and psychological symptom in people with dementia (PwD), occurring with a frequency of between 13-50.4% according to recent studies, and the rate increases as the severity of cognitive decline increases. The burden on caregivers is considerable. This trial is a randomized controlled crossover trial conducted in Greece. The following measures were used: the Mini-Mental State Examination, Addenbrooke's Cognitive Examination Revised, Geriatric Depression Scale, Functional Rating Scale for Symptoms in Dementia and Neuropsychiatric Inventory. According to the results the most effective nonpharmacological intervention for reducing agitation/aggressive behaviour in PwD was music therapy, followed by aromatherapy and massage, and finally physical exercise.

Clinical and biomarker profiling of prodromal Alzheimer's disease in workpackage 5 of the Innovative Medicines Initiative PharmaCog project: a 'European ADNI study'.

BACKGROUND: In the field of Alzheimer's disease (AD), the validation of biomarkers for early AD diagnosis and for use as a surrogate outcome in AD clinical trials is of considerable research interest. OBJECTIVE: To characterize the clinical profile and genetic, neuroimaging and neurophysiological biomarkers of prodromal AD in amnestic mild cognitive impairment (aMCI) patients enrolled in the IMI WP5 PharmaCog (also referred to as the European ADNI study). METHODS: A total of 147 aMCI patients were enrolled in 13 European memory clinics. Patients underwent clinical and neuropsychological evaluation, magnetic resonance imaging (MRI), electroencephalography (EEG) and lumbar puncture to assess the levels of amyloid ß peptide 1-42 (Aß42), tau and p-tau, and blood samples were collected. Genetic (APOE), neuroimaging (3T morphometry and diffusion MRI) and EEG (with resting-state and auditory oddball event-related potential (AO-ERP) paradigm) biomarkers were evaluated. RESULTS: Prodromal AD was found in 55 aMCI patients defined by low Aß42 in the cerebrospinal fluid (Aß positive). Compared to the aMCI group with high Aß42 levels (Aß negative), Aß positive patients showed poorer visual (P = 0.001), spatial recognition (P < 0.0005) and working (P = 0.024) memory, as well as a higher frequency of APOE4 (P < 0.0005), lower hippocampal volume (P = 0.04), reduced thickness of the parietal cortex (P < 0.009) and structural connectivity of the corpus callosum (P < 0.05), higher amplitude of delta rhythms at rest (P = 0.03) and lower amplitude of posterior cingulate sources of AO-ERP (P = 0.03). CONCLUSION: These results suggest that, in aMCI patients, prodromal AD is characterized by a distinctive cognitive profile and genetic, neuroimaging and neurophysiological biomarkers. Longitudinal assessment will help to identify the role of these biomarkers in AD progression.

Plasma protein biomarkers of Alzheimer's disease endophenotypes in asymptomatic older twins: early cognitive decline and regional brain volumes.

There is great interest in blood-based markers of Alzheimer's disease (AD), especially in its pre-symptomatic stages. Therefore, we aimed to identify plasma proteins whose levels associate with potential markers of pre-symptomatic AD. We also aimed to characterise confounding by genetics and the effect of genetics on blood proteins in general. Panel-based proteomics was performed using SOMAscan on plasma samples from TwinsUK subjects who are asymptomatic for AD, measuring the level of 1129 proteins. Protein levels were compared with 10-year change in CANTAB-paired associates learning (PAL; n = 195), and regional brain volumes (n = 34). Replication of proteins associated with regional brain volumes was performed in 254 individuals from the AddNeuroMed cohort. Across all the proteins measured, genetic factors were found to explain ~26% of the variability in blood protein levels on average. The plasma level of the mitogen-activated protein kinase (MAPK) MAPKAPK5 protein was found to positively associate with the 10-year change in CANTAB-PAL in both the individual and twin difference context. The plasma level of protein MAP2K4 was found to suggestively associate negatively (Q < 0.1) with the volume of the left entorhinal cortex. Future studies will be needed to assess the specificity of MAPKAPK5 and MAP2K4 to eventual conversion to AD.

Practical cut-offs for visual rating scales of medial temporal, frontal and posterior atrophy in Alzheimer's disease and mild cognitive impairment.

BACKGROUND: Atrophy in the medial temporal lobe, frontal lobe and posterior cortex can be measured with visual rating scales such as the medial temporal atrophy (MTA), global cortical atrophy - frontal subscale (GCA-F) and posterior atrophy (PA) scales, respectively. However, practical cut-offs are urgently needed, especially now that different presentations of Alzheimer's disease (AD) are included in the revised diagnostic criteria. AIMS: The aim of this study was to generate a list of practical cut-offs for the MTA, GCA-F and PA scales, for both diagnosis of AD and determining prognosis in mild cognitive impairment (MCI), and to evaluate the influence of key demographic and clinical factors on these cut-offs. METHODS: AddNeuroMed and ADNI cohorts were combined giving a total of 1147 participants (322 patients with AD, 480 patients with MCI and 345 control subjects). The MTA, GCA-F and PA scales were applied and a broad range of cut-offs was evaluated. RESULTS: The MTA scale showed better diagnostic and predictive performances than the GCA-F and PA scales. Age, apolipoprotein E (ApoE) ε4 status and age at disease onset influenced all three scales. For the age ranges 45-64, 65-74, 75-84 and 85-94 years, the following cut-offs should be used. MTA: ≥1.5, ≥1.5, ≥2 and ≥2.5; GCA-F, ≥1, ≥1, ≥1 and ≥1; and PA, ≥1, ≥1, ≥1 and ≥1, respectively, with an adjustment for early-onset ApoE ε4 noncarrier AD patients (MTA: ≥2, ≥2, ≥3 and ≥3; and GCA-F: ≥1, ≥1, ≥2 and ≥2, respectively). CONCLUSIONS: If successfully validated in clinical settings, the list of practical cut-offs proposed here might be useful in clinical practice. Their use might also (i) promote research on atrophy subtypes, (ii) increase the understanding of different presentations of AD, (iii) improve diagnosis and prognosis and (iv) aid population selection and enrichment for clinical trials.

Plasma lipidomics analysis finds long chain cholesteryl esters to be associated with Alzheimer's disease.

There is an urgent need for the identification of Alzheimer's disease (AD) biomarkers. Studies have now suggested the promising use of associations with blood metabolites as functional intermediate phenotypes in biomedical and pharmaceutical research. The aim of this study was to use lipidomics to identify a battery of plasma metabolite molecules that could predict AD patients from controls. We performed a comprehensive untargeted lipidomic analysis, using ultra-performance liquid chromatography/mass spectrometry on plasma samples from 35 AD patients, 40 elderly controls and 48 individuals with mild cognitive impairment (MCI) and used multivariate analysis methods to identify metabolites associated with AD status. A combination of 10 metabolites could discriminate AD patients from controls with 79.2% accuracy (81.8% sensitivity, 76.9% specificity and an area under curve of 0.792) in a novel test set. Six of the metabolites were identified as long chain cholesteryl esters (ChEs) and were reduced in AD (ChE 32:0, odds ratio (OR)=0.237, 95% confidence interval (CI)=0.10-0.48, P=4.19E-04; ChE 34:0, OR=0.152, 95% CI=0.05-0.37, P=2.90E-04; ChE 34:6, OR=0.126, 95% CI=0.03-0.35, P=5.40E-04; ChE 32:4, OR=0.056, 95% CI=0.01-0.24, P=6.56E-04 and ChE 33:6, OR=0.205, 95% CI=0.06-0.50, P=2.21E-03, per (log2) metabolite unit). The levels of these metabolites followed the trend control>MCI>AD. We, additionally, found no association between cholesterol, the precursor of ChE and AD. This study identified new ChE molecules, involved in cholesterol metabolism, implicated in AD, which may help identify new therapeutic targets; although, these findings need to be replicated in larger well-phenotyped cohorts.

FASTKD2 is associated with memory and hippocampal structure in older adults.

Memory impairment is the cardinal early feature of Alzheimer's disease, a highly prevalent disorder whose causes remain only partially understood. To identify novel genetic predictors, we used an integrative genomics approach to perform the largest study to date of human memory (n=14 781). Using a genome-wide screen, we discovered a novel association of a polymorphism in the pro-apoptotic gene FASTKD2 (fas-activated serine/threonine kinase domains 2; rs7594645-G) with better memory performance and replicated this finding in independent samples. Consistent with a neuroprotective effect, rs7594645-G carriers exhibited increased hippocampal volume and gray matter density and decreased cerebrospinal fluid levels of apoptotic mediators. The MTOR (mechanistic target of rapamycin) gene and pathways related to endocytosis, cholinergic neurotransmission, epidermal growth factor receptor signaling and immune regulation, among others, also displayed association with memory. These findings nominate FASTKD2 as a target for modulating neurodegeneration and suggest potential mechanisms for therapies to combat memory loss in normal cognitive aging and dementia.

Random Forest ensembles for detection and prediction of Alzheimer's disease with a good between-cohort robustness.

Computer-aided diagnosis of Alzheimer's disease (AD) is a rapidly developing field of neuroimaging with strong potential to be used in practice. In this context, assessment of models' robustness to noise and imaging protocol differences together with post-processing and tuning strategies are key tasks to be addressed in order to move towards successful clinical applications. In this study, we investigated the efficacy of Random Forest classifiers trained using different structural MRI measures, with and without neuroanatomical constraints in the detection and prediction of AD in terms of accuracy and between-cohort robustness. From The ADNI database, 185 AD, and 225 healthy controls (HC) were randomly split into training and testing datasets. 165 subjects with mild cognitive impairment (MCI) were distributed according to the month of conversion to dementia (4-year follow-up). Structural 1.5-T MRI-scans were processed using Freesurfer segmentation and cortical reconstruction. Using the resulting output, AD/HC classifiers were trained. Training included model tuning and performance assessment using out-of-bag estimation. Subsequently the classifiers were validated on the AD/HC test set and for the ability to predict MCI-to-AD conversion. Models' between-cohort robustness was additionally assessed using the AddNeuroMed dataset acquired with harmonized clinical and imaging protocols. In the ADNI set, the best AD/HC sensitivity/specificity (88.6%/92.0% - test set) was achieved by combining cortical thickness and volumetric measures. The Random Forest model resulted in significantly higher accuracy compared to the reference classifier (linear Support Vector Machine). The models trained using parcelled and high-dimensional (HD) input demonstrated equivalent performance, but the former was more effective in terms of computation/memory and time costs. The sensitivity/specificity for detecting MCI-to-AD conversion (but not AD/HC classification performance) was further improved from 79.5%/75%-83.3%/81.3% by a combination of morphometric measurements with ApoE-genotype and demographics (age, sex, education). When applied to the independent AddNeuroMed cohort, the best ADNI models produced equivalent performance without substantial accuracy drop, suggesting good robustness sufficient for future clinical implementation.

Clinical workout for the early detection of cognitive decline and dementia.

Aging is the major risk factor for the development of human neurodegenerative maladies such as Alzheimer's, Huntington's and Parkinson's diseases (PDs) and prion disorders, all of which stem from toxic protein aggregation. All of these diseases are correlated with cognitive decline. Cognitive Decline is a dynamic state from normal cognition of aging to dementia. According to the original criteria for Alzheimer's Disease (AD) (1984), a clinical diagnosis was possible only when someone was already demented. The prevalence rates of Cognitive Decline (mild cognitive impairment plus dementia) are very high now and will be higher in future because of the increasing survival time of people. Many neurological and psychiatric diseases are correlated with cognitive decline. Diagnosis of cognitive decline is mostly clinical (clinical criteria), but there are multiple biomarkers that could help us mostly in research programs such as short or long, paper and pencil or computerized neuropsychological batteries for cognition, activities of daily living and behavior, electroencephalograph, event-related potentials, and imaging-structural magnetic resonance imaging (MRI) and functional (fMRI, Pittsburgh bound positron emission tomography, FDG-PET, single photon emission computerized tomography and imaging of tau pathology)-cerebrospinal fluid proteins (Abeta, tau and phospho-tau in AD and α-synuclein (αSyn) for PD). Blood biomarkers need more studies to confirm their usefulness. Genetic markers are also studied but until now are not used in clinical praxis. Finally, in everyday clinical praxis and in research workout for early detection of cognitive decline, the combination of biomarkers is useful.

Influence of age, disease onset and ApoE4 on visual medial temporal lobe atrophy cut-offs.

BACKGROUND: Visual assessment of medial temporal lobe atrophy (MTA; range 0-4, from no atrophy to increasing atrophy of the choroid fissure, temporal horns and hippocampus) is a sensitive radiological marker of Alzheimer's disease (AD). One of the critical elements for visual MTA assessment is the cut-off score that determines deviation from normality. METHODS: In this study, we assessed the sensitivity and specificity of different MTA cut-off scores to classify control subjects, individuals with mild cognitive impairment (MCI) and AD patients from two large independent cohorts, AddNeuroMed and Alzheimer's Disease Neuroimaging Initiative. Of note, we evaluated the effects of clinical, demographic and genetic variables on the classification performance according to the different cut-offs. RESULTS: A cut-off of ≥1.5 based on the mean MTA scores of both hemispheres showed higher sensitivity in classifying patients with AD (84.5%) and MCI subjects (75.8%) who converted to dementia compared to an age-dependent cut-off. The age-dependent cut-off showed higher specificity or ability to correctly identify control subjects (83.2%) and those with MCI who remained stable (65.5%). Increasing age, early-onset disease and absence of the ApoE ε4 allele had a stronger influence on classifications using the ≥1.5 cut-off. Above 75 years of age, an alternative cut-off of ≥2.0 should be applied to achieve a classification accuracy for both patients with AD and control subjects that is clinically useful. CONCLUSION: Clinical, demographic and genetic variables can influence the classification of MTA cut-off scores, leading to misdiagnosis in some cases. These variables, in addition to the differential sensitivity and specificity of each cut-off, should be carefully considered when performing visual MTA assessment.

Could language deficits really differentiate Mild Cognitive Impairment (MCI) from mild Alzheimer's disease?

Naming abilities seem to be affected in Alzheimer's disease (AD) patients, though MCI individuals tend to exhibit greater impairments in category fluency. In this study we: (1) detect language deficits of amnestic MCIs (aMCIs) and mild AD (mAD) participants and present their language performance (the Boston Diagnostic Aphasia Examination - BDAE scores) according to educational level, (2) study the diagnostic value of language deficits according to the cognitive state of the participants. One hundred nineteen participants, 38 normal controls (NC), 28 aMCIs and 53 mADs, were recruited randomly as outpatients of 2 clinical departments and administered clinical, neuropsychological and neuroimaging assessment. Language abilities were assessed by the adapted Greek edition of the BDAE (2nd edition). Our results indicate that verbal fluency, auditory, reading comprehension and narrative ability are the main language abilities to be affected in mADs, although they are almost intact in NCs and less vulnerable in aMCIs. Narrative ability seems to be significantly impaired in mADs but not so in aMCIs. Six language subtests of the BDAE assess safely the above deficits. This brief version of the BDAE discriminated mADs from the other 2 groups 92.5% of the time, NCs 86.8% and aMCI 67.9% of the time in order to save time and to be accurate in clinical practice.

Whole-exome sequencing and imaging genetics identify functional variants for rate of change in hippocampal volume in mild cognitive impairment.

Whole-exome sequencing of individuals with mild cognitive impairment, combined with genotype imputation, was used to identify coding variants other than the apolipoprotein E (APOE) ε4 allele associated with rate of hippocampal volume loss using an extreme trait design. Matched unrelated APOE ε3 homozygous male Caucasian participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected at the extremes of the 2-year longitudinal change distribution of hippocampal volume (eight subjects with rapid rates of atrophy and eight with slow/stable rates of atrophy). We identified 57 non-synonymous single nucleotide variants (SNVs) which were found exclusively in at least 4 of 8 subjects in the rapid atrophy group, but not in any of the 8 subjects in the slow atrophy group. Among these SNVs, the variants that accounted for the greatest group difference and were predicted in silico as 'probably damaging' missense variants were rs9610775 (CARD10) and rs1136410 (PARP1). To further investigate and extend the exome findings in a larger sample, we conducted quantitative trait analysis including whole-brain search in the remaining ADNI APOE ε3/ε3 group (N=315). Genetic variation within PARP1 and CARD10 was associated with rate of hippocampal neurodegeneration in APOE ε3/ε3. Meta-analysis across five independent cross sectional cohorts indicated that rs1136410 is also significantly associated with hippocampal volume in APOE ε3/ε3 individuals (N=923). Larger sequencing studies and longitudinal follow-up are needed for confirmation. The combination of next-generation sequencing and quantitative imaging phenotypes holds significant promise for discovery of variants involved in neurodegeneration.

Classification and prediction of clinical diagnosis of Alzheimer's disease based on MRI and plasma measures of α-/γ-tocotrienols and γ-tocopherol.

BACKGROUND: The aim of this study was to evaluate the accuracy of combined structural magnetic resonance imaging (MRI) measures and plasma levels of vitamin E forms, including all eight natural vitamin E congeners (four tocopherols and four tocotrienols) and markers of vitamin E oxidative/nitrosative damage, in differentiating individuals with Alzheimer's disease (AD) and mild cognitive impairment (MCI) from cognitively intact control (CTL) subjects. METHODS: Overall, 81 patients with AD, 86 with MCI and 86 CTL individuals were enrolled from the longitudinal multicentre AddNeuroMed study. MRI and plasma vitamin E data were acquired at baseline. MRI scans were analysed using Freesurfer, an automated segmentation scheme which generates regional volume and cortical thickness measures. Orthogonal partial least squares to latent structures (OPLS), a multivariate data analysis technique, was used to analyse MRI and vitamin E measures in relation to AD and MCI diagnosis. RESULTS: The joint evaluation of MRI and plasma vitamin E measures enhanced the accuracy of differentiating individuals with AD and MCI from CTL subjects: 98.2% (sensitivity 98.8%, specificity 97.7%) for AD versus CTL, and 90.7% (sensitivity 91.8%, specificity 89.5%) for MCI versus CTL. This combination of measures also identified 85% of individuals with MCI who converted to clinical AD at follow-up after 1 year. CONCLUSIONS: Plasma levels of tocopherols and tocotrienols together with automated MRI measures can help to differentiate AD and MCI patients from CTL subjects, and to prospectively predict MCI conversion into AD. Our results suggest the potential role of nutritional biomarkers detected in plasma-tocopherols and tocotrienols-as indirect indicators of AD pathology, and the utility of a multimodality approach.