Criteria and Neuropsychologic tests

DEMENTIA
A. Criteria: We use DSM-IV for the diagnosis of Dementia, Depression and AD, NINCDS-ADRDA for AD, NINDS-AIREN for Vascular Dementia, Lund-Manchester for Fronto-temporal Dementia and Criteria for LBD (McKeith, 1996, 2006)

B. Neuropsychological tests

• The most common forms of dementia are Alzheimer's disease (AD), vascular dementia, Fronto-temporal Dementia and Lewy Body dementia. The duration of neuropsychological assessment of a demented patient is about 40 -60 minutes and many elderly individual people enjoy performing it. The tests we use for the assessment of patients are: For the determination of the stage of the disease Clinical Dementia Rating (CDR) and Global Deterioration Scale (GDS). For global cognitive disorders the CAMCOG (Roth et al., 1986, Tsolaki et al, 2000) which includes Mini Mental State Examination MMSE (Mini Mental State Examination) (Folstein et al, 1975, Fountoulakis et al, 2000). Hindi Mental State Examination (HMSE) is used for illiterate patients. For Memory Disorders Rivermead Behavioural Memory Test (RBMT) and Rey Auditory - Verbal Learning Test (RAVLT) (Rey, A. (1958, Kounti et al 2004 ). For language disorders Pyramids and Palms trees, Boston Naming Test, some subtests of Boston Diagnostic Aphasia Examination (BDAE), Psycholinguistic Assessment of Language Processing of Aphasia (PALPA) and Verbal Fluency Test. For executive function, processing speed and attention Stroop test (Jensen et al, 1966)., Digit Backwards test, Trail Making Test A and B, Wisconsin test, Luria three step and Alternative Hand Movement. For the assessment of Activities of Daily Living Functional Rating Scale for Symptoms of Dementia (FRSSD), Instrumental activities of daily Living (IADL), ADL-Is and Functional and Cognitive Assessment Scale (FUCAS) (Kounti et al, 2006) and for neuropsychiatric symptoms Neuropsychiatric Inventory (NPI). For depression and anxiety Hamilton-17 or Geriatric Depression Scale or Hospital Anxiety and Depression Scale (HADS) or Cornell scale. Hachinski score is used for exclusion of vascular or mixed dementia.

MILD COGNITIVE IMPAIRMENT

Mild cognitive impairment (MCI) is a transitional state between normal aging and AD. The subjects experience cognitive problems that do not interfere with their daily activities. The clinical criteria we use for the diagnosis of MCI are described by Petersen et al, 1999.

The tests we use for Mild Cognitive Impairment are MOCA, Clock drawing, Rey auditory verbal learning test (immediate and free delayed recall), Verbal fluency (animals), Boston naming test, Stroop card 1 - Stroop card 3, Trail making test A and B, Symbol Digit substitution test, Rey figure (Copy and delayed recall).

All the above, scales which are used for the assessment of Dementia and Mild Cognitive Impairment, are translated and validated in the Greek elderly population. All the literature is available.

Laboratory Examinations

1. Blood Tests
Blood tests are performed in all patients. Routine blood examination including haematological (haemoglobuline etc) and biochemical (glucose, cholesterol, etc) as well as TSH and the levels of homocysteine, folic acid and B12, which are affected in dementia are measured. In some patients that are included in clinical trials or research projects blood tests are performed for the identification for genes that are believed to be implicated in Alzheimer's disease.

2. CSF tests
Cerebrospinal fluid (CSF) is a clear colourless protective fluid, which is produced in the ventricles of the brain at a rate of 500ml/24h. The CSF volume in the brain is 100-150 ml, therefore it is replaced about 4-5 times a day It is in direct contact with the brain's extra-cellular space, therefore any pathological changes observed in the brain can be reflected in certain biomarkers in the CSF.

CSF samples are taken from all patients, by lumbar puncture, at the L3/L4 or L4/L5 interspace, performed at hours 9:30-10:30 am, with patients lying on their back for one hour after puncture.The samples are stored at -80 degrees Celsius until further examination. CSF-Ab42 was determined using a sandwich ELISA (INNOTEST b amyloid (1±42) Innogenetics, Ghent, Belgium). CSF-htau levels were determined in all patients using the INNOTEST hTau-Antigen sandwich ELISA (Innogenetics, Ghent, Belgium) for the measurement of total tau, both normal and hyperphosphorylated-tau. CSF Fas levels were determined with the human sAPO-1/Fas ELISA (Bender MedSystems, Vienna, Austria).

3. Auditory event related potentials (AERP)

Auditory event related potentials are performed almost in all MCI patients using a simple discrimination task, the so-called oddball paradigm. In this task, two stimuli were presented in a random series with one of the two occurring relatively infrequently, i.e., the oddball. The auditory event related potentials use two different tones, an interstimulus interval of several seconds, with the target oddball stimulus presented less frequently than the nontarget or standard stimulus. The subject is required to distinguish between the two tones by responding to the target (e.g. mentally counting) and not responding to the standard (Squires et al, 1976). Patients must pay attention in distinguishing the tones, in order for the examination to be as accurate as possible.

The event related potential activity was recorded at the Fz and Pz electrode sites of the 10-20 system using gold-plated electrodes affixed with electrode paste and tape, referred to linked earlobes at the A1, A2 sites with a forehead ground and impedance at the lowest possible level. For all recordings, the electrode impedances were below 5 kO and they were checked periodically during the recording session. For artefact suppression an AC filter function was performed. For the purpose of reduced impedance, a special type of paste is used (Elefix Nihon-Kohden, EEG paste Z-401 CE). The auditory event related potentials are analyzed by means Neuropack 4 (Nihon-Kohden, Tokyo).

MRI
In agreement with Radiology Departments , MRI scans are performed in the majority of patients with cognitive disorders. Each MRI examination consists of the following scans: 3 plain localizer; 19 sec, Sag MPRAGE 3D for volumetry, 0.94x0.94x1.2 slice thickness, 9:32 min, (Quality assurance, that is inspection of the image at local site, if Quality meets our criteria go on with protocol, if quality is insufficient, immediately repeat Sag MPRAGE 3D for volumetry), PD/T2 for improved segmentation relaxometry (T1 map, 2x2x3 EPI read out, whole brain, 10 min; T2 map 1x1x3 2-3 ax slices, 5 min, all centers except Perrugio), Voluntary for all sites except Perrugio: Spectroscopy (4 voxels - Perrugio; 2 voxels - KCL, Kupio, Lods,), Phantom scans at two time points: Study start, study end.

Educational Programs

As our memory clinic is part of a University Department, the education of students including scientific lectures and meetings is an important function. The medical students and the neuro-psychologists have the opportunity to participate in the activities of the Memory Clinic as a part of their formal training. In collaboration with Greek Alzheimer Disease and Related Disorders Association there are three training programs: One for families and caregivers every Tuesday in Charisio Old People Home between 9:00-10:30 in the morning, one for health care professionals every Friday afternoon 16:00-18:00, and one for young health care professionals from different cities of Greece five hours every day for two months including not only lectures but also attendance of all the programs which are organized for patients with Mild Cognitive Impairment and Dementia in Day Centers of our Association.

European and American projects

1. DESCRIPA (Development of Screening guidelines and diagnostic Criteria for Predementia Alzheimer's disease)

This project is funded by the EU through the Fifth Framework Programme (FP5). The primary goal of the program is to reach an evidence-based European consensus on the identification of subjects with Alzheimer's disease in their early stage. The other aims of the project are to develop diagnostic and clinical criteria for in the general population. The clinical criteria will be based on pooled data from six prospective studies of subjects with reported mild cognitive problems that have investigated markers of pre-dementia AD. These include demographic variables, cognitive functioning, brain atrophy, b-amyloid 1-42 and tau concentrations in the cerebrospinal fluid (CSF), and the apolipoprotein E genotype The guidelines will be based on five population-based studies that have investigated markers of predementia AD.

2. ICTUS (Impact of Cholinergic Treatment Use)
This program was also funded by the EU through the Fifth Framework Programme (FP5). The primary goal of the project was to take advantage of the differences in prescription rates across Europe in order to examine whether long-term treatment with AChE I modifies the rate of change of Clinical Dementia Rating scale (CDR; a score providing a global rating of the severity of dementia) in European AD patients.

3. ENIR (Foresight study for the development of a European NeuroImage Repository)
This project was funded by the EU through the Sixth Framework Programme (FP6). The ENIR project had the scope to carry out the development of a large and shared European multidimensional repository of high resolution MRI images of normal brains and brains with different neurodegenerative disorders (e.g. Alzheimer's, Parkinson's disease, etc.) completed by clinical, genetic and neuropsychological data. The huge variability of brain morphology affects the judgement of what constitutes normality or the comparison among different brain groups. In order to model and manage this variability, a wide amount of brain images and information on the sources of variability is needed. This obviously cannot be collected from a single centre, but requires brain images from many centers. A similar European repository does not exist at the present time due to the lack of a structured communication network among centres and of the huge difference of acquisition protocols and clinical information collected from the patients.This project aims also to identify standardized procedures in order to make the best use of existing repositories, in view of their increased integration towards the development of the future European infrastructure.

4. MIRAGE (Multi-Institutional Research in Alzheimer's Genetic Epidemiology)
The MIRAGE Study (Multi-Institutional Research in Alzheimer's Genetic Epidemiology) is a National Institutes of Health (NIH) funded research project based at Boston University School of Medicine. The goal of MIRAGE is to identify genetic and non-genetic risk factors for Alzheimer's disease (AD). Currently, the MIRAGE project has 12 study sites in the United States, Canada, and Germany, and a collaborating MRI analysis site at UC Davis. Building upon the work that has been done in this project since 1991, MIRAGE researchers will collect medical, family history, demographic and lifestyle information, draw blood for DNA and analysis and capture data from magnetic resonance imaging (MRI) to evaluate the association between vascular and genetic risk factors and AD in 1000 families including Caucasians, African Americans, and Japanese Americans.

5. INNOMED (Innovative Medicines for Europe)
The discovery and development of new drugs is very costly and attrition rates are high. Initiatives to reduce the rate of attrition during later phases are clearly desirable and if successfully implemented will reduce development costs. The InnoMed proposal addresses the complex issues associated with the future of biomedical research in the EU, and addresses ways of achieving accelerated development of safe and more effective medicines, aiming to revitalize the European biopharmaceutical research environment. InnoMed's wide consortium base, being led by the European Federation of Pharmaceutical Industry and Associations (EFPIA), guarantee's a commitment from all the stakeholders needed to change the process of drug development in Europe.

The course for addressing the necessary changes is to first develop a Strategic Research Agenda (SRA) that will encompass the whole path from discovery of a new drug target to the validation and approval stages of a new drug compound. This SRA is already in the process of being elaborated involving all the relevant stakeholders via meetings and workshops and four key bottlenecks in the drug development process have been identified: Safety, Efficacy, Knowledge Management, Training and Education. The elaboration of this SRA will be performed in a first stage within the frame of the European Technology Platform (ETP) and, will, of course, be subject to regular updating. The resulting comprehensive strategy with a detailed roadmap will reveal a variety of concrete research topics to be deployed within the ETP. The implementation of these research topics will deliver added value to the drug discovery and development process and to individual stakeholders. InnoMed will demonstrate the validity of the approach through two research sub-projects: AddNeuroMed, which will develop and validate novel surrogate markers based upon in vitro and in vivo models in animals and humans, using Alzheimer's disease as a testing platform. PredTox will deliver new biomarkers of toxicity and a greater understanding of mechanisms of toxicity.

6 EDAR (Beta amyloid oligomers in the early diagnosis of AD and as marker for
treatment response)

The aim of the present project is to investigate whether beta amyloid oligomers in cerebrospinal fluid, plasma, and serum can be used for the early diagnosis of AD and whether they can be used as a marker of treatment response. In addition, it will be investigated whether genes known to be involved in beta amyloid processing influence levels of these markers. Oligomers will be measured using two techniques. The first is based on ultrasensitive immuno-polymerase chain reaction and will be developed during the project. The second is based on a combination of immunoprecipitation and ELISA and has already been developed by one of the partners. Measurements will be performed in cerebrospinal fluid, serum, and plasma samples of 100 subjects with AD, 250 subjects with mild cognitive impairment (a prodromal stage of AD), 100 subjects with other types of dementia, and 50 control subjects. In order to investigate the potential of beta amyloid oligomers to be used as marker of treatment response, cerebrospinal fluid samples and blood samples will be collected 9 and 18 months after baseline in 60 subjects with AD and 60 with mild cognitive impairment.

CLINICAL TRIALS

Many clinical trials with new medications, national or international were run in our Memory Clinic such as AWARE study. There are also three new clinical trials now.

Collaboration with Greek Association of Alzheimer's Disease and Related Disorders ( GAADRD )

The same person who is responsible for our Memory Clinic is President of the Greek Association of Alzheimer's Disease and Related Disorders ( GAADRD ). Therefore the Memory Clinic and GAADRD are closely correlated. This is a non governmental organization, which was founded in 1995 and is member of the Alzheimer Europe and Alzheimer Disease International. It consists of neurologists, psychiatrists, Psychologists, Gerontologists, Biologists, Social Workers, Nurses who have been especially trained and educated.

The Association is governed by a seven member board, voted by the General Assembly of its members every two years.

Services Provided To Patients with Dementia and Mild Cognitive Department: Diagnosis, Therapeutic Programmes, Neuropsychological Assessment, Memory, attention and language exercises, Memory, attention and language exercises through PC, Dual task, Reality Orientation, Ecological multi-sensory tasks, Training from normal elder to elder with Alzheimer's disease, Cognitive Exercises for illiterate AD patients, Stress Management Techniques, Relaxation Techniques Programme Counseling, Cognitive Music therapy, Passive music therapy, Art therapy, Occupational Therapy, Physical Exercises, Physic therapy, Mental Imagery Therapy, Cognitive Motion Therapy, Cognitive Processing of Current Events, Individual Counselling for Patients with Early Dementia, Educational Programme For Patients with Early Dementia, Family Therapy, Individual Counselling, Support Groups and Counselling.

It provides clear, comprehensive and accurate information on all forms of dementia; on caring, legal and financial matters. It produces booklets (e.g. translation of the Alzheimer's Europe manual and the Children's Brochure), publishes its own leaflets (terminally, 12 page leaflet 10.000 issues are printed each time) reviewing all the activities of GAADRD and presenting all the progress in AD in scientific and social levels. It runs courses, meetings and Pan-Hellenic conferences every two years. Our every two year conferences of our association are unique opportunities to review the state of art in the diagnosis and management of dementia in a multi-disciplinary manner. Our conference brings together scientists, clinicians, health-care workers, families and people with dementia themselves. It provides a perfect chance, to make new friends, to start new collaborations and to enhance existing ones. Five Pan-Hellenic Inter-Scientific Alzheimer Conferences have been carried out until now. Professionals and informal carers give lectures, covering all the aspects of AD. Day care centers :1. Day Center Charissio Old People's Home 2. Day Center in Panorama of Thessalniki - KIFI. 3, Unit "Agia Eleni" which includes two day centers, a unit for caregivers and a unit for Home support. Soon the Greek Federation consisting of 21 cities all over Greece will be ready. We involve, support, encourage and establish associations in different parts of Greece. All the expenses needed to construct the memorandum of an association are being carried by our association. Professionals are trained to consult, and health professionals are being educated to promote best practices in the field of supporting patients and caregivers. We are increasing extraordinarily rapidly. At the moment the association has a staff of thirty-seven people (full time).GAADRD, is a member of Alzheimer Europe (AE) and Alzheimer Disease International (ADI) and contributes to worldwide efforts in the fight against dementia.

CONCLUSIONS

All the above efforts have as targets:

• To provide a complete assessment of a person's memory status, through clinical examination, neuropsychological assessment, results of blood tests, CSF tests and MRI scans
  
• To detect and assess dementing disorders as early as possible and carry out a differential diagnostic procedure to identify their aetiologies
  
• Plan the future care and provide advice to patients and their caregivers, with respect to medical, psychological and social issues
  
• Provide direct support to patients and caregivers in the form of counselling, discussions with caregivers, and therapeutically-oriented work groups (e.g. memory training groups)
  

REFERENCES