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  • 1. Subject-Specific EEG Analysis for Objective Assessment of Dementia Table of contents: Subject-Specific EEG Analysis for Objective Assessment of Dementia........................................1 Table of contents:.....................................................................................................................1 1. Summary..............................................................................................................................2 2. Study objectives...................................................................................................................2 3. Background..........................................................................................................................2 4. Study design.........................................................................................................................4 4.1. Number of patients .......................................................................................................4 4.2. Duration........................................................................................................................4 5. Study participant entry.........................................................................................................4 5.1. Inclusion/Exclusion criteria .........................................................................................5 6. Supportive studies................................................................................................................5 6.1 Serial magnetic resonance imaging...............................................................................5 6.2 Serial blood sample taking.............................................................................................5 7. EEG/ERP recording procedure............................................................................................5 7.1 Baseline EEG.................................................................................................................5 7.2 Functional EEG tests.....................................................................................................6 7.2.1. Photic driving responses............................................................................................6 7.2.2. Auditory Event-related responses..............................................................................6 7.3. Equipment for EEG/ERP recording..............................................................................6 8. Data collection ....................................................................................................................6 8.1. Longitudinal Study.......................................................................................................7 8.1.1. Baseline Visit.............................................................................................................7 8.1.2. Follow up Visit..........................................................................................................7 9 Study supervision..................................................................................................................7 10 Publication policy...............................................................................................................7 11 Reference............................................................................................................................8 Appendix A..............................................................................................................................9 Appendix B............................................................................................................................10 Criteria for group with probable Alzheimer’s disease.......................................................10 Criteria for group with mild cognitive impairments..........................................................10 Criteria for group of normal elderly subjects.....................................................................10 Appendix C............................................................................................................................11 Table 1. Schedule of events for subjects with Mild Cognitive Impairments.....................11 Table 2. Schedule of events for subjects with probable Alzheimer’s disease...................11 Table 3. Schedule of events for normal subjects...............................................................12 1
  • 2. 1. Summary The aim of this protocol is to collect data and test developed mathematical models for the early diagnosis of Alzheimer’s disease (AD). The information obtained will be used to develop the most appropriate diagnostic procedure for subsequent patients. The study will be prospective, serial and multicentre. Between 500-600 patients (these will include 100 normal elderly subjects, 200 subjects with mild cognitive impairments and 200 subjects with probable Alzheimer’s disease), will be recruited and studied within 24 months, every 6 months. Mini-Mental State Examinations (MMSE), CAMCOG (the cognitive and self-contained part of the Cambridge Examination for Mental Disorders of the Elderly) and serial 1.5 Tesla structural magnetic resonance imaging (MRI) results as a confirmation studies will be acquired. The electroencephalogram (EEG) data, collected during routine procedure in Neurophysiology Departments (Derriford Hospital, Plymouth and Wonford Hospital, Exeter), will be used. In addition, they will have their event-related potential (ERP) recorded using different paradigms. The additional recordings do not require the placing of any additional electrodes and should take an hour. Note: At least 28 scalp electrodes are needed for SHU’s evoked potential measurements to allow ICA analysis, or for applying ICA to the EEGs. New and existing algorithms for EEG and ERP analyses will be applied to identify perspective EEG and ERP markers which can be used for the early diagnosis of AD. 2. Study objectives The main aim of this project is to determine the best possible biomarkers from EEG and ERP data and how these should be analysed for objective assessment of different stages of AD. The secondary aims are: • to collect biomedical information. The database will include serial records for the same subjects. • to develop new models specifically designed to classify clinically difficult cases of mild cognitive impairment. • to create a generally accessible data repository, for serial EEG records, which can be used to describe longitudinal changes in the brain structure of people with dementia. A hypothesis is: there is an electrophysiological marker or combination of markers able to perform an early diagnosis of Alzheimer’s disease with sensitivity of 80% and specificity of 80% among subjects with mild cognitive impairment. 3. Background Alzheimer’s disease is the most common neurodegenerative disorder characterized by cognitive and intellectual deficits and behaviour disturbance. The clinical diagnosis of AD is imprecise with an accuracy rate of ~90% using consensus criteria for probable AD but definite AD requires autopsy confirmation [], and diagnostic accuracy is far lower at early and pre-symptomatic stages of AD when confusion with other dementias is common [, ]. Since therapy is most effective at symptom onset, early diagnosis of AD is highly desirable before neurodegeneration becomes severe. Thus, early diagnosis and effective treatment of AD are the critical issues in dementia research. The EEG has been used as a tool for diagnosing AD for several decades starting from EEG invention. The hallmark of EEG abnormalities in AD patients is a shift of the power spectrum to lower frequencies and a decrease in coherence of fast rhythms [, , ]. These abnormalities are thought to be associated with functional disconnections among cortical areas resulting from death of cortical neurons, axonal pathology, cholinergic deficits, etc. Studies in which different methods were used on the same population demonstrated that an estimated diagnostic accuracy 2
  • 3. of spectral and visual EEG analyses is approximately 80% [, , , ]. It is commonly accepted [, ], that improvement of the accuracy of differential diagnosis and early detection of AD can be achieved by: • subject specific approach, • longitudinal studies on nonlinear dynamics of the EEG, • drug effects studies on the EEG dynamics, • linear and nonlinear functional connectivity measurement among cortical regions in AD. Thus, we are going to study the EEG dynamics in different functional condition over all brain in the AD, using nonlinear approach in different stage of the disease, which has not been studied systematically. The ERP is composed of a number of underlying independent component, or source, signals, whose effects at a measurement electrode combine to produce the measured ERP together with on-going EEG and any artefactual signals such as instrumentation noise or eye movement and blink artefacts. We can conjecture that one or more of these independent components is more strongly correlated to AD than the others. If these components could be identified, we would have a more specific and accurate marker for AD than is obtainable from the average, in which the effects of these specific components tends to be masked by the other components and artefactual components. This negative influence is even stronger when there is trial-to-trial variability in which some of the components probably vary between trials. Our partners have developed a method based upon the technique of Independent Components Analysis of extracting the independent components on a single trial basis and free of EEG and artefactual signals. They have already found evidence of differences in the amplitudes and latencies of some of these components on the single trial basis between AD patients and normal, healthy subjects in the case of the P300 ERP. It is considered important to extend the measurements and analysis on a larger group of AD or demented subjects and it will be convenient to carry these measurements out during this study as the patients become available. The equipment is available for the measurement of 32 channel recordings of the P300, CNV, and Readiness Potential. In EEG, the activation procedures or functional tests enhance the manifestation of latent neurophysiological mechanisms or pre-existing abnormalities, and may induce abnormal findings in an otherwise normal EEG. Intermittent photic stimulation is one of the most important functional tests during neurophysiological examinations. It can induce in the EEG photic driving - a physiologic response consisting of rhythmic activity time-locked to the stimulus at a frequency identical or harmonically related to that of the stimulus. In the EEG spectrogram, driving appears as sharp amplitude peaks at these frequencies. Intermittent photic stimulation is easily performed and requires minimal cooperation from the patients, thus making this technique useful for the clinical evaluation of demented patients. Recent studies using quantitative EEG analysis have shown abnormal fundamental driving responses to photic stimulation and abnormal interhemispheric coherence [] in dementia. Intermittent photic stimulation induces not only fundamental harmonic responses but also other harmonic responses in higher frequency bands. Recent studies provide a lot of evidence that not only alpha oscillation but also oscillation in higher frequency bands such as beta and gamma may be involved in the process of information in brain [, , ]. In our study, we are going to investigated source localisation of harmonically induced oscillation during photic stimulation, the difference between fundamental and harmonic responses for different stimulation frequency and harmonic responses attenuation in rest period. There have been several studies that confirm ERPs are useful tools for assessing changes in cognitive brain functions. For example, in recent studies of the P300, two distinct subtypes of response are recorded regarding stimulus novelty [, ]. Correctly detected task-relevant known stimuli generate a parietal maximal P300 (target P300), whereas nontarget, unknown stimuli requiring no behavioural response generate an earlier latency, front-central P300 (novelty P300), 3
  • 4. which is considered to be a CNS index of the orienting response. It has been also demonstrated that the latency, amplitude, and scalp topography of the novelty P300 are affected by aging processes [, ]. These suggest that recording of both novelty P300 and target P300 in patients with dementia might be useful for evaluation of their cognitive deterioration. In our study, we are going to investigate source localisation of different ERP components (including the P300 and the CNV) and differences between target and novelty ERP components dynamics. Preliminary work of our partners has indeed shown that from the scalp components of the independent components of the ERPs, it is possible to use established methods for solving the inverse problem to localise within the brain the sources of the independent component signals, as represented by their equivalent electrical dipoles. 4. Study design 4.1. Number of patients The target is 500 cases, but assuming drop out will complete studies on 600 study participants. 120 normal elderly subjects 240 subjects with mild cognitive impairment 240 subjects with probable Alzheimer’s disease. 4.2. Duration The trial will be conducted in two phases over 3 years. Phase 1: the collection of data (24 months, data collection points: 0, 6, 12, 18, 24 months), and phase 2: the analysis of data (12-36 months). 5. Study participant entry The participant recruited for the study will be patients under the care of the consultants of the Memory clinic, working in Plymouth and Exeter. The control subjects matched for age, gender, and education level will be recruited from the community. Patients with mild cognitive impairment or with probable Alzheimer’s disease will be identified on the basis of consecutive referrals to the Departments of Clinical Neurophysiology by the consultants of the Memory clinic. The referrals will be intercepted before reaching the Consultant Neurophysiologist (For data collection process flow-chart see Appendix A). In the course of interview Consultant in the Memory Clinic asks the appropriate study participant to consider fully suggestion to take part in the study. The interview will include a verbal explanation of the reason for the research and what is involved as far as the patient is concerned, this will be supplemented by a leaflet, and the study participant will be asked to sign a consent form. To secure regular visits of study participant he will be asked for agreement to receive reminders before every scheduled visit. Time given to decide to take part in the research should be at least 24 hours. Next day, Memory Clinic’s nurse will make phone contact with potential study participant and ask him for decision and prompt to sign the agreement for study participation. If consent for serial MRI and EEG/ERP recordings is acquired, participant will receive referrals for EEG/ERP and MRI, a CAMCOG interview will be carried out. This CAMCOG interview will take approximately one hour to complete [, ]. Then, the study participant’s EEG/ERP will be recorded in Department of Clinical Neurophysiology in Derriford or Wonford by physiological measurement technician. Also the study participant’s 1.5 T structural MRI will be obtained in Departments of medical physics & biomedical engineering (Derriford and Wonford hospitals). After one year, Memory clinic’s nurse will make phone contact with study participant and/or his carer and ask them to held next data collection point. 4
  • 5. 5.1. Inclusion/Exclusion criteria All study participants will be between 55 and 90 years of age [, ], have an informant able to provide an independent evaluation of functioning and will speak English. All subjects must be willing and able to undergo all testing procedures including MRI scan and agree to longitudinal follow-up [, , , ]. Specific psychoactive medications will be excluded. General inclusion/exclusion criteria are shown below. Detailed inclusion/exclusion criteria appear in the appendix B 1. Normal subjects: MMSE scores between 24 and 30, a CDR of 0, non-depressed, non- MCI and non-demented. 2. MCI subjects: a memory complaint, have objective memory loss measured by education adjusted scores, a CDR of 0.5, absence of significant levels of impairments in other cognitive domains, essentially preserved activities of daily living, and an absence of dementia. 3. AD subjects: MMSE between 18 and 26, CDR of 0.5 or 1.0, and meet CAMCOG criteria for probable AD. 6. Supportive studies In the order a confirmation of the diagnosis and belonging to each study group study participants will undergo following procedures. 6.1 Serial magnetic resonance imaging All study participants will have approximately annual (see Appendix C) MRI imaging as supportive evidence. Three-dimensional T1-weighted MRI will be done on a 1.5 T Intera or a 1 T Magnetom Expert MR scanners in Departments of medical physics & biomedical engineering (Derriford and Wonford hospitals) with a fast spoiled gradient-recalled acquisition in the steady state sequence yielding 124 contiguous 1,5 mm coronal slices of 256x256 voxels (acquisition parameters: TR/TE/NEX/FLIP—35/5/1/35) []. 6.2 Serial blood sample taking All study participants blood samples will be collected by Memory Clinic’s nurse at the data collection point (see Appendix C). Blood sample will be collected after specific permission of the patients in the informed consent form. Blood samples will be divided into serum, plasma, and buffy coat and stored in liquid nitrogen for future analysis. 7. EEG/ERP recording procedure Patients included in the study will attend the Neurophysiology Department for routine EEG recording. Recording will commence when the patient has understood the relevant paradigm. The EEG/ERP records will be conducted with agreement of commonly accepted procedure which use 10/20 electrode placement system. The additional recordings do not require the placing of any additional electrodes. The scalp potentials will be amplified, digitized at 256 sample rate with 22 bit accuracy (19 channels) and stored. The EEG/ERP records that will be validated by the EEG technician should be pre-processed using (0-100 Hz) low pass filtering techniques and averaging. The additional procedure (baseline EEG recording, photic driving responses EEG recording and auditory event-related responses EEG recording) is likely to take an hour [, , , , , , , , , , ]. 7.1 Baseline EEG In addition to routine EEG, an eyes-closed and eyes-opened EEG will be recorded for three minutes each from all participants at the beginning of the additional study session []. These 5
  • 6. records will be used for comparative analysis with data acquired from another experiments. The next two procedures will enable investigators to measure the ERP. These procedures will be accompanied breaks for rest and additional instructions for study participants. 7.2 Functional EEG tests 7.2.1. Photic driving responses EEG signals will be recorded during a state of relaxed wakefulness, during intermittent photic stimulation at frequencies of 5, 10, 15 Hz, and during relaxed wakefulness between stimulations [, , , , , ]. The subjects will keep their eyes closed throughout the experiment. Each stimulation consisted of flashes presented at a fixed frequency for 50-60 s, with the same periods between stimulation runs. The photostimulator should have a lamp with flashes of approximately white light having duration of less than 20 µs. The lamp will be positioned at a distance of 25 cm from the eyes, with dim surrounding light. 7.2.2. Auditory Event-related responses The auditory P300 ERP will be obtained using an auditory oddball paradigm [, , , , , ]. Binaural audiometric thresholds will determine for each subject using a 1000Hz tone. The evoked response stimulus will be presented to both ears using stereo speakers at amplitude comfortable for their hearing level. The stimulus consist of tone bursts 100ms in duration, including 5ms inset and offset envelopes. Tones of 1000Hz and 2000Hz will be presented in a random sequence with the tones occurring in 65% and 20% of the trials respectively. The remaining 15% of the trials should consist of novel sounds presented randomly. These will include 60 unique environmental sounds that will edited to 200ms duration. A total of 1000 stimuli, including frequent 1000Hz (650 stimuli), infrequent 2000Hz tones (200 stimuli) and novel sounds (150 stimuli) will delivered to each subject with an interstimulus interval of 1.0-1.3 seconds. The subjects will be instructed to press a button each time they heard the 2000Hz tone. With frequent breaks (e.g. approximately three minutes of rest every five minutes), the data collection process will last about 30 minutes per subject with each session proceeded by a 1 minute practice session without the novel sounds. Auditory CNV ERP recordings will also be made. The paradigm is: 4s recording, warning stimulus at t = 1s (click), imperative stimulus at t = 2s (1 kHz tone), subject presses button to terminate the tone. 7.3. Equipment for EEG/ERP recording • EEG computer system which have appropriate facilities and ability to run appropriate software for EEG recording, pre-processing, storage and transfer of collected data for analysis • Photostimulator (trail generator, tripod, lamp) • Computer system to generate tones via headphones, which must have appropriate storage facilities and the ability to run software for sound synthesis • Purpose-designed P300/CNV ERP computer system with 32 input channels. P300 paradigm: target tone frequency 2 kHz, non-target tone frequency 1 kHz, target tone occurrence 20%, non-trget tone occurrence 80%, tone duration 50 ms, interstimulus interval 2s, • Electrodes and leads as for recording EEG • Consumables like preparing gel, conducting gel, tissues, Electrodes etc. 8. Data collection We plan to enter 500 cases (100 controls, 200 AD and 200 MCI), but assuming drop out will be completed studies on 600 cases (120 controls, 240 AD and 240 MCI). All subjects will have 6
  • 7. clinical/cognitive assessments, structural MRI and EEG study at defined time points. For reason to decrease study work, these study should be spread in time. MCI subjects will be studied five times at 0, 6, 12, 18 and 24 months because they have a high risk for AD development which is target of our study. AD subjects will be studied three times at 0, 12 and 24 months. Age matched controls subjects will be studied two times at 6 and 18 months. EEG/ERP records and structural MRI with clinical information will be collected in Memory Clinic which then will be anonymised in hospitals (Derriford, Wonford) and send for advanced data processing and analysis to the main technical participant - University of Plymouth. Collected data will be recorded on CD or DVD with CAMCOG data and transferred to the study supervisor. This data will include patient’s unique number, number of visit, current CAMCOG and MMSE results, MRI data, EEG data in ASCII format with records descriptions. 8.1. Longitudinal Study 8.1.1. Baseline Visit The purpose of the baseline visit is to determine the eligibility of the subject for the proposed study and to collect measures that will be used as a reference to assess change. Consent will be obtained before any portion of the baseline visit is initiated. Demographics, family history, vital signs, physical exam, and psycho-neurological exam will be performed. Subjects will undergo series of evaluations including a MMSE and CAMCOG. A Clinical Dementia Rating Scale will be obtained as well as concurrent medications. Subjects meeting eligibility will be scheduled to return for next visits. Eligibility will be determined according to the Inclusion/Exclusion criteria outlined above. 8.1.2. Follow up Visit Follow up visits will be carried out at 12 month intervals either in person or by telephone contact. A complete set of clinical and neuropsychological measures and structural MRI will be collected at each time point that EEG studies are collected so that change on EEG data can be correlated with change in clinical measures. At the present time, visits are planned at 12 month intervals. However, for patients with MCI, collection of EEG data may be valuable at the six month time point since this cohort of subjects may show sufficient change on quantitative EEG analysis after only six months. A synopsis of the study visits can be found in appendix D in table 1, 2 and 3 respectively. 9 Study supervision Central supervision: the Steering Committee is responsible for the protocol, quality control, interim analyses of the data and final analysis and reporting of the study. Local supervision: the Principal Investigators are responsible for the data collection in their centers. The Project Manager, … is responsible for the financial and administrative management of the project. … is responsible for the clinical coordination of the project and the contact between the centers. … and … are responsible for the data management and the development of new algorithms, in collaboration with … 10 Publication policy The steering committee is responsible for publication of the data. Depending on the journal’s restriction of the number of co-authors choose journals which do not restrict. All researchers and clinicians who contributed will be co-authors. 7
  • 8. 11 Reference 1. Chiappa KH: Evoked potentials in clinical medicine. New York, Raven Press, Ltd., 1990. 2. Danilova NN Functional States: Mechanisms and Diagnostics (in Russian). Moscow University Press, Moscow, Russia. 1985 3. Drake ME Jr, Shy KE, Liss L. Quantitation of photic driving in dementia with normal EEG Clin Electroencephalogr. 1989 Jul;20(3):153-5 4. Folstein MF, Folstein SE, McHugh PR. “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198. 5. Fox, N.C.; Crum, W.R.; Scahill, R.I.; Stevens, J.M.; Janssen, J.C.; Rossor, M.N., "Imaging of onset and progression of Alzheimer’s disease with voxel-compression mapping of serial magnetic resonance images" Lancet 2001 pp. 201-205 6. Fukushima T. Application of EEG-interval-spectrum-analysis (EISA) to the study of photic driving responses Arch Psychiatr. Nervenkr. 1975 May 28;220(2):99-105 7. Jacques G. et al., “Multiresolution analysis for Early Diagnosis of Alzheimer’s disease”, Proceedings of the 26th Annual International conference of the IEEE EMBS, San Francisco, CA, USA, September 1-5, 2004 8. Jeong, J. EEG dynamics in patients with Alzheimer’s disease. Clinical Neurophysiology,115 (7), 1490-1505, 2004 9. Kikuchi M, Wada Y, Koshino Y Differences in EEG harmonic driving responses to photic stimulation between normal aging and Alzheimer's disease Clin Electroencephalogr. 2002 Apr;33(2):86-92. 10. Knopman DS, DeKosky ST, Cummings JL, et al. Practice parameter: Diagnosis of dementia (an evidence-based review): Report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001; 56:1143-1153. 11. Lazarev VV, Simpson DM, Schubsky BM, Deazevedo LC Photic driving in the electroencephalogram of children and adolescents: harmonic structure and relation to the resting state. Braz J Med Biol Res. 2001 Dec;34(12):1573-84. 12. Polich J., P300 in clinical applications, In Electroencephalography, E. Niedermeyer, F. Lopez Da Silva, Ed. Philadelphia: Williams and Wilkins, 1999, pp. 1073-1091. 13. Petersen R.C., Mild cognitive impairment as a diagnostic entity J Internal Medicine 2004; 256: 183-194 14. Roth, m., Huppert, F.A., Tym, E. and Mountjoy, C.Q. (1988) CAMDEX: THE Cambridge examination for mental disorders of the elderly. Cambridge: Cambridge University Press. 15. Schneider L.S. Mild Cognitive Impairment Am J Geriatr Psychiatry 2005; 13: 629-632 16. Toshimitsu M. et al., A new EEG method for estimating cortical neuronal impairment that is sensitive to early stage Alzheimer’s disease, Clinical Neurophysiology, 113 (2002) 1052-1058. 17. Wada, Y., Nanbu, Y., Jiang, Z.-Y., Koshino, Y. and Hashimoto, T. Electroencephalographic abnormalities in patients with presenile dementia of the Alzheimer type; quantitative analysis at rest and during photic stimulation. Biol. Psychiatry 41: 217-225, 1997 18. Wada, Y., Nanbu, Y., Shiraishi, J., Koshino Y. and Hashimoto, T. Topographic EEG analysis of photic driving responses in patients with dementia of the Alzheimer type. Brain Topogr. Today 577-582, 1998. 19. Yamaguchi S., Tsuchiya H., Yamagata S., Toyoda G., Kobayashi S., Event-related brain potentials in response to novel sounds in dementia, Clinical. Neurophysiology, vol. 112, no. 2, pp. 195-203, 2002. 8
  • 9. Appendix A Potential study participants Complains on memory loss GP Potential participants interception point Diagnosis/prescription of treatment Referral Memory Clinic Demographics, family history, inclusion/exclusion EEG criteria, obtain consent, Psychiatrist, Referral (Department of Clinical phone contacts & Physician, Neurophysiology, EEG data appointments, Neurologist Derriford and MMSE, CAMDEX, Wonford, UoP) Re ferr al neuropsychiatric inventory M RId ata MRI Data with personal information (Department of Medical Physics, Derriford and Wonford) Data anonymisation (R&D Department in Derriford and Wonford) Data without personal information Data processing, data analysis (UoP) Scheme of EEG data collection process. Description: Memory clinics are usually run by Consultants in Old Age Psychiatry, Geriatric medicine or occasionally Neurology. Multi-disciplinary teams in memory clinics will vary from clinic to clinic depending on what service they are providing from assessment through to intervention, treatment and support. Most Teams consist of a consultant (Psychiatrist, Physician or Neurologist) a mental health or memory clinic nurse and sometimes a psychologist. Some teams will also have an occupational therapist. The consultant role is initially to establish a diagnosis with all the information collected by the team and where appropriate prescribe medication. The consultant may as part of the assessment arrange for a range of tests such as blood tests and a brain scan. Many clinics operate a Triage system, which means when a referral is first made to a memory clinic the nurse will often be the first point of contact. 9
  • 10. Appendix B Criteria for group with probable Alzheimer’s disease Inclusion criteria for group with probable Alzheimer’s disease − Definite or probable Alzheimer’s disease − Mini-Mental State Examination (MMSE) scores between 18 – 26 − Clinical Dementia Rating (CDR) 0.5 – 2.0. Exclusion criteria group with probable Alzheimer’s disease − No diagnosis (do not meet the criteria for a diagnosis by CAMCOG) − Possible Alzheimer’s disease − Definite, probable or possible Dementia another type − Alzheimer’s disease together with Dementia another type (by CAMCOG criteria) − Previous history of epilepsy − Any evidence of clouding of consciousness. Criteria for group with mild cognitive impairments Inclusion criteria for group with mild cognitive impairments − a memory complaint, − absence of significant levels of impairments in preserved activities of daily living − MMSE scores between 24 – 30, − CDR = 0.5. Exclusion criteria group with mild cognitive impairments − No mild cognitive impairments (do not meet the criteria for a diagnosis by CAMCOG) − Definite or probable Alzheimer’s disease − Definite, probable or possible Dementia another type − Previous history of epilepsy − Any evidence of clouding of consciousness. Criteria for group of normal elderly subjects Inclusion criteria for group normal elderly subjects − No mild cognitive impairments (do not meet the criteria for a diagnosis by CAMCOG) − No depressive illness − No anxiety or phobic neurosis − No paranoid or paraphrenic illness − MMSE scores between 24 – 30, − CDR = 0. Exclusion criteria group normal elderly subjects − Mild cognitive impairments (do not meet the criteria for a diagnosis by CAMCOG) − Definite, probable or possible Alzheimer’s disease − Definite, probable or possible Dementia another types − Previous history of epilepsy − Any evidence of clouding of consciousness. 10
  • 11. Appendix C Table 1. Schedule of events for subjects with Mild Cognitive Impairments Visit Events 1(baseline) 2 3 4 5 0 month 6 month 12 month 18 month 24 month Explain study, Obtain consent X Demographics, Family History X Inclusion and Exclusion Criteria X X X X X History, Physical Exam, X X X X X Neurological Exam Vital Signs X X X X X Depression Rating Scale X X X X X Mini Mental State Examination X X X X X Neuropsychiatric Inventory X X X X X Clinical Dementia Rating Scale X X X X X Concomitant Medications X X X X X MRI X X X Blood sample collection X X X X X EEG X X X X X Phone contact X X X X X Table 2. Schedule of events for subjects with probable Alzheimer’s disease Visit Events 1(baseline) 2 3 0 month 6 month 12 month 18 month 24 month Explain study, Obtain consent X Demographics, Family History X Inclusion and Exclusion Criteria X History, Physical Exam, X X X Neurological Exam Vital Signs X X X Depression Rating Scale X X X Mini Mental State Examination X X X Neuropsychiatric Inventory X X X Clinical Dementia Rating Scale X X X Concomitant Medications X X X MRI X X X Blood sample collection X X X EEG X X X 11
  • 12. Phone contact X X X Table 3. Schedule of events for normal subjects Visit Events 1(baseline) 2 0 month 6 month 12 month 18 month 24 month Explain study, Obtain consent X Demographics, Family History X Inclusion and Exclusion Criteria X History, Physical Exam, X Neurological Exam Vital Signs X X Depression Rating Scale X X Mini Mental State Examination X X Neuropsychiatric Inventory X X Clinical Dementia Rating Scale X X Concomitant Medications X X MRI X X Blood sample collection X EEG X X Phone contact X X 12