EARLY DETECTION OF MILD COGNITIVE IMPAIRMENT (MCI) IN THE ELDERLY WITHIN THE COMMUNITY

CONFERENCES
TOPIC: EPIDEMIOLOGY

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Address correspondence to: Dr. Luis Fornazzari
Centre for Addiction and Mental Health
33 Russell Street
Toronto, ON.
M5S 2S1
Tel: (416) 595-6662
Fax: (416) 595-6287
Email: lfornazz@arf.org

 
Abstract

Alzheimerís Disease (AD) and other dementias are the main causes of cognitive impairment in the elderly.  Cognitive impairment is a significant source of morbidity and mortality.  AD and other dementias affect at least 5% of the population aged 65 and older and perhaps as much as 30% over the age of 80 years.  As the population increases in age, the prevalence of dementias grows; the frequency of AD doubles every five years after the age of 65.  This will lead to an overall decrease in the quality of life for the population and an increase in time and finances spent in health maintenance.  Despite the prevalence and morbidity of cognitive impairment, very few brief, non intrusive and culturally- and literacy-appropriate screening tests exist for its detection and diagnosis.   To address this, we will devise and validate a brief battery of: neuropsychological tests; genetic and biochemical markers; and neuroimaging techniques intended to identify Mild Cognitive Impairment (MCI), the intermediary state between the normal aging process and the development of dementia. To accomplish this, we will recruit 120 adults currently living in the community who meet the inclusion criteria.  These study participants will be administered a series of standard and novel neuropsychological tests; they will have blood samples drawn, fractionated, and stored for the analysis of current and future genetic and biochemical markers of AD (e.g. APOE genotyping, serum Ab assays etc.); and will undergo structural-functional neuroimaging (using SPECT and possibly fMRI).  These initial tests will be followed by re-testing at 6, 12, and 18 month intervals.  The successful identification of MCI in the elderly using a quick, non-intrusive and highly reliable test battery will allow early intervention with effective symptomatic treatments (e.g. Aricept, Exelon, Remynil, Propentophylline), behavioral-social interventions, and future treatments directed at the primary disease process itself (these are currently being actively investigated and might include drugs directed at inhibiting Ab production or aggregation, anti-inflammatory agents, antioxidants such as Vitamin E, or estrogen analogues).
This will allow the prolonged quality of life and prolonged independent community living with substantial savings in terms of both human emotional costs and economic costs.
 

INTRODUCTION

    Cognitive impairment in the elderly is a significant cause of morbidity and mortality.  Dementias, found within the community and in the acute or chronical medical care setting, are a common cause of cognitive impairment1.  There is rising public health and clinical management concern about this disorder because it is an important cause of loss of functionality and decreased quality of life.  Despite the prevalence and morbidity of cognitive impairment, very few brief, non-intrusive methods exist for its detection, differential diagnosis, or follow-up.  To address this, we propose to develop and validate a brief battery of simple, culturally and literacy appropriate, neuropsychological tests, genetic and biochemical markers as well as functional neuroimaging tests (SPECT scan).

     The purpose of this study is to develop a very brief and sensitive battery of tests that will be able to identify Mild Cognitive Impairment within the elderly living independently within the community.

     Early detection, in its preclinical stage, allows for better treatment.  The maintenance of the cognitive and behavioural capabilities of the elderly by prompt and adequate intervention will lead to the preservation of the elderly within their own familiar independent-community living setting as long as possible.  Their family and social network will remain intact, thus sustaining their quality of life.  There will be reduced need for acute hospitalizations, and by prolonging useful independent community living, there will be a significant postponement of (or even avoidance of) chronic institutionalization.  Cumulatively, this will provide major benefits both in terms of reduced human suffering and in terms of financial costs for acute and chronic institutional care.

     This pilot study will strive to achieve two strategies found in the "Ontarioís Strategy for Alzheimer Disease and Related Dementias: a plan for action".  These consist of physician training (in the administration and interpretation of battery of tests) and the formation of coordinated specialized centres for the diagnosis and support for Alzheimerís disease (through our unique network of the University of Toronto dealing with cognitively impaired patients).   These include Toronto Hospital Memory Clinic, Rotman-Baycrest, Womanís College ? Sunnybrook Health Centre and Centre for Research in Neurodegenerative Diseases.
 

Mild Cognitive Impairment - Dementias

     Alzheimerís Disease (AD) and the other dementias affect at least 5% of the population over the age of 65 years and perhaps as much as 30% of the population over the age of 80 years2.  With the aging of the population, there is an associated increase in the prevalence of dementia.   The number of Canadians older than 65 years of age will grow from todayís 3.6 million to 5 million by the year 2011 and then climb to 9 million by 2031; the fastest growing group corresponds to the very old (age 80 and over)2.   Higher health costs and a greater need for institutionalization are the result, becoming even more significant in the future. According to Canadaís auditor generalís report of 1998, the changing demographics could mean that government spending on social security and health care could rise from the 1996 level of 11.6% to between 14.7% and 20.7% of the gross domestic product by 20312.  Based on the "Canadian Study of Health and Aging" epidemiological study, it is believed that over $3.9 billion is currently spent annually for the treatment of dementias in the present ~252600 Canadians, ~67% of which have AD3.  The number of Canadians with AD will more than double by the year 20314.
Large financial costs of palliative care for AD and other dementias can be attributed to nursing home care (formal services at least $21 924/year taking into consideration all severity levels)4.  Maintaining the patient at home (informal care) reduces the cost to $479/month4.

    With the advent of symptomatic treatments (such as Aricept®, Exelon®, Remynil®, Propentophylline®), and particularly the anticipated advent of treatments directed at the pathogenesis of these diseases (eg. drugs currently under development to inhibit Ab production [Elan pharmaceuticals, Brystol-Myers-Squibb/ Sibia], NSAIDS, Estrogen/ estrogen analogues, vitamin E, etc.) make early diagnosis (especially preclinical diagnosis) imperative.  Early detection, preferably during its preclinical stage, would yield the possibility of better outcome and the maintenance of better quality of life for a longer duration.   Because Mild Cognitive Impairment (MCI) is by itself a significant cause of morbidity as well as harbinger of progression to AD in approximately 25% of cases13  (definitions and explanations of MCI are found in section III), administration of compounds which block the disease process would be highly appropriate in individuals with MCI, providing that MCI could be effectively diagnosed before it had progressed to AD.
 
 

    Our pilot study consists of a prospective long-term follow-up project designed to:
1) Test the predictive value of a simple neuropsychological test battery.
2) Test the predictive value of a simple of SPECT scan.
3) Collect biological samples (blood, post-mortem CSF and brain tissue) which can be used to examine genetic (eg. APOE _4 status) and biochemical markers (eg serum/ CSF Aß42 levels) of early AD.
 
 

     We consider the brief neuropsychological battery of tests devised in this study essential to the medical and non-medical community for awareness and intervention purposes.  It is designed to detect very early signs of AD, basically the detection of the transitional state between normal aging and dementia known as Mild Cognitive Impairment (MCI).  This leads to the possibility of the aforementioned outcomes (i.e. decreased costs, improved quality of life, independence and functionality, etc.).   Many of the current tests actually in use are not designed for early detection, take a long time to administer and are not necessarily of adequate sensitivity and specificity5-8.  This battery is a construct of tests that could solve these difficulties, and are presently in use in studies such as Columbia NY, North Bronx Project, Mayo Clinic MCI Project, and UCLA Project of MCI.   These projects, unlike our own proposal, are found outside of Ontario and therefore do not take into account its culture, health care system and ethnic make-up.
 

Alzheimerís Disease and other dementias

     This pilot study is based on clinical and neuropathological evidence of a transitional state between the normal, physiological aging process and the development of dementia9,10.  A variety of terms and concepts exist to define this state.  The variations in cognitive functioning in the elderly have been defined by "benign senescent forgetfulness" (1962), "limited dementia"(1982), "questionable dementia"(1982), "mild cognitive decline"(1982), "mild dementia"(1984), "age associated memory impairment"(1986), "minimal dementia" (1986), and "mild cognitive impairment"(1991)11.  Each expression consists of a set of diagnostic criteria differing in the age of onset, the degree of cognitive decline, the subjective experiences of memory impairment, etc.11.
 

     The practical construct of Mild Cognitive Impairment (MCI) is a relatively new concept that has been under intense investigation by some academic groups (Columbia University, Mayo Clinic, etc.).   The DSM-IV refers to the pre-clinical stage of AD as the stage of Age-Related Cognitive Decline12; it has not implemented the expression and concept of MCI yet.  MCI can be used to describe the "intermediate state of cognitive functioning in which a decline from a previously higher level has occurred which is not severe enough to fulfill the criteria of dementia"11.  MCI has been characterized by memory impairment beyond that expected for normal aging but without being diagnosed with dementia13.  Other cognitive domains are believed to remain intact13.  Adults with MCI can thus be differentiated from normal controls and those with mild AD.

     MCI has been confirmed in another study in which the authors demonstrated the presence of poor word-finding ability, decrease ability for abstract reasoning and decline in memory14.
In another similar study, a decline in verbal memory was found to be the earliest sign in the preclinical stage and was shown to be a useful marker for diagnosing AD15.  Different batteries of neuropsychological tests have been employed by the groups investigating MCI.  For instance, the study from Columbia University used the Boston Naming Test, Immediate Recall on the Selective Reminding Test, and the Similarities subtest of WAIS-R, which differ from the tests used in this pilot study.

     The cognitive portion of the neuropsychological battery devised in our proposal is composed of a series of tests that have all been validated and harmonized in different studies of dementias in Canada and the United States16-23.   We have selected a subset of tests from larger battery of formal, validated tests which are too cumbersome to be administered as a quick screening method.
These subset of tests were selected due to their brevity, their easy administration and also due to the fact that they require little or no literacy skills; they were combined together in order to identify preclinical stages of AD.  This is a novel approach to screening and is not yet a  wide-spread practice.
 
 

     Genetic and biochemical tests, when coupled with the aforementioned cognitive tests, may also be useful for identifying individuals who may be at risk for developing AD.  Such genetic tests may be based upon specific intronic or exonic nucleotide sequence differences in the APOE gene24, bAPP 25, PS2 26 or bAPP 27, all of which have been associated with late-onset sporadic AD in some studies.  The use of such genetics predictors as an adjunct in the diagnosis of clinically diagnosed AD has already been proven28.  The utility of these tests in individuals without clear-cut AD however, is the subject of much confusion29.  Thus, in asymptomatic individuals at relatively low risk for development of AD the use of APOE genotypes (and by implication other genotypes associated with non-deterministic polymorphisms in other genes) is generally felt not to be sufficiently accurate to warrant predictive testing30.  However, the utility of these tests in individuals with subtle cognitive abnormalities is much less clear.  Some studies31,32 suggest that APOE e4 is increased in individuals with non-vascular cognitive impairment (OR = 7.0; 95% CI 2.5-19.0) or late-onset AD (OR = 8.8; 95% CI 3.7-21.0)31.  On the other hand, some studies33-35 have not found utility in APOE genotyping (but have not tested other genetic predictors of progression of MCI to florid AD).
 

This disparity likely arises from the lack of statistical power in some of these studies (sample sizes were typically less than 29 individuals progressing to AD), the use of less stringent inclusion criteria (e.g. inclusion of self-referred individuals with "memory problems but no dementia", and/or the failure to take into consideration interactions between genotype, family history of dementia, age, sex, and prior medication use (e.g. hormone replacement therapy).  In this study, genotypes at relevant susceptibility loci will be determined independent of clinical status and progression.  Our statistical analysis will be conducted using logistic regression techniques which will evaluate non-additive allelic associations (e.g. APOE, e4 and polymorphisms at other loci) and adjust for confounding effects of age and sex.
 

     A variety of biochemical tests for AD (serum or CSF, Ab/Tau ratios, neuronal thread protein levels, etc.) have been proposed to assist in the diagnosis of AD.  While the validity of these particular tests in the diagnosis of AD is still unclear, it is likely that within the duration of this study (or shortly thereafter) improvements upon these tests or other tests will be validated for their diagnostic utility in AD.  We therefore intend to store aliquots of plasma from blood samples taken at initiation, 6 months, 12 months, and 18 months.  We will then examine these samples using at least assay of serum Ab42 and Ab42 and other newer validated tests that might be developed during the course of this study.  These longitudinally prospectively collected samples will then allow us to analyze not only whether a specific test value is diagnostically or predictively useful but also whether changes in that test value have predictive utility in determining which subjects will progress to florid AD.

     All the subjects of the study will be genotyped as they are identified (eg. the chromosome 12 late onset AD locus36) at PS1, PS2, APOE, APP and any other AD-related genetic loci using standard methods developed by this group24,26,36-38.
We will also test for other novel genotyping, such as the CYP2D6B allele, which has been associated with Lewy-Body Disease, a variant of AD39.  It is quite likely that, in the future, the identity of other AD related genes will be discovered.  If the need for a retrospective analysis of genotypes at these putative loci should become feasible, the validity of the statistical design of the study would not be altered because the genotype is a stable characteristic that is assayed independently of the clinical phenotype.

     These tests will allow us to discern whether particular genetic profiles predispose towards one or more of the common causes of cognitive impairment in the elderly, and that prior knowledge of such genotypes would alert physicians to take appropriate action in patients presenting with subtle cognitive problems.  In the same vein, it is likely that in the next 24 months one or more biochemical assays will be developed which will act as markers of  "disease presence" or "disease activity".  For instance, there is growing suspicion that measurements of serum Ab42 might be used either as a marker of AD presence, or more likely as a marker of AD disease activity.  Currently, there are a number of technical problems is these assays for serum Ab and it is also likely that other biochemical assays will be developed which might be more sensitive or more accurate than serum Ab levels.  By prospectively collecting and storing blood at study entry, 6 months, 12 months and 18 months of follow-up, it will then be possible to retrospectively analyze whether any of the existing or newly developed biological assays have any true utility in predicting progression from MCI to AD.
 
 

Neuroimaging
     Structural abnormalities in specific areas of the brain have also been found in the preclinical stage of AD.  One such abnormality is the atrophy of the hippocampal formation; this has been shown to be a useful marker and predictor of subsequent AD.  Neuroimaging modalities such as the MRI, CT scans, and functional neuroimaging, particularly the Single Photon Emission Computerized Tomography (SPECT) are used to identify structural as well as metabolic irregularities.

SPECT scanning in our pilot study:
     A triple-headed SPECT system (Prism 3000, Picker International, Inc., Cleveland, OH), interfaced to a high performance computer (DEC AXP/RISC at 133 MHz with 64 bit data processing) will be used for SPECT imaging of rCBF.  This is a state-of-the-art neuroimaging SPECT system with spatial resolution of 7-9mm comparable to that of PET systems.

rCBF Scanning
     Whereas our clinical and research rCBF SPECT studies have involved 99mTc-HMPAO since 1987, we have started to use a new rCBF agent called 99mTc-ethyl cysteinate dimer (ECD) that has recently been approved for clinical use.  ECD offers several advantages over HMPAO including improved stability, reduced extracerebral uptake, higher image contrast, and reduced radiation doses.  We will use this agent for this study.

     For rCBF SPECT, each subject will receive an intravenous injection of 20mCi of ECD with eyes open and ears unplugged in a quiet room.  Scanning will begin 30 minutes post injection.  For each scan, 120 7.5-sec projection images will be obtained over a period of 15 minutes using 30 angle intervals on a 128 x 128 matrix over 3600 by rotating each head 1200.
Images will be reconstructed in 3 orthogonal planes including transverse, coronal, and sagittal planes using a stereotaxic standardization technique we described previously to facilitate neuroanatomical localization on SPECT images40.

    These images will be used to identify rCBF abnormality patterns along anterior-posterior and right-left axes by using visual analysis, where we will use a 7 grade rating scale ranging from scale (-3) to (+3) as follows: scale (-3), deficit; (-2) and (-1), moderate and mild low activity, respectively; (0), baseline; (+1) and (+2), mild and moderate high activity, respectively; (+3), highest activity.   A deficit will be defined as a clear disconnection in brain activity in more than three continuous slices.  Quantitative rCBF measures will also be obtained to facilitate correlation analysis of rCBF with neuropsychological and neurological variables.  rCBF will be quantified using a normalization technique in which rCBF will be normalized to the cerebellum.  This quantification will be done by using our previously described fully automated stereotaxic software program to identify anatomical regions40,41.
 
 

A. PARTICIPANTS

     The participants for this study will include one hundred and twenty adults of both genders (60 males and 60 females).   The sample size of 120 was derived by taking into account the prevalence of Alzheimerís disease in the population as well as the possible drop out rates and mortality rates in the study.  The participants will be selected from within the community (the inner city of Toronto) and will possess the inclusion criteria required in order to partake in this study.
 

1. Inclusion Criteria
Participants will qualify as long as they
a) Are 55 years of age or older,
b) Are living within the community,
c) Are willing to participate in the entire study including the initial assessment and follow-ups at the 6, 12, and 18 month stage.
d) Have signed a written consent form indicating agreement to participate in the study.
e) Agree to being screened in order to rule out any previously undiagnosed but obviously present cases of dementia, psychosis, serious medical conditions.
2. Exclusion Criteria
Participants will not be eligible to partake in the study if they
a) Show some sort of cognitive deterioration, including DSM-IV and NINCDS-ADRA criteria for AD, or other known clinical causes of cognitive impairment such as: thyroid disorders, B12 and Folate deficiencies, Syphispis and other venereal disease, HIV, serious kidney or liver disease, etc.
b) Have a history of transient ischemic attacks or stroke.
c) Have a score of higher than 4 on the Modified Hachiuski Ischemic Scale.
d) Have a CT or MRI consistent with other causes of cognitive deficits (ie. stroke, lacunar infarcts, brain trauma, tumor, etc.)
e) Possess any other cause of primary neurodegenerative disorder; eg. Parkinsonís Disease.
 

     This pilot study consists of a prospective examination of the natural history of each participant across three points in time.  The progress of each participant will be measured at the 6, 12, and 18 month period.   Different methods of control will be present in this study:
1. Each participant will act as his own control across the three points in time.  A participantís progress and cognitive performance at admission and the 18 month period will be compared.  Partial analysis will be done at the 6 and 12 month period to detect the pattern of change.
2. Control for the instruments the neuropsychological battery of tests used will be achieved by comparing it to a "Gold Standard" for MCI.
3. The cognitive evolution between the different genotype groups (presence or absence of one or more "risk" alleles) through time will be another form of control and variable to consider.
4. Functional SPECT scan will be conducted on the subjects at the beginning of the study and at 18 months.

1. Recruitment
     The one hundred and twenty adults of 55 years of age and older will be recruited from within the community of Toronto; this includes community centers, seniorsí homes, community health centers, the General Practitionerís office, etc.  We already have the cooperation of general Health Community Clinics, and seniorsí organizations for participation in the study.
     All criteria must be followed in order to be eligible to enter the study.  It is expected that all participants will agree to the 6, 12 and 18 month follow up tests (eg. Blood test, SPECT, etc.).

2. Informed Patient Consent
     Participants that meet the criteria of the study will sign the Informed Consent document in order to participate.  All details of the study will be fully explained and any results arising from it will be kept confidential.  The participant is free to withdraw at any time without compromising his/her follow-up with the different institutions participating in the study.
 
 

     Initially, all participants will be screened to see whether or not they meet the inclusion criteria and do not possess any exclusion criteria.  A general physical examination and a standardized neurological examination will be conducted at the assessment period to determine eligibility.
In order to remove any treatable causes of dementia, each participant will undergo a series of lab tests (following the Canadian Study of Health and Aging) comprising of:
1) Cell Blood Count test (CBC)
2) Test for Thyroid Stimulating Hormone levels (TSH)
3) Test for neurosyphilis (VDRL)
4) b12 and Folate blood level
5) Test for metabolic screening (liver and kidney disease, etc.)
6) Chest X-ray  ( if none taken in the last 12 months)
At the assessment period, a complete list of medications (prescribed or non-prescribed) taken by the participant in the past 12 months will be required.  At follow-up visits, any new concurrent medications taken must be declared.

     Suitable candidates for the study will then go through a neuropsychological battery of tests, arranged in a specific sequence in order to promote interest and reduce discomfort.   Both trained and non-trained health professionals can administer these tests.   In order to ascertain a high level of reliability, all tests will be conducted similarly for each participant in each of the visits.
The combination of validated tests include (see Appendix 1):
1) Standardized Mini-Mental State Examination (Molloy & Clarnette)
2) Clock Drawing Test   ( Freedman et al., 1994)
3) Memory Impairment Screen (Buschke et al. 1999)
4) Trail Making Test ( Partington & Leiter, 1949)
5) Cross Cultural Smell Identification Test (Doty, et al. 1996)
6) Time and Change Test (Nikolaus et al. 1995)
7) Letter (FAS) and category (Animal Naming) fluency  (Crossley, et al.  1997)
8) Bayer Activities of Daily Living (B-ADL)  (Hindmarch, et al. 1998)
9) Quality of Life-Alzheimerís Disease (QOL-AD)  (Logsdon et al.)
 

This brief battery will be compared with the Gold Standard Battery to detect MCI, which includes the following (see Appendix 2):
1) Delayed Word List Recall  ( Mohs et al., 1997)
2) NYU Paragraph Recall Test, Immediate and Delayed  (Kluger et al.)
3) Buschke Free and Cued Selective Reminding Test ( Buschke &Grober,  1987)
4) Symbol Digit Modalities Task ( Smith, 1982)
5) Digit Cancellation Task (Mohs et al., 1997)
6) Maze  (Mohs et al., 1997)
7) Letter-Number Sequencing (Wechsler, 1997)
8) Verbal Fluency-Categories  (Morris et al., 1989)
9) Clock Drawing  (Freedman et al.,1994)
10) Quality of Life-Alzheimerís Disease (Logsdon et al.)

Blood tests and SPECT will be conducted at beginning of the study and at the 18 month period.  Any biochemical or structural changes arising throughout the course of the study can thus be detected.
The neuropsychological battery of tests will be administered to each participant at all stages of the study (initial, 6, 12, and 18 month periods).
(see Flow Chart)
 

 
1) Subjects will act as their own control from baseline on until the end of the study.
2) The primary question, comparing the results of our mini-battery with an accepted Gold Standard for the diagnosis of MCI, will be based on classifying each subject into one of two categories, a) MCI or b) AD, following the conclusion of the 18 month project.  AD will be defined according to the DSM-IV/ ICD-10 diagnostic criteria.
3) Differentiation of the significance of the other parameters contributing to the classification of the primary question, such as morphological-functional neuroimaging, neurogenetic tests and other possible peripheral markers, will be evaluated using Chi-square in order to compare rates and proportions.

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1Gauthier, S., Burns, A., Pettit, W.  Alzheimerís Disease in Primary Care, Martin Dunitz Ltd, London, c1997, 56p.

2 Bushke, L.  Canadaís greying population.  CMAJ Aug. 10 1999;161(3):239.

3 Ostbye, T., Crosse, E.  Net economic costs of dementia in Canada.  Can Med Assoc J  1994;151(10):1457-64.

4 Hux, M.J., OíBrien, B.J., Iskedjian, M., Goeree, R., Gagnon, M., Gauthier, S.  Relation between severity of Alzheimerís disease and costs of caring.  CMAJ 1998;159(5):457-65.

5 Dalton, J.E., Pederson, S.L., Blom, B.E., Holmes, N.R.  Diagnostic errors using the Short Portable Mental Status Questionnaire with a mixed clinical population.  Journal of Gerontology  1987;42(5):512-14.

6 Nelson, A., Fogel, B.S., Faust, D.  Bedside cognitive screening instruments.  The Journal of Nervous and Mental Disease  1986;174(2):73-83.

7 MacKenzie, D.M., Copp, P., Shaw, R.J., Goodwin, G.M.  Brief cognitive screening of the elderly: a comparison of the Mini-Mental State Examination (MMSE), Abbreviated Mental Test (AMT) and Mental Status Questionnaire (MSQ).  Psychological Medicine  1996;26:427-30.

8 Smyer, M.A., Hofland, B.F., Jonas, E.A.  Validity study of the Short Portable Mental Status Questionnaire for the elderly.  JAGS  1979;27(6):263-69.

9Almkvist, O., Basun, H., Backman, L., et al.  Mild cognitive impairment: an early stage of Alzheimerís disease?  J Neural Transm  1998; Suppl 54:21-29.

10 Hulette, C.M., Welsh-Bohmer, K.A., Murray, M.G., Saunders, A.M., Mash, D.C., McIntyre, L.M.  Neuropathological and neuropsychological changes in "normal" aging: evidence for preclinical Alzheimer Disease in cognitively normal individuals.  Journal o f Neuropathology and Experimental Neurology 1998;57(2):1168-1174.

11 Wolf, H., Grunwald, M., Ecke, G.M., et al.  The prognosis of mild cognitive impairment in the elderly.  J Neural Transm 1998; Suppl 54:31-50.

12 American Psychiatric Association.  Diagnostic and Statistical Manual of Mental Disorders, fourth edition.  Washington, DC; APA, 1994.

13 Peterson, R.C., Smith, G.E., Waring, S.C., et al.  Mild cognitive impairment: clinical characterization and outcome.  Arch Neurol  1999;56:303-8.

14 Jacobs, D.M., Sano, M., Doonief, G., Marder, K., Bell, K.L., Stern, Y.  Neuropsychological detection and characterization of preclinical Alzheimerís disease.  Neurology 1995 May;45(5):957-62.

15 Howieson, D.B., Dame, A., Camicioli, R., Sexton, G., Payami, H., Kaye, J.A.  Cognitive markers preceding Alzheimerís dementia in the heatlhy oldest old.  JAGS  1997;45:584-9.

16  Freedman, M., Leach, L., Kaplan, E., et al.  Clock drawing: a neuropsychological analysis.  New York: Oxford University Press, 1994.

17 Buschke, H., Kuslansky, G., Katz, M., et al.  Screening for dementia with the Memory Impairment Screen.  Neurology  1999;52:231-8.

18  Partington, J.E., Leiter, R.G.  Partingtonís Pathway Test.  The Psychological

Service Center Bulletin, 1, 9-20.

19 Doty, R.L., Marcus, A., Lee, W.W.  Development of the 12-item cross-cultural smell identification test (CC-SIT).  Laryngoscope  1996;106:353-6.

20 Nikolaus, T., Bach, M., Specht-Leible, N., Oster, P., Schlierf, G.  The timed test of money counting: a short physical performance test for manual dexterity and cognitive capacity.  Age and Ageing  1995;24:257-8.

21 Crossley, M., DíArcy, C., Rawson, N.S.B.  Letter and category fluency in community-dwelling Canadian seniors: a comparison of normal participants to those with dementia of the Alzheimer or vascular type.  J of Clinical and Experimental Neuropsychology  1997;19(1):52-62.

22 Hindmarch, I., Lehfeld, H., de Jongh, P., Erzigkeit, H.  The Bayer Activities of Daily Living Scale (B-ADL).  Dement Geriatr Cogn Disord  1998;9(Suppl 2):20-26.

23 Logsdon, R.G., Gibbons, L.E., McCurry, S.M., Teri, L.  Quality of life in Alzheimerís disease: patient and caregiver reports.  J Ment Health Aging, in press.

24  Saunders, A., Strittmatter, W.J., Schmechel, S., et al.  Association of Apolipoprotein E allele E4 with the late-onset familial and sporadic Alzheimer Disease.  Neurology 1993; 43:1467-1472

25 Kehoe, P., Williams, J., Holmans, P. et al.  Association between PS-1 intronic polymorphism and late onset Alzheimerís disease.  Neuroreport  1996 Sep 2;7(13):2155-2158.

26  Rogaev, E.I., Sherrington, R., Rogaeva, E.A., et al.  Familial Alzheimerís disease in kindreds with missense mutations in a novel gene on chromosome 1 related to the Alzheimerís Disease type 3 gene.  Nature 1995;376:775-778.

27  Wavrant-De Vrieze, F., Crook, R., Holmans, P., et al.  Genetic variability at the amyloid-beta precursor protein locus may contribute to the risk of late-onset Alzheimerís disease.  Neurosci Lett  1999;269(2):67-70.

28  Mayeux, R., et al.  Utility of the Apolipoprotein E genotype in the diagnosis of Alzheimerís disease.  Alzheimerís Disease Centers Consortium on Apolipoprotein E and Alzheimerís Disease.  NEJM 1998;338(8):506-511.

29  Soininen, H.S., Scheltens, P.  Early diagnostic indices for the prevention of Alzheimerís disease.  Ann Med  1998 Dec;30(6):553-559.

30  Relkin, N.R., Kwon, Y.J., Tsai, J., Gandy, S.  Then National Institute on Aging/Alzheimerís Association recommendations on the application of apolipoprotein E genotyping to Alzheimerís disease.  Ann N Y Acad Sci  1996 Dec 16;802:149-176.

31  Traykov, L., Rigaud, A.S., Caputo, L.,  et al.  Apolipoprotein E phenotypes in demented and cognitively impaired patients with and without cerebrovascular disease.  Eur J Neurol 1999;6(4):415-421.

32  Brayne, C., Harrington, C.R., Wischik, C.M.  Apolipoprotein E genotype in the prediction of cognitive decline and dementia in a prospectively studied elderly population.  Dementia  1996 May-Jun;7(3):169-74.

33  Tierney, M.C., Szalai, J.P., Snow, W.G., et al.  A prospective study of the clinical utility of ApoE genotype in the prediction of outcome in patients with memory impairment.  Neurology  1996 Jan;46(1):149-54.

34  Jack, C.R. Jr, Peterson, R.C., Xu, Y.C., et al.  Prediction of AD with MRI-based hippocampal volume in mild cognitive impairment.  Neurology  1999 Apr 22;52(7):1397-403.

35  Wolf, H., Grunwald, M., Ecke, G.M., et al.  The prognosis of mild cognitive impairment in the elderly.  J Neural Transm Suppl  1998;54:31-50.

36  Rogaeva, E., Premkimar, S., Song, Y. et al.  Evidence for an Alzheimer Disease susceptibility locus on chr 12, and for further locus heterogeneity.  JAMA  1998;280:614-618.

37  Sherrington, R.,  Rogaev, E., Liang, Y., et al.  Cloning of a gene bearing missense mutations in early onset familial Alzheimerís disease.  Nature  1995;375:754-760.

38  Karlinsky, H., Vaula, G., Gaines, J.L., et al.  Molecular and prospective phenotypic characterization of a pedigree with Familial Alzheimer Disease and a missense mutation in codon 717 of the B-amyloid Precursor Protein (APP) gene.  Neurology  1992;42:1445-1453.

39  Saitoh, T., Xia, Y., Chen, X., et al.  The CYP2D6B mutant allele is overrepresented in the Lewy body variant of Alzheimerís disease.  Ann Neurol  1995 Jan;37(1):110-112.

40 Tsao, J., Stundzia, A., Ichise, M.  Fully automated establisment of stereotaxic image orientation in six degrees of freedom for technetium-99mm-ECD SPECT.  J Nucl Med  1998; 39:503-508.

41  Ichise, M., Golan, H., Ballinger, J.R., Blackman, A., Moldofsky, H.  Regional differences in technetium-99mm ECD clearance on brain SPECT in healthy subjects.  J Nucl Med  1997;38:1253-1260.

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