Presentation on theme: "SCREENING TOOLS FOR MCI (mild cognitive impairment)"— Presentation transcript:
1 SCREENING TOOLS FOR MCI (mild cognitive impairment) J. Wesson Ashford, M.D., Ph.D.Clinical Professor (affiliated)Department of Psychiatry & Behavioral SciencesStanford UniversitySenior Research ScientistStanford / VA Aging Clinical ResearchStanford University and VA Palo Alto Health Care SystemInternational Conference on Alzheimer’s diseaseJuly 12, 2010Slides at: (Dr. Ashford’s lectures)
2 Disclosures for Dr. Ashford Alzheimer’s AssociationMember, Northern California Branch Scientific Advisory BoardAlzheimer’s Foundation of AmericaMedical Advisory Board memberChair, Memory Screening Advisory BoardJournal of Alzheimer’s DiseaseClinical EditorDeveloping a memory test:MemTrax – for computers, internet, audience presentationsPartner with HAPPYneuronConsultant for Orasi, Inc.Developing MEG test for ADShare owner in Satoris, Inc.Developing proteomics test for ADShare owner, consultant for Neurotez, IncDeveloping Leptin as a treatment for AD
3 Screening Tools for MCI (outline of presentation) Definition of Mild Cognitive Impairment (MCI)Dementia signs without social impairmentIs it “cost-worthy” to screen for MCI?Estimate based on benefits, costs, incidence, sensitivity, specificityUnderstanding the progression of Alzheimer’s diseaseGompertz Hazard Curve in early AD pathological changes, geneticsCentral concept of change over time – Gompertz Survival CurveExisting cognitive tools for MCI screeningMMSE, BAS, MIS, MCIS, episodic memory tests, MemTraxBiomarkers for MCI screeningGenetics, CSF, blood, brain scanning, EEG/ERP/MEGFuture directions for MCI screeningLongitudinal assessmentMemTrax – quick, fun games for precise memory measurement
4 Diagnostic Criteria For Dementia Of The Alzheimer Type (DSM-IV, APA, 1994) Multiple Cognitive Deficits1. Memory ImpairmentEspecially new learning, a prominent early symptom2. Other Cognitive Impairment:Aphasia, apraxia, agnosia, or executive dysfunctionDeficits sufficiently severe to impair Social/Occupational functioningCourse Shows Gradual Onset And DeclineMust represent a decline from a previous level of functioningDeficits Are Not Due to:1. Other CNS Conditions2. Substance Induced ConditionsDo Not Occur Exclusively during DeliriumNot Due to Another Psychiatric Disorder
5 Mild Cognitive Impairment Essentially normal functional activities Cognitive complaintNot normal for age1/3 AD,1/3 not,1/3 both.Not dementedCognitive declineEssentially normal functional activitiesMCIMemory impaired?YesAmnestic MCINon-amnestic MCISingle domainYesNoSingle non-memorycognitive domain impaired?Multiple domainMemoryimpairment only?Amnestic MCISingle domainYesNoAmnestic MCIMultiple domainCPPetersen: J Int Med, 2004Petersen, Ronald C MN
6 What’s the Difference? Normal Aging Occasional loss of memory for words and names.Slowed processing speed.Difficulty sustaining attention when faced with competing environmental stimuli.No functional impairment.MCIMemory impairment beyond that expected for age, increasing over last six to 12 months.Other cognitive functions generally unimpaired.Daily function not significantly impaired.Not demented.Source: Dr. Pierre Tariot, University of Rochester Medical Center.“What is on the Horizon for Alzheimer’s Disease Research?“6
7 Cognitive Continuum Normal Mild Cognitive Impairment Dementia CPAdded to series , MCPetersen, Ronald C MN
8 Mild Cognitive Impairment NormalMCIAD0.51CDR (clinical dementia rating scale)Petersen, Ronald C MN
9 AAMI / MCI/ early AD -- DEMENTIA ALZHEIMER’S DISEASE COURSE(calculated from the CERAD data set)The best model to fit the progression,both mathematically and biologically,is the Gompertz survival curve(99.7% fit to mean changes over time):S(t) = exp(Ro/alpha *(1- exp (alpha * t)))(Time-Index Scale)AAMI / MCI/ early AD DEMENTIAAshford et al., 1995
11 Is it worth screening for Alzheimer’s disease or MCI? “If there was treatment for AD, I'd recommend screening,but there is no disease-modifying therapy."Anonymous Alzheimer expert -2008“All older adults benefit from memory screening becauseit detects cognitive problems before memory loss is noticeable.”Healthy Aging, 2008; repost, 2010“Memory Screening: Is it Worth It?”
12 Alzheimer's Disease Is Under-diagnosed Early AD is subtle, the diagnosis continues to be missedIt is easy for family members to avoid the problem and compensate for the patientPhysicians tend to miss the initial signs and symptomsLess than half of AD patients are diagnosedEstimates are that 25%–50% of cases remain undiagnosedDiagnoses are missed at all levels of severity: mild, moderate, severeUndiagnosed AD patients often face avoidable social, financial, and medical problemsEarly diagnosis and appropriate intervention may lessen disease burdenEarly treatment may substantially improve overall courseNo definitive laboratory test for diagnosing AD existsEfforts to develop biomarkers, early recognition by brain scan12
13 Why MCI Screening Is Important to Consider Cognitive impairment is disruptive to human well- being and psychosocial functionCognitive Impairment is potentially a prodromal condition to dementia and Alzheimer’s disease (AD)Dementia is a very costly condition to individuals and societyWith the aging of the population, there will be a progressive increase in the proportion of elderly individuals in the worldScreening will lead to better care13
14 No Testing: What happens without screening? Total PopulationRisk=PP’PDo not have ADHave ADNo effective interventionHelena Kraemer, 2003
15 Testing: What happens with testing? Helena Kraemer, 2003Total PopulationSpecificity = SpSensitivity = SeP’PADNo ADSeSe’Sp’SpUnnecessary intervention OK No effective intervention Effective intervention$ Testing $Testing $ Testing $ Testing$ Intervention $ InterventionIatrogenic Damage? Clinical Wash Clinical Wash Clinical GainMajor(?) Loss Minor (?) Loss Minor(?) Loss Major(?) GainSome gainFalse Positive True Negative False Negative True Positive
16 Factors for Deciding whether a Screening Test is Cost-Effective Benefit of a true positive screenBenefit of a true negative screenCost of a false positive screenCost of a false negative screenIncidence of the disease (in population)Test sensitivity (in population)Test specificity (in population)Test cost
17 $W = Cost–Worthiness Calculation $W > ($B x I x Se) – ($C x (1-I) x (1-Sp)) - $T BENEFIT$B = benefit of a true positive diagnosisEarlier diagnosis may mean proportionally greater savingsEstimate: (100 years – age ) x $1000Save up to $50,000 (e.g., nursing home cost for 1 year)(after treatment cost deduction at age 50, none at age 100)(cost-savings may vary according to your locale)True negative = real peace of mind (no money)COST$C = cost of a false positive diagnosis$500 for further evaluation(time, stress of suspecting dementia)False negative = false peace of mind (no price)I = incidence (new occurrences each year, by age)Se = sensitivity of test = True positive / ISp = specificity of test = True negative / (1-I) = (1-False positive/(1-I)$T = cost of test, time to take (Subject, Tester)Kraemer, Evaluating Medical Tests, Sage, 1992
18 Benefits of Early Alzheimer Diagnosis: Social Undiagnosed AD patients face avoidable problemsSocial, financialEarly education of caregiversHow to handle patient (choices, getting started)Advance planning while patient is competentWill, proxy, power of attorney, advance directivesReduce family stress and misunderstandingCaregiver burden, blame, denialPromote safetyDriving, compliance, cooking, etc.Patient’s and family’s right to knowEspecially about genetic risksPromote advocacyFor research and treatment development18
19 Benefits of Early Alzheimer Diagnosis Medical Early diagnosis and treatment and appropriate intervention may:improve overall course substantiallylessen disease burden on caregivers / societySpecific treatments now available for dementia(anti-cholinesterases, memantine)Improve cognitionImprove function (ADLs)Delay conversion from Mild Cognitive Impairment to ADSlow underlying disease process, the sooner the betterDecreased development of behavior problemsDelay nursing home placement, possibly over 20 monthsDelay nursing home placement longer if started earlier
20 Benefits of Early Treatment of Alzheimer’s Disease Neurophysiological pathways in patients with AD are still viable and are a target for treatmentOpportunity to reduce from a higher level:Functional declineCognitive declineCaregiver burdenNeed to estimate net benefit monetarily(key factor in determining case for screening)Estimate benefit = (100 years – age ) x $1000Purpose:To emphasize the point that patients with moderate to severe AD can still benefit fromdrug treatmentKey Points:There are a number of benefits to treating. Based on current data from imaging and other noninvasive studies in patients with AD as well as autopsies of patients with AD, we have recognized that the levels of degeneration in the brain may be substantially less than previously thought (based on studies in the late 1970s and 1980s).Much more cellular content and signaling remain viable late in the disease, which represents an opportunity for intervention.Early treatment and effective therapies for patients with moderate to severe AD may help provide opportunities to slow symptomatic decline in function and cognition, and reduce caregiver burden.
23 Cost of False-Positive Screen Referral of normal individual for further testing(more specific testing)Value of individual’s timeCost of additional testingEstimate cost = $500 per false-positive screenThis does not and should not include the cost of untoward results of misdiagnosis, medication side-effects, or malpractice – quality management should address these
24 Other Benefits and Costs of Screening Benefit of true-positive screen = intangiblePeace of mindPlan further into futureCost of false-negative screen = washDelay in diagnosis and treatmentNo different from current condition
25 INCIDENCE OF MCI (Hazard per year) Based on estimate of 4 million AD patients with dementia in US in 2000, with an incidence that doubles every 5 years, illness duration of 8 years.Assume average of 5 years from onset of MCI to onset of dementia
26 U(t) = Ro * exp (alpha * t) The Gompertz survival curve explains99.7% of male and female mortalityVariance between 30 and 95 y/o:U(t) = Ro * exp (alpha * t)(Incidence for a to a + 1 year)JW Ashford, MD PhD, 2003; See: Raber et al., 2004
27 U(t) = Ro * exp (alpha * t) Using the Gompertz equationto model rate of dementiaincrease with age:U(t) = Ro * exp (alpha * t)
40 Critical Factors for Developing Cost-Effective Screening Develop benefit of a true positive screen- Need effective disease slowing treatmentsDefine value of genetic testing- Need to recognize central role of APOE genotypeDetermine sensitivity and specificity of tests- Parameters must apply to populationNeed to determine cost-worthiness- This must be determined for each testSpecific tests must be optimally sequenced- Frequent cognitive screens triggering biomarker tests
41 Need to Develop Better Screening and Early Assessment Tools Trait factors – determine at 50 y/o to plan screeningGenetic vulnerability testing (or family history)Vulnerability factors (education, occupation, head injury, blood pressure)State factors (begin annually at appropriate age)Early recognition (10 early warning signs), ADLsScreening tools (6th vital sign in elderly)Brief clinical screens vs. computerized testsTests need to assess likely level of functionDetecting early change over timeMeasuring rate, predicting progressionPositive diagnostic testsCSF – amyloid levels low (early), tau levels elevated (MCI)Brain scan – PET – f-DG, f-DDNP, f-amyloid ligands (early)Dementia severity tested on “time-index” continuum
42 Alzheimer's Disease Top 10 Warning Signs (not early) Recent memory changes affecting daily lifeChallenges in problem solving and planningDifficulty performing familiar tasksDisorientation to time and/or placeDifficulty understanding visual images and/or spatial relationshipsProblems with spoken and written language (eg, paraphasia, agraphia)Misplacing thingsPoor judgmentWithdrawal from activities (eg, social, work)Changes in personality and/or moodNeed a Top 10 Early Warning SignsAlzheimer's Association. 10 Signs of Alzheimer's. Available at: Accessed April 20, 2009.42
43 Challenges With the Mini-Mental State Examination Mini-Mental State Exam (MMSE)Folstein MF, et al. J Psychiatr Res. 1975;12:Several items do not provide adequate informationAdds noise rather than discrimination between demented and nondemented individuals, particularly in early AD, MCIPoor range for measuring changeLarge standard error of measurementPoor power for assessing medication benefitInadequate screening toolToo longBetter, shorter tests are availableCopyright is being enforced (test is not free)Ashford JW. Aging Health. 2008;4:43
49 Implications of Item Characteristic Curves for Patient Testing REMOVE POOR ITEMS, ESPECIALLY THOSE THAT ADD NOISESELECT ITEMS THAT BETTER PERTAIN TO FOCUS OF STUDYMAXIMIZE INFORMATION OBTAINED PER MINUTE OF TESTINGDECREASE VARIABILITY IN TESTIMPROVE ACCURACY, PRECISIONDEVELOP BETTER SCREENING TESTSON-LINE COMPUTATION -
50 Relatively Brief Cognitive and Memory Tests Name of TestAuthorAnimal Naming in 1 minuteRey Auditory Verbal Learning TestAbbreviated Mental TestHalstead, 1943Rey, 1958Hodkinson, 1972Short Portable Mental Status Questionnaire (SPMSQ)Pfeiffer, 1975Clifton Assessment Procedures for the Elderly-Cognitive Assessment Scale (CAPE-CAS)Pattie, 1981Blessed 6-ItemKatzman, 1983Visual memory, category fluency, temporal orientationEslinger, 1985Short Test of Mental StatusKokmen, 1987Delayed Word Recall test (DWR)Knopman, 1989Memory Impairment ScreenBuschke, 1999Three Words–Three ShapesWeintraub, 2000General Practitioner Assessment of Cognition (GP-COG)Brodaty, 20026-Item ScreenerCallahan, 2002Ashford JW. Aging Health. 2008;4:50
51 Relatively Brief Cognitive and Memory Tests (cont.) Name of TestAuthorEfficient Office-Based Assessment of CognitionKarlawish, 2003Mini-CogBorson, 2003Rapid Dementia Screening Test (RDST)Kalbe, 2003Brief Alzheimer Screen (BAS)Mendiondo, 2003Short Cognitive Evaluation Battery (SCEB)Robert, 2003AB Cognitive Screen)(ABCS)Molloy, 2005Quick & Easy (Q&E)Dash, 2005Mild Cognitive Impairment Screen (MCIS)Shankle, 2005Blessed Memory Test/Category FluencyKilada, 200510-Item Free Recall With Serial Position Effect AnalysisTractenberg, 2005From Ashford, Aging Health. (2008) 4(4):Ashford JW. Aging Health. 2008;4:51
52 Screening tools tested for MCI 3-word memory +clock draw (MiniCog, Borson) + FAQ (Functional Activity Questions) – Steenland et al., 20083-word memory + temporal orientation + “spell WORLD backwards” + category naming – BAS (Brief Alzheimer Screen) – Mendiondo et al., 2003(only test based on item construct validity)4-word memory (deep encoding – MIS, Buschke) + Isaacs Set Test (category fluency) – Chogard et al., 20085-word memory, 4 sets – Gialaouzidis, 201010-word memory with computation (MCIS) – Shankle et al.Internet tools:Test Your Memory – 10 skill assessment – Brown et al., 2010Computer Self Test – 6 cognitive domains – Canon, Dougherty, 2010Memtrax – Computer Memory Game – Ashford et al., 2006Note: word memory is American tradition; name & address memory is English tradition
55 Brief Alzheimer Screen (BAS) Repeat these three words: “apple, table, penny”.So you will remember these words, repeat them again.What is today’s date?D = 1 if within 2 days.Spell the word “WORLD” backwardsS = 1 point for each word in correct order“Name as many animals as you can in 30 seconds, GO!”A = number of animals“What were the 3 words I asked you to repeat?” (no prompts)R = 1 point for each word recalledBAS = 3 x R /3 x A x D x SMendiondo, Ashford, Kryscio, Schmitt., J Alz Dis 5:391, 2003
58 Brief Alzheimer Screen (BAS) ROC for Univ. Kentucky ADRC Clinic Cases Schmitt et al., 2006
59 Spearman Correlations Between Neuropsychological and MRI Volumetric Data Grey Mat.White Mat.Right Hipp.Left Hippo.Right EntoLeft EntoMISControls0.180.1120.1850.243–0.085–0.205MCI–0.022–0.2130.430a0.3780.1560.21AD–0.1000.0330.1920.23–0.012–0.061FCSRT learning0.250.2490.0480.252–0.214–0.152–0.044–0.2430.469a0.3830.374a0.424a–0.032–0.224–0.0910.211–0.074–0.168FCSRT delayed0.1610.1360.0280.233–0.325–0.295–0.010–0.2670.554b0.426a0.407a–0.1260.2860.451a0.1040.081Abbreviations: AD, Alzheimer Disease; ento, entorhinal; hipp., hippocampus; mat., matterFCSRT, Free and Cued Selective Reminding Test; MIS, Memory Impairment Screen;a Significant correlations are flagged with P < .05.b Significant correlations are flagged with P < .001.
60 The MCIS For Clinical Practice & Research Takes 10 MinutesAccuracy1-4 is:96-97% for Normal vs. Mild Cognitive Impairment.99% for Normal vs. Mild Dementia.Improves Signal:Noise Ratio by 100% over standard scoring methods5.16 culturally unbiased, equivalent wordlists randomly selected without replacement in each patient to minimize test-retest effects5.Available in English, Spanish and Japanese.Adopted in all Medicare regions.1Shankle et al. PNAS. 20052Trenkle et al. J. Alz. Dis3Cho et al. Jap. J. Exp. Med4Tabara et al. Hypertension Research5Shankle et al. Alz. & Dementia, 2009.
61 Developing The Measurement Technology: Memory Patterns Raw CWL Data Matrix of Recalled and Forgotten Words(eg: )Correspondence Analysis1(Multivariate Gaussian-Distributed Optimal Patient & Word Score Vectors)Logistic RegressionROC Curve AnalysisAge-Specific PrevalenceClassification algorithm &Memory Performance Index (MPI) scaling1This method explains the maximum possible amount of the raw data’s variance for the class of linear methods.In contrast to FA & PCA, Correspondence analysis accounts for differences due to heterogeneous samples.Optimal Scores Vary By:List PositionExposure FrequencyDelayBeing Recalled or NotItem Responses Are Usually Scored As 0 or 1: All Items Have Equal ValueWord 1Word 2Word 3Word 4Word 5Word 6Word 7Word 8Word 9Word 10Wordlist Memory Task: 4 Trials1Kendall & Stuart, The Advanced Theory of Statistics2Shankle et al. PNAS. 2005
62 Wordlist Development 600 nouns met these criteria 1 million common nouns.Frequency, range, and diversity of usage statistics paralleled CERAD and ADAS-Cog Wordlists600 nouns met these criteriaConstructed 10-word lists that met the following requirementsEach word:could be used only once.could only have 1 or 2 syllableshas unique letter or sound.has no homonyms or antonyms in list.has low associability with all other list words.Each target list word can be matched on all above criteria with a word in its accompanying distracter list.16 Wordlists Met All Above Criteria(Subjects Must Be Tested 9 Times Before They See The Same Wordlist Twice)
63 MCIS Performance Summary Study ComparisonsROC AccuracySensitivitySpecificityNormal vs. MCI* (3 Validation Studies)1,2,396-97%94-96%88-100%Normal vs. MCI Due To Alzheimer’s Disease1,299%98%92%Normal vs. MCI Due To Non-Alzheimer’s Disease1,296%91%88%Normal vs. Mild Dementia1Normal vs. Asymptomatic CI (Primary Care Sample)293%86%*The underlying etiologies of the MCI syndrome in the primary care, community and academic samples included Alzheimer’s disease, Lewy Body disease, Parkinson’s disease, Frontal Temporal Lobe dementia, normal pressure hydrocephalus, cerebrovascular disease, alcohol dependence, traumatic brain injury, metabolic disorders, and depressive pseudo-dementia.Psychometric PropertiesPositive Predictive Value for MCI1,286-100%Negative Predictive Value for Normal Aging1,296-99%Within-Subject Inter-Rater Reliability: Office Staff vs Neuropsych. (Cronbach alpha)20.87 ± 0.07Validity compared to Clinical Diagnosis (Kappa statistic)20.92 ± 0.09False Negative Rate Based on Long-Term Care Claims After 3 years exposure: N=250,0004%1Shankle et al. PNAS: Trenkle et al. J. Alz Dis: 2007.3Cho et al. Am J. Alz Dis Other Dem Cohen et al. National Underwriter, 2009.
65 Comparing Standard Recall & MCIS Scoring Method (MPI) Regression of Recall Scores or MCIS Scoring Method (MPI) Score AgainstAge, Gender, Education, Race, Method of Administration & Wordlist Used1N=121,481 Applicants for Long-Term Care Insurance: AgesDelayed, Immediate or Total Free RecallR2 = % of variance explainedMPI ScoreR2 = 55.5% of variance explainedEffect sizes (Cohen’s d) were as follows:Effect of Race, gender, and wordlist on MPI Score were negligible (<0.02)Effect of Education & phone vs. in-person testing on MPI Score were small ( )Effect of Age on MPI Score was large (0.68)Effect of all covariates on Free Recall scores was negligible or small (< 0.09)1Shankle et al. Alz. And Dementia. 5; 2009:
66 Time to Administer Available Short Screening Tests Top cognitive tests studied for BRIEF SCREENING for MCIBrief Alzheimer Screen 2 – 3 minMini-cog + FAQ minMIS + Isaacs Set Test 4 – 6 minMCIS minA suitably accurate cognitive test for MCI is not available.Because on variability between individuals, MCI screening requires longitudinal assessment!!
67 Need to Develop More Sensitive and Specific Tools for MCI Genetic vulnerability testing (trait risk)APOE genotype + age is among the best currentlyImprove awareness of vulnerability factors, ask the “right questions” of the patient or informant (education, occupation, head injury)Early recognition “10 warning signs”Activities of daily living (ADLs), behavior changes, forgettingIncrease suspicion and use available screening tools (while new and better tools/tests are developed)"6th vital sign" in elderlyUtilize current diagnostic tests that can best identify probable ADCerebrospinal fluid: tau levels, amyloid levelsBrain scan, PET scan: f-2DG, f-DDNP, f-amyloid-ligandsMore routine use of mild dementia severity assessmentsDetect early change over timeMeasure rate of change, predict progression67
68 Memory / MCI / Dementia Screening Test Need test for cognitive screening of patients for early Alzheimer’s diseaseTest needs to be on multiple platformsDoctor’s officesBest if computerized for rapid, objective assessmentInternet-based testingCD-ROM distributionKiosk administration (eg, drug stores, shopping malls)Test needs to be very brief (~1-minute)Multiple test-forms needed so it can be repeated often (quarterly)Annual screening annually after age 50 yearsRepeated every 3 months for individuals over 65 years or with concerns/risk factorsVariety of versions allow daily testing as an exerciseAny change over time needs to be detectedThe test should be free (or cost very little)68
69 MEMTRAX - Memory Test (For Dementia Screening, Cognition Assessment) Test to screen patients for dementia, AD: Subjects are asked to respond to images that are repetitions of previously shown images.Computerized test (computer or web - 3 minutes)KIOSK administration (clinic check-in)Group administration (Power-Point – 6 minutes)On the paper & pencil version, each slide is shown for 5 seconds. The test-taker is ask to fill in the circle next to the number for a repeated slide. After a practice set, the 50-slide test takes 4 minutes and 10 seconds.For the computerized test, each image is shown for 3 seconds, and the subject pushes the space bare to indicate recognition of a repeated picture.Estimate level (based on 2,000 patients, caregivers)>90% very good80-90% good70-80% consider mild cognitive impairment<70% dementia
70 MEMTRAX Memory Test116 subjects – mostly elderly normals, some young, some dementia patientsFalse positive errors (false recognition) – 33(64);6(58);47(27)—4,18,23,34(1);1,2,8(0)- mean – 8.3% (sd-14.5%) errors per itemFalse negative errors (failure to recognize) – 35(33);27(20);5(16)—32(4);24(3);45(3)- second presentation (#15): mean- 10.5% (sd-6.2%) errors per item- third presentation (#10) mean – 5.7% (sd-2.5%) errors per item- second 10 vs. same third 10: 10.5% (sd-3.4%) vs 6.6% (sd-2.5%)
73 CONCLUSIONS on MEMTRAX A short, computerized test provides a measure of cognitive function, including memory and attention, on a robust continuum, establishing a baseline of cognitive function and potentially predicting the presence of dementiaComputerized version – 2-3 minutes, fun game, provides reaction time measurePaper&Pencil, with PowerPoint slide show, can be given to a large audienceTesting for reliability and validity are Classical Test Theory conceptsModern Test Theory examines performance across individual items on a continuum(varied by first repeat vs second repeat, number of slides between first show and first repeat, etc.Analysis for maximum likelihood level of cognition (both recognition and attention), provides information about dementia probabilityInformation about visuo-spatial and language function is available
74 MEMTRAX - Memory Test (to detect AD onset) New test to screen patients for AD:World-Wide Web – based testingCD-distributionKIOSK administration (grocery stores, drug stores)Determine level of ability / impairmentTest takes about 1-minuteTest can be repeated often (e.g., weekly, quarterly)Any change over time can be detectedExperimental tests at:Social network tests at:Clinical test at:
75 Comprehensive Screening Plan At age 50 years: initial screen, review risksReview dementia family history – strongly consider APOE genotypingReview of systems, vital signsBrief cognitive evaluation – establish baseline for longitudinal assessmentComplete blood count (CBC), B12, cholesterolBegin yearly assessments if high riskAt age 55–60 years: follow-up assessmentsBrief cognitive evaluation using longitudinal measures!!CBC, B12, cholesterolAt age 65 years and older: begin annual assessmentsBrief cognitive evaluation watching longitudinal changes75
76 Secondary Screen: Specific Testing More cognitive testingComplete orientation testingTest ability to name animals and vegetables in 1 minuteAsk for recall of 10 items after distractionTest praxisDraw clock, cubeTalk with a knowledgeable informantAsk questions about activities of daily livingAsk questions about depression, sleep76
77 Potential AD Biomarkers Probably not cost-worthy as screening tests, but may be useful for secondary screeningBlood, urine Aβ40? Aβ42? Neuritic threads?Most studies suggest not helpful, may be wrongProtein levels in blood – Leptin, ProteomicsLower Leptin predicts MCI progression to dementiaCSF: Aβ40? Aβ42? Others Aβ species?Possibly highly predictiveCSF: tau, p-tauAssess active disease progression.EEG/MEG/ERPNeuroimagingStructural (volumetric assessments)Functional (FDG-PET, SPECT)Specific protein imaging (PET)
78 Serum Leptin levels and cognition in the elderly In elderly, higher serum leptin appears to protect against cognitive decline (5 yr prospective study, 2,871 elders, Holden et al., 2009)Patients with AD have lower serum leptin levels compared to controls, independent of BMI (Power et al., 2001)Data: Satoris, Inc.20ADLeptin (ng/ml)10MiIdNormalSevereModerate7878
79 PROTEOMICS:Expression patterns of Alzheimer disease (AD)signature proteins discriminate between plasmasamples from patients with AD and controls.Britshgi & Wyss-Coray, 2009Correlation networks of Alzheimer disease (AD) signature proteins in plasma of controls without dementia and patients with AD.
80 CSF in Alzheimer’s Disease, both MCI and Dementia patients: Low Aβ and High Tau Concentration (pg/mL)AβTauSunderland T, et al. JAMA. 2003;289:80
82 ADNI Data – CSF ABeta, total tau Comparisonp-value33 vs 34<.000133 vs 4434 vs 440.08Normal vs MCI0.57Normal vs Mild AD0.15MCI vs Mild AD0.20Comparisonp-value33 vs 340.0733 vs 440.6734 vs 440.99Normal vs MCI0.05Normal vs Mild AD<.01MCI vs Mild AD0.0682
83 ADNI CSF Data – total tau Number of participants that provided CSF at baselineAges +std of participants that provided CSF at baselineAPOE genotypeNormalMCIMild AD3367 (72%)82 (44%)29 (31%)3424 (26%)81 (44%)42 (45%)442 (2%)22 (12%)22 (24%)APOE genotypeNormalMCIMild AD3375.8 ± 5.075.4 ± 8.476.3 ± 8.63475.8 ± 6.073.9 ± 6.775.6 ± 6.64477.0 ± 1.472.2 ± 6.069.8 ± 7.0CSF ABeta levels ± stdCSF tau levels ± stdAPOE genotypeNormalMCIMild AD33212.4 ± 48.4189.1 ± 59.8168.8 ± 52.334156.0 ± 47.8148.4 ± 42.4139.0 ± 27.244126.0 ± 2.8119.8 ± 23.5116.2 ± 22.3APOE genotypeNormalMCIMild AD3367.8 ± 26.983.6 ± 40.8123.8 ± 68.63481.8 ± 42.6122.4 ± 72.7113.3 ± 42.04471.0 ± 2.8110.6 ± 45.9128.9 ± 53.183
84 Future directions for MCI screening Successful treatments for MCIAPOE genotyping – routine at 50 y/oPreventive measures based on geneticsLongitudinal assessment of memoryComputer games to monitor cognitionquick, fun, inexpensiveCan beta-amloid deposition be controlled by mental, physical exercises, better sleep?