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Preclinical Stage Alzheimer's Disease Defining and Characterizing the Transition Between Normal and Pathological Cognitive Aging Richard J. Caselli, MD.

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Presentation on theme: "Preclinical Stage Alzheimer's Disease Defining and Characterizing the Transition Between Normal and Pathological Cognitive Aging Richard J. Caselli, MD."— Presentation transcript:

1 Preclinical Stage Alzheimer's Disease Defining and Characterizing the Transition Between Normal and Pathological Cognitive Aging Richard J. Caselli, MD Department of Neurology, Mayo Clinic Arizona Funding: NIA P30AG19610, NIA R01AG031581, and the Arizona Alzheimer’s Research Consortium

2 Definitions 1.Dementia is the disabling impairment of multiple cognitive functions. It is not memory loss alone. 2.Mild Cognitive Impairment 1.Single domain 1.Amnestic (memory loss alone) 2.Non-amnestic (language, executive, spatial) 2.Multiple domain 3.Preclinical Alzheimer’s disease is…? 1.Objective: 1.Neuropsychological decline 2.Abnormal imaging (MRI, fMRI, FDG, PiB) 3.CSF Biomarkers 4.Neuropathology 2.Subjective: symptoms without “objective findings”

3 The Genetic Basis of Alzheimer’s Disease Causative (Consider genetic testing and counselling) Chromosome 21: (APP)Chromosome 21: (APP) Chromosome 14: Presenilin 1Chromosome 14: Presenilin 1 Chromosome 1: Presenilin 2Chromosome 1: Presenilin 2 Susceptibility Chromosome 19: Apolipoprotein E TOMM40 Milder Risk Factors CYP46 GAB2 SORL1 Other

4 APOE e4 - a Susceptibility Gene Variant Associated with Alzheimer’s Disease - 1993 60 65 70 75 80 85 1.0 0.8 0.6 0.4 0.2 0 Proportion of each genotype unaffected Age at onset 2/3 2/4 3/3 3/4 4/4

5 Global APOE Allele Distribution: Highest e4 (Corbo and Scacchi, Am Hum Genet 1999) E2E3e4 Pygmies0.0570.5360.407 Khoi San 0.0770.5530.370 Papuans0.1450.4860.368 Lapps0.0500.6400.310 Nigerians0.0270.6770.296 Sudanese0.0810.6190.291 Cayapas0.00.7200.280 Polynesian s 0.1100.6300.260 Aborigines0.00.7400.260

6 Global APOE Allele Distribution: Lowest e4 (Corbo and Scacchi, Am Hum Genet 1999) E2E3e4 Sardinians0.0500.8980.052 Greeks0.0540.8780.068 Chinese0.1050.8240.071 Turks0.0610.8600.079 Moroccans0.0650.8500.085 Mayans0.00.9110.089 Spaniards0.0520.8560.091 Italians0.0600.8490.091 Japanese0.0480.8510.101

7 Defining Preclinical MCI (NIA-AA 2011) <

8 Methods Subject selectionSubject selection –APOE Genotyping –Screening tests –APOE and ADC Cohorts Screening testsScreening tests –Medical history –Neurologic Exam –Psychiatric Exam –Folstein MMSE –Hamilton Depression Scale Test Procedures –Neuropsychology –PET (FDG, PiB) –MRI (volumetric, DTI) –Other Longitudinal Study –Every 2 years Statistical Model –Isolate longitudinal change from entry performance –Linear vs quadratic

9 Brain Imaging

10 DTI of 50-70 year old Healthy APOE e4 Carriers (courtesy of Leslie Baxter) (13 e4 carriers vs 18 e4 noncarriers, mean age 60 yrs)

11 PIB PET in Presymptomatic 60 YO’s (Reiman EM et al, PNAS 2009)

12 APOE modifies the association between A  load and cognition in cognitively normal older adults Kantarci et al. Neurology 2012 PiB retention by APOE status 408 cognitively normal adults in their 70s and 80s participated in the population- based Mayo Clinic Study of Aging (MCSA) Pittsburgh compound B (PiB) PET study from January 2009 through March 2011 34% had high amyloid load on PiB PET (PiB positive)

13 APOE modifies the association between A  load and cognition in cognitively normal older adults Kantarci et al. Neurology 2012 Associations between cortical PiB retention and standardized cognitive domain scores according to APOE status Interaction between APOE status and PiB retention (p<0.05; sequential ANOVA): memory function visual-spatial performance global cognition ● APOE ε2 carrier ● APOE ε3 homozygote ● APOE ε4 carrier

14 Neuropathology

15 Neuropathology in APOE e4 Carriers: Tampere Autopsy Series (Finland) (Kok et al, Ann Neurol 2009)

16 AD Pathology in Young APOE e4 Carriers (Kok et al, Ann Neurol 2009) 40% of 50-59 yo e4’s have AP’s40% of 50-59 yo e4’s have NFT’s

17 AD Pathology in Normal Elderly: SHRI Subject Data

18 Neuropsychology APOE e4 effectAPOE e4 effect Superimposed CV risk factor effectsSuperimposed CV risk factor effects Correlates of preclinical frontal amyloidCorrelates of preclinical frontal amyloid

19 NC (n=498) e3/4 (n=238) e4/4 (n=79) p Age (yr) 61.458.456.8<.001 Ed (yr) 15.415.415.4.98 % Female 69.168.968.4.99 % FDR 52.868.887.2<.001 % >1 Epoch 73.173.184.8.08 Duration(yrs)4.75.15.7.01 Longitudinal Modeling of Age-Related Memory Decline and APOE e4 (Normal Controls from APOE and ADC Cohorts)

20 Auditory Verbal Learning Test

21 Onset of diverging memory trajectories (5 year blocks) at similar age as presymptomatic amyloid deposition, MRI, FDG, and PIB changes completes the clinical-pathological pairing that defines Alzheimer’s disease (Caselli RJ et al, NEJM 2009)

22 APOE e4 Carrier Vulnerability Increased memory decline with fatigueIncreased memory decline with fatigue Greater adverse cognitive effects of lorazepamGreater adverse cognitive effects of lorazepam Greater decline in problem solving with anxietyGreater decline in problem solving with anxiety Worse outcomes from neurological injuries: head trauma, cardiac arrest, subarachnoid hemorrhageWorse outcomes from neurological injuries: head trauma, cardiac arrest, subarachnoid hemorrhage Brain radiation and chemotherapy effects less clearBrain radiation and chemotherapy effects less clear

23

24 Aerobic Fitness and Visual Memory Performance Low Risk GroupHigh Risk Group CFT VRT

25 Lorazepam Challenge (Stonnington et al, 2009) Mean Groton Maze Learning Trials Total Errors score over time. (p=.04) Mean AVLT Long Term Percent Recall score over time (p=.005). Solid circles indicate ApoE ε4 carriers (n=18), open circles indicate noncarriers (n=18), solid lines indicate the lorazepam period, and dashed lines indicate the placebo period. Matched pairs, mean age 60 years.

26 Prevalence of CV Risk Factors E4 HMZ E4 HTZ E4 NC Totalp HTN32.4%31.4%37%34.9%.1 DM1.4%5.4%10.3%8.1%.01 CIG28.8%22.1%32%28.7%.01 CHOL33.8%33.5%35.2%34.6%.6 CVany54.8%54.5%60.4%58.1%.27 MI2.7%6.3%7.9%7.0%.23

27 Added Impact of CV Risk Factors (Any of HTN, DM, CHOL, CIG) on e4 Homozygotes P <.001 P = NS Caselli RJ et al, Neurology 2011 (in press)

28 Frontal Lobe Battery Frontal Lobe Battery (APOE Cohort alone) Psychomotor SpeedPsychomotor Speed –Controlled Oral Word Association Test –WAIS-R Digit Symbol Substitution Working MemoryWorking Memory –PASAT 2 and 3 second versions –WAIS-R Mental Arithmetic –WAIS-R Digit Span Problem SolvingProblem Solving –Wisconsin Card Sorting Test

29 NC (n=356) e3/4 (n=194) e4/4 (n=71) p Age (yr) 57.256.055.6.37 Ed (yr) 15.515.715.5.57 % Female 69.470.685.9<.001 % FDR 56.17287.2<.001 % >1 Epoch 74.777.887.3.07 Duration(yrs)6.26.36.6.72 Entry Demographics Caselli RJ et al, Neurology 2011, in press

30 Results: AVLT (Cohorts are Comparable) Current Study: APOE Cohort, n= 621 Prior study: Combined APOE and ADC Cohort, n=815 P=.009P=.03 P=.04 P=.01

31 Results Summary (avlt adjusted) R (w avlt) P P(avlt adj) C/NCHMZ/NCC/NCHMZ/NC COWA.12.78.6.95.81 DSS.21.01.12.03.23 PASAT-2.22.06.004.08.01 PASAT-3.22.02.01.03.03 DigSp.001.49.51.65.75 Arith.035.20.05.33.12 WCST-Ca.23.88.99.91.92 WCST-Er-.28.91.56.80.74 WCST-PE-.25.81.24.99.42

32 Results: Working Memory (PASAT) Linear, p=.06HMZ linear p=.004 Linear, p=.02HMZ linear, p=.01

33 Iowa Gambling Task (age 50 and older) e4 HMZ e4 HTZ e4 NC p n163564 age 63.1 (7.6) 64.9 (7.8) 63.9 (7.6) NS educ 16.3 (2.0) 15.9 (2.5) 16.1 (2.4) NS T-score 49.1 (9.5) 49.7 (9.7) 49.5 (8.8) NS Net Raw 17.0 (27.1) 16.9 (28.3) 16.9 (26.0) NS $$-$264.69-$221.69-$311.72NS

34 Neuropsychology Battery Intellectual DomainsIntellectual Domains –Memory –Executive –Language –Spatial –“General” SubjectiveSubjective –Observer –Self Behavioral –Depression –Anxiety –Paranoia –Somatization –Aggression

35 LinearQuadratic Gene dose AVLT-LTM*.001.009.005 SRT-total free* <.001<.001<.001 CFT recall.25.42.44 VRT correct*.045.004<.001 WCST-Cat.88.16.09 PASAT-3 sec.02.16.10 COWAT.84.38.27 TMT-A.83.72.68 BNT.03.25.88 Token.07.70.60 WAIS-Similar.96.13.14 WAIS-Vocab.008.57.72 JLO.10.56.11 Faces.78.19.25 CFT-copy.43.19.97 WAIS-Blocks.04.45.28

36 LinearQuadratic Gene Dose MMSE.02.41.19 DRS*.001<.001.001 WAIS-Info.01.92.37 FAQ.09.04.06 Observer.27.29.08 Self.02.06.33 Ham-D.09.31.72 Beck.26.96.89 PAI-Depress.51.07.17 PAI-Anxiety.06.64.75 PAI-Paranoia.18.04.12 PAI-Aggress.96.35.49 PAI-Neg Image.29.17.46

37 Memory

38 Preclinical Battery (age 50-65) NCn=258HTZn=110HMZn=59P (NC v HMZ) Age 57.2 (4.6) 57.4 (4.3) 56.2 (4.9).15 Education 15.6 (2.3) 16.1 (2.4) 15.8 (2.4).53 AVLT-LTM 9.6 (3.1) 9.2 (3.4) 9.8 (3.5).72 SRT-free 87.8 (11.0) 88.4 (10.7) 88.0 (10.2).95 VRT 7.0 (1.8) 7.0 (1.9) 6.6 (1.9).10 DRS 140.9 (3.0) 140.8 (2.6) 141.4 (2.3).34

39 Summary Presymptomatic neuropathology, neuroimaging, and neuropsychological changes in genetically predisposed individuals define and characterize preclinical stage Alzheimer’s diseasePresymptomatic neuropathology, neuroimaging, and neuropsychological changes in genetically predisposed individuals define and characterize preclinical stage Alzheimer’s disease Preclinical stage AD begins in APOE e4 carriers on average during our 50’s with a clinical lag time of 10-15 years.Preclinical stage AD begins in APOE e4 carriers on average during our 50’s with a clinical lag time of 10-15 years. Stress such as CV risk factors, medications, fatigue, and anxiety as well as physical fitness have a greater impact on e4 carriers (especially homozygotes) than on e4 noncarriersStress such as CV risk factors, medications, fatigue, and anxiety as well as physical fitness have a greater impact on e4 carriers (especially homozygotes) than on e4 noncarriers Despite preclinical frontal amyloid deposition, the earliest neuropsychological change reflects medial temporal dysfunction likely due to NFT pathologyDespite preclinical frontal amyloid deposition, the earliest neuropsychological change reflects medial temporal dysfunction likely due to NFT pathology Despite longitudinal declines on memory sensitive measures, cross sectional comparisons using these same tests fail to distinguish preclinical AD from controlsDespite longitudinal declines on memory sensitive measures, cross sectional comparisons using these same tests fail to distinguish preclinical AD from controls

40 APOE Collaborators Banner/Good SamaritanBanner/Good Samaritan Eric M. Reiman, MD*Eric M. Reiman, MD* Kewei Chen, PhDKewei Chen, PhD Adam Fleisher, MDAdam Fleisher, MD Anita PalantAnita Palant Dan BandyDan Bandy ASUASU Graciela Gonzalez, PhDGraciela Gonzalez, PhD Mayo Clinic JacksonvilleMayo Clinic Jacksonville Rosa Rademakers, PhDRosa Rademakers, PhD University of ArizonaUniversity of Arizona Alfred Kaszniak, PhDAlfred Kaszniak, PhD Geoffrey Ahern, MD, PhDGeoffrey Ahern, MD, PhD Stephen Rapcsak, MDStephen Rapcsak, MD Duke University Allen Roses, MDAllen Roses, MD Ann Saunders, PhDAnn Saunders, PhD Mike Lutz, PhDMike Lutz, PhD TGen Matt Huentleman, PhD Barrow Neurological Institute Leslie Baxter, PhD Jiong Shi, MD Sun Health Research Institute Marwan Sabbagh, MD Thomas Beach, MD Paul Coleman, PhD Mayo Clinic Arizona Dona Locke, PhD Amylou Dueck, PhD Sandra Yee-Benedetto, MA Bruce Henslin Jessie Jacobsen Marci Zomok, RN Charlene Snyder, DNP Bryan Woodruff, MD UCSF Yadong Huang, PhD Nga Bien-Ly, PhD Aubrey Bernardo, PhD


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