Progression of MCI
What To Tell Your Patients

                 Should we worry about mild memory problems?


Alex Mitchel...
Healthy
                                      (older)
            Healthy




Comment:

This was the original, simple
view...
The Natural History of Dementia
                   (Brain Volume / Intracranial Volume)



                               ...
Healthy

     Healthy


                 Memory
                Problems
                                  MCI
           ...
Healthy
                                                            (resilient)
     Healthy

                            ...
Proportion meta-analysis plot [random effects]


Reversible Dementia                    Bayer et al,201987

              ...
Simple Definition Peterson (Mayo Defn) 1997/1999/2001

      1. Subjective Memory complaints
             Spontaneous or a...
What is the Risk of Dementia in MCI?
Comment:

Probably the first attempt to
define the annual conversion
rate (ACR) in MCI from 1993
Progression, Peterson, 1999

              MCI → AD 12%/yr
    100

      90

      80

      70
                         ...
100                                                                                                0
                     ...
Weakness in Model?

• Problems
  – 1-2% Die per year
  – 2-5% Recover per year
  – 10-20% Lost to follow-up


• Need
  – I...
Pooled Analysis - Methods
•   Focus on robust studies   Type        Dementia   AD    N=
    – Follow-up 3yrs+
            ...
Long Term Studies 5yrs+


Annual Rate of Conversion (%)
12


                                               Hansson et al ...
ACR
20
                 Medium+Long Term Studies 3yrs+
18


16


14


12


10


 8


                                     ...
Long Term Studies 3yrs+
                                                                           ACR to AD

            ...
100
                                                                                                                  8

 ...
MCI Concept as a “Predictor Test”
MCI in Clinical Practice
Cache County Study – Clinical Value of MCI

          Develop     No Dementia
          Dementia




MCI       55         ...
1



0.9       Post-test Probability
                                  Baseline Probability    MCI+    MCI-

0.8



0.7


...
P-Tau and MCI

               Develop    No Dementia
               Dementia




 MCI with P-   132        78            6...
1.00




           Post-test Probability
                                         MCI+ P-tau+

0.90                      ...
Summary

• MCI is not a single disease but a syndrome of convenience

• People with and without MCI may or may not decline...
RCPsych09 - Progression of Mild Cognitive Impairment - What To Tell Your Patients (June09)
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RCPsych09 - Progression of Mild Cognitive Impairment - What To Tell Your Patients (June09)

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This is a short 20min presentation on the risk of progression of mild cognitive impairment presented at the Royal College of Psychiatrists June 2009 as invited speaker.

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RCPsych09 - Progression of Mild Cognitive Impairment - What To Tell Your Patients (June09)

  1. 1. Progression of MCI What To Tell Your Patients Should we worry about mild memory problems? Alex Mitchell Srini Malladi Moj Feshki Sujeeve Sanmaganatham RCPsych AGM 2009
  2. 2. Healthy (older) Healthy Comment: This was the original, simple view of cognitive impairment Dementia in later life
  3. 3. The Natural History of Dementia (Brain Volume / Intracranial Volume) 90% Pathological Burden PRE-SYMPTOMATIC 30 MMSE Diagnosis PRE-CLINICAL 85% Mild Cognitive Impairment 80% 23v24 CLINICAL Disease Severity Mild Dementia 75% 20v21 Moderate Dementia 70% 11v12 Death Severe Dementia 9v10 T-10 T-5 T T+5 T+ 0 10 Time in Years
  4. 4. Healthy Healthy Memory Problems MCI With SMC FTD Comment: This is a more sophisticated view taking into account grades of cognitive decline Dementia VaD from the previous slide AD LBD Mixed
  5. 5. Healthy (resilient) Healthy No MCI Memory but SMC Problems MCI With SMC FTD Comment: This is an advanced view stratifying for subject and objective cognitive problems. Dementia VaD The proportion of people with “reversible dementia” was unclear…..now shown over AD LBD Mixed
  6. 6. Proportion meta-analysis plot [random effects] Reversible Dementia Bayer et al,201987 Cunha et al,301990 0.3462 (0.2420, 0.4624) 0.2364 (0.1606, 0.3268) Freter et al,491998 0.2296 (0.1727, 0.2949) Walstra et al,481997 0.1953 (0.1384, 0.2631) Roberts and Caird,321990 0.1818 (0.1372, 0.2337) • 32 Studies Massoud et al,582000 0.1475 (0.0698, 0.2617) Katzman et al,281989 0.1250 (0.0518, 0.2407) • 4100 cases of dementia Liu HC et al,351991 0.1091 (0.0577, 0.1828) Hogh et al,541999 0.1038 (0.0637, 0.1574) Erkinjuntti et al,211987 0.1011 (0.0620, 0.1533) McMurdo et al,391993 0.0851 (0.0237, 0.2038) Liu CK et al,381992 0.0814 (0.0334, 0.1605) Ames et al,371992 0.0811 (0.0303, 0.1682) Nitrini et al,421995 0.0800 (0.0352, 0.1516) Farina et al,531999 0.0718 (0.0475, 0.1035) Skoog et al,401993 0.0544 (0.0238, 0.1044) Varga et al,361991 0.0533 (0.0246, 0.0987) Livingston et al,311990 0.0465 (0.0057, 0.1581) Sahadevan et al,551999 0.0400 (0.0110, 0.0993) Ogunniyi et al,511998 0.0390 (0.0081, 0.1097) Thal et al,251988 0.0387 (0.0208, 0.0653) Van der Cammen et al,241987 0.0303 (0.0008, 0.1576) Hedner et al,221987 0.0290 (0.0035, 0.1008) Evans et al,271989 0.0273 (0.0057, 0.0776) Chui and Zhang,461997 0.0273 (0.0057, 0.0776) Burke et al,572000m 0.0270 (0.0007, 0.1416) Von Strauss et al,561999 0.0168 (0.0062, 0.0361) Liu CK et al,501998 0.0167 (0.0004, 0.0894) White et al,441996 0.0133 (0.0027, 0.0383) Philpot and Levy,231987 0.0000 (0.0000, 0.0698) Brodaty et al,291990 0.0000 (0.0000, 0.0342) Kua et al,471997 0.0000 (0.0000, 0.0787) combined 0.0733 (0.0505, 0.0998) 0.0 0.2 0.4 0.6 proportion (95% confidence interval)
  7. 7. Simple Definition Peterson (Mayo Defn) 1997/1999/2001 1. Subjective Memory complaints Spontaneous or affirmed? 2. Normal activities of daily living Normal or near normal? 3. Memory impaired for age 1.5SD? 4. No dementia Questionable dementia? Winblad B, Palmer K, Kivipelto M, et al. Mild cognitive impairment—beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med 2004;256:240–6. Portet F, Ousset PJ, Visser PJ, Frisoni GB, Nobili F, Scheltens P, Vellas B, Touchon J . Mild cognitive impairment (MCI) in medical practice: a critical review of the concept and new diagnostic procedure. Report of the MCI Working Group of the European Consortium on Alzheimer's Disease. Journal Of Neurology Neurosurgery And Psychiatry 2006;77 (6): 714-718 .
  8. 8. What is the Risk of Dementia in MCI?
  9. 9. Comment: Probably the first attempt to define the annual conversion rate (ACR) in MCI from 1993
  10. 10. Progression, Peterson, 1999 MCI → AD 12%/yr 100 90 80 70 Control → AD 1-2%/yr 60 100 50 90 Initial 12 24 36 48 exam Months 80 70 60 50 Initial 12 24 36 48 exam Months Petersen RC et al: Arch Neurol 56:303, 1999
  11. 11. 100 0 4 16 90 28 80 40 52 70 64 76 60 88 50 100 40 Comment: 30 Summary of the Petersen (Mayo) clinic model of linear 20 decline approximating 12% per annum. 10 0 Baseline Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Crude Mayo MCI Model Extrapolation
  12. 12. Weakness in Model? • Problems – 1-2% Die per year – 2-5% Recover per year – 10-20% Lost to follow-up • Need – Inception vs Completer studies – Long term studies – Class and setting stratified
  13. 13. Pooled Analysis - Methods • Focus on robust studies Type Dementia AD N= – Follow-up 3yrs+ Classical 10x 17x 2511 – Sample n > 50 Partial 12x 9x 4644 • Expecting ?20 papers CDR 2x 10x 902 – 65 studies CIND 5x 2x 2308 – 15 long term – 41 medium and long AACD 6x 4x 1392 – Sample = 11,756 Comment: Our attempt to redefine progression in MCI
  14. 14. Long Term Studies 5yrs+ Annual Rate of Conversion (%) 12 Hansson et al (2007) 10 Larrieu et al (2002) Bozoki et al (2001) 8 Dickerson et al (2007) Aggarwal et al (2005) Visser & Verhey (2008) 6 Busse et al (2006) Grober et al (2000) Visser et al (2006) Devanand et al (2007) Annerbo et al (2006) Ishikawa & Ikeda (2007) 4 Hogan & Ebly (2000) Ganguli et al (2004) 2 Tyas et al (2004) Years of Observation 0 4 5 6 7 8 9 10 Triangle = Specialist Centres (clinical) Square = Community Studies (non-clinical)
  15. 15. ACR 20 Medium+Long Term Studies 3yrs+ 18 16 14 12 10 8 y = -5.9607Ln(x) + 16.633 6 R2 = 0.1857 4 2 Years of Observation 0 2 3 4 5 6 7 8 9 10 Triangle = Dementia Square = Alzheimer’s disease
  16. 16. Long Term Studies 3yrs+ ACR to AD All 0.10 Specialist Settings 0.09 0.09 0.09 0.09 0.08 0.08 0.07 0.07 0.06 0.06 0.05 0.05 0.04 0.04 0.04 0.04 0.03 0.02 0.01 0.00 Classical MCI Partial MCI CDR=0.5 CIND AACD
  17. 17. 100 8 90 18 MCI-Stable 24 Recovered 31 37 20 80 Died 43 50 Dementia 57 22 70 65 19 74 17 60 16 85 14 10 9 50 100 12 8 10 7 6 40 8 5 6 4 30 3 4 20 2 2 1 10 0 0 Baseline Year 1 Year 2 Year 3 Year 4 Year 5 Year 6 Year 7 Year 8 Year 9 Year 10 Year 15 Advanced All Case MCI Model Extrapolation
  18. 18. MCI Concept as a “Predictor Test” MCI in Clinical Practice
  19. 19. Cache County Study – Clinical Value of MCI Develop No Dementia Dementia MCI 55 65 45.8% PPV No MCI 104 3042 96.7% NPV 34% (se) 98% (Sp) Prevalence = 5%
  20. 20. 1 0.9 Post-test Probability Baseline Probability MCI+ MCI- 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 Pre-test Probability 0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
  21. 21. P-Tau and MCI Develop No Dementia Dementia MCI with P- 132 78 63% PPV Tau No P-tau 31 147 83% NPV 163 225 Prevalence = 5% 81% (Se) 65% (Sp)
  22. 22. 1.00 Post-test Probability MCI+ P-tau+ 0.90 MCI+ P-Tau- Baseline Probability MCI+ 0.80 MCI- 0.70 0.60 0.50 0.40 0.30 0.20 0.10 Pre-test Probability 0.00 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1
  23. 23. Summary • MCI is not a single disease but a syndrome of convenience • People with and without MCI may or may not decline • The risk of dementia has been over-simplified to 10-15% ACR • The actual risk of decline is about half this • However other risks including early mortality can occur • Further work is needed to map risks in SMC without MCI.

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