1. Anne Rita Øksengård MD, PhD, Postdoc KI, 091006
The applicability of the proposed new research criteria for AD How useful and valide are these in an clinical setting ? A Swedish Brain Power Initiative
Anne Rita Øksengård
MD, PhD, Postdoc KI,
091006

2. Aims
To compare the clinical criteria for AD based on the traditionel criteria used in everyday clinical dementia diagnostics according to the National guidelines (ICD-10 / DSM-IV) with the Dubois-criteria.
Hypotheses:
1. Could one expect to diagnose AD earlier; in a prodromal phase, using the Duboiscriteria instead of the clinical traditionel criteria in a naturalistic patient sample reffered to an ordinary memory clinic ?
2. Would more of the clinical diagnosed MCI patients get an AD diagnosis if the Dubois-criteria is beeing used ?

4. Dubois et al, Lancet Neurology, 2007

5. Background
The diagnoses of AD according to the ICD 10 / DSM-IV is like a two-step rocket:
Step 1) The criteria for DEMENTIA has to be fullfilled
Obligation:
The symptoms HAVE to interfere with the ADL and /or SOCIAL -function
Step 2) The diagnosing of the cause(s) and ethiology

6. The Memory Clinic, Huddinge, Karolinska University Hospital
App new patients / year. Majority < 65 years with light memory problems. Semi-selected group, however referrals from whole county + hospital referral area giving a heterogenous group according to socio-economic background living standard, education etc.
Dementia team: nurses, geriatricians, neurologists, psychiatrists, neuropsychologists, speech-therapist, social worker, work-therapist [Standard assessment and consensus diagnostic meetings ]

7. Diagnostic procedures according to Evidence Based Medicine
”sources”
Clinical history
included history
from relatives
Clinical criteria and consensus
ICD 10/ DSM-IV/
NINCDS
MCI-consensus
Clinical
Diagnosis
Medical
examination
EEG ?
According to this introduction , I will like to remind you of this flow chart earlier shown by prof Wahlund….. And I will for the rest of my talk focus elaborateon the evidence for and role of functional imaging methods in dementia diagnostics.
Blood / CSF
Neuroimaging
Cognitive tests
MMSE, RAVLT
MRI / SPECT / PET
Treatment /Care

8. All dementia diagnostics depends on:
The physician’s individuel capacity to intergrate their own clinical experience with EBM and transfering this knowledge to each individuel patient at any level of the health care system; at the speciallistlevel such as a memory clinic with selected referred patients or in General Pratice where the prevalence of dementia is much lower.
Exquisit knowledge about HOW the diagnostic tools functions in the different populations / settings according to the actual prevalence of the disease.
Ref: Oksengard, AR; Winblad B. Current Opinion in Psychiatry, 2004

9. METHODS
ALL available patient journals between retrospectively examined (N= 600)
A random sample of 150 patients retrospectively re-diagnosed by two experienced clinicians within SBP workforce (KN + ARÖ) with inter-rater reliability of 0.69
All relevant clinical information, but NOT the results of RAVLT and biomarkers (MRI, SPECT / PET, CSF) NOR Apo E were available for the clinicians .
Inclusion criteria: Having performed at least RAVLT and one other diagnostic test.
Exclusion criteria: Cerebral tumor and bleeding.

10. Clinical diagnoses after re-diagnosing: N=150 Mean MMT = 26 p, Mean age 59 år (range 41-78) 66% women

11. Case 1, man 59 y Referral from ”Privat preventive medical clinic”:
59 year old man, works as an IT-consultant. Married, two teen-age daughters living at home. Non-insulin craving diabetes since Treated against hypertension and depression.
Heredity: mum with AD, died in her 70-ties.
- Since 1-1/12 years worsening of subjective memory complaints. More difficult to remember names and looses his words when speeking in meetings; objectievly noticed by his co-workers who also say that he is not functioning as previously; he works slower, has difficulties in completing projects, misses meetings, looses coustumers because he is doing mistakes. Periodically depressed
- According to his wife he often forgets what they have been doing together and can not speech about it shortly after. He has also been lost when travelling abroad and this worries her. No problems in well-known surroundings. He has quit sailing, do not want to go to the assamblies in Rotary anymore. Drives without anyproblems.
Physical examination: ok. MMSE = 26 /30 (year: -1 p, recall: - 2 p, substraction: -1 p). Slightly depressed. Normal bloodtests. Cerebral CT normal.
WHAT DIAGNOSE ??? ? ..

12. Dementia : Definition according to ICD-10
Objective memory loss: delayed recall
Reduction of at least one additive cognitive function (abstact thinking, attention, performing dual tasks etc..)
Obvoius reduction compared to previous level of functioning
No confusion
Reduction of motivation / social ability / emontional control
Symptoms standing for at least 6 months

13. Dubois et al, Neurology, 2007

14. Rey Auditory Verbal Learning Test RAVLT
Dubois- criteria
Core diagnostic criteria:
A 1) Presence of early and significant episodic memory impairment that objectively progresses over 6 mts
A 2) TEST: Ex. RAVLT delayed recall: Cut-off: of 15
A 3) ONLY reduction in delayed recalll or other cognitive problems

15. Case 1, man 59 y Rey Auditory Verbal Learning Test:
I. CORE criteria Dubois: A) Reduction in episodic memory function and delayed recall:
Rey Auditory Verbal Learning Test:
- RAVLT total: =36 / 75
- RAVLT delayed recall: 5/15 (cut-off 6 / 7)
Ref:Andresson C et al, Demnt Geriatr Cogn Disord, 2007.
II. ADDITIVE/ Supportive features: Biomarkers:
B) MRI: Slight medial temporal lobe atrophy, grade 2 /4 enligt Scheltens skala (ref >2)
Ref: Scheltens P et al. J Neurol Neurosurg Psychiatr,
C) Lumbal Punction: CSF: Beta-amyloid = 450 (ref<427ng/L), fosfo-tau = 73 (ref >74ng/L) och total tau = 438 (ref>445 ng/L).
Ref: Wallin Å et al. Demt Geriatr Cogn Disorder, 2006.
D) SPECT: slightly reduced CBF in the left temporal and parietal lobe; grad 2 / 4 according to BRASS (pat >2).
Ref: Radau PE et al. Proc.SPIE Image, 2000.
EEG showing slow waves, no spikes
APO Epsilon4 homozygot
DIAGNOSis according to Dubois ????

16. Medial Temporallobsatrofi
Duboiskriteriarna
Supportive feature B:
Reduced volume hippocampus and /or addjecent areas om MRI.

17. CSF Dubois-criteria Supportive feature C: - Total Tau - Phospho Tau
CSF pathology: at least ONE biomarker abnormal:
- Total Tau
- Phospho Tau
- Aβ - 42
Age and gender normative data ?

18. Specific pattern on functional neuroimaging
Dubois-criteria
Supportive feature D:
Reduction in metabolism; CBF / glucose:
SPECT
SPECT vs PET ?

19. Valid reference values ? ?
Background:
MRI: Scheltens et al: 1992 ??? What about younger subjects in early phase of cognitve decline ? Is everything that is NOT NORMAL really an expression of an ongoing neurodegenerative process ???
CSF: huge differences in cut-off values and refererence standards from lab to lab. Harmonization protocols is needed !
SPECT: semi-quantitative – what is normal ???
PET: no access in a normal clinical setting

20. In clinical routine diagnostic work-up not ALL procedures are fullfilled:
Tests/
Patients
(N)
RAVLT
MTA
CBF
CSF
Total-tau
A-beta 42
Phospho-tau
150
110
122
117 63 54 46
RAVLT = Rey Auditory Verbal Learning Test MTA = Medial Temporal lobe Atrophy CBF = Cerebral Blood Flow CSF = Cerebro Spinal Fluid

21. Correlation between ”raw”clinical diagnosis and pathological boimarkers
Pathological marker
MCI
N = 78 AD
N = 23
RAVLT 21 22
MTA 3 4
CBF 12
CSF all markers 9
Total
4 / 21
12 / 22

22. Are we ready to use the Duboiscriteria in our daily clinical work ?
Oksengard AR, Cavallin L, Axelsson R , Andresson C, Nägga K, Winblad B, Jönhagen M E, Wahlund LO.
“The applicability of the proposed new research criteria for Alzheimer’s disease in a naturalistic memory clinic sample. A Swedish Brain Power Inititative to enhance the diagnostic accuracy of dementia work-up “.
Results:
- The Duboiscriteria are valid in 50 % of the AD patients in a highly selected group of clinically diagnosed AD patients.
- Experienced clinicians do valid AD diagnostics without the added information about biomarkers .
- In our group of 78 clinically diagnosed MCI patients; 4 patients would classify as pre-AD patients according to the Duboiscriteria
- MCI patients who might be in a prodromal phase of AD should be identified and be follow-ed up within the frame of a clinical setting.

23. Discussion and conclusion: How should we diagnose dementia ?
Clinically AD =Phenotype
Biochemically AD: Pathological biomarkers = Biotype
Genetically AD=Genotype
Ref: Crister Nilsson, Läkartidningen Nr 20, 2009
Creation and valididation of new methods and new criteria is needed
E.g within SBP Arto Nordlund, Bo Johansson & more
Dementia diseases should be taken care of by multidiciplinary teams in collaboration between primary – and specialist health care
National guidelines – hearing nov 2009; Katarina Nägga
Need for national harmonization on clinical demetia diagnostics
SBP: How to perform clinical demetia diagnostics: national work-shops
SBP: Diagnostic protocol
Harmonzation on a Nordic level : NordForsk + SBP
National guidelines – hearing nov 2009

24. Many thanks to:
Swedish Brain Power in interaction with staff at Huddinge and Malmö Memory Clinic
Collaborators and co-authors:
Lena Cavallin, Neuroradiology, Huddinge
Rimma Axelsson, Nuclear medicine, Huddinge
Christin Andersson, Neuropsychology, Huddinge
Katarina Nägga, MAS, Skåne
Bengt Winblad, NVS, KI
Maria Eriksdotter Jönhagen, NVS, KI
Lars-Olof Wahlund, NVS, KI
National guidelines – hearing nov 2009