Interactions between vascular dementia and Alzheimer’s disease

1. GAL-INT-6The safety and efficacy of galantamine in patients with Vascular dementia orAD with cerebrovascular disease Sean Lilienfeld MD, FCP, MMedJanssen Research Foundation

2. Interactions between vascular dementia and Alzheimer’s disease VaD AD Mixed Erkinjuntti T

3. Reminyl in vascular and mixed dementia: trial inclusion criteria Patients with dementia secondary to cerebrovascular disease (CVD) with or without AD • Probable Vascular dementia according to NINDS-AIREN criteria • Mixed dementia according to NINCDS-ADRDA criteria of possible Alzheimer’s disease with CVD and NINDS-AIREN criteria of possible VaD • MMSE at screening 10–25 and ADAS-Cog score at screening  12 • Positive radiology per NINDS-AIREN criteria

4. Inclusion CriteriaProbable Vascular Dementia (NINDS-AIREN) A. Dementia (decline from previous higher level of functioning): • established by clinical examination and confirmed by neuropsychological test • deficits in two or more areas of cognition • no disturbance of consciousness, delirium, psychosis, severe aphasia, or major sensorimotor impairment precluding neuropsychological testing • absence of systemic disorders or other brain diseases such as Alzheimer’s Disease (EXCEPT CEREBROVASCULAR DISEASE) that could account for the dementia

5. Inclusion CriteriaProbable Vascular Dementia (NINDS-AIREN) B. Cerebrovascular disease: • focal neurologic signs consistent with previous stroke (even with negative stroke history) • evidence of relevant cerebrovascular disease by CT or MRI scan

6. Inclusion CriteriaProbable Vascular Dementia (NINDS-AIREN) C. A relationship must exist between the dementia and the cerebrovascular disease: • onset of dementia within 3 months of a recognised stroke • abrupt deterioration in cognitive functions • fluctuating, stepwise progression of cognitive deficits

7. Inclusion CriteriaMixed Dementia (Possible AD with CVD) • NINCDS-ADRDA criteria for possible Alzheimer's disease and NINDS-AIREN criteria for possible Vascular Dementia • Dementia established by clinical examination and confirmed by neuropsychological test • Deficits in two or more areas of cognition • Progressive worsening of memory and other cognitive functions no disturbance of consciousness • Absence of systemic disorders or other brain diseases (EXCEPT AD and CEREBROVASCULAR DISEASE) that could account for the dementia

8. Inclusion CriteriaMixed Dementia (Possible AD with CVD) • Radiologic evidence (satisfying the NINDS-AIREN radiologic criteria) as documented on a CT or MRI scan less than 12 months old of: • Multiple (2 or more) basal ganglion/white matter infarcts or lacunes and/or • Single strategically placed infarct in angular gyrus/thalamus/basal forebrain/Anterior Cerebral Artery or Posterior Cerebral Artery territory and/or • Extensive periventricular white matter lesions.

9. Exclusion Criteria • Other neurodegenerative disorders • Other causes of cognitive impairment • Relevant medical conditions eg. ulcers, bladder obstruction, severe hepatic, renal, pulmonary, cardiac diseases

10. NINDS-AIREN Radiology • multiple large-vessel infarcts • single strategically placed infarct [angular gyrus, thalamus, basal forebrain, posterior or anterior cerebral artery territory] • multiple basal ganglia and white matter lacunes • extensive periventricular white matter lesions • combinations of these

11. Patient characteristics Placebo Reminyl 24 mg/day (n = 196) (n = 396) Female 46% 48% Mean age (years) 75.2 75.0 Mean MMSE score 20.2 20.7 Diagnosis Mixed dementia 50% 48% Vascular dementia 41% 43% Uncertain per MD 9% 9%

12. ADAS-cog Scores: Placebo patients Over 6 Months Treatment group Combined Placebo (n = 162) Mixed D Placebo (n = 87) Deteriorated 2 Probable VaD Placebo (n = 67) 1 0 Mean change +/- SE in ADAS-cog/11 -1 -2 Improved -3 Baseline 2 3 4 5 1 6 Time (months)

13. ADAS-cog Scores: Placebo patients Over 6 Months Treatment group Mixed D Placebo (n = 87) 3 Deteriorated Probable VaD Placebo (n = 67) 2 1 Mean change +/- SE in ADAS-cog/11 0 -1 Improved -2 Baseline 2 3 4 5 1 6 Time (months) D = 2.2 p = 0.013

14. NPI Scores: Placebo patients Over 6 Months Treatment group Placebo 2 Mixed D Placebo Deteriorated Probable VaD Placebo 1 Mean change (+/- SE) in total NPI 0 -1 Improved -2 Baseline 2 3 4 5 1 6 Time (months)

15. NPI Scores: Placebo patients Over 6 Months Treatment group 2 Mixed D Placebo Deteriorated Probable VaD Placebo 1 Mean change (+/- SE) in total NPI 0 -1 Improved -2 Baseline 2 3 4 5 1 6 D = 0.4 p = 0.43 Time (months)

16. DAD Scores: Placebo patients Over 6 Months Treatment group Placebo Mixed D Placebo 2 Improved Probable VaD Placebo 1 0 -1 Mean change (+/- SE) in total DAD -2 -3 -4 Deteriorated -5 -6 Baseline 2 3 4 5 1 6 Time (months)

17. DAD Scores: Placebo patients Over 6 Months Treatment group Mixed D Placebo Probable VaD Placebo 1 Improved 0 -1 -2 -3 Mean change (+/- SE) in total DAD -4 -5 -6 Deteriorated -7 -8 Baseline 2 3 4 5 1 6 D = 4.7 p = 0.032 Time (months)

18. Efficacy results • ADAS-cog positive • CIBIC-plus positive • NPI positive • DAD positive

19. Conclusions • Using NINDS-AIREN criteria physicians were able to differentiate patients with “probable” vascular dementia and “mixed” dementia • Observed rates of deterioration in a cognitive scale, a neuropsychiatric scale and a functional scale, are different in the 2 placebo groups, thus these patients are indeed different clinical populations

20. Conclusions • Patients with “mixed” dementia deteriorate at rates similar to those seen in clinical trials in patients with probable AD over 6 months whereas patients with probable VaD remain essentially at baseline over 6 months

21. GalantamineSignificantly Improved Both Primary Endpoints and Both Secondary Endpoints • The current efficacy tools are able to detect differences between actively treated and placebo treated patients with a magnitude similar to that seen in trials in patients with AD