Geriatric Grand Rounds

Transcription

1 Geriatric Grand Rounds Tuesday, January 29, :00 noon Dr. Bill Black Auditorium Glenrose Rehabilitation Hospital Cardiovascular Risks Factors and Dementia Christian Bocti,, MD, FRCP(C) Clinical Associate Professor, University of Montreal Division of Neurology,, Maisonneuve-Rosemont Hospital January 2008 To receive the poster, and handouts via , subscribe to our ing list at our web site Disclosure of Potential Conflict of Interest Speaker s s Bureau: Janssen-Ortho, Pfizer,, Novartis, Bristol-Myers Myers- Squibb, Merck-Frosst Advisory Boards Janssen-Ortho, Pfizer Learning objectives : To examine the emerging link between cognitive disorders and cardiovascular risk factors. To review the most current clinical concepts of vascular cognitive impairment and mixed dementia (AD+CVD). To review the highlights from the Third Canadian Consensus Conference on Dementia. To discuss optimal prevention and treatment strategies for patients with dementia associated with cerebrovascular disease.

2 Vascular Dementia: Multi-Infarct Dementia The Heart The Brain Source: S Salloway Multi-infarct dementia: multiple strokes Segmented MRI of the brain showing multiple strokes (top) Pathology showing ischemic infarct: neuronal loss, gliosis(bottom) S Black, SHC & UofT Additive (synergistic?) effects of AD and CVD Prevalence of post-stroke stroke dementia At 3 months : 23-55% (vs 3% in controls) At one year: 11-31% Predictive factors: Volume of stroke Medial temporal atrophy White matter changes Pre-existing existing HTN Older age Low education Prior stroke Diabetes AF Snaphaan L, de Leeuw FE. Stroke. 2007;38: ; Tatemichi 1992; Pohjasvaara 1997

3 Post- stroke Dementia Cognitive impairment increased long term dependence and was associated with higher mortality (61% vs. 25%) Tatemichi et al, 1992; Desmond et al, 2002 Vascular Dementia: An evolving concept 1. Vascular Dementia: the traditional definition of multi-infarct infarct dementia (MID) greatly underestimates the global impact of cerebrovascular disease (CVD) on cognition and behaviour. 2. Most current criteria are based on this view of MID and thus do not lead to effective treatment strategies for the majority of patients with CVD and cognitive disorders NINDS-AIREN criteria for VaD Decline in memory + intellectual abilities (2 domains) Must interfere with patient functioning independently of physical defects Evidence for cerebrovascular disease (CVD) from Neuroimaging (high interobserver variability) Physical examination Possible or probable relationship between dementia and CVD (possible = 3 groups) Investigator assessment based on temporal relationship of dementia to the cerebrovascular event (within 3 months), and other factors Roman GC, et al. Neurology 1993;43:250-60; van Straaten ECW et al. Stroke 2003 Vascular Dementia: Lack of sensitivity of criteria CIVIC: : a C5R study on the diagnosis of VaD Sensitivity / Specificity against clinical diagnosis; CADDTC : 0.24 / 0.98 ICD-10: 0.29 / 0.98 HIS: 0.41 / 0.92 NINDS/AIREN: 0.42 / DSM IV: 0.77 / 0.80 Rockwood et al, CJNS 2003

4 Vascular Dementia: Lack of sensitivity of criteria Neuropathological study of 110 cases 42 % of VaD did not have inaugural stroke 30% of clinically diagnosed VaD cases had significant Alzheimer s s pathology Sensitivity/ specificity of clinical criteria: CADDTC : 0.56 / 0.74 HIS: 0.56 / 0.66 NINDS/AIREN: 0.58 / 0.73 Bacchetta J et al. Neurobiol Aging SIVD: Subcortical ischemic vascular dementia Extensive white matter hyperintensities on MRI Swartz, Black S&W, U of T SIVD May be the most prevalent form of VCI 76% of patients in a large VaD trial (n=444) had white matter changes (WMC) on imaging 25% had multiple lacunes (non exclusive) 223 of 242 (92%) of those who met NINDS radiological criteria had extensive WMC Scheltens P, Ann NY Acad Sci % of dementia cases in MRC study had evidence of small vessel disease Neuropathology Group MRC CFAS, Lancet 2001 In most autopsy series, mixed dementia (AD/CVD) is the most prevalent In population-based autopsy series: Pure AD: 24-36% Mixed dementia (AD/CVD): 36-45% VaD: 2-16% 2 (Snowdon et al. 1997; Lim et al. 1999; MRC-CFAS CFAS 2001; Knopman et al. 2003)

5 sont requis pour visionner cette image. A new, more inclusive concept: Vascular Cognitive Impairment Spectrum of conditions including: 1) Vascular Cognitive Impairment, No Dementia (VCIND( VCIND) 2) Vascular Dementia Several subtypes: multi-infarct infarct dementia (MID( MID) single strategic infarct subcortical ischemic vascular dementia (SIVD( SIVD) 3) Mixed Alzheimer s s and Cerebrovascular Disease (CVD) Bowler & Hachinski Neurology 1993; O Brien JT et al, Lancet Neurology 2003 VCI Prevalence and Outcomes In the Canadian Study of Health and Aging, the prevalence per 1000 over age 65 was VCIND 26 VaD 15 AD/CVD 9 Overall total VCI was 50/1000 (vs( 51/1000 for AD ) Risk of death within 5 years was similar for AD and VCI (RR 1.8) (Rockwood et al, Neurology 2000) Survival in VaD,, mixed dementia and AD 3 rd Canadian Consensus Conference on Diagnosis and Treatment of Dementia Topic 3 Diagnosis and differential diagnosis of dementia for the primary care practitioner and consultant: clinical aspects QuickTime et un décompresseur TIFF (LZW) The validity of the Vascular Dementia clinical criteria is widely variable. An approach to diagnosis based on all the available evidence (presence of vascular risk factors, clinical course, presence of a prominent dysexecutive syndrome, available imagery) is recommended. Knopman, Continuum Robillard, Alzheimer s & Dementia, 2007

6 Topic 2 - Future directions (13) The proposal to develop new criteria for VCI has merit. The criteria should move away from the models of post-stroke dementia, and multi-infarct dementia. Moreover, they should emphasize opportunities for prevention of impairment that arises as a consequence of potentially modifiable cerebrovascular disease, even though cognitive impairment has been under-recognized as a manifestation of target organ damage. Screening batteries for VCI Differences with AD Rockwood et al. Alzheimer s & Dementia, 2007 Cognitive Profile in VCI vs AD MEMORY LOSS IS KEY IN AD EXECUTIVE DYSFUNCTION IS KEY IN VaD initiating, planning, organization, attention, problem solving There can be a memory disorder in VaD,, but it is not prominent: recall helped with cues MMSE is not sensitive to executive dysfunction MoCA One page 30 points 10 minutes Sensitivity for MCI: 90% Specificity for MCI: 87%

7 5-minute protocol : short MoCA 5 words : registration recall recognition Orientation - 6 items «F» words in 1 minute OPTION: add 2 tests Clock drawing «Animals» in 1 minute QuickTime et un décompresseur TIFF (LZW) sont requis pour visionner cette image. HIV Dementia Scale Power C, Selnes OA, Grim JA, McArthur JC 1995 The HIV dementia scale as a screening tool for vascular MCI Sensitivity of the HDS Preventing dementia? MMSE DRS HDS Bocti C, Belleville S, Gauthier S. VASCOG 2007.

8 Common Risk Factors for Cognitive Impairment (VaD( and AD) Age Midlife hypertension (Kivipelto et al 2001; Launer et al 2001) Elevated cholesterol (Kivipelto et al,2001) APOE E4 (Slooter et al, 1997) Homocysteine (Seshadri S et al. NEJM 2002; Dufouil C Ann Neurol 2003) Hypertension and Dementia Honolulu-Asia Aging Study 3703 Japanese-Americans followed for 36 years and reexamined in 1991 for dementia Untreated mid-life hypertension associated with later dementia (VaD or AD): if dbp>90, OR ~4; if sbp>160, OR~4.8 In 243 decedents, sbp > 160 showed low brain weight and more neuritic plaques; dbp > 95 had more hippocampal NFT (LaunerLauner et al and Petrovitch et al, Neurobiol.. Aging, 2000) Hypertension and dementia Study of Osteoporotic Fractures 9700 women 65+; f-up f = 6.8 years 119 had strokes and happened to have pre- post cognitive tests Pre-existing existing HTN was a powerul predictor of cognitve decline following stroke OR=4.07 ( ) 12.1) Elkins JS et al. Neurol ;58(1):68-74 Elkins JS et al. Neurol ;58(1):68-74

9 Hypertension treatment helps to prevent dementia: 1) Syst-Eur Treating hypertension reduces the incidence of dementia - Syst-Eur 2400 patients > age 60, SBP , no dementia Treatment (CCB +/- ACE-I I +/- diuretic) or placebo Median MMSE = 29, f-up f median 2 yrs (up to 4 yrs) Annual MMSE: outcome MMSE < placebo vs 11 treated patients declined (ie( ie vs 3.8 per 1000 patient years) (Forette et al, Lancet 1998) QuickTime et un décompresseur TIFF (non compressé) sont requis pour visionner cette image. Hanon & Forette, 2004 Hypertension treatment helps to prevent dementia: 2) PROGRESS Inclusion: Previous stroke/tia treated with ACE-I I (perindopril( perindopril) ) +/- diuretic (indapamide( indapamide) 6105 randomized; 87% adherence; f-up f 4yrs Absolute reduction of 4% for stroke Reduction of 45% of cognitive decline and 34% of dementia with recurrent stroke. Absolute reduction of cognitive decline: 1.9% Hypertension treatment helps to prevent dementia: 2) PROGRESS QuickTime et un décompresseur TIFF (non compressé) sont requis pour visionner cette image. Tzourio et al., Arch Int Med 2003

10 Statins and dementia pathology Neuropathological burden of AD tangles WAS related to statin use the odds ratio for each unit increase in Braak NFT stage in statin users vs nonusers was 0.44 (95% CI: 0.20 to 0.95) Li et al. Neurology 2007 WAS NOT related to statin use Statin use any time prior to death (17.9%) was not related to global AD pathology or infarctions. Arvanitakis et al. Neurology 2008 Statins and Dementia Risk CSHA-2: Comparison of 492 new dementia cases to 823 controls. Lipid-lowering agents associated with lower risk of AD in those aged 65-79, after correcting for sex, education, health rating, to 0.26 ( ).88) Rockwood et al, Arch Neur,, 2002) US VA study with 700,000 subjects taking simvastatin and over 50,000 subjects taking atorvastatin aged >64 years. Hazard ratio for incident dementia for simvastatin is 0.46 (CI , p < ) Wolozin et al. BMC Med 2007 Statins and CIND Risk Case control study from the Canadian Study of Health and Aging, cases (n = 347) had developed CIND and controls (n = 693) had no cognitive impairment. Statin use was associated with a lower odds of incident CIND in those <80 years of age (OR 0.37; 95% CI ) but not for those aged above 80 years (OR 0.56; 95% CI ). Clinical evidence consistent with a cholinergic deficit in VaD Cholinergic markers in VaD patients 1-3 ChAT AChE activity ACh in CSF of VaD patients Correlates with behavioral symptoms 4 Vascular lesion involvement of cholinergic pathways: 5 not present in controlsc moderate to severe in 25% of AD patients moderate to severe in 66% of VaD D patients Rockwood Perry EK, et al. J Neurol Sci 1977;34: Wallin A, Gottfries CG. Pharmacopsychiatry 1990;23: Kalaria RN, Ballard CG, Ince PG, et al. Novartis Found Symp 2001;235: Tohgi H, et al. J Neural Transm 1996;103: Swartz RH, Sahlas DJ, Black SE. Journal of Stroke and CerebroVascular Diseases, 2003.

11 Trajectories of cholinergic pathways within the cerebral hemispheres of the human brain Visual rating of WMH within cholinergic pathways correlated with DRS scores Selden et al., Brain (1998), 121, Stroke, 2005 Loss of cholinergic pathways in Vascular Dementia ChEI in AD-CVD and VaD Myelin stain in VaD vs Control (upper figure) AChE stain in Control vs VaD vs AD (lower figure) Tomimoto et al DGCD, 2005 Knopman, Dementia Continuum

12 Clinical Studies of ChE Inhibitors in VaD Galantamine Patients with possible AD with CVD or probable VaD (NINDS-AIREN); MMSE Active treatment: n=396; placebo: n=196 Randomized, placebo controlled trial, 6 months Galantamine 24mg showed beneficial effects on cognition, behavioural symptoms and activities of daily living. Results driven by majority who had mixed dementia Adverse events: nausea,vomiting, similar as in AD trials. Clinical Studies of ChE Inhibitors in VaD Donepezil Patients with possible or probable VaD,, with MMSE (n=1219); AD excluded clinically. 2 parallel randomized, placebo controlled trials, 24 weeks Donepezil 5 showed beneficial effects on cognition and global function. (CIBIC+) 10 mg beneficial in cognition and ADLs,, with trend for global function. Adverse events (G-I) & discontinuation rates similar to AD trials for 5 mg, somehat higher for 10 mg. Erkinjuntti T et al. Lancet 2002;359: Black SE et al., Stroke 2003; Wilkinson D et al. Neurology rd Canadian Consensus Conference on Diagnosis and Treatment of Dementia Topic 7: Recommendations Topic 7 Management of dementia with a cerebrovascular component Christian Bocti, MD, FRCPC Chris Frank, MD Sandra Black, MD, FRCPC Alzheimer s & Dementia, Use of cholinesterase inhibitors in dementia due to combined Alzheimer s and Cerebrovascular Disease: There is fair evidence of benefits of small magnitude for galantamine in cognitive, functional, behavioral, and global measures in AD with CVD. Galantamine can be considered a treatment option for mixed Alzheimer s with Cerebrovascular Disease. (Grade B, Level 1) 8. Use of cholinesterase inhibitors in probable/possible vascular dementia using the NINDS-AIREN diagnostic criteria: a) There is insufficient evidence for or against the use of galantamine; (Grade C, Level 1) b) There is fair evidence of benefits of small magnitude for donepezil in cognitive and global outcomes, with less robust benefits on functional measures. Donepezil can be considered a treatment option for Vascular Dementia. (Grade B, Level 1)

13 Conclusions Vascular dementia redefined as VCI: include milder degree of cognitive impairment. Prevention of dementia is theoretically possible: HTN very much undertreated! Using more sensitive screening tests such as the MoCA, or the HDS,, is essential. Some molecules approved for Alzheimer s disease have shown some benefits for mixed dementia (galantamine) and VaD (donepezil) Stroke 2007;38:7-8.