Presentation on theme: "Diagnosis and Treatment of Alzheimer Disease and Dementia: Results from the Third Canadian Consensus Conference Dr. Howard Chertkow Sir Mortimer B."— Presentation transcript:
1Diagnosis and Treatment of Alzheimer Disease and Dementia: Results from the Third Canadian Consensus Conference Dr. Howard Chertkow Sir Mortimer B. Davis - Jewish General Hospital Dept. of Clinical Neuroscience; Lady Davis Institute, McGill University
2Pfizer, Janssen, Lundbeck, Servier, Neurochem, Novartis Disclosure StatementHC has been a paid consultant or received honoraria for participation in CME/advisory boards or grant funding from:Pfizer, Janssen, Lundbeck, Servier, Neurochem, Novartis
3ObjectivesTo update current diagnosis and treatments for AD and the dementias across the continuumPrimary Prevention: rationaleMCI : new evidenceMild to Moderate AD: current standards and new approachesModerate to Severe AD: new rx possibilities
4Most asked questions Dementia prevention strategies? What should we do for MCI?When should we use biomarkers to diagnose AD?When should we test genes for AD?When should we stop cholinesterase inhibitors?When should patients stop driving?What do you do for mixed dementia?Where are the drugs to slow/stop AD?
5Any individual with Mild AD should be told to stop driving Any individual with mild AD and MMSE of less than 24 should be told to stop drivingAny individual with impairment in multiple IADLs or a single ADL should be told to stop drivingBecause of anxiety, on-road driving tests are not a fair evaluation of driving ability in a demented individual - neuropsych and clinical testing is better
6Regarding mild cognitive states: MCI and CIND are identical labels (European vs. American Amnestic MCI always leads to Alzheimer DiseaseIn the >65 year population, there are twice as many individuals with CIND as there are with dementiaThe evidence suggests that Donepezil is effective in MCI and should be offered to all MCI patients
7Projected Prevalence of Dementia (per 1,000) 1991 - 2031 800All Dementias700600AD500400300x 2x 3200Doubling of dementia > 2013; trebling > 2030.Assumes no treatment or preventionData used in modeling disease in Canada (POHEM)Vascular10019912001201120212031CSHA Working Group CMAJ 1994; 150:
8Projected Prevalence of AD 300,000 Alzheimer’s Cases Today - > 750,000 Projected Within a Generation850750650150250350450550750500000’sIn Canada, AD affects 5% of people aged > 65 years and 25% of those > 85 years of age. This represents 316,500 cases of AD.Two-thirds of these patients are women and 50% require institutionalized care. By 2030, these numbers are predicted to double.Worldwide, Alzheimer’s Disease International estimates that 12 million people are affected with AD and these numbers can be expected to double by the year 2025.300200020112031Canadian Study of Health & Aging Working Group. CMAJ 1994; 150:
9AD 47% 19% VaD 9% Other Mixed = 10% 3% 2% DLB 2% FTD 5% Feldman et al, 2003: Accord StudyNeuroepidemiology,22;265-74
10Defining Dementia A decline from a previous level of function Demonstrable impairment of memory (DSM-3)Other impairment in at least one of:language (naming)Judgement/frontal lobe functionconstruction/visuospatial functionabstractionpersonalityImpairment is sufficient to interfere with function and Activities of Daily Living.Insidious, and > 6 months (ICD-10)
11Facts about dementia and AD 250,000 dementia cases in Canada778,000 dementia cases by 2031Annual cost = 3.9 billion dollars747/1125 (66%) of dementia cases in CSHA were due to AD95% sporadicIncidence / Prevalence with agePatterson et al., Can J Neurol. Sci 2001Ostbye et al., CMAJ 1994
12Differential Diagnosis of Dementia Other dementiasFrontal lobe dementiaCreutzfeldt-Jakob diseaseCorticobasal degenerationProgressive supranuclear palsyMany others8%Vascular dementiasMulti-infarct dementiaBinswanger’s disease5%Lewy body dementiasParkinson’s disease Diffuse Lewy body disease Lewy body variant of AD7%Vascular dementiasand AD10%AD and Lewy body dementias5%AD65%There are number of different dementias of which AD is the most common form.Due to the lack of acceptable biological markers, the diagnosis of dementia is primarily clinical. The diagnostic guidelines and criteria are included in the National Institute of Neurological and Communicative Disorders and Stroke—the Alzheimer’s Disease and Related Disorders Association (NINCDS-ADRDA), American Academy of Neurology (AAN), Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV), the International Classification of Diseases (ICD-10) of the World Health Organization (1992), and the Mini-Mental State Examination (MMSE).Accurate diagnosis of dementia that could account for the progressive memory and other cognitive deficits may be often difficult. The first step in the differential diagnosis of dementia is to exclude any reversible dementias, in which the conditions are reversed after proper treatment, ie, vitamin B12, folic acid, or thiamine deficiency, hypothyroidism, or any other systemic causes of symptoms except organic brain syndromes, ie, AIDS-related or alcohol- induced.The other, nonreversible dementias are characterized by similar symptom presentation but are differentiated based on etiology. A common characteristic seen among many of these disorders is the cholinergic deficit with the exception of progressive supranuclear palsy, frontal lobe dementia, and Pick’s disease. In addition, many patients may have multiple etiologies that may explain their dementia, ie, mixed dementia, AD with Lewy bodies.Small GW et al. JAMA. 1997;278:Morris JC. Clin Geriatr Med. 1994;10:
15ACE-inhibitors are the recommended medication to treat vascular and mixed dementia There is no specific medication to treat vascular dementiaThe presence of vascular lesions increases occurrence of clinical dementia by a factor of 2The presence of vascular lesions increases occurrence of clinical dementia by a factor of 20
16Vitamin E should be offered to all memory impaired individuals to slow rate of progression. There is insufficient evidence to offer cholinesterase inhibitors or memantine to mild AD patientsCertain cognitive therapy programs (but not general cognitive stimulation) have been demonstrated to improve symptoms of memory loss and delay progressionCholinesterase inhibitors have proven efficacy at all stages of dementia, and should be carefully considered as therapy
17Third Canadian Consensus Conference on Diagnosis and Treatment of Dementia March 9-11, Hotel Delta President Kennedy Montreal, Quebec
18ProcedureSteering committee of national academic leaders (neurology, geriatric medicine, geriatric psychiatry)Sponsorship by CNS, C5R, CGS, CAGP, CFPC.Funding by CIHR, FRSQ, ASC, sponsoring organizations, and pharma (1/2)8 topics, led by national authorities, with writing committees (42 authors)Literature searches, evidence-based reviewsPreparation of recommendations and background reviewsWeb posting of 203 rec’s, voting by 42 authorsConsensus = 80% approvalDiscussion at meeting of “non-consensus” recommendations, revision, re-voting.147 recommendations reached consensusThese were rated as high, medium, low education priorities by an FP panel.Only high and medium recommendations are presented here.
19Criteria for assigning levels of evidence 1Evidence obtained from at least 1 properly randomized controlled trial.2aEvidence obtained from well-designed controlled trials without randomization.2bEvidence obtained from well-designed cohort or case-control analytic studies, preferably from more than 1 centre or research group.2cEvidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments are included in this category.3Opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees.
20Grades of recommendations CriteriaAThere is good evidence to support this manœuvreBThere is fair evidence to support this manœuvre.CThere is insufficient evidence to recommend for or against this manœuvre, but recommendations may be made on other grounds.DThere is fair evidence to recommend against this procedure.EThere is good evidence to recommend against this procedure.
21Christopher Patterson Topic 1Assessment and management of risk factors, and primary prevention strategiesChristopher PattersonMacMaster UniversityAngela GarciaChris McKnightDessa SadovnikRobin Hsuing
23Cummings, J. L. (2004). "Alzheimer's disease Cummings, J. L. (2004). "Alzheimer's disease." N Engl J Med 351(1):Cummings, J. L. (2004)."Alzheimer's disease.“N Engl J Med 351(1):
24Risk factors for developing AD Definite RiskPutative-RecentPutative-OlderProtectiveagewomendepressionNSAIDSApo E4Low educationHead traumaEstrogen?Family historyVascular factorsalcoholSmoking?MCIHyper-tensionAluminum?
25Pharmacological Approach Vascular Prevention Hypertension:Syst-Eur study (Forette eta al., Lancet, 1998)PROGRESS Study (Perindopril Protection Against Recurrent Stroke Study, Lancet, 2001)SCOPE Study (Study on Cognition and Prognosis in the Elderly, Int Conf ADAD, 2002)Hyperlipidemia (Rockwood et al., Arch Neurol, 2002)Epidemiological data linking use of statins with prevalence of dementia2 intervention studies with negative results (PROSPER, Lancet 2002; MRC/BHF, Lancet 2004)Atrial FibrillationDiabetesSmokingThe presence of cerebral lacunar infarcts Increases the rate of dementia by a factor of 20 strokeSnowdon et al, JAMA (1997), vol. 277,
26Brookmeyer, Gray & Kawas, Am J Publ Health 88 (9), 1337-1342 1998 . The 5/50 plan:Delaying the onset of AD by 5 years would be associated with a reduction in AD prevalence of 50%A modest delay, such as 1 year, would reduce AD/dementia prevalence by 5%.Brookmeyer, Gray & Kawas, Am J Publ Health 88 (9),
27Recommendations Topic 1 There is good evidence to treat systolic hypertension (>160mm) in older individuals. (Level 1, Grade A) In addition to reducing the risk of stroke, the incidence of dementia may be reduced. The target BP should be 140mm or less.While ASA and statin medications following myocardial infarction; antithrombotic treatment for non-valvular atrial fibrillation; and correction of carotid artery stenosis >60% have been shown to reduce the risk of stroke, (Level 1) there is insufficient evidence to recommend for or against these measures for the specific purpose of primary prevention of dementia. (Grade C)While there are many reasons for treating type 2 diabetes, hyperlipidemia and hyperhomocysteinemia, there is insufficient evidence to recommend treatment of these conditions for the specific purpose of reducing the risk of dementia. (Level 2, Grade C)There is insufficient evidence to recommend for or against the prescription of NSAIDs for the sole purpose of reducing the risk of dementia. (Level 2, Grade C)There is good evidence to avoid the use of estrogens alone or together with progestins for the sole purpose of reducing the risk of dementia. (Level 1, Grade E)
28Recommendations6,7,10.While there is insufficient evidence to make a firm recommendation, physicians may advocate for strategies:to reduce head injuryfor greater educationto wear appropriate protection during during administration of pesticides, fumigants.fertilizers and defoliantsThere is insufficient evidence to recommend for or against :supplementation with vitamins E or C for the prevention of dementia (Level 2, Grade C.)[High dose vitamin E (>400 units/day) is associated with excess mortality and should not be prescribed (Level 1, Grade E.)]higher levels of physical or mental activity for the specific purpose of reducing the incidence of dementia.While there is insufficient evidence to make a firm recommendation for the primary prevention of dementia, physicians may choose to advise their patients about the potential advantages of increased consumption of fish, reduced consumption of dietary fat and moderate consumption of wine. (Level 2, Grade C)8, 9.!11.!
29Concept, utility, and management of MCI and CIND Topic 2Concept, utility, and management of MCI and CINDHoward Chertkow, Howard BergmanFadi Massoud, Yves JoannetteZiad Nasreddine, Sylvie Belleville
30Complaints in “Normal Cognitive Aging” SHORT VERSIONEven “normal” people may complain of memor changesProblems include:Trouble concentrating in the presence of distractionDecreased ability to attend multiple channelsDifficulty multi-taskingDifficulty recalling names of acquaintancesSpatial memory problemsSlowing of reaction timeDelayed verbal memory becomes mildly decreasedKey PointsOne of the problems in diagnosing dementia is distinguishing it from “normal” cognitive aging.Even people undergoing “normal” aging (80% of the population) may experience changes in memory after the age of 40.The problems that are commonly listed by people experiencing “normal” cognitive aging include:Trouble concentrating in the presence of distractionDecreased ability to attend to multiple channelsDifficulty multi-taskingDifficulty recalling names of people who are acquaintancesSpatial memory problemsSlowing of reaction timeDelayed verbal memory becomes mildly decreasedThese individuals will score "normal" for age and education on neuropsychological tests.ReferencesJonker C et al. Memory complaints and memory impairment in older individuals. J Am Geriatr Soc 1996;44:44-49.Derouesne C et al. Memory complaints in the elderly: a study of 367 community-dwelling individuals from 50 to 80 years old. Arch Gerontol Geriatr Suppl 1989;1:Jonker C et al. J Am Geriatr Soc, 1996; Derouesne C et al. Arch Gerontol Geriatr Suppl, 1989.
31CIND Prevalence Over Age 65 Dementia(n = 861)(n = 1132)65 to 74yrs11.0%2.4%75 to 84yrs24.0%11.2%>85yrs30.3%34.7%Overall16.8%8.0%Graham J et al: Lancet 349: , 1997
33Model of Continuum of Cognition with Aging NormalMild cognitive impairmentProbable ADFunctionDementiaDefinite AD/DementiaAgeJacob we will need to put in 2 animation buttons with dotted rectanglesFirst dotted rectangle will be around normal and will fade out at the next mouse clickSecond dotted rectangle around normal and mild cognitive impairment (roughly half way down between the MCI and probable AD line of decline
34Mild Cognitive Impairment Memory complaintsMemory impaired for age ( generally 1.5 SD)General cognitive function: normal for ageNormal activities of daily livingNot meeting dementia criteriaClinical Dementia Rating Score of 0.5Petersen RC et al Arch Neurol 56(3)
35Recommendations (18)Physicians should be aware that most dementias may be proceeded by a recognizable phase of mild cognitive decline. Physicians should be familiar with the concept of mild cognitive impairment (or cognitive impairment not dementia) as high risk state for decline and dementiaThere is currently inadequate evidence to recommend one term or label (MCI, CIND) over another.There is inadequate evidence to advise MCI patients and their families that the patient is already showing signs of dementia, or to treat MCI as equivalent to dementia. (Recommendation grade C, Evidence level II)There is fair evidence that physicians should closely monitor individuals who have MCI or CIND, because of the known increased risk of both dementia and death that has been documented. (Recommendation grade B, Evidence level II)
36Detecting MCI: The MoCA SHORT VERSIONMontreal Cognitive Assessment (MoCA), a cognitive screening tool for detection of MCI30-point scaleMCI = MOCA <26Using a cut-off score <26 provides sensitivity of 80%, and specificity of 91% to distinguish MCI from normalAvailable free in English and French atKey PointsThe Montreal Cognitive assessment (MoCA) is a brief cognitive screening tool with high sensitivity and specificity for detecting MCI as currently conceptualized even in patients performing in the normal range on the MMSE.In a study evaluating its effectiveness in diagnosing MCI, detected most MCI patients, and outperformed the MMSE by a wide margin.It is a 30-point scale.Using a cut-off score of <26 provides sensitivity was 80% to detect MCI, and specificity of 91% to distinguish MCI from normal.The MoCA is a screening tool providing an indication of abnormal cognitive performance. To diagnose MCI vs. dementia, assessment of functional abilities is necessary. It is always safest to monitor patients over time at several visits before concluding that MCI or dementia are present.ReferencesNasreddine ZS et al. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53(4):Nasreddine et al. ,JAGS,, 2005.,vol 53,
37RecommendationsIn cases where there is suspicion of cognitive impairment or concern about the patient’s cognitive status, and the MMSE score is in the “normal” range (24-30), tests such as the MoCA, DemTect, or CMC, could be administered. These would help to demonstrate objective cognitive loss. (Level II, Grade B)There is good evidence that the addition of in- depth neuropsychological testing can be recommended to aid in confirmation of the diagnosis. (Level 1, Grade A)
38Recommendations – Non pharmacological therapies The evidence at the present time is insufficient to conclude that organized cognitive intervention is beneficial to preventing progression in MCI or warrants prescription. (Recommendation Grade C, Evidence level I).There is fair evidence that physicians and therapists should promote engagement in cognitive activity as part of an overall "healthy lifestyle" formulation for elderly individuals with and without memory loss. (Recommendation Grade B, Evidence level I).There is fair evidence that physicians and therapists should promote physical activity at an intensity level that is adapted to the persons' overall physical capacities, as part of a "healthy lifestyle" for older individuals with and without memory loss. (Recommendation Grade B, evidence level II).Current evidence is insufficient to conclude that a specific program of physical training warrants prescription in MCI patients in order to prevent progression to dementia. (Recommendation Grade C, evidence level III).
39Common Risk Factors for Developing MCI SHORT VERSIONElevated systolic BP1Hypertension2Elevated cholesterol in mid-life3Low level of education4African-American descent4Cerebral infarcts evident on MRI4Depression4Mechanisms may be vascular atherosclerotic mechanisms, or directly through hastening the pathophysiology of AD.Key PointsRecognizing risk factors can help lead to the identification of patients with MCI and promoting prevention.Common risk factors for developing MCI include:Elevated systolic BP1Hypertension2Elevated cholesterol in mid-life3Low level of education4African-American descent4Cerebral infarcts evident on MRI4Depression4The risk factors listed above are similar to those for dementiaThe mechanisms behind MCI development are heterogenous and still poorly understood. Effects may be mediated via vascular atherosclerotic mechanisms, the metabolism of amyloid, other pathological mechanisms of AD, or a mixture.ReferencesLauner LJ et al. The association between midlife blood pressure levels and late-life cognitive function. The Honolulu-Asia Aging Study. JAMA 1995;274(23):Carmelli D et al. Midlife cardiovascular risk factors, ApoE, and cognitive decline in elderly male twins. Neurology 1998;50(6):Kivipelto M et al. Midlife vascular risk factors and late-life mild cognitive impairment: A population-based study. Neurology 2001;56(12):Lopez OL et al. Risk factors for mild cognitive impairment in the Cardiovascular Health Study Cognition Study: part 2. Arch Neurol 2003;60(10):1 Launer LJ et al. JAMA, 1995; 2 Carmelli D et al. Neurology, 1998;3 Kivipelto M et al. Neurology, 2001; 4 Lopez OL et al. Arch Neurol, 2003.
41Are cholinergic deficits important in AD symptoms? Originally decreased cholinergics in AD thought to parallel decreased dopamine in Parkinson Disease“Cholinergic Hypothesis of AD” in 1970’sResearchers now reject this theory as insufficientDecreased Acetylcholine may be non-specificAbnormalities in other chemical systems present as wellGABA, glutamine, SeritoninD. Drachman (1997), NEJM, vol.336,
42Donepezil in MCITo evaluate efficacy & safety of donepezil therapy for treating patients with MCI24-wk, RCT, DB, placebo study in US270 patients with predefined evidence of MCIRandomization 1:1 (donepezil:placebo)donepezil (5 mg/d for 6w then 10 mg/d)Clinical Global Impression of Change for MCI (CGIC-MCI)NYU Paragraph Delayed RecallNYU Paragraph Immediate Recall; Modified ADAS-cog, WMS-R Digit Span Backwards, Symbol Digit and Patient Global AssessmentObjectivesDesignPrimarySecondarySalloway S et al 2003 Neurology S
43Patient Global Assessments MCI40Donepezil* (n=83)35Placebo (n=100)Improved61.4% Donepezil51.0% PlaceboWorse1.2% Donepezil14.0% Placebo30Patients (%)252015*P=0.007105Very much improvedMuch improvedMinimally improvedUnchangedMinimally worseMuch worseVery much worseFully evaluable at week 24
44MCI 3-year Trial with Vitamin E and Donepezil MemoryImpairment=MCIAlzheimer’sdiseaseDonepezilPlacebo61218243036MonthsPetersen et al, New England Journal, (2005,) vol.352,
45Conversion to AD by Treatment Group 1 yr2 yr3 yr1.00.90.8Probabilityof notconvertingto AD0.7Donepezil0.6Vitamin EPlacebo0.5D–P P=0.416E–P P=0.9120.42004006008001,0001,200Time on MCI study (days)CP
46Conversion to AD by ApoE Status 1.00.8Probabilityof notconvertingto AD0.6ApoE4 negative0.4ApoE4 positiveP<0.00010.22004006008001,0001,200Time on MCI study (days)CP
47Probability of Converting to AD For Apoe E4 Positive Participants
48RecommendationsThere is currently insufficient evidence to recommend for the use of cholinesterase inhibitors in MCI. (Recommendation Grade C, Evidence level I)
49Disease-modifying Treatments Ginkgo BilobaMild efficacyNon-regulated productEstrogensCompelling epidemiological dataDisappointing intervention trialsNSAID’s/PrednisoneVery mild efficacyProhibitive side effect profileVitamine EOne major RCT showed delayed progression of AD (death, institutionalization, deteriorating function and dementia) with high doses (1000 UI BID) (Sano et al., NEJM 1997)
50Clinical Studies in MCI SHORT VERSIONTreatmentsFindingsEstrogen, combined Estrogen/Progesterone ERTNegativeAnti-inflammatories, NSAIDsStatinsPreliminary positiveNootropics (Piracetam – pyrrolidine acetamide)AMPA modulator (Ampakine CX516)Anti-oxidants (e.g., Vitamin E)Mixed resultsKey PointsThere have been several randomized controlled studies carried out on MCI patients and normal subjects in the past few years, as well as studies currently ongoing, that have examined effectiveness at preventing dementia.Estrogen, combined Estrogen/Progesterone ERT showed negative results in the large WHIMs prevention trials.Anti-inflammatories and NSAIDs have demonstrated negative results to date.Statins have shown positive findings in a small preliminary randomized controlled trial, and larger trials are still ongoing.Piracetam and ampakine CX516 has produced only negative results in prevention trials thus far.Anti-oxidant trials (including gingko biloba) are still ongoing.It is important to note that none of the treatments listed above are approved or have been proven to work in the prevention of dementia.ReferencesPetersen RC et al. Current concepts in mild cognitive impairment. Arch Neurol 2001;58:Almkvist O et al. Mild cognitive impairment – an early stage of Alzheimer's disease? J Neural Trans Suppl 1998;54:21-29.Sramek JJ et al. Mild cognitive impairment: emerging therapeutics. Ann Pharmacother 2000;34:N.B. None of these treatments are proven or approvedPetersen RC et al. Arch Neurol, 2001; Almkvist O et al. J Neural Trans Suppl, 1998; Sramek JJ et al. Ann Pharmacother, 2000.
51RecommendationsThere is currently fair evidence to recommend against the use of NSAIDs in MCI. (Recommendation Grade D, Evidence level I)There is currently fair evidence to recommend against the use of estrogen replacement therapy in MCI. (Recommendation Grade D, Evidence level I).There is currently fair evidence to recommend against the use of Ginkgo biloba in MCI. (Recommendation Grade D, Evidence level I).There is currently fair evidence to recommend against the use of vitamin E in MCI. (Recommendation Grade D, Evidence level I)As vascular risk factors and comorbidities impact on the development and expression of dementia, they should be screened for and treated optimally in MCI. (Recommendation Grade B, Evidence level II)
52Topic 3Diagnosis and differential diagnosis of dementia for the primary care practitioner and consultant: clinical laboratory, imaging, markersHoward Feldman, Hyman Schipper,Alain Robillard, Andrew Kertesz,Claudia Jacova, Dessa SadovnickTiffany Chow, Michael Borrie
53Recommendations - clinical diagnosis The diagnosis of dementia remains clinical. There is good evidence to retain the diagnostic criteria currently in use. (Grade A, Level II)The sensitivity of clinical diagnosis for possible or probable Alzheimer's disease based on the NINDS-ADRDA criteria remains high. The specificity is lower. The continued use of the NINDS-ADRDA criteria is recommended. (Grade A, Level I)'Mild' Alzheimer's disease can be diagnosed with a high degree of specificity, when the presenting clinical picture is one of memory impairment. (Grade B, Level I)
54Recommendations Neuropsychology testing Neuropsychological testing is a useful adjunct in the diagnosis and differential diagnosis of dementia. (level II grade B)The diagnosis and differential diagnosis of dementia is currently a clinically integrative one. Neuropsychological testing alone cannot be used for this purpose and should be used selectively in clinical settings (level II grade B)
56Tau Isoforms & Antibodies 1.Blennow & Hampel (2003), Lancet Neurology2. Hampel et al., (2004), Archives of General Psychiatry
57CSF T-Tau: 2 Assays: Innogenetics Athena Elevated in: Head trauma StrokeEncephalitisGuillain-BarreALSBut Normal in:DepressionParkinson’s DiseaseAlcohol overuseFelt to be non-specific marker of neuronal destruction1.Blennow & Hampel (2003), Lancet Neurology2. Hampel et al., (2004), Archives of General Psychiatry
58CSF T-Tau Sensitivity 1.Blennow & Hampel (2003), Lancet Neurology 2. Hampel et al., (2004), Archives of General Psychiatry
59Abeta42 ELISA 1.Blennow & Hampel (2003), Lancet Neurology 2. Hampel et al., (2004), Archives of General Psychiatry
60CSF ABeta 42 CSF levels of Total Abeta disappointing as CSF marker ABeta 42 is principal component of plaquesDecreased ABeta 42 found in diverse CNS diseases including:MSAALSCJD1.Blennow & Hampel (2003), Lancet Neurology2. Hampel et al., (2004), Archives of General Psychiatry
61CSF ABeta42 Sensitivity 1.Blennow & Hampel (2003), Lancet Neurology 2. Hampel et al., (2004), Archives of General Psychiatry
65Phospho-Tau Several Varieties found to be ↑’d in AD ? Reflects abnormal phosphorylation in AD and not neuronal damage more generally?P-Tau 18/231, 181, 199, 231, 396/404Not ↑’d instroke or Creutzfeldt-Jakob dzALS, Parkinson’sDepressionVascular, frontotemporal, or Lewy Body Dementia
67Summary until Now AB42 and Total-Tau Phospho-Tau Highly sensitive tests (80-90%)Highly specific relative to healthy controlsBut other dementias correctly classified60% of the time (relative to clinical diagnosis)70% of the time (relative to pathological diagnosis)Phospho-TauClassifies FTD well (spec. 92%)VD/LBD classified ~70% correctly
68Recommendations on Biomarkers To Primary Care PhysiciansBiological markers for the diagnosis of AD should not, at this juncture, be included in the battery of tests routinely used by primary care physicians to evaluate subjects with memory loss (Recommendation Level C). Consideration for such specialized testing in an individual case should prompt referral of the patient to a neurologist or geriatrician engaged in dementia evaluations or a Memory Clinic.
69Recommendations on Biomarkers To SpecialistsAlthough highly desirable, there currently exist no blood- or urine-based AD diagnostics that can be unequivocally endorsed for the routine evaluation of memory loss in the elderly. The non-invasiveness of such tests, if and when they become available, would be suitable for mass screening of subjects with memory loss presenting to specialists in their private offices and Memory Clinics.Due to their relative invasiveness and availability of other fairly accurate diagnostic modalities (clinical, neuropsychological and neuroimaging), CSF biomarkers need not be performed in all subjects undergoing evaluation for memory loss (Recommendation Level C).
70Recommendations on Biomarkers a) CSF biomarkers may be considered in the differential diagnosis of AD where there are atypical features and diagnostic uncertainty (level II Level B). For example, CSF biomarkers may prove useful in differentiating frontal variants of AD from FTD.When a decision to obtain CSF biomarkers is made, combined Aß1-42 and p-tau concentrations should be measured by validated ELISA (Recommendation Level A). It may be best to convey the CSF samples to a centralized facility (commercial or academic) with a track record in generating high-quality, reproducible data.CSF biomarker data in isolation are insufficient to diagnose or exclude AD (Recommendation Level C). They should be interpreted in light of clinical, neuropsychological, other laboratory and neuroimaging data available for the individual under investigation
72Atrophy in Alzheimer’s disease The distribution of atrophy corresponds to the clinical picture: medial temporal lobe structures such as the hippocampus are involved in learning and episodic memory.Posterior temporal and anterior parietal areas on the dominant (left) side are involved in language and semantic memory (meaning of concepts).Atrophy of the brain in AD: Medial temporal lobes are affected first and most severelyFigure from: 8.
74Clarfield criteria for CT: age < 70new onset dementia , < 1 yearatypical presentationrapid unexplained deteriorationunexplained focal signs, symptomshead injuryincontinence, gait ataxianeed for reassurance of patient, family1.Clarfield, CMAJ, (1991), vol.144(7),2.Patterson et al., (1999) CMAJ, vol.160,(Supp.12),S1-15
75Recommendations-structural There is fair evidence to support the selective use of CT or MRI scanning in the work-up for dementia – per 1999 Guidelines (Level ii, Grade B)There is fair evidence to support use of structural neuroimaging to rule in concomitant cerebrovascular disease that can affect patient management. (Grade B, Level II-ii)There is fair evidence to support the use of structural neuroimaging to track the progression of AD in clinical trials, especially if the morphometry is combined with neuropsychological testing.
77SPECT scan of normal control vs AD Alzheimer’s DiseaseSandra E. Black-S&W-U of T
78Recommendations - functional imaging There is fair evidence that functional imaging with PET or SPECT scanning might assist specialists in the differential diagnosis of dementia, particularly those with questionable early stage dementia or those with frontotemporal dementia. There is variability across centers, with requisite expertise in these modalities that needs to be taken into account in determining utility. (Level II, B)fMRI and MRS scanning are not recommended for use by family physicians or specialists to make or differentiate a diagnosis of dementia in people presenting with cognitive impairment. They remain very promising research tools. (Level of Evidence 3, Grade of Evidence B)
79Recommendations – B12, homocysteine It is recommended that serum Cbl (B12) levels be determined in all older adults suspected of dementia or cognitive decline. (Grade B, Level 2)Older adults found to have low Cbl levels should be treated with Cbl (either oral or parenteral forms), because of potential improvement of cognitive function and the deleterious effects of low Cbl levels on multiple organ systems, besides the effects on cognition. (Grade B, Level 2)There is currently insufficient evidence to support the need for serum homocysteine (tHcy) levels to be determined in older adults suspected of dementia or cognitive decline (Grade C, Level 3)There is currently insufficient evidence that treatment of elevated serum homocysteine (tHcy) levels affects cognition. (Grade C, Level 3)Determination of serum folic acid or RBC folate in older adults in Canada is optional, and may be reserved for patients with celiac disease, inadequate diets, or other conditions that prevent them from ingesting grain products. (Grade E, Level 2)
80Genetics and Dementia: Risk Factors, Diagnosis, & Management Topic 4Genetics and Dementia: Risk Factors, Diagnosis, & ManagementGing-Yuek Robin HsiungA. Dessa Sadovnick
81Genetic susceptibility risk factors Genetic screening with APOE genotype in asymptomatic individuals in the general population is not recommended because of the low specificity and sensitivity. (Grade E, Level 2)Genetic testing with APOE genotype is not recommended for the purpose of diagnosing AD because the positive and negative predictive values are low. (Grade E, Level 2)
82Management of mild to moderate Alzheimer's disease Topic 5Management of mild to moderate Alzheimer's diseaseDavid Hogan, Malcolm HingPeter Bailey, Krista LanctotLinda Thorpe
83Outcome measures used in AD and AD + CVD trials Function (DAD, ADCS-ADL, BrADL)Cognition (ADAS-Cog, MMSE)Global (CIBIC-plus)Speaker notesBecause AD and AD with cerebrovascular disease (AD + CVD) affect many clinical domains besides cognitive function, clinical trials currently use a number of outcome measures to assess the effects of treatment on these domains.ReferencesADCS-ADL: Galasko D, Bennett D, Sano M, et al. An inventory to assess the activities of daily living for clinical trials in Alzheimer’s disease. The Alzheimer’s Disease Cooperative Study. Alzheimer Dis Assoc Disord 1997;11(suppl 2):S33-S39.DAD: Gelinas I, Gauthier L, McIntyre M, Gauthier S. Development of a functional measure for persons with Alzheimer's disease: the disability assessment for dementia. Am J Occup Ther 1999;53:SCGB: Vitaliano PP, Russo J, Young HM, Becker J, Maiuro RD. The screen for caregiver burden. Gerontologist 1991;31:76-83.CIBIC-plus: Schneider LS, Olin JT, Doody RS, et al. Validity and reliability of the Alzheimer’s Disease Cooperative Study—Clinical Global Impression of Change. Alzheimer Dis Assoc Disord 1997;11(suppl 2):S22-S32ADAS-Cog: Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s disease. Am J Psychiatry 1984;141:Blesa R. Galantamine: therapeutic effects beyond cognition. Dement Geriatr Cog Disord 2000;11(suppl 1):28-34.Cummings JL. The Neuropsychiatric Inventory: assessing psychopathology in dementia patients. Neurology 1997;48(suppl 6):S10-S16.Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:Behaviour (NPI)Caregiver burdenSCGB, ACTS
84Available AChE inhibitors for AD SelectivityT1/2Starting doseMinimal effective doseUsual recommended dose (mg)DonepezilAChEIApprox.70 h5 Qam5-10 mg/dGalantamineAChEI &Nicotinic modulator7-10 h4 bid8 bid8-12 bidRivastigmineAChEI & BuChEI1-2 h1.5 bid3 bid3-6 bidSpeaker notesCurrently, the only agents approved in Canada for use in the treatment of AD inhibit the breakdown of ACh by AChE. These include:Donepezil (Aricept®; Pfizer)Rivastigmine (Exelon®; Novartis)Galantamine (Reminyl®; Janssen-Ortho)All of these agents inhibit acetylcholinesterase; galantamine is also an allosteric modulator of nicotinic acetylcholine receptors, increasing their sensitivity to stimulation by ACh.Donepezil, the first of these agents to become available in Canada, is a noncompetitive, reversible agent.Rivastigmine binds noncompetitively and pseudo-irreversibly to the acetylcholinesterase enzyme.ReferencesAricept® Product Monograph, 2004Reminyl® Product Monograph, 2004Exelon® Product Monograph, 2004
85Frequency of prescription and cost Cost in Canada: $ /year
86Galantamine maintains cognitive benefits in AD over 12 months Improvement*Mean change (± SE) in ADAS-Cog/11 from baselineGalantamine 24 mg / galantamine 24 mgPlacebo / galantamine 24 mgHistorical placebo groupSpeaker notesIn another pivotal trial, Raskind et al tested the safety and efficacy of galantamine 24 mg or 32 mg daily or placebo among 636 patients with mild-to-moderate AD (MMSE and ADAS-Cog ≥ 12).A 6-month double-blind phase (completed by 438 patients) was followed by a 6-month open-label phase (completed by 268 patients) in which all patients received galantamine 24 mg daily.The primary efficacy measures included ADAS-Cog/11 and CIBIC-plus; secondary efficacy measures included the Disability Assessment for Dementia (DAD).As shown on this slide, patients who received galantamine 24 mg daily throughout the trial maintained their cognitive function at or above baseline for the entire 12-month study duration.At 6 months, observed-case analysis found that the differences in ADAS-Cog/11 between galantamine and placebo-treated groups were 3.9 points for the 24-mg daily group and points for the galantamine 32-mg daily group (latter not shown; both groups, p < vs placebo). The differences were also significant on intent-to-treat analysis (both groups, p < vs placebo).Patients on galantamine 24 mg daily for the entire 12 months maintained their baseline scores (as shown on this slide).Patients who were started on galantamine 24 mg daily after 6 months of placebo still received some benefit, but were not able to recoup the decline they had experienced during the first 6 months of the study. This group was significantly below baseline (as well as below the galantamine 24-mg group; p < 0.05) by the end of the study.For ethical reasons, patients were not left on placebo for the full 12-month period. In this slide, therefore, the results of the Raskind study are shown together with an extrapolated curve of decline that would be expected for untreated patients.Double-blindOpen-label extensionDeterioration*p < 0.05 vs placebo / galantamineand NS from baselineMonthsRaskind MA, et al. Neurology 2000;54:2261; Torfs K, et al. Neurobiol Aging 2000;21(suppl 1):1109AStern RG, et al. Am J Psychiatry 1994;151:390
88However, Response to these drugs is variable. Changes in psychometric performance gives impression of small effects.Are these drugs worth it?
89Cholinesterase Inhibitors Should Be Considered In Patients With Mild To Moderate Ad (Standard) Although Studies Suggest A Small Average Degree Of BenefitVitamin E(1000 I.U. Po Bid)Should Be Considered In An Attempt To Slow Progression Of Ad (Guideline)
90AChEIs: meta-analysis Lanctôt et al CMAJ 2003 Lanctot, K. L., N. Herrmann, et al. (2003). "Efficacy and safety of cholinesterase inhibitors in Alzheimer's disease: a meta-analysis." CMAJ 169(6):Background: Cholinesterase inhibitors (ChEIs) are the only drugs marketed for the treatment of Alzheimer's disease. Despite numerous randomized controlled trials, the efficacy and safety of this group of medications has not been quantified. Our objective was to quantitatively summarize data on the efficacy and safety of ChEIs in Alzheimer's disease in a format useful to clinicians. Methods: We performed a meta-analysis of randomized, double-blind, placebo-controlled, parallel-group trials of currently marketed ChEIs (donepezil, rivastigmine and galantamine), used in therapeutic doses for at least 12 weeks, from which a cognitive outcome was reported. Studies were identified through 3 electronic databases searched to May 2002, pharmaceutical companies and journals. We extracted the proportions of subjects who responded, experienced adverse events, discontinued treatment for any reason or discontinued treatment because of adverse events. Results: In the 16 identified trials that met the inclusion criteria, 5159 patients were treated with a ChEI and 2795 received a placebo. The pooled mean proportion of global responders to ChEI treatment in excess of that for placebo treatment was 9% (95% confidence interval [95% CI] 6%-12%). The rates of adverse events, dropout for any reason and dropout because of adverse events were also higher among the patients receiving ChEI treatment than among those receiving placebo, the excess proportions being 8% (95% CI 5%-11%), 8% (95% CI 5%-11%) and 7% (95% CI 3%-10%), respectively. The numbers needed to treat for 1 additional patient to benefit were 7 (95% CI 6-9) for stabilization or better, 12 (95% CI 9-16) for minimal improvement or better and 42 (95% CI ) for marked improvement; the number needed to treat for 1 additional patient to experience an adverse event was 12 (95% CI 10-18). Interpretation: Treatment with ChEIs results in a modest but significant therapeutic effect and modestly but significantly higher rates of adverse events and discontinuation of treatment. The numbers needed to treat to benefit 1 additional patient are small.
91AChEIs: Numbers Needed to Treat Lanctot et al CMAJ 2003 For global response : improvementNNT = 12 (95% CI 9-16)For cognitive response: improvement 4 pts ADASNNT = 10 (95% CI 8-15)For harm: adverse eventNNT = 12 (95% CI –10-18)Comparison to other disordersDepression NNT = 4Psychosis NNT = 35 year prevention stroke, MI or death = 29-86NNTs in other disordersPsychosis NNT 3 with neurolepticsDepression NNT 4 with antidepressants5 year prevention stroke, MI or death with antihypertensives 29-86
92Meta-analysis Richie et al. Am J Geriatr Psychiatry 2004; 12:358–369 All three drugs had similar cognitive efficacy, with donepezil and rivastigmine showing a dose effect across the dosing levels studied.Dropout rates were greater with galantamine and rivastigmine.
93Memantine Voltage Dependency in Alzheimer’s Disease MagnesiumPhysiological Magnesium BlockLow to Moderate Affinity Antagonist Memantine(Ki = 0.5 µM)MemantineMDepolarizationCa2+–50 mVSynaptic Activity–20 mVResting State–70 mVPurpose:To illustrate memantine’s voltage dependency and how it blocks pathological activation ofthe receptors while preserving cognitive abilityKey Points:Under normal conditions, magnesium is a natural channel blocker in the ion channel pore.Magnesium is highly voltage dependent, which means it is easily and quickly displaced from the channel pore by depolarization.In contrast, memantine, when bound within the channel pore, remains, so that during chronic depolarization, it continues to block excess calcium influx.However, when a cognitive event occurs and depolarizes the neuron, memantine quickly leaves the channel and allows the signal to be transmitted.In this manner, memantine blocks pathologic glutamatergic signaling while allowing for physiological glutamatergic processes.Reprinted from Neuropharmacology, Vol 38, CG Parsons, W Danysz, G Quack. Memantine is a clinically well toleratedN-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data, pages , copyright 1999, with permission from Elsevier.
94Memantine Selectively Blocks Pathological Activation of NMDA Receptors Memantine BlocksGlutamatergic Activation andChronic NeurodegenerationPathological Activation of NMDA ReceptorsMemantine Facilitates Cognitive ActivityRestMAbnormalCa2+Ca2+MNoiseNoiseSignalNoisePurpose:To illustrate how memantine works hypotheticallyKey Points:Pathological conditions are illustrated at the left side of the screen. Glutamatergic activation of NMDA receptors increases calcium influx into the neuron, resulting in an increase in background noise, which interferes with signal detection, and subsequently impairs cognitive processing.Memantine binds to the ion channel pore and normalizes conditions by reducing calcium influx and background noise, which allows relevant signals to be detected.MagnesiumGlutamateCalciumMemantineMReprinted from Neuropharmacology, Vol 38, CG Parsons, W Danysz, G Quack. Memantineis a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a reviewof preclinical data, pages , copyright 1999, with permission from Elsevier.
95Recommendations – on cholinesterase inhibitors 14a. All three cholinesterase inhibitors available in Canada are efficacious for mild to moderate AD. They are all viable treatment option for most patients with mild to moderate AD.(Grade A, Level I)14b. While all three cholinesterase inhibitors available in Canada have efficacy for mild to moderate AD, equivalency has not been established in direct comparisons. Selection of which agent to be used will be based on adverse effect profile, ease of use, familiarity and beliefs about the importance of the differences between the agents in their pharmacokinetics and other mechanisms of action. (Grade B, Level I)14c. All physicians prescribing these agents should be aware of the contraindications and precautions with the use of cholinesterase inhibitors. (Grade B, Level III)!
96Recommendations – on cholinesterase inhibitors con’d 14d. If adverse effects occur with a cholinesterase inhibitor, the agent should either be discontinued (if the side effects are judged to be disabling and/or dangerous), or the dose of the agent should be decreased with an option to retry the higher dose after four weeks if the lower dose is tolerated (if the side effects are judged to be minor in severity). (Grade B, Level III)14g. Patients can be safely switched from one cholinesterase inhibitor to another. The decision of when to make a switch is based on the judgment of the prescribing physician and the patient (or their proxy). (Grade B, Level III)14h. Patients can be switched from a cholinesterase inhibitor to memantine. The decision of when to make a switch is based on the judgment of the prescribing physician and the patient (or their proxy). There is no published guidance as to how to switch from a cholinesterase inhibitor to memantine, but a report presented at a meeting indicates that it can be done safely. (Grade B, Level III)
97Recommendations – Memantine and Ghinkgo 15a. Memantine is an option for patients with moderate stages of AD. Its use in mild stages of AD is not recommended. (Grade B, Level I)15b. Combination therapy of a cholinesterase inhibitor and memantine is rational (as the medications have different mechanisms of action), appears to be safe and may lead to additional benefits for patients with moderate to severe AD. This would be an option for patients with AD of a moderate severity. (Grade B, Level I)18d. While Ginkgo biloba is a safe agent, its use can not be recommended for the treatment of dementia. Further methodologically sound trials are required. (Grade C, Level I)
98Recommendations – non-pharmacological therapy in Mild AD 7a. There is good evidence to indicate that individualized exercise programs have an impact on functional performance in persons with mild to moderate dementia. (Grade A, Level 1)7b. There is insufficient research evidence to come to any firm conclusions about the effectiveness ofcognitive training/cognitive rehabilitationenvironmental interventionsother non-pharmacological therapeutic interventions in improving and/or maintaining cognitive and/or functional performance in persons with mild to moderate dementia. (Grade C, Level 1)
99RecommendationsMedications for the treatment of AD should be discontinued when:The patient and/or their proxy decision-maker decides to stop;The patient refuses to take the medication;The patient is sufficiently non-adherent with the medication that continued prescription of it would be useless, and it is not possible to establish a system for the administration of the medication to rectify the problem;There is no response to therapy after a reasonable trial;The patient experiences intolerable side effects;The comorbidities of the patient make continued use of the agent either unacceptably risky or futile (e.g., terminally ill); or,The patient's dementia progresses to a stage where there is no significant benefit from continued therapy. (Grade B, Level III)After stopping therapy for AD, patients should be carefully monitored and if there is evidence of a significant decline in their cognitive status, functional abilities or the development/worsening of behavioural challenges consideration should be given to reinstating the therapy. (Grade B, Level III)
100Anti-Inflammatory studies in AD LengthOutcomeSubjectsAuthorHydroxychloroquine18 mosnegn=168Van Gool et alPrednisone12 mosn= 138Aisen et alNaproxenn= 351Rofecoxibn= 692Reines et alNimesulide3 mosn= 40Diclofenac6 mosneg *n= 41Scharf et alIndomethacin6 monthsposn=Rogers et alCelecoxibabstractVan Gool et al: Lancet 2001; 358 (9280) month parallel group placebo controlled study of hydroxychloroquine in min to mild AD. Dose 200 or 400 mg day. N= 168 randomized subjects. Outcome measures primary IDDD and ADAS cog. Results NS. No benefit on rate of declineAisen PS et al Neurology 2000; 54 (3) month Prednisone study and 16 week washout. RCT double blind parallel group placebo controlled n=138 subjects randomized. Outcome measure ADAS cog ITT. Result negativeAisen PS et al JAMA 2003 Effects of rofecoxib or naproxen in AD: Multicenter RCT placebo controlled 1 year duration 3 arms rofecoxib (25 mg qd), naproxen (220 mg BID) or placebo. Primary outcome ADAS cog. Secondary CDR SB, NPI, QOL AD, time to attain significant end points including 4 point decline on ADAS cog, 1 stage worsening on CDR, 15 point decline on ADCS ADL, institutionalization, or death. No Significant differences of either rofecoxib or naproxen vs placebo on primary outcomes or secondary outcomes. More SAEs and fatigue, dizziness hypertensionReines SA et al Neurology (1) 66-71: double blind multicenter placebo controlled RCT mild to moderate AD dose 25 mg daily. 12 months. Key efficacy ADAS cog and CIBIC +. Completers n= 481 / 692 randomized subjects. NS on ADAS cog or CIBIC plus.Aisen PS et al Neurology 2002:58(7) Nimesulide a COX II preferred Cyclo-oxygenase inhibitor 12 week RCT plac controlled parallel group trial. Dose nimesulide 100 mg BID for 12 weeks followed by 12 week open label study. NS effect on cognition, ADL, affect or behavior.Scharf S et al Neurology 1999: 53 (1) Diclofenac/Misoprostol n=41 mild to moderate AD 25 week prospective double blind placebo controlled RCT. Primary outcome ADAS cog, GDS, CGIC, MMSE and IADL, PSMS, caregiver rated Global Impression of Change. NS between groups though trends seen. 50% withdrawal rates in the D/M subgroupRogers J et al Neurology : 6 month double blind placebo controlled RCT dose mg /day indomethacin in mild to moderate Adimprovement described on ADAS cog. High AE rate of indomethacin drop outCelecoxib absract only from Stockholm Springfield meeting 2002Naproxen acts through cyclooxgenase inhibition; not protective against cell toxicity
101CNS Cholesterol Metabolism Abeta AsecretasecholesterolPoirier J. Trends in Molecular Medicine (2003)
102Cholesterol and Beta-Amyloid The stiffening of the membrane due to cholesterol loading may decrease alpha secretase cleavage of APP by inhibiting lateral movement and the required contact between enzyme and substrateBodovitz S. et al., 1996
103Atorvastatin in AD Atorvastatin 80 mg vs placebo 12 month RCT mild to moderate ADConcurrent AchEIs allowedEvaluable data on 63 subjects OC n = 46ADAS cog, CGIC benefit reported at 12 monthsAdditional benefit on LDLOf those signing informed consent 98 subjects12 screen failures;15 withdrew prior to screen8 withdrew after baseline visitSparks L et al 8th International Montreal Springfield Conference 2004
104Recommendations18a. Vitamin E supplementation is not recommended for the treatment of AD. (Grade E, Level I)18b. The use of the synthetic antioxidant idebenone is not recommended for the treatment of AD.(Grade D, Level I)18c. The administration of vitamin B1, B6, B12 and/ or folic acid supplements to persons suffering from AD who are not deficient in these vitamins is not recommended. (Grade D, Level III)!
105Recommendations18e. The use of an anti-inflammatory drug is not recommended for the treatment of the cognitive, functional or behavioural manifestations of a dementia. (Grade D, Level I)18f. The use of a HMG-CoA reductase enzyme inhibitor is not recommended for the treatment of the cognitive, functional or behavioural manifestations of a dementia. (Grade D, Level III)18g. Hormone replacement therapy (estrogens combined with a progestagen) or estrogen replacement therapy (estrogen alone) is not recommended for the cognitive impairments of women with AD. (Grade B, Level I)18h. There is insufficient evidence to recommend the use of androgens (e.g., testosterone) to treat AD in men. (Grade C, Level I)
106Amyloid vaccination: reduced plaques and improved cognition NATURE MEDICINE • VOLUME 7 • NUMBER • JANUARY 2001Vaccination with Ab peptide prevents memory deficits in an animal model of Alzheimer’s disease (Morgan et al., 2001)Ab immunization reduces behavioural impairment and plaques in a model of Alzheimer’s disease (Janus et al., 2001)Tg2576 transgenic miceSlide courtesy of Dr. Howard Feldman
107PDAPP Transgenic mice 13 months Hippocampal Dentate GyrusOverexpress mutant human APP driven bya platelet derived (PD) growth factor promoterTransgenic Mouse:APP mutationAb42- injected mice at 6 weeksSlide courtesy of Dr. Howard FeldmanSchenk et al., Nature 1999:
108Post Vaccination Meningoencephalitis Fig 1a (top left)Fig 1b (top right)Fig 3a (bottom left)Fig 3b (bottom right)Reference:Nicoll J.A.R., et al., “Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report” Nature Medicine, Apr 2003, 9(4):Slide courtesy of Dr. Howard FeldmanNicoll JAR et al Nature Medicine, Apr 2003, 9(4):
109Fig 1c (top left) Fig 1d (top right) Fig 1e (bottom left) Fig 1f (bottom right)Reference:Nicoll J.A.R., et al., “Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report” Nature Medicine, Apr 2003, 9(4):Nicoll JAR Nature Medicine, 2003, 9(4):
110GAG-MimeticsGlycosaminoglycans (GAGs) contribute to the amyloidogenic cascade by promoting the Aβ fibrillogenic process that leads to plaque formationCan low molecular weight GAG-mimetic compounds that bind to soluble Aβ peptides promote their clearance?Neurochem inc.-Alzhemed -Phase 3 trials-first was negative - unable to demonstrate a benefit..second is ongoing
111Driving Recommendations 25b. No single brief cognitive test (e.g., MMSE) or combination of brief cognitive tests has sufficient sensitivity or specificity to be used as a sole determinant of driving ability. Abnormalities on cognitive tests such as the MMSE, clock drawing and Trails B should result in further in-depth testing of driving ability. (Grade B, Level III)25c. Driving is contraindicated in persons who, for cognitive reasons, have an inability to independently perform multiple instrumental activities of daily living (e.g., medication management, banking, shopping, telephone use, cooking) or any of the basic activities of daily living (e.g., toileting, dressing). (Grade B, Level III)25d. The driving ability of persons with earlier stages of dementia should be tested on an individual basis. (Grade B, Level III)!!
112Driving Recommendations 25e. A health professional-based comprehensive off- and on-road driving evaluation is the fairest method of individual testing. (Grade B, Level III)25f. In places where comprehensive off and on-road driving evaluations are not available, clinicians must rely on their own judgment. (Grade B, Level III)26g. For persons deemed safe to drive, reassessment of their ability to drive should take place every 6 to 12 months. (Grade B, Level III)25h. Compensatory strategies are not appropriate for those deemed unsafe to drive. (Grade B, Level III)
113Recommendations – organization and funding of care 28c. Shared care models for the management of patients with mild to moderate AD and dementia should be developed and evaluated. This will require the acceptance of joint responsibility on the part of primary care practitioners and specialty services in delivering care to patients with dementia. (Grade C, Level III)28d. Dementia care must be adequately funded and reimbursed. Inadequate remuneration should not be a barrier to the delivery of good dementia care. (Grade C, Level III)
114Clinical practice guidelines for severe Alzheimer's disease Topic 6Clinical practice guidelines for severe Alzheimer's diseaseNathan HerrmannSerge Gauthier
115Cognition in MSAD Donepezil Plus Memantine 3.532.521.510.5Change From Baseline-0.5-1-1.5-2Memantine/donepezil-2.5Placebo/donepezilDesign: Randomized double blind placebo controlled RCT add on treatment to donepezil. 24 weeks. Maintenance dose of 20 mg daily memantine.Inclusion: MMSE 5-14 at baseline + 6 months of donepezil stable dose for at least 3 months.Primary outcomes: SIB and ADCS ADLSecondary outcomes: CIBIC + adapted from ADCS CGIC; NPI 12 items, Rating scale for Geriatric patitents care dependency subscaleN=404 randomized 50/50 spit (202 memantine and 201 placebo)85% completer rate for memantine/donepezil and 75% placebo/donepezil completer rateSIB + P<0.001 and ADCS ADL + P=0.028CIBIC + P=0.027NPI significant on total score-3-3.548121824Treatment WeekLS mean difference-1.2-1.9-3.0-2.6-3.4P value0.0570.006< 0.0010.004< 0.001N = 404Tariot PN et al. JAMA, 2004, 291(3):317-24
116Cognition (SIB) Moderate to Severe AD P<.00016-6-4-2246-8-10-12P=.0051P<.0009P<.0001P=.0078P=.00014Clinicalimprovement2P<.001P=.002Difference in SIB ScoreBaselineLS Mean Change From Baseline ± SE-2MMSE 11.8MMSE 7.9ClinicaldeclineDonepezilMemantine-4PlaceboPlacebo-648121824ITT LOCF41228LOCFEndpointStudy WeekStudy WeekDonepezil MMSE 5-17Memantine MMSE 3-14Feldman et al. Neurology. 2001;57:Reisberg et al. N Engl J Med. 2003;348:
117Memantine Plus Donepezil Reduced Behavioral Changes 5+ 3.74ChangeIn NPIScore(ITT LOCF)321-0.1-1Memantine+ DonepezilPlacebo+ DonepezilTariot et al, JAMA 2004: 291:
118RecommendationsPatients with severe AD can be treated with ChEIs, memantine or the combination. Expected benefits would include modest improvements in cognition, function and behavior and/or slower decline.[I]Treatment with ChEIs and/or memantine should persist until clinical benefit can no longer be demonstrated. Treatment should not be discontinued simply because of institutionalization.[III]The management of BPSD should begin with appropriate assessments, diagnosis, and identification of target symptoms and consideration of safety of the patient, their caregiver and others in their environment.[III]Non-pharmacological treatments should be initiated first. Approaches that may be useful for severe AD include behavioural management for depression, and caregivers/staff education programs for a variety of behaviours. Music and multi-sensory intervention (Snoezelen) are useful during treatment sessions but longer-term benefits have not been demonstrated.[I]
119RecommendationsPharmacological interventions should be initiated concurrently with non-pharmacological approaches in the presence of severe depression, psychosis or aggression that puts the patient or others at risk of harm.[III]Pharmacological interventions for BPSD should be initiated at the lowest doses, titrated slowly and monitored for effectiveness and safety.[III]Attempts to taper and withdraw medications for BPSD after a period of three months of behavioural stability should occur in a standardized fashion.[I]Risperidone, and olanzapine can be used for severe agitation, aggression and psychosis. The potential benefit of these and other antipsychotics must be weighed against the potentially increased risk of cerebrovascular events and mortality [I]Benzodiazepines should be used only for short periods as p.r.n. agents.[I]SSRIs can be used for the treatment of severe depression.[III]If BPSD fail to improve after appropriate non-pharmacological and pharmacological interventions, refer to a specialty service.[III]There is insufficient evidence to recommend for or against the use of trazadone in the management of non psychotic agitated patients
120Management of dementia with a cerebrovascular component Topic 7Management of dementia with a cerebrovascular componentSandra Black,Christian Bocti
121Vascular dementia (VaD) and AD+CVD: NINDS−AIREN criteria Probable VaDDementia severe enough to interfere with ADLsCVD (focal signs, CT/MRI evidence of relevant lesions)A relationship between the above two disordersPossible VaDDementia and focal signs, but no confirmatory CT/MRITemporal relationship between dementia and stroke is unclearCVD with cognitive deficit of subtle onset and variable courseAD+CVDPossible VaD + clinical/imaging evidence for relevant CVDSpeaker notesThis slide summarizes the criteria for vascular dementia developed by the National Institute of Neurological Disorders and Stroke (NINDS) and Association Internationale pour la Recherche et l’Enseignement en Neurosciences (AIREN).Dementia, a necessary criterion for probable VaD, is defined as memory impairment, together with impairment in at least two other cognitive domains (orientation, attention, language, visuospatial functions, executive functions, motor control, and praxis), severe enough to interfere with ADLs and confirmed with neuropsychological testing.Other conditions that could account for deficits in memory and cognition (eg, delirium, psychosis, severe aphasia, major sensorimotor impairment, systemic disorders, or AD) are excluded.Cerebrovascular disease (CVD) is defined by the presence of focal neurological signs such as hemiparesis, lower facial weakness, Babinski sign, sensory deficit, hemianopia, and dysarthria consistent with stroke, in addition to neuroimaging evidence of relevant CVD (eg, multiple large vessel infarcts, a strategically located infarct, multiple lacunes in basal ganglia and white matter).A relationship between the dementia and the CVD may be inferred by an onset of dementia within 3 months after a stroke, an abrupt cognitive deterioration, or a fluctuating stepwise progression of cognitive deficits.Clinical features consistent with probable VaD includeEarly gait disturbanceEarly unsteadiness or frequent unprovoked fallsEarly urinary symptoms not related to urologic diseasePseudobulbar palsySubcortical deficits (eg, emotional incontinence, psychomotor retardation).
122Hyperintensities (HI) Affecting ACh WM Tracts Deep white HISelden NR et al. Brain 1998;121:External capsule HIExtensive periventricular HIRH Swartz, S&W, U of T
123Recommendations Use of non-pharmacologic interventions There is currently insufficient evidence to recommend the use of cognitive training for vascular dementia. (Grade C, Level II-1)Other therapeutic interventionsInvestigations for vascular risk factors. It is recommended that vascular risk factors are identified in all patients with vascular cognitive impairment. (Grade C, Level III)Treating hypertension. There is some evidence that treating hypertension may prevent further cognitive decline associated with cerebrovascular disease. There is no compelling evidence that one class of agent is superior to another; calcium channel blockers or ACE-inhibitors may be considered. (Grade B, Level I) Treatment for hypertension should be implemented for other reasons, including the prevention of recurrent stroke. (Grade A, Level I)
124RecommendationsAntiplatelet therapy with aspirin. There is currently no evidence to support the use of aspirin to specifically treat dementia associated with cerebrovascular disease. (Grade C, Level III) Aspirin or other antiplatelet therapies should be used for prevention of recurrent ischemic stroke in appropriate patients (Grade A, Level I) (AHA Guidelines, Stroke 2006)Nimodipine in vascular dementia. There is insufficient evidence for or against the use of Nimodipine for VaD (Grade C, Level I)Use of memantine. There is some evidence of small magnitude of cognitive benefit that is not captured in global measures for patients with VaD. There is insufficient information to recommend memantine for the treatment of vascular dementia. (Grade C, Level I).
125Recommendations – on use of cholinesterase inhibitors 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)Use of cholinesterase inhibitors in probable/possible vascular dementia using the NINDS-AIREN diagnostic criteria:There is insufficient evidence for or against the use of galantamine; (Grade C, Level 1)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)
126Robin Hsiung Dessa Sadovnik Topic 4Genetic and DementiaRobin HsiungDessa Sadovnik
131Diagrammatic representation of APP domains Signal peptideHeparin binding site 1Acidic domainsGlobular (cys) domainsCuBDZnBD-1Heparin binding site 2KPIOX-2CHOGrowth Promoting regionGlycosylated domainsA bd b a gSecretase sitesTransmembrane domainZnBD-2Exon 15Cytoplasmic domain
132Primary structure of A amyloid Senile plaqueAmyloidCongophilicAngiopathyb secretase a secretase g secretaseNH TEEISEVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKK---COOH
133A and Pathogenesis of AD TransmembraneAPPExtracellularIntracellularAPP mutations increaseb-secretase cleavageAb42 peptideAmyloidogenicg-secretase activity increased by PS1/PS2 mutationsa-secretaseNon-amyloidogenicAbOligomer aggregate
135Hypothetic situations for counseling II-5 is symptomatic, so she should be the first to test in this familyIII-3 & III-4 are eligible for predictive genetic testing (PGT)II-7 & III-4 are still at risk because their mothers died before age of onsetIII-7 would like PGT, but II-6 does notIII-6 is a minorIII-5 is pregnant
136Number of 1st degree relative affected Relative Risk of AD in a patient with positive family history but no clear autosomal dominant inheritanceNumber of 1st degree relative affectedAge of OnsetRelative Risk95% C. I.160-695.32.8-1070-792.380 and over2.61.3-5.overal3.52 or moreoverall7.5From Table 2.1 Chapter 2. Atlas of Alzheimer Disease
137Predictive genetic testing for asymptomatic “at risk” individuals (where there is autosomal dominant inheritance)predictive genetic testing (PGT) can be offered to “at risk” individuals (Grade B, Level 2). These would include first-degree relatives of an affected individual with the mutation (e.g., children and siblings), as well as cousins
138Recommendations – on testing for genetic risk factors Genetic susceptibility risk factorsGenetic screening with APOE genotype in asymptomatic individuals in the general population is not recommended because of the low specificity and sensitivity. (Grade E, Level 2)Genetic testing with APOE genotype is not recommended for the purpose of diagnosing AD because the positive and negative predictive values are low. (Grade E, Level 2)
139Ethical issues in dementia Topic 8Ethical issues in dementiaJohn Fisk, Lynn BeattieMartha Donnelly, Anna ByszewskiFrank J. Molnar
140Disclosure of the diagnosis of dementia John D. Fisk, B. Lynn Beattie, Martha Donnelly, Anna Byszewski and Frank Molnar.
141The process of diagnostic disclosure for persons with cognitive impairment or dementia must begin as soon as the possibility of cognitive impairment is suspected. (Level 3, Grade A: 88%)During the initial investigations of complaints or suspicions of cognitive loss, the patient’s understanding and attitudes about cognitive loss and dementia, as well as that of their family members/caregivers should be established.
142Both the diagnosis of dementia and the disclosure of the diagnosis must be considered processes that provide opportunities for education and discussion. (Level 3, Grade A: 100%)
143The potential for adverse psychological consequences must be assessed and addressed through education of the patient and family/caregivers. (Level 3, Grade B: 100%)
144Once a diagnosis is established, this must be disclosed to the patient and their family/caregivers in a manner that is consistent with the expressed wishes of the patient. (Level 3, Grade B:88%)
145Follow-up plans must be made and discussed at the time of diagnostic disclosure. (Level 3, Grade A: 97%)
146The process of diagnostic disclosure must be evaluated.
147Requirements:The existence of barriers to the implementation of guidelines for clinical practice in the diagnostic disclosure of dementia must be addressed.This includes, but is not limited to education of primary care physicians about the existence of such guidelines as well as in the early differential diagnosis of and treatment of dementia.
148Requirements:Primary care physicians must also have available to them knowledge of available support services for patients and their care providers.
149Ethical Considerations for Decision-Making for Treatment and Research Participation
150A diagnosis of dementia, or other forms of cognitive impairment, does not preclude competence to provide informed consent for treatment or for participation in research.Competency must be considered as the ability to make an informed decision about participation in the particular context of the specific treatment or study.
151At present there is insufficient evidence to recommend a specific standardized method for determining the competency of persons with dementia for decision-making for treatment or research.
152Therefore, for all research, the procedures that are used to evaluate the ability of the potential subject to understand the nature of the research, the consequences of participation (i.e. potential risks and benefits) and alternative choices must be described.
153Clinicians and researchers have to consider the obtaining of consent for treatment and research as a process. One that involves both the patient with dementia and their family or caregivers.
154Since research is commonly conducted in a health care setting, the distinctions between the clinician’s role in the management of the individual’s health care and his/her potential role in the conduct of research must be clearly understood by everyone. So too must the procedures that represent standard care and research.
155For the clinician and researchers, it is important to recognize that the interests of the person with dementia and those of a substitute decision-maker may differ.They have an obligation to determine, to the best of their ability, that the decisions made by proxies regarding treatment and research are based on the prior attitudes and values of the patient.
156As Alzheimer’s disease and other forms of cognitive impairment are often progressive neurodegenerative conditions, the potential that competency for decision-making will change over time must be recognized. This may lead to a change from one of obtaining the patient’s ongoing consent to one of obtaining ongoing assent.Throughout treatment and research there is a need for ongoing monitoring and re-affirmation of consent/assent.
157Conclusions: Mild Cognitive Impairment: Mild to Moderate AD: No suggested symptomatic/preventative therapyMild to Moderate AD:AchEIs standard of careAmyloid modifying therapies in clinicGuide to driving cessationModerate to Severe AD:Efficacy for donepezil + memantineVascular/Mixed Dementia: CI’s-some evidence
158Conclusions: Current trials for: amyloid antiaggregants/gamma secretase inhibitorscholesterol modulating drugsother modulators of glial response incl vaccinesneurotrophin like agentsglutamatergic/AMPA modulating drugs
159Regarding mild cognitive states: MCI and CIND are identical labels (European vs. American) Amnestic MCI always leads to Alzheimer DiseaseIn the >65 year population, there are twice as many individuals with CIND as there are with dementiaThe evidence suggests that Donepezil is effective in MCI and should be offerred to all MCI patients
160Vitamin E should be offerred to all memory impaired individuals to slow rate of progression. There is insufficient evidence to offer cholinesterase inhibitors or memantine to mild AD patientsCertain cognitive therapy programs (but not general cognitive stimulation) have been demonstrated to improve symptoms of memory loss and delay progressionCholinesterase inhibitors have proven efficacy at all stages of dementia, and should be carefully considered as therapy
161ACE-inhibitors are the recommeded medication to treat vascular and mixed dementia There is no specific medication to treat vascular dementiaThe presence of vascular lesions increases occurrence of clinical dementia by a factor of 2The presence of vascular lesions increases occurrence of clinical dementia by a factor of 20
162Any individual with Mild AD should be told to stop driving Any individual with mild AD and MMSE of less than 24 should be told to stop drivingAny individual with impairment in multiple IADLs or a single ADL should be told to stop drivingBecause of anxiety, on-road driving tests are not a fair evaluation of driving ability in a demented individual - neuropsych and clinical testing is better
163Funding Support FRSQ Canadian Institutes for Health Research Alzheimer’s Society of Canada
164Industrial Support Pfizer Inc. Novartis Inc. Janssen-Ortho Inc. Neurochem Inc.Lundbeck Inc.