Diagnosis and Treatment of Alzheimer Disease and Dementia: Results from the Third Canadian Consensus Conference Dr. Howard Chertkow Sir Mortimer B.

Diagnosis 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

Pfizer, Janssen, Lundbeck, Servier, Neurochem, Novartis
Disclosure Statement HC has been a paid consultant or received honoraria for participation in CME/advisory boards or grant funding from: Pfizer, Janssen, Lundbeck, Servier, Neurochem, Novartis

Objectives To update current diagnosis and treatments for AD and the dementias across the continuum Primary Prevention: rationale MCI : new evidence Mild to Moderate AD: current standards and new approaches Moderate to Severe AD: new rx possibilities

Most 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?

Any 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 driving Any individual with impairment in multiple IADLs or a single ADL should be told to stop driving Because of anxiety, on-road driving tests are not a fair evaluation of driving ability in a demented individual - neuropsych and clinical testing is better

Regarding mild cognitive states: MCI and CIND are identical labels (European vs. American
Amnestic MCI always leads to Alzheimer Disease In the >65 year population, there are twice as many individuals with CIND as there are with dementia The evidence suggests that Donepezil is effective in MCI and should be offered to all MCI patients

Projected Prevalence of Dementia (per 1,000) 1991 - 2031
800 All Dementias 700 600 AD 500 400 300 x 2 x 3 200 Doubling of dementia > 2013; trebling > 2030. Assumes no treatment or prevention Data used in modeling disease in Canada (POHEM) Vascular 100 1991 2001 2011 2021 2031 CSHA Working Group CMAJ 1994; 150:

Projected Prevalence of AD
300,000 Alzheimer’s Cases Today - > 750,000 Projected Within a Generation 850 750 650 150 250 350 450 550 750 500 000’s In 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. 300 2000 2011 2031 Canadian Study of Health & Aging Working Group. CMAJ 1994; 150:

AD 47% 19% VaD 9% Other Mixed = 10% 3% 2% DLB 2% FTD 5%
Feldman et al, 2003: Accord Study Neuroepidemiology,22;265-74

Defining 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 function construction/visuospatial function abstraction personality Impairment is sufficient to interfere with function and Activities of Daily Living. Insidious, and > 6 months (ICD-10)

Facts about dementia and AD
250,000 dementia cases in Canada 778,000 dementia cases by 2031 Annual cost = 3.9 billion dollars 747/1125 (66%) of dementia cases in CSHA were due to AD 95% sporadic Incidence / Prevalence  with age Patterson et al., Can J Neurol. Sci 2001 Ostbye et al., CMAJ 1994

Differential Diagnosis of Dementia
Other dementias Frontal lobe dementia Creutzfeldt-Jakob disease Corticobasal degeneration Progressive supranuclear palsy Many others 8% Vascular dementias Multi-infarct dementia Binswanger’s disease 5% Lewy body dementias Parkinson’s disease Diffuse Lewy body disease Lewy body variant of AD 7% Vascular dementias and AD 10% AD and Lewy body dementias 5% AD 65% 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:

Classifying Dementia Cortical Dementias (68%) Alzheimer’s Disease
Definite Probable Possible Frontotemporal (Picks) Focal Dementias Progressive aphasia Semantic dementia Reversibles (3%) depression drugs tumor subdurals metabolic Non-reversible 97% Subcortical Dementia Multi-infarct (10%) Mixed AD, MID (15%) Lewy Body Dem. NPH PSP Other HIV,Parkinsons

Therapeutic Strategies
Detection Latency Traumatisms Vascular risk factors Symptomatic Treatment Cholinergic replacement therapy Symptoms Induction Genetic/hereditary Secondary Prevention (“Mild cognitive Impairment”) Antioxydants Anti-inflammatories Neurotrophic factors Estrogens Pathogenesis Primary Prevention Vaccine Estrogen NSAID Ginkgo Disease Vascular Prevention

ACE-inhibitors are the recommended medication to treat vascular and mixed dementia
There is no specific medication to treat vascular dementia The presence of vascular lesions increases occurrence of clinical dementia by a factor of 2 The presence of vascular lesions increases occurrence of clinical dementia by a factor of 20

Vitamin 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 patients Certain cognitive therapy programs (but not general cognitive stimulation) have been demonstrated to improve symptoms of memory loss and delay progression Cholinesterase inhibitors have proven efficacy at all stages of dementia, and should be carefully considered as therapy

Third Canadian Consensus Conference on Diagnosis and Treatment of Dementia March 9-11, Hotel Delta President Kennedy Montreal, Quebec

Procedure Steering 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 reviews Preparation of recommendations and background reviews Web posting of 203 rec’s, voting by 42 authors Consensus = 80% approval Discussion at meeting of “non-consensus” recommendations, revision, re-voting. 147 recommendations reached consensus These were rated as high, medium, low education priorities by an FP panel. Only high and medium recommendations are presented here.

Criteria for assigning levels of evidence
1 Evidence obtained from at least 1 properly randomized controlled trial. 2a Evidence obtained from well-designed controlled trials without randomization. 2b Evidence obtained from well-designed cohort or case-control analytic studies, preferably from more than 1 centre or research group. 2c Evidence obtained from comparisons between times or places with or without the intervention. Dramatic results in uncontrolled experiments are included in this category. 3 Opinions of respected authorities, based on clinical experience, descriptive studies or reports of expert committees.

Grades of recommendations
Criteria A There is good evidence to support this manœuvre B There is fair evidence to support this manœuvre. C There is insufficient evidence to recommend for or against this manœuvre, but recommendations may be made on other grounds. D There is fair evidence to recommend against this procedure. E There is good evidence to recommend against this procedure.

Christopher Patterson
Topic 1 Assessment and management of risk factors, and primary prevention strategies Christopher Patterson MacMaster University Angela Garcia Chris McKnight Dessa Sadovnik Robin Hsuing

The Alzheimer Brain

Cummings, 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):

Risk factors for developing AD
Definite Risk Putative-Recent Putative-Older Protective age women depression NSAIDS Apo E4 Low education Head trauma Estrogen? Family history Vascular factors alcohol Smoking? MCI Hyper-tension Aluminum?

Pharmacological 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 dementia 2 intervention studies with negative results (PROSPER, Lancet 2002; MRC/BHF, Lancet 2004) Atrial Fibrillation Diabetes Smoking The presence of cerebral lacunar infarcts Increases the rate of dementia by a factor of 20  stroke Snowdon et al, JAMA (1997), vol. 277,

Brookmeyer, 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),

Recommendations 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)

Recommendations 6,7,10. While there is insufficient evidence to make a firm recommendation, physicians may advocate for strategies: to reduce head injury for greater education to wear appropriate protection during during administration of pesticides, fumigants.fertilizers and defoliants There 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. !

Concept, utility, and management of MCI and CIND
Topic 2 Concept, utility, and management of MCI and CIND Howard Chertkow, Howard Bergman Fadi Massoud, Yves Joannette Ziad Nasreddine, Sylvie Belleville

Complaints in “Normal Cognitive Aging”
SHORT VERSION Even “normal” people may complain of memor changes Problems include: Trouble concentrating in the presence of distraction Decreased ability to attend multiple channels Difficulty multi-tasking Difficulty recalling names of acquaintances Spatial memory problems Slowing of reaction time Delayed verbal memory becomes mildly decreased Key Points One 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 distraction Decreased ability to attend to multiple channels Difficulty multi-tasking Difficulty recalling names of people who are acquaintances Spatial memory problems Slowing of reaction time Delayed verbal memory becomes mildly decreased These individuals will score "normal" for age and education on neuropsychological tests. References Jonker 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.

CIND Prevalence Over Age 65
Dementia (n = 861) (n = 1132) 65 to 74 yrs 11.0% 2.4% 75 to 84 yrs 24.0% 11.2% > 85 yrs 30.3% 34.7% Overall 16.8% 8.0% Graham J et al: Lancet 349: , 1997

Model of Continuum of Cognition with Aging
Normal Mild cognitive impairment Probable AD Function Dementia Definite AD/Dementia Age Jacob we will need to put in 2 animation buttons with dotted rectangles First dotted rectangle will be around normal and will fade out at the next mouse click Second dotted rectangle around normal and mild cognitive impairment (roughly half way down between the MCI and probable AD line of decline

Mild Cognitive Impairment
Memory complaints Memory impaired for age ( generally 1.5 SD) General cognitive function: normal for age Normal activities of daily living Not meeting dementia criteria Clinical Dementia Rating Score of 0.5 Petersen RC et al Arch Neurol 56(3)

Recommendations (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 dementia There 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)

Detecting MCI: The MoCA
SHORT VERSION Montreal Cognitive Assessment (MoCA), a cognitive screening tool for detection of MCI 30-point scale MCI = MOCA <26 Using a cut-off score <26 provides sensitivity of 80%, and specificity of 91% to distinguish MCI from normal Available free in English and French at Key Points The 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. References Nasreddine 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,

Recommendations In 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)

Recommendations – 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).

Common Risk Factors for Developing MCI
SHORT VERSION Elevated systolic BP1 Hypertension2 Elevated cholesterol in mid-life3 Low level of education4 African-American descent4 Cerebral infarcts evident on MRI4 Depression4 Mechanisms may be vascular atherosclerotic mechanisms, or directly through hastening the pathophysiology of AD. Key Points Recognizing risk factors can help lead to the identification of patients with MCI and promoting prevention. Common risk factors for developing MCI include: Elevated systolic BP1 Hypertension2 Elevated cholesterol in mid-life3 Low level of education4 African-American descent4 Cerebral infarcts evident on MRI4 Depression4 The risk factors listed above are similar to those for dementia The 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. References Launer 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.

Are 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’s Researchers now reject this theory as insufficient Decreased Acetylcholine may be non-specific Abnormalities in other chemical systems present as well GABA, glutamine, Seritonin D. Drachman (1997), NEJM, vol.336,

Donepezil in MCI To evaluate efficacy & safety of donepezil therapy for treating patients with MCI 24-wk, RCT, DB, placebo study in US 270 patients with predefined evidence of MCI Randomization 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 Recall NYU Paragraph Immediate Recall; Modified ADAS-cog, WMS-R Digit Span Backwards, Symbol Digit and Patient Global Assessment Objectives Design Primary Secondary Salloway S et al 2003 Neurology S

Patient Global Assessments
MCI 40 Donepezil* (n=83) 35 Placebo (n=100) Improved 61.4% Donepezil 51.0% Placebo Worse 1.2% Donepezil 14.0% Placebo 30 Patients (%) 25 20 15 *P=0.007 10 5 Very much improved Much improved Minimally improved Unchanged Minimally worse Much worse Very much worse Fully evaluable at week 24

MCI 3-year Trial with Vitamin E and Donepezil
Memory Impairment =MCI Alzheimer’s disease Donepezil Placebo 6 12 18 24 30 36 Months Petersen et al, New England Journal, (2005,) vol.352,

Conversion to AD by Treatment Group
1 yr 2 yr 3 yr 1.0 0.9 0.8 Probability of not converting to AD 0.7 Donepezil 0.6 Vitamin E Placebo 0.5 D–P P=0.416 E–P P=0.912 0.4 200 400 600 800 1,000 1,200 Time on MCI study (days) CP

Conversion to AD by ApoE Status
1.0 0.8 Probability of not converting to AD 0.6 ApoE4 negative 0.4 ApoE4 positive P<0.0001 0.2 200 400 600 800 1,000 1,200 Time on MCI study (days) CP

Probability of Converting to AD For Apoe E4 Positive Participants

Recommendations There is currently insufficient evidence to recommend for the use of cholinesterase inhibitors in MCI. (Recommendation Grade C, Evidence level I)

Disease-modifying Treatments
Ginkgo Biloba Mild efficacy Non-regulated product Estrogens Compelling epidemiological data Disappointing intervention trials NSAID’s/Prednisone Very mild efficacy Prohibitive side effect profile Vitamine E One major RCT showed delayed progression of AD (death, institutionalization, deteriorating function and dementia) with high doses (1000 UI BID) (Sano et al., NEJM 1997)

Clinical Studies in MCI
SHORT VERSION Treatments Findings Estrogen, combined Estrogen/Progesterone ERT Negative Anti-inflammatories, NSAIDs Statins Preliminary positive Nootropics (Piracetam – pyrrolidine acetamide) AMPA modulator (Ampakine CX516) Anti-oxidants (e.g., Vitamin E) Mixed results Key Points There 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. References Petersen 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 approved Petersen RC et al. Arch Neurol, 2001; Almkvist O et al. J Neural Trans Suppl, 1998; Sramek JJ et al. Ann Pharmacother, 2000.

Recommendations There 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)

Topic 3 Diagnosis and differential diagnosis of dementia for the primary care practitioner and consultant: clinical laboratory, imaging, markers Howard Feldman, Hyman Schipper, Alain Robillard, Andrew Kertesz, Claudia Jacova, Dessa Sadovnick Tiffany Chow, Michael Borrie

Recommendations - 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)

Recommendations 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)

Biomarkers

Tau Isoforms & Antibodies
1.Blennow & Hampel (2003), Lancet Neurology 2. Hampel et al., (2004), Archives of General Psychiatry

CSF T-Tau: 2 Assays: Innogenetics Athena Elevated in: Head trauma
Stroke Encephalitis Guillain-Barre ALS But Normal in: Depression Parkinson’s Disease Alcohol overuse Felt to be non-specific marker of neuronal destruction 1.Blennow & Hampel (2003), Lancet Neurology 2. Hampel et al., (2004), Archives of General Psychiatry

CSF T-Tau Sensitivity 1.Blennow & Hampel (2003), Lancet Neurology
2. Hampel et al., (2004), Archives of General Psychiatry

Abeta42 ELISA 1.Blennow & Hampel (2003), Lancet Neurology

CSF ABeta 42 CSF levels of Total Abeta disappointing as CSF marker
ABeta 42 is principal component of plaques Decreased ABeta 42 found in diverse CNS diseases including: MSA ALS CJD 1.Blennow & Hampel (2003), Lancet Neurology 2. Hampel et al., (2004), Archives of General Psychiatry

CSF ABeta42 Sensitivity 1.Blennow & Hampel (2003), Lancet Neurology

T-Tau: Specificity Hulstaert et al. Neurology1999;52:1555-1562
Multicentre retrospective review of clinically diagnosed patients with: AD – 150 subjects Controls (healthy & neurologic) –100 Non-AD Dementia: Vascular 33 FTD 11 NPH 20 Other degenerative 15/79

Specificity of T-Tau, AB42 Hulstaert et al. Neurology 1999;52:1555-1562
AD vs. Cntrl AD vs. other dementia AB42 81% 59% Tau 70% 57% AB42,Tau 87% 58%

Phospho-Tau Antibodies

Phospho-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, 396/404 Not ↑’d in stroke or Creutzfeldt-Jakob dz ALS, Parkinson’s Depression Vascular, frontotemporal, or Lewy Body Dementia

CSF Phospho-Tau Sensitivity

Summary until Now AB42 and Total-Tau Phospho-Tau
Highly sensitive tests (80-90%) Highly specific relative to healthy controls But other dementias correctly classified 60% of the time (relative to clinical diagnosis) 70% of the time (relative to pathological diagnosis) Phospho-Tau Classifies FTD well (spec. 92%) VD/LBD classified ~70% correctly

Recommendations on Biomarkers
To Primary Care Physicians Biological 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.

To Specialists Although 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).

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

Structural Neuroimaging

Atrophy 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 severely Figure from: 8.

Hippocampal volume in Alzheimer’s disease
AD Normal tMTL width = 2.6 mm tMTLwidth = 14.6 mm Speaker notes Comparison of hippocampal size using the thinnest medial temporal lobe (tMTL) width between a 68-year-old woman with Alzheimer’s disease (AD) and a 67-year-old woman normal control. Dark lines cross the thinnest width of the hippocampus and arrowheads indicate hippocampal boundaries. ©Gao FQ and Black SE, Sunnybrook & Women’s College Health Sciences Centre, U of T

Clarfield criteria for CT:
age < 70 new onset dementia , < 1 year atypical presentation rapid unexplained deterioration unexplained focal signs, symptoms head injury incontinence, gait ataxia need for reassurance of patient, family 1.Clarfield, CMAJ, (1991), vol.144(7), 2.Patterson et al., (1999) CMAJ, vol.160,(Supp.12),S1-15

Recommendations-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.

SPECT scan of normal control vs AD
Alzheimer’s Disease Sandra E. Black-S&W-U of T

Recommendations - 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)

Recommendations – 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)

Genetics and Dementia: Risk Factors, Diagnosis, & Management
Topic 4 Genetics and Dementia: Risk Factors, Diagnosis, & Management Ging-Yuek Robin Hsiung A. Dessa Sadovnick

Genetic 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)

Management of mild to moderate Alzheimer's disease
Topic 5 Management of mild to moderate Alzheimer's disease David Hogan, Malcolm Hing Peter Bailey, Krista Lanctot Linda Thorpe

Outcome measures used in AD and AD + CVD trials
Function (DAD, ADCS-ADL, BrADL) Cognition (ADAS-Cog, MMSE) Global (CIBIC-plus) Speaker notes Because 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. References ADCS-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-S32 ADAS-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 burden SCGB, ACTS

Available AChE inhibitors for AD
Selectivity T1/2 Starting dose Minimal effective dose Usual recommended dose (mg) Donepezil AChEI Approx. 70 h 5 Qam 5-10 mg/d Galantamine AChEI & Nicotinic modulator 7-10 h 4 bid 8 bid 8-12 bid Rivastigmine AChEI & BuChEI 1-2 h 1.5 bid 3 bid 3-6 bid Speaker notes Currently, 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. References Aricept® Product Monograph, 2004 Reminyl® Product Monograph, 2004 Exelon® Product Monograph, 2004

Frequency of prescription and cost
Cost in Canada: $ /year

Galantamine maintains cognitive benefits in AD over 12 months
Improvement * Mean change (± SE) in ADAS-Cog/11 from baseline Galantamine 24 mg / galantamine 24 mg Placebo / galantamine 24 mg Historical placebo group Speaker notes In 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-blind Open-label extension Deterioration *p < 0.05 vs placebo / galantamine and NS from baseline Months Raskind MA, et al. Neurology 2000;54:2261; Torfs K, et al. Neurobiol Aging 2000;21(suppl 1):1109A Stern RG, et al. Am J Psychiatry 1994;151:390

Galantamine at 36 months: Responder analysis
Speaker notes This slide shows the percentage of patients with a given level of response to continuous treatment with galantamine 24 mg daily over 36 months. In this analysis, 80% of patients had an increase in ADAS-Cog/11 scores that was ≤ 20 points; the expected increase in untreated patients would be 20 to 22 points. Thus, at least 80% of the patients in this study derived cognitive benefits from continuous long-term treatment with galantamine. Remarkably, 17.6% actually maintained or improved their cognitive capabilities for the entire 3-year study interval, and over half had an increase of 10 points or less. These data are also consistent with the idea that galantamine is a disease-modifying drug. Reference Raskind MA, Peskind ER, Truyen L, Kershaw P, Damaraju CV. The cognitive benefits of galantamine are sustained for at least 36 months: a long-term extension trial. Arch Neurol 2004;61: Copyright © 2004, American Medical Association. All rights reserved. n = 119 Change in ADAS-Cog score over 36 months Raskind MA, et al. Arch Neurol 2004;61:252

However, Response to these drugs is variable.
Changes in psychometric performance gives impression of small effects. Are these drugs worth it?

Cholinesterase Inhibitors
Should Be Considered In Patients With Mild To Moderate Ad (Standard) Although Studies Suggest A Small Average Degree Of Benefit Vitamin E (1000 I.U. Po Bid) Should Be Considered In An Attempt To Slow Progression Of Ad (Guideline)

AChEIs: 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.

AChEIs: Numbers Needed to Treat Lanctot et al CMAJ 2003
For global response : improvement NNT = 12 (95% CI 9-16) For cognitive response: improvement 4 pts ADAS NNT = 10 (95% CI 8-15) For harm: adverse event NNT = 12 (95% CI –10-18) Comparison to other disorders Depression NNT = 4 Psychosis NNT = 3 5 year prevention stroke, MI or death = 29-86 NNTs in other disorders Psychosis NNT 3 with neuroleptics Depression NNT 4 with antidepressants 5 year prevention stroke, MI or death with antihypertensives 29-86

Meta-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.

Memantine Voltage Dependency in Alzheimer’s Disease
Magnesium Physiological Magnesium Block Low to Moderate Affinity Antagonist Memantine (Ki = 0.5 µM) Memantine M Depolarization Ca2+ –50 mV Synaptic Activity –20 mV Resting State –70 mV Purpose: To illustrate memantine’s voltage dependency and how it blocks pathological activation of the receptors while preserving cognitive ability Key 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 tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data, pages , copyright 1999, with permission from Elsevier.

Memantine Selectively Blocks Pathological Activation of NMDA Receptors
Memantine Blocks Glutamatergic Activation and Chronic Neurodegeneration Pathological Activation of NMDA Receptors Memantine Facilitates Cognitive Activity Rest M Abnormal Ca 2+ Ca 2+ M Noise Noise Signal Noise Purpose: To illustrate how memantine works hypothetically Key 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. Magnesium Glutamate Calcium Memantine M Reprinted from Neuropharmacology, Vol 38, CG Parsons, W Danysz, G Quack. Memantine is a clinically well tolerated N-methyl-D-aspartate (NMDA) receptor antagonist—a review of preclinical data, pages , copyright 1999, with permission from Elsevier.

Recommendations – 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) !

Recommendations – 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)

Recommendations – 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)

Recommendations – 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 of cognitive training/cognitive rehabilitation environmental interventions other 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)

Recommendations Medications 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)

Anti-Inflammatory studies in AD
Length Outcome Subjects Author Hydroxychloroquine 18 mos neg n=168 Van Gool et al Prednisone 12 mos n= 138 Aisen et al Naproxen n= 351 Rofecoxib n= 692 Reines et al Nimesulide 3 mos n= 40 Diclofenac 6 mos neg * n= 41 Scharf et al Indomethacin 6 months pos n= Rogers et al Celecoxib abstract Van 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 decline Aisen 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 negative Aisen 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 hypertension Reines 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 subgroup Rogers 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 out Celecoxib absract only from Stockholm Springfield meeting 2002 Naproxen acts through cyclooxgenase inhibition; not protective against cell toxicity

CNS Cholesterol Metabolism
Abeta  Asecretase cholesterol Poirier J. Trends in Molecular Medicine (2003)

Cholesterol 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 substrate Bodovitz S. et al., 1996

Atorvastatin in AD Atorvastatin 80 mg vs placebo
12 month RCT mild to moderate AD Concurrent AchEIs allowed Evaluable data on 63 subjects OC n = 46 ADAS cog, CGIC benefit reported at 12 months Additional benefit on LDL Of those signing informed consent 98 subjects 12 screen failures; 15 withdrew prior to screen 8 withdrew after baseline visit Sparks L et al 8th International Montreal Springfield Conference 2004

Recommendations 18a. 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) !

Recommendations 18e. 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)

Amyloid  vaccination: reduced plaques and improved cognition
NATURE MEDICINE • VOLUME 7 • NUMBER • JANUARY 2001 Vaccination 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 mice Slide courtesy of Dr. Howard Feldman

PDAPP Transgenic mice 13 months
Hippocampal Dentate Gyrus Overexpress mutant human APP driven by a platelet derived (PD) growth factor promoter Transgenic Mouse: APP mutation Ab42- injected mice at 6 weeks Slide courtesy of Dr. Howard Feldman Schenk et al., Nature 1999:

Post 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 Feldman Nicoll JAR et al Nature Medicine, Apr 2003, 9(4):

Fig 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):

GAG-Mimetics Glycosaminoglycans (GAGs) contribute to the amyloidogenic cascade by promoting the Aβ fibrillogenic process that leads to plaque formation Can 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

Driving 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) ! !

Driving 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)

Recommendations – 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)

Clinical practice guidelines for severe Alzheimer's disease
Topic 6 Clinical practice guidelines for severe Alzheimer's disease Nathan Herrmann Serge Gauthier

Cognition in MSAD Donepezil Plus Memantine
3.5 3 2.5 2 1.5 1 0.5 Change From Baseline -0.5 -1 -1.5 -2 Memantine/donepezil -2.5 Placebo/donepezil Design: 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 ADL Secondary outcomes: CIBIC + adapted from ADCS CGIC; NPI 12 items, Rating scale for Geriatric patitents care dependency subscale N=404 randomized 50/50 spit (202 memantine and 201 placebo) 85% completer rate for memantine/donepezil and 75% placebo/donepezil completer rate SIB + P<0.001 and ADCS ADL + P=0.028 CIBIC + P=0.027 NPI significant on total score -3 -3.5 4 8 12 18 24 Treatment Week LS mean difference -1.2 -1.9 -3.0 -2.6 -3.4 P value 0.057 0.006 < 0.001 0.004 < 0.001 N = 404 Tariot PN et al. JAMA, 2004, 291(3):317-24

Cognition (SIB) Moderate to Severe AD
P<.0001 6 -6 -4 -2 2 4 6 -8 -10 -12 P=.0051 P<.0009 P<.0001 P=.0078 P=.0001 4 Clinical improvement 2 P<.001 P=.002 Difference in SIB Score Baseline LS Mean Change From Baseline ± SE -2 MMSE 11.8 MMSE 7.9 Clinical decline Donepezil Memantine -4 Placebo Placebo -6 4 8 12 18 24 ITT LOCF 4 12 28 LOCF Endpoint Study Week Study Week Donepezil MMSE 5-17 Memantine MMSE 3-14 Feldman et al. Neurology. 2001;57: Reisberg et al. N Engl J Med. 2003;348:

Memantine Plus Donepezil Reduced Behavioral Changes
5 + 3.7 4 Change In NPI Score (ITT LOCF) 3 2 1 -0.1 -1 Memantine + Donepezil Placebo + Donepezil Tariot et al, JAMA 2004: 291:

Recommendations Patients 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]

Recommendations Pharmacological 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

Management of dementia with a cerebrovascular component
Topic 7 Management of dementia with a cerebrovascular component Sandra Black, Christian Bocti

Vascular dementia (VaD) and AD+CVD: NINDS−AIREN criteria
Probable VaD Dementia severe enough to interfere with ADLs CVD (focal signs, CT/MRI evidence of relevant lesions) A relationship between the above two disorders Possible VaD Dementia and focal signs, but no confirmatory CT/MRI Temporal relationship between dementia and stroke is unclear CVD with cognitive deficit of subtle onset and variable course AD+CVD Possible VaD + clinical/imaging evidence for relevant CVD Speaker notes This 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 include Early gait disturbance Early unsteadiness or frequent unprovoked falls Early urinary symptoms not related to urologic disease Pseudobulbar palsy Subcortical deficits (eg, emotional incontinence, psychomotor retardation).

Hyperintensities (HI) Affecting ACh WM Tracts
Deep white HI Selden NR et al. Brain 1998;121: External capsule HI Extensive periventricular HI RH Swartz, S&W, U of T

Recommendations 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 interventions Investigations 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)

Recommendations Antiplatelet 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).

Recommendations – 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)

Robin Hsiung Dessa Sadovnik
Topic 4 Genetic and Dementia Robin Hsiung Dessa Sadovnik

From Chromosome to base pairs

Autosomal Dominant Pattern
only one copy of the disease gene is needed to develop phenotype

Autosomal Recessive Pattern
two copies of the disease gene are needed to develop phenotype

Genes associated with AD

Diagrammatic representation of APP domains
Signal peptide Heparin binding site 1 Acidic domains Globular (cys) domains CuBD ZnBD-1 Heparin binding site 2 KPI OX-2 CHO Growth Promoting region Glycosylated domains A b d b a g Secretase sites Transmembrane domain ZnBD-2 Exon 15 Cytoplasmic domain

Primary structure of A amyloid
Senile plaque Amyloid Congophilic Angiopathy b secretase a secretase g secretase NH TEEISEVKMDAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVIATVIVITLVMLKKK---COOH

A and Pathogenesis of AD
Transmembrane APP Extracellular Intracellular APP mutations increase b-secretase cleavage Ab42 peptide Amyloidogenic g-secretase activity increased by PS1/PS2 mutations a-secretase Non-amyloidogenic Ab Oligomer aggregate

Genes associated with FTD

Hypothetic situations for counseling
II-5 is symptomatic, so she should be the first to test in this family III-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 onset III-7 would like PGT, but II-6 does not III-6 is a minor III-5 is pregnant

Number of 1st degree relative affected
Relative Risk of AD in a patient with positive family history but no clear autosomal dominant inheritance Number of 1st degree relative affected Age of Onset Relative Risk 95% C. I. 1 60-69 5.3 2.8-10 70-79 2.3 80 and over 2.6 1.3-5. overal 3.5 2 or more overall 7.5 From Table 2.1 Chapter 2. Atlas of Alzheimer Disease

Predictive 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

Recommendations – on testing for genetic risk factors
Genetic 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)

Ethical issues in dementia
Topic 8 Ethical issues in dementia John Fisk, Lynn Beattie Martha Donnelly, Anna Byszewski Frank J. Molnar

Disclosure of the diagnosis of dementia
John D. Fisk, B. Lynn Beattie, Martha Donnelly, Anna Byszewski and Frank Molnar.

The 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.

Both 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%)

The potential for adverse psychological consequences must be assessed and addressed through education of the patient and family/caregivers. (Level 3, Grade B: 100%)

Once 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%)

Follow-up plans must be made and discussed at the time of diagnostic disclosure. (Level 3, Grade A: 97%)

The process of diagnostic disclosure must be evaluated.

Requirements: 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.

Requirements: Primary care physicians must also have available to them knowledge of available support services for patients and their care providers.

Ethical Considerations for Decision-Making for Treatment and Research Participation

A 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.

At 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.

Therefore, 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.

Clinicians 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.

Since 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.

For 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.

As 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.

Conclusions: Mild Cognitive Impairment: Mild to Moderate AD:
No suggested symptomatic/preventative therapy Mild to Moderate AD: AchEIs standard of care Amyloid modifying therapies in clinic Guide to driving cessation Moderate to Severe AD: Efficacy for donepezil + memantine Vascular/Mixed Dementia: CI’s-some evidence

Conclusions: Current trials for:
amyloid antiaggregants/gamma secretase inhibitors cholesterol modulating drugs other modulators of glial response incl vaccines neurotrophin like agents glutamatergic/AMPA modulating drugs

Regarding mild cognitive states: MCI and CIND are identical labels (European vs. American)
Amnestic MCI always leads to Alzheimer Disease In the >65 year population, there are twice as many individuals with CIND as there are with dementia The evidence suggests that Donepezil is effective in MCI and should be offerred to all MCI patients

Vitamin 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 patients Certain cognitive therapy programs (but not general cognitive stimulation) have been demonstrated to improve symptoms of memory loss and delay progression Cholinesterase inhibitors have proven efficacy at all stages of dementia, and should be carefully considered as therapy

ACE-inhibitors are the recommeded medication to treat vascular and mixed dementia
There is no specific medication to treat vascular dementia The presence of vascular lesions increases occurrence of clinical dementia by a factor of 2 The presence of vascular lesions increases occurrence of clinical dementia by a factor of 20

Any 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 driving Any individual with impairment in multiple IADLs or a single ADL should be told to stop driving Because of anxiety, on-road driving tests are not a fair evaluation of driving ability in a demented individual - neuropsych and clinical testing is better

Funding Support FRSQ Canadian Institutes for Health Research
Alzheimer’s Society of Canada

Industrial Support Pfizer Inc. Novartis Inc. Janssen-Ortho Inc.
Neurochem Inc. Lundbeck Inc.

Diagnosis and Treatment of Alzheimer Disease and Dementia: Results from the Third Canadian Consensus Conference Dr. Howard Chertkow Sir Mortimer B.

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Diagnosis and Treatment of Alzheimer Disease and Dementia: Results from the Third Canadian Consensus Conference Dr. Howard Chertkow Sir Mortimer B.

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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:

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