National Press Foundation R. Scott Turner, MD, PhD Director, Memory Disorders Program Professor, Department of Neurology Georgetown University Washington, DC memory.georgetown.edu

Case 1 A 64 year old judge was referred by her PCP for evaluation of memory loss. Her husband reports memory loss and repeating questions for about 18 months. Her colleagues and law clerks have expressed concerns due to several small mistakes. She reports that she has “fallen a little behind at work”, and is planning to retire in 1 month because she has lost the “trust and confidence” of her colleagues…

Case 1 She has a history of well-controlled hypertension and takes only an anti- hypertensive medication. She has no other medical or psychiatric history. There is no history of stroke, TIA, alcohol abuse, gait disorder, falls, or head trauma. Her parents died in their 60’s of “old age”. She works as a judge and lives with her husband. She states that at one time her IQ was “170”.

Risk factors for AD Age Family history/genetics –ApoE polymorphism –Minority Downs syndrome Head injury with LOC Smoking Hypertension Diabetes Stroke Low education, occupational level

NIH conference April 2010 Factors that may affect risk of both AD & cognitive decline with aging (ARHQ publication 10-E005; Plassman et al., Annals of Internal Medicine; Archives of Neurology, 2011) Increase risk –ApoE4, diabetes, current smoking, depression Decrease risk –Physical activity, Mediterranean diet/vegetable intake, cognitive training/cognitively engaging activities 5

ADLs Complex –Working, living alone, driving, keeping appointments, handling finances, daily medications… Basic –Dressing, bathing, grooming, toileting, walking, transfers, eating…

Case 1 Pleasant, cooperative, and well- appearing elderly woman. Vital signs normal, as is the general medical examination. Mental status examination reveals good attention with deficits in memory, orientation, language, and visuospatial skills. The MMSE score is 25/30, with points off for orientation and memory, consistent with a mild dementia.

MMSE is Alzheimer’s disease- centric

Case 1 The remainder of the neurological examination reveals normal eye movements, strength, tone, sensation and coordination. There are no signs of parkinsonism. Reflexes are 2+ and symmetric. Gait is normal. There are no asymmetric features.

Case 1 A CBC, chemistry panel, thyroid function tests, and B 12 were all normal. A test for syphilis was negative. A head MRI revealed cortical atrophy and periventricular white matter changes (“small vessel ischemic changes”). No tumor, hemorrhage, subdural hematoma, or large cerebral infarct. Neuropsychologic evaluation confirmed mild dementia, with deficits in memory, language, visuospatial skills, and frontal/executive function, and a lower than expected IQ.

Case 1 …has multiple cognitive deficits which impair her functional abilities and represent a cognitive decline. There is no evidence for delirium or depression by history, examination, or laboratory evaluation. Diagnosed with mild dementia due to probable Alzheimer’s disease.

Case 1 prescribed a cholinesterase inhibitor; effects and side-effects of the drug were discussed. advised to continue treatment for hypertension with her primary care physician. discussed prognosis, advance directives, and limitations concerning complex ADLs, including driving, handling finances, taking medications... recommended ad libitum physical activity, social activity, and mental activity. Qualified and interested, thus offered enrollment in a 12 month clinical trial of drug x (add-on to current drug therapy).

> 65 years old SS established 1935

21 September 2009 World Alzheimer Day; World Alzheimer Report released

Clinical Criteria for AD Probable AD (NINCDS-ADRDA) –Dementia on clinical examination and neuropsychologic testing –Deficits in two or more areas of cognition –Progressive worsening –No disturbance of consciousness –Onset 40-90, usually > 65 –All else ruled out McKhann et al, Neurol 1984

Clinical Criteria for AD Possible AD –Dementia with atypical presentation or course for AD –With a second disorder which may cause dementia Definite AD –Probable AD diagnosed clinically –Brain tissue diagnostic for AD McKhann et al, Neurol 1984

Diagnostic criteria A. Dementia Interferes with ability to function at work or at usual activities A decline from a previous level of functioning Not delirium or psychiatric disorder Diagnosed by history, examination Involves at least 2 cognitive domains: Memory Reasoning and judgment Visuospatial Language Personality, behavior, comportment Alzheimer’s and Dementia, April 2011

Diagnostic criteria A. Probable AD Dementia Insidious onset Worsening of cognition over time Amnestic vs. non-amnestic presentation Not due to another dementia diagnosis B. Probable AD with evidence of AD pathophysiology A  (CSF or amyloid PET) Neuronal injury (CSF tau, FDG-PET, structural MRI) Alzheimer’s and Dementia, April 2011

Neuropathology of AD Cruz et al, PNAS 1997

Kretzschmar, 2009

Reagan Pathologic Criteria for AD LikelihoodLowIntermediateHigh Neuritic plaques and neurofibrillary tangles A more limited distribution or severity Limbic regionsNeocortex CERAD plaque scoreinfrequentmoderatefrequent Braak and Braak stagingI/IIIII/IVV/VI Neurobiology of Aging 18, S1-S2, 1997

Amyloid Precursor Protein (APP) catabolism AA NH 2 COOH  -secretase p3  -secretase (presenilin) AA  -secretase  -secretase (BACE-1)

Apolipoprotein E (ApoE) Strittmatter et al, Science 1993 Genetics of sporadic AD

The amyloid cascade APP----->soluble A  --->insoluble A  -->neuronal-->neuronal amyloid morbidity mortality diffuse plaque, NP NFT, ghost tangles loss of synapses, enzymes loss of neurotransmitters excitotoxicity inflammatory responses apoptosis? mitochondrial & oxidative injury Normal cognition >memory loss-->dementia-->death (mild, moderate, severe) APP, PS-1, and PS-2 mutations ApoE4 Downs Age ? Turner, Seminars in Neurology 2006

The amyloid cascade APP----->soluble A  --->insoluble A  -->neuronal-->neuronal amyloid morbidity mortality diffuse plaque, NP NFT, ghost tangles loss of synapses, enzymes loss of neurotransmitters excitotoxicity inflammatory responses apoptosis? mitochondrial & oxidative injury Normal cognition >memory loss--->dementia-->death (mild, moderate, severe) A  immunization?  - or  - secretase inhibitors? Turner, Seminars in Neurology 2006

The amyloid cascade APP----->soluble A  --->insoluble A  -->neuronal-->neuronal amyloid morbidity mortality diffuse plaque, NP NFT, ghost tangles loss of synapses, enzymes loss of neurotransmitters inflammatory responses excitotoxicity apoptosis? mitochondrial & oxidative injury Normal cognition >memory loss--->dementia-->death (mild, moderate, severe) cholinesterase inhibitors memantine Turner, Seminars in Neurology 2006

FDA-approved drugs for dementia due to AD Donepezil (Aricept) tablet, orally-disintegrating tablet 5 mg daily, increase to 10 mg daily after 4-6 weeks; then 23 mg daily after 3 months (optional) Rivastagmine (Exelon) capsule, transdermal patch, liquid 1.5 mg twice daily, increase to 3, 4.5, and 6 mg twice daily in 2 week intervals 1 patch daily (4.6 mg daily, increase to 9.5 mg daily after 4 weeks) Galantamine (Razadyne, Razadyne ER) tablet, ER capsule, liquid 4 mg twice daily, increase to 8 and 12 mg twice daily in 4 week intervals for ER, 8 mg daily, increase to 16 and 24 mg daily in 4 week intervals Memantine (Namenda, Ebixa) tablet, liquid Start 5 mg daily, increasing in 1 week intervals up to 10 mg twice daily

Donepezil (Aricept) Rogers et al, Neurology 1998

Donepezil (Aricept) Rogers et al, Eur Neuropsychopharmacology 1998

Confidential Avid 18 F-PET Aß - Amyloid Imaging Healthy 74 F MMSE 30 AD 77 F MMSE F-AV45 Distinguishes Patients with AD from Cognitively Normal Controls

CSF biomarkers Shaw et al, Annals Neurology 2009 A  42 Tau Normal AD

Langbaum et al, Neuroimage 2009 FDG- PET: AD MCI

AD brains reveal atrophy -- particularly in regions mediating higher cognitive functions

MRI atrophy in MCI & AD McDonald et al, Neurology 2009

CSF Aβ42 FDG-PET MRI hipp CSF tau Cog Fxn

Prevalence of MCI Petersen et al, Archives of Neurology 2009

MCI: Rates of Progression to Dementia Petersen et al, Archives of Neurology 2009

MCI Progression Petersen et al, Archives Neurology 2009

Goals of AD therapy Cure Arrest Progression Symptomatic Therapy (NOW) Natural Course Cognition Time

Phase II Bapinezumab with PIB-PET Rinee et al, Lancet Neurology, March 2010

Summary We are witnessing a growing epidemic of dementia in the US and the world, most of which is AD The amyloid hypothesis is alive and well, and does not exclude other important and essential pathologic processes The genetics of familial AD provides the strongest evidence for the amyloid hypothesis Despite recent high-profile failures, many active trials target A  /amyloid generation or clearance Other AD trials target other essential pathologic processes, with the probable result of a therapeutic cocktail (as now…)

Summary Current (FDA-approved) therapies for AD provide consistent yet modest, temporary, and palliative benefits We are searching for disease-modifying treatments to halt dementia progression, or prevent dementia onset We are in need of validated biomarkers for: screening, diagnostic accuracy, evidence of efficacy, reduction of the cost of clinical trials (decreased numbers of participants) Treatments and prevention will increasingly target subjects with MCI, then healthy high-risk individuals Future treatments will be tailored to ApoE genotype (pharmacogenomics, personalized medicine)

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