National Press Foundation R. Scott Turner, MD, PhD Director, Memory Disorders Program Professor, Department of Neurology Georgetown University Washington, DC memory.georgetown.edu [email protected].
Download ReportTranscript National Press Foundation R. Scott Turner, MD, PhD Director, Memory Disorders Program Professor, Department of Neurology Georgetown University Washington, DC memory.georgetown.edu [email protected].
National Press Foundation R. Scott Turner, MD, PhD Director, Memory Disorders Program Professor, Department of Neurology Georgetown University Washington, DC memory.georgetown.edu [email protected] 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 antihypertensive 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 wellappearing 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 diseasecentric 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 B12 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 www.actionalz.org/about_wad.asp 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 • Ab (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 Likelihood Low Intermediate High Neuritic plaques and neurofibrillary tangles A more limited distribution or severity Limbic regions Neocortex CERAD plaque score infrequent moderate frequent Braak and Braak staging I/II III/IV V/VI Neurobiology of Aging 18, S1-S2, 1997 Amyloid Precursor Protein (APP) catabolism Ab NH2 COOH b-secretase (BACE-1) a-secretase g-secretase (presenilin) p3 g-secretase Ab Genetics of sporadic AD Apolipoprotein E (ApoE) Strittmatter et al, Science 1993 The amyloid cascade Downs APP----->soluble Ab--->insoluble Ab-->neuronal-->neuronal amyloid morbidity mortality diffuse plaque, NP NFT, ghost tangles APP, PS-1, loss of synapses, enzymes and PS-2 ApoE4 loss of neurotransmitters mutations ? excitotoxicity inflammatory responses apoptosis? Age mitochondrial & oxidative injury Normal cognition--------->memory loss-->dementia-->death (mild, moderate, severe) Turner, Seminars in Neurology 2006 The amyloid cascade Ab immunization? APP----->soluble Ab--->insoluble Ab-->neuronal-->neuronal amyloid morbidity mortality diffuse plaque, NP NFT, ghost tangles b- or gloss of synapses, enzymes secretase loss of neurotransmitters inhibitors? excitotoxicity inflammatory responses apoptosis? mitochondrial & oxidative injury Normal cognition--------->memory loss--->dementia-->death (mild, moderate, severe) Turner, Seminars in Neurology 2006 The amyloid cascade APP----->soluble Ab--->insoluble Ab-->neuronal-->neuronal amyloid morbidity mortality diffuse plaque, NP NFT, ghost tangles loss of synapses, enzymes loss of neurotransmitters cholinesterase inflammatory responses inhibitors excitotoxicity memantine apoptosis? mitochondrial & oxidative injury Normal cognition--------->memory loss--->dementia-->death (mild, moderate, severe) 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 18F-AV45 Distinguishes Patients with AD from Cognitively Normal Controls Avid 18F-PET Aß-Amyloid Imaging AD 77 F MMSE 24 Healthy 74 F MMSE 30 Confidential Tau CSF biomarkers AD Normal Shaw et al, Annals Neurology 2009 Ab42 FDGPET: AD MCI Langbaum et al, Neuroimage 2009 AD brains reveal atrophy -particularly in regions mediating higher cognitive functions MRI atrophy in MCI & AD McDonald et al, Neurology 2009 FDG-PET CSF Aβ42 MRI hipp Cog CSF tau 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 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 Ab/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) memory.georgetown.edu