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Conflicts of Interest Update in the Diagnosis, � No Conflicts of Interest Treatment and Prevention of Dementia* Katherine Julian, M.D. Professor of Clinical Medicine University of California, San Francisco August 7, 2013 Case Questions... EM is a 67 year-old woman with a h/o high blood pressure. Brought in by husband who is reporting that patient’s personality has changed � Does EM have dementia or over the last year. She is becoming more Alzheimer’s Disease (AD)? suspicious, and at times talks and “doesn’t make � How do I make the sense”. diagnosis? 1

Outline AD Prevalence � AD estimated prevalence � Clinical Presentation 24.3 million world-wide � Diagnosis in 2001 � Predicted rise to 42.3 � Updates in Treatment million in 2020 � Updates in Prevention � 81.1 million by 2040 � Resources � Lifetime risk of dementia after age 65 is 17-20% � Costs $150 billion/yr Ferri CP, et al. Lancet 2005; Simmons BB et al. AAFP 2011 Dementia Types Pathophysiology of AD � Neuritic plaques � Alzheimer’s: most common, 70% � Amyloid precursor protein cleaved � Vascular dementia: approx 17% � Makes b eta amyloid protein � Other types: 13% � Accumulation initiates cell death � Neurofibrillary tangles � Parkinson-related � filaments of abnormally phosphorylated tau protein � Alcohol � Loss of neurons � Dementia with Lewy Bodies Cholinergic, noradrenergic, � serotonergic neurotransmitters � Is it amyloid deposition that kills neurons OR are neurons being damaged by something else? 2

Risk Factors for AD/Dementia Clinical Presentation of Dementia � Cognitive changes � Age � Personality changes � Down’s syndrome � Changes in day-to-day functioning � Head trauma � IADLs that require calculation/planning first to be � Fewer years of formal education impaired � Psychiatric symptoms � Female sex � Problem Behaviors � Family history � Dementia under-diagnosed � Vascular risk factors (DM, htn, smoking) � High index of suspicion � Ask caregivers/surrounding family and friends Rapid Screening for Cognitive Definitions of Dementia* by Impairment DSM5 � Routine screening not recommended; complete Dementia screen for those who screen positive � Variety of office screening tests � No longer using the term “dementia” � Neurocognitive disorder � MMSE sens 80-85% � 7-min screen sens 93% � Due to… � Alzheimer’s Disease � MOCA sens 90% � Vascular Disease � Clock drawing sens 97% � Lewy Body, etc J Hort JT, et al. European Journal of Neurology, 2010 3

DSM5 Neurocognitive Disorders DSM5 Neurocognitive Disorders (NCD) (NCD) � Minor neurocognitive disorder � Major neurocognitive disorder � Modest cognitive decline from a previous baseline � Evidence of substantial cognitive decline in one or more � Can be in any domain (ex: memory, language, executive function, domains etc) � Based on pt’s concerns AND knowledgeable informant (or clinician) � Based on pt’s concerns AND knowledgeable informant (or AND clinician) AND � Decline in neurocognitive performance (1-2 SD below normal) on � Decline in neurocognitive performance (>2 SD below normal) formal testing or equivalent clinical evaluation on formal testing or equivalent clinical evaluation � Cognitive decline doesn’t interfere with independence but � Cognitive decline is sufficient to interfere with requires some compensation independence (ex: requires assistance with IADLs or � Can’t occur due to delirium ADLs) � Deficits can’t be from another mental disorder (ex: depression) � Example: Mild cognitive impairment: impairment doesn’t � Can’t occur due to delirium affect function � Deficits can’t be from another mental disorder Work-Up of Cognitive “Reversible” Dementias…do they exist? Impairment � Meta-analysis in 2003 � American Academy of Neurology � 5620 subjects; potentially reversible causes in 9%; recommendations: 0.6% actually resolved � Vitamin B12, thyroid, depression screen � Causes of “dementia” in meta-analysis � Other tests as indicated: blood count, urine � 56% AD 20% vascular tests, liver tests, syphilis test, lumbar puncture � 1% metabolic 0.9% depression � 0.1% medications � Neuro imaging (CT or MRI) � 15% Other (NPH, subdural hematoma, B12, tumor, � Do we need to do this? Parkinson’s disease, HIV, frontal lobe) Clarfield AM. Archives of Internal Medicine, 2003;163. 4

“Reversible” Dementias…do they Neuro-Imaging – Updates exist? � Most reversible dementias were in patients who: � Semi-quantitative MRI � Were relatively young � Medial temporal lobe atrophy in AD � Had mild or atypical symptoms � New studies looking at hippocampal and cortical thickness � Neuroimaging detected conditions in 2.2% � PET with fluorodeoxyglucose measures glucose metabolism ( 18 F-FDG-PET) � 0.9% tumor, 1% NPH, 0.3% SDH � Hypometabolism in temporal/parietal regions � Most did not change course of illness � Approved in US for dx purposes of AD in early stages � Reversible dementias less common � Sens/spec estimate 86% (wide variation) � Must weigh costs/benefits of neuro-imaging � PET with beta-amyloid ligands will visualize beta-amyloid deposition � AGS recommends imaging: age <60, rapid decline (weeks/months), CA, HIV, anti-coagulation � May overlap with other brain pathologies Clarfield AM. Archives of Internal Medicine, 2003;163. Example of 18 F-FDG-PET Diagnosis of AD – Updates � Abnormal CSF biomarkers � Low beta-amyloid � Increased tau/phosphotau concentrations � No consensus on cutoff points for real practice � Perfusion SPECT � Resolution less but less expensive Alzheimer’s Disease Neuroimaging Initiative, Jan 2010 5

Diagnostic Instruments Diagnostic Instruments � Mini Mental Status Exam � MMSE � Maximum score 30 � Survey of 18,056 adults � Score <24 suggests delirium or dementia � Scores relate to age � Decline of 4 points over 1-4 years significant � Median score 29 in those 18-24 years � Scores correlated with education level; inversely � Median score 25 in those >80 years correlated with age � Scores relate to educational level � Not sensitive in people with higher levels of � Median score 29 in those with >9 years schooling education � Median score 22 in those with 0-4 years schooling Crum RM et al. JAMA, 1993;269(18) Diagnostic Instruments…Take Diagnostic Instruments…Take Home Points Home Points � Caution in interpreting MMSE score � Highly educated individuals � Consider appropriate age/education median scores � Hopkins Verbal Learning Test � MMSE scores for age/education: � Given 12 words; check recall on 3 different trials http://www.angelfire.com/retro/michaelpoon168/mini_ � Decoy words given mental_state_examination_normative%20data.htm � Neuropsychological testing (accessed 7/9/13) � May be better in detecting early impairment in highly � Median LR for positive result 6.3 (CI 3.4-47) educated individuals � If positive initial screen, can consider further testing if appropriate Holsinger T, et al. JAMA, 2007;297. Holsinger T, et al. JAMA, 2007;297. 6

Diagnostic Instruments…Take Case Home Points � Tests not quite ready for “prime time”… 78 year-old woman recently diagnosed with � PET scanning (although approved) Alzheimer’s Disease. MMSE score is 19. � MRI What should you do next? � CSF ß-amyloid Start an acetylcholinesterase inhibitor 1. 84% � CSF tau (ex: donepezil or aricept) � APOEε4 genotyping Start memantine 2. � Not enough evidence for USPSTF to Do not start any medications at this 3. recommend screening for dementia in primary 14% time 2% 0% care Discuss with the family/patient their 4. . . . . . . . . . . . . y n a t t i t h e t r t c n a i a a t w m s n s a e t s m o u wishes regarding treatment t n r c a t o s t r D D i S a t S Symptomatic Treatment of Memory Treatment of AD Disturbance � Clarify goals � Cholinesterase Inhibitors delay degradation of � Preserve function and independence acetylcholine at the synaptic cleft. Indicated for mild- � Maintain quality of life moderate Alzheimer’s Disease � Minimize excess disability and ensure safety � Donepezil (Aricept)--5-10mg/day � Make long-term decisions early � Rivastigmine (Exelon)--6-12mg/day � Treatment Options � May cause weight loss � Symptomatic treatment of memory disturbance � Galantamine (Razadyne)--24-32mg/day or patch 4.6- 9.5mg � Symptomatic treatment of behavioral disturbance � May cause weight loss � Disease-modifying treatment 7