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Treatment of Neurodegenerative Disorders

Treatment of Neurodegenerative Disorders. Stephen P. Salloway, MD, MS Butler Hospital and Brown Medical School. Disclosure.

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Treatment of Neurodegenerative Disorders

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  1. Treatment of Neurodegenerative Disorders Stephen P. Salloway, MD, MS Butler Hospital and Brown Medical School

  2. Disclosure Research Support, Consultation and Honorarium: Eisai, Pfizer, Johnson and Johnson, Forest, Lilly, Novartis, Aventis, Athena, Ono, Neurochem, Elan, Myriad and Sention, NIH, Alzheimer’s Association Off label discussion of CHEI for mild cognitive impairment and Memantine for mild-moderate AD

  3. Life Expectancy in Years Year Most of Us Will Be Living Out Our Full Lifespan and a Major Goal Is Healthy (Brain) Aging • Median survival of women in the longest-lived countries has increased 3 months per year since 1840 Oeppen J et al. Science. 2002;296:1029-1031

  4. 2000 2010 2020 2030 2040 2050 Projected Prevalence of AD 4 Million AD Cases Today—Over 14 Million Projected Within a Generation 16 14.3 14 11.3 12 10 8.7 Millions 8 6.8 5.8 6 4 4 2 0 Year Evans DA et al. Milbank Quarterly. 1990;68:267-289.

  5. Established Age Apolipoprotein E ε4 genotype 4/4 increases risk 8 fold, any 4 increases risk 3 fold Chromosome 1, 14, 21 mutations Family history of dementia-RR 3.5 Family history of Down syndrome-RR 2.7 Head trauma with LOC-RR 1.8 History of Depression-RR 1.8 Others Low educational level, female gender Alzheimer’s Disease Risks Geldmacher, 2001; Knopman, 2002

  6. Age is the biggest risk factor for AD

  7. Teaching Old Dogs New Tricks • 2 year study, old beagles (7-11 years; n=48) 4 groups divided into 1) antioxidant-fortified diet, 2) program of behavioral enrichment, 3) both, or 4) neither. • Discrimination and reversal learning ability decline progressively with advanced age in beagles, but the rate of decline was delayed by both behavioral enrichment and antioxidant supplementation. • Behavioral enrichment and antioxidant supplementation combined were more effective than either alone. Milgram et al., Neurobiology of Aging 26 (2005) 77–90.

  8. Keeping Our Synapses Healthy • Stay mentally and physically active-read, do crossword puzzles, play bridge and games, walk, exercise, go to the gym • Stay involved with people and projects- socialize, pursue hobbies and volunteer work, learn new things, play music, participate in church activities • Control risk factors-weight, BP, chol, blood sugar, stop smoking • Eat a balanced diet with Vit E-animals on calorie restriction live longer, low calories may decrease risk of AD. ? Red wine-resveratrol

  9. Mod-Severe AD Mild-Mod AD,

  10. Normal Aging • Psychomotor Slowing • Taking longer to do things • A 75 year old marathon runner takes twice the time to complete the race as he or she did at age 25. • Recalling names or trouble finding specific words • “What did I come here for?” • Troublesome signs • Being repetitive and not just for emphasis • Not coming up with the names or words later • Not recalling that conversations or events ever took place • Not realizing that there is a memory problem

  11. John A. Kelley in the Boston Marathon Age 27 Time: 2:37:07 (1st Place) 1935 Age 83 Time: 5:42:54 1991

  12. Ed Whitlock, Age 73 Ed Whitlock’s Fastest Times Since Turning 70 EVENT TIME AGE 5,000 meters 18:22 73 10,000 meters 37:33 73 15,000 meters 58:55 72 Marathon 2:54:49 73 • First person over 70 to break the three-hour mark. • Ran Toronto Waterfront Marathon in 2:54:49, placing 26th out of 1,690 finishers. • Was a runner in high school and university, then stopped running for 20 years. • Began running again at age 41.

  13. MCI Amnestic Alzheimer’s Disease MCI Multiple Domains Slightly Impaired Alzheimer’s Disease Vascular Dementia (VaD)? Normal Aging Frontotemporal Dementia (FTD) Lewy Body Dementia (LBD) Primary Progressive Aphasia (PPA) Parkinson’s Disease (PD) Alzheimer’s Disease MCI Single Non- Memory Domain Subtypes of Mild Cognitive Impairment

  14. Not all patients with MCI have AD, but almost all patients with AD pass through an MCI stage

  15. What is Mild Cognitive Impairment? • Disorder of short-term memory (> 1.5 SD) • Misplacing things a lot • Hard to recall messages, remember details, and appointments • Normal functioning overall • More than a nuisance • Risk factor for AD (12-15% per year)

  16. Subtle Findings in MCI MMSE=26 MMSE=21 MCI AD

  17. 1/29/2004 MMSE=26

  18. Volume of AD Cases by Specialty Specialists providing care Number of dementia patientsin physician’s practice 180 Other7% Psych8% 120 121 99 Neuro18% 60 63 48 0 PCP67% IM Neuro Psych GP/FP Source: NDTI (Diagnosis codes: 3310, 2900, 2901, 2902, 2903, 2904, 3109, 2912), Moving Annual Total (MAT). March 2001. Source: Market Measures, February 2000.

  19. Recommendations for Screening • At annual physical or when warning signs appear • Ask the patient and a knowledgeable informant about any problems with memory, mood, behavior or problems driving • Do a baseline MMSE and clock drawing • If time is short do the 3 word recall during the exam and clock drawing

  20. Neurodegenerative Disorders • Protein dysmetabolism • Vulnerable cell populations • Neural systems affected • Specific regions and neurotransmitters • Clinical phenotype • Systems linked to cognitive and behavioral changes • Disability • Age dependent onset • Genetic and environmental risk factors • ApoE and head injury

  21. Age Amyloid Deposition 10 Microglial Changes 20 Neurofibrillary Tangles 30 Neuronal Loss/ Neurochemical Changes 40 Dementia 50 60 70 The Temporal Course of Neuropathological Changes of AD in Down’s Syndrome Mann DMA. BMJ. 1997(Oct 25);315:1078-1081

  22. Courtesy of Dr. Mark Mintun

  23. Braak Staging of AD Trans-entorhinal (I-II) Limbic (III-IV) Isocortical (V-VI)

  24. Change in Hippocampal Volume from Normal Aging through AD % of nlconversion rate>50% of nl 9%1-50% 26%1st % 50% Normal AD MCI Jack Neurology 1999;52:1397-1403

  25. PET for the Diagnosis of Dementia • Medicare Guidelines • Atypical course for AD and FTD is suspected • Comprehensive eval conducted by a physician experienced in dementia • PET reading done by a physician experienced in dementia imaging • No prior SPECT or PET • Clinical trials using PET for dx of early dementia may be covered

  26. Amyloid Imaging • Pittsburgh compound

  27. Assessment • Clinical history • Primary symptoms from patient and informant • Onset and course • Gradual, abrupt • Were there “events”? • Determining baseline cognitive and functional ability

  28. Assessment Domains • Cognitive • Memory, language • Fluctuations? • Activities of daily living (ADLs) • IADLs, BADLs, driving, hobbies • Behavioral • Mood, irritability, impatience, apathy • Delusions, visual hallucinations, paranoia • Substance use • Sleep, appetite IADLs = instrumental ADLs; BADLs = basic ADLs

  29. Assessment • Motor and Gait • weakness, numbness, lateralizing? • Parkinsonism • Bladder control • Other medical conditions and medications • Family history: dementia, psychiatric, neurological

  30. Modern medicine relies on the premise of early diagnosis and treatment to prevent or delay morbidity.

  31. Moderate AD Age 79 Aug 2000 Age 82 Oct 2002 Age 84 2004 Age 77 Sep 1998 MMSE: 15 MMSE: 12 MMSE: 19 MMSE 10

  32. p-value = 0.0001 (Kruskal-Wallis ANOVA) 300 AD DLBD* 250 PD* NC 200 LBV** 150 100 50 0 MF ChAT There is a Pronounced Cholinergic Deficit Early in LBD *p<0.05 compared to AD; p<0.001 Compared to NC (Dunn’s multiple comparisons test); **p<0.001 compared to AD and NC (Dunn’s multiple comparisons test); Tiraboschi P, Hansen LA, Alford M. Neurology. 2000;54:407-411

  33. Cholinesterase Inhibitors for AD • Tacrine (Cognex) • Donepezil (Aricept) • Physostigmine SR (Synapton) • Rivastigmine (Exelon) • Metrifonate • Galantamine

  34. Benefits of CHEI for AD • Stabilize functioning during the first year and make subsequent decline more gradual • Delay time to nursing home placement • May decrease behavioral symptoms • Show some benefit in moderate severe stages of AD • The CHEI’s have similar efficacy but may have differences in tolerability and ease of use

  35. Donepezil Pivotal Trials ADAS-cog scores in mild to moderate AD 2.5 1.5 Clinical improvement 0.5 Baseline -0.5 Mean change from baseline ( SE) Clinical decline -1.5 Donepezil 5 mg/d Donepezil 10 mg/d Placebo -2.5 -3.5 Baseline 6 12 18 24 30 Study week Rogers SL, et al. Neurology.1998;50:136-145.

  36. Delay Time to Nursing Home Placement

  37. Most Common Side-Effects With Cholinesterase Inhibitors • Gastrointestinal • Nausea, Vomiting, Loose stools, Diarrhea • Anorexia and weight loss • Vivid Dreaming Symptoms are usually transient and dose related-titrate slowly and take with food A small percentage become agitated on CHEI’s

  38. MCI - Amnestic

  39. Cognitive Change in the 24 week Donepezil MCI Trial P=.007 P=.044 (n=130) (n=132) (n=83) (n=100) ITT-LOCF FE* *FE=fully evaluable Salloway et al. Neurology. 2004;63:651-657.

  40. Results of the 36 month ADCS MCI Conversion Trial • Conversion rate to dementia was 13% per year, 98% determined to be to AD • APOE-ε4 + 55.1%.Rate of conversion was significantly higher in the APOE4 positive group • There was no significant effect of donepezil or vitamin E on conversion over the full 3 year study • Donepezil appeared to decrease the probability of conversion for up to 18 months and delay the conversion to dementia by 6 months overall • The delay to conversion was greatest in the APOE4 positive group

  41. Lancet 2004;363: 2105-2115

  42. X X X No driving at night No driving on highways Local driving only Not Driving Gets lost No strange places Driving Evaluation Driving and Dementia Normal Driving No driving due to crash Bad Option!

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