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

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

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

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Projected Prevalence of AD 16 14 12 0 2 4 6 8 10 2000 20102020203020402050 4 5.8 6.8 8.7 11.3 14.3 Millions 4 Million AD Cases Today Over 14 Million Projected Within a Generation Year Evans DA et al. Milbank Quarterly. 1990;68:267-289.

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Alzheimers Disease Risks Established Age Apolipoprotein E 4 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 Geldmacher, 2001; Knopman, 2002

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Age is the biggest risk factor for AD

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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) 7790.

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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

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Mild-Mod AD, Mod-Severe AD

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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

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

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Ed Whitlock, Age 73 First person over 70 to break the three-hour mark. Ran Toronto Waterfront Marathon in 2:54:49, placing 26 th 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. Ed Whitlocks 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

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

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

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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)

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Subtle Findings in MCI MMSE=26MMSE=21 MCIAD

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1/29/2004MMSE=26

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Volume of AD Cases by Specialty Source: NDTI (Diagnosis codes: 3310, 2900, 2901, 2902, 2903, 2904, 3109, 2912), Moving Annual Total (MAT). March 2001. Source: Market Measures, February 2000. 120 0 IM Specialists providing careNumber of dementia patients in physicians practice NeuroPsych 180 99 63 121 60 GP/FP 48 PCP 67% Neuro 18% Psych 8% Other 7%

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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

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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

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Mann DMA. BMJ. 1997(Oct 25);315:1078-1081 The Temporal Course of Neuropathological Changes of AD in Downs Syndrome Age 10 20 30 40 50 60 70 AmyloidDeposition Microglial Changes Neurofibrillary Tangles Neuronal Loss/ NeurochemicalChanges Dementia

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Courtesy of Dr. Mark Mintun

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

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

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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

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Amyloid Imaging Pittsburgh compound

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

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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 Domains Assessment IADLs = instrumental ADLs; BADLs = basic ADLs

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

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

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

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