Treatment of Treatment of Neurodegenerative Disorders Neurodegenerative Disorders Stephen P. Salloway, MD, MS Stephen P. Salloway, MD, MS Butler Hospital and Butler Hospital and Brown Medical School Brown Medical School
Transcript
Slide 1
Slide 2
Treatment of Neurodegenerative Disorders Stephen P. Salloway,
MD, MS Butler Hospital and Brown Medical School
Slide 3
Slide 4
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
Slide 5
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
Slide 6
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.
Slide 7
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
Slide 8
Age is the biggest risk factor for AD
Slide 9
Slide 10
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.
Slide 11
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
Slide 12
Slide 13
Mild-Mod AD, Mod-Severe AD
Slide 14
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
Slide 15
Age 27 Time: 2:37:07 (1 st Place) 1935 Age 83 Time: 5:42:54
1991 John A. Kelley in the Boston Marathon
Slide 16
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
Not all patients with MCI have AD, but almost all patients with
AD pass through an MCI stage
Slide 19
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)
Slide 20
Subtle Findings in MCI MMSE=26MMSE=21 MCIAD
Slide 21
1/29/2004MMSE=26
Slide 22
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%
Slide 23
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
Slide 24
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
Slide 25
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
Slide 26
Slide 27
Courtesy of Dr. Mark Mintun
Slide 28
Braak Staging of AD Trans-entorhinal (I-II)Limbic
(III-IV)Isocortical (V-VI)
Slide 29
% 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
Slide 30
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
Slide 31
Amyloid Imaging Pittsburgh compound
Slide 32
Slide 33
Assessment Clinical history Primary symptoms from patient and
informant Onset and course Gradual, abrupt Were there events?
Determining baseline cognitive and functional ability
Slide 34
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
Slide 35
Assessment Motor and Gait weakness, numbness, lateralizing?
Parkinsonism Bladder control Other medical conditions and
medications Family history: dementia, psychiatric,
neurological
Slide 36
Modern medicine relies on the premise of early diagnosis and
treatment to prevent or delay morbidity.
Slide 37
Moderate AD Age 77 Sep 1998 Age 79 Aug 2000 Age 82 Oct 2002
MMSE: 19 MMSE: 15MMSE: 12 Age 84 2004 MMSE 10