1. ©pspilman2015

2.  The hippocampus & cortex are
areas of brain affected by AD
 “Hippocampus” means
“seahorse”, it is important for
spatial memory*.
2
*Maguire J. Neurosci. 1997
©pspilman2015

3.  Neurons store information
 Neurons communicate with
each other through synapses
 In AD, synaptic connections
are lost
 Then dendrite “branches” are
lost
 Eventually, the neurons dies
Other cell types are involved:
 Oligodendricytes
 Astrocytes
 Microglia
 Endothelia 3
©pspilman2015

4.  AD brain tissue has
microscopic Ab plaques &
 Neurofibrillary tangles
 The brain shrinks in
advanced AD
 Hippocampus can virtually
disappear
4
©pspilman2015

5.  There are currently ~
3-4 million people in
the US with AD.
 The available drugs
provide only
temporary
symptomatic relief.
 New approaches
are necessary.
5
 There is greater freedom to explore new
ideas using a pharmaceutical model in an
academic setting.
©pspilman2015

6.  We identified a
compound “F03”
that increases
pro-cognitive
sAPPa.
 F03* is now in
clinical trials for
Mild Cognitive
Impairment
(MCI)
“Anti-AD”
6
*Spilman Brain Res. 2014
We also have an improved version of F03 moving
toward clinical trials!
©pspilman2015

7.  Early & accurate
diagnosis &
treatment are
key.
 More than one
intervention will
likely be
necessary.
 Drugs are more
likely to work if
health is
improved.
Early diagnosis of
cognitive
impairment
Healthstyle
support
“Multimodal
treatment”
7
See a description of Dr. Dale E. Bredesen’s MEND in Impact Aging
(www.impactaging.com) Sept 2014 & Aug 2015
©pspilman2015

8. Intake
Scientific/biochemical
bases for how what/when
we eat & how
medications we take
affect cognition are
presented.
The importance of social
interaction, intellectual
challenges, exercise, &
general health to the
preservation of cognition
are discussed.
8
©pspilman2015

9.  Exercise improves
cognitive function!
 Use body & mind together
by dancing, playing tennis
or golf, or by yoga practice
 Strength building is equally
important – it increases
Brain-Derived Neurotrophic
Factor (BDNF)*
9*Nascimento Curr. Alz. Dis. Res. 2014©pspilman2015

10.  Walking/hiking combined
with a navigational*
challenge is excellent for
spatial memory.
 Walk with a friend.
 Take a break from “Nav”
apps – look at a map!
Try new routes, and re-enforce with
return trips.
*Brown, J. Neurosci. 2014
10
©pspilman2015

11.  Reduced estrogen/androgen associated
with decreased bone density.
 Have calcium levels measured,
supplement if necessary
 Have vitamin D3 levels measured
 Strength training increases bone density.
 Sunscreen may reduce vitamin D
conversion to active form
There is correlation between bone density &
cognitive decline*.
*Zhou, Curr Alzheimer Res. 2014
11
©pspilman2015

12.  Brain debris,
including Ab, are
cleared during sleep.
 Memories are
consolidated during
sleep.
 Lack of sleep impairs
cognition* &
increases disease.
 Keep room dark &
cool.
Avoid chronic use of sleep
aids such as zolpidem** &
diphenhydramine# if possible.
12
*Kreutzmann, Neuroscience. 2015; **Levy Expert Rev Clin Pharmacol. 2014;
#Chen, Acta Pharmacol Sin. 2001
©pspilman2015

13.  Apnea (cessation of
breathing while sleeping)
leads to damage to the
brain*.
 Apnea prevents restorative
sleep & can cause vascular
disease.
 It is caused by chronic
respiratory disease,
inflammation, orthopedic or
neurological issues.
13
*Arli, Appl Neuropsychol Adult. 2014
 A CPAP mask can help.
 Also address causative
health issues, like obesity.
©pspilman2015

14. 14
 Chronic stress increases tau
phosphorylation & tangles.
 Exercise & sleep relieve stress.
 Yoga & daily meditation are
also good - meditation
preserves gray matter
(neurons).
 Pets, comedy, & music all
reduce stress.
 Mindful-Based Stress
Reduction increases
“functional connectivity.*”
 Some “stress” is good.
*Wells, Neurosci. Lett. 2014
©pspilman2015

15.  Creating music stimulates brain areas
important for neurogenesis (new cell
formation)
 Learn to play an instrument…
 …even your own voice
 Music triggers memory
 A great book: Oliver Sacks’
Musicophilia
 A great documentary:
Alive Inside - Music & Memory
15
©pspilman2015
*Cuddy Annal NY Acad Sci 2015

16.  Humor, comedy & laughter can
effectively relieve stress.
 Social laughter is correlated with an
elevated pain threshold”.*
 A great book: Norman Cousin’s
Anatomy of an illness.
 Laughter can relieve stress &
depression.
 Laughter Improves short-term memory.
 Kawaii (cuteness) improves focus.
*Dunbar et al Proc Biol Sci. 2012 Mar 22;279(1731):1161-7
16
©pspilman2015

17.  Loss of sensory input impairs
cognition*.
 Hearing – have it tested, get hearing
aids.
 Have aldosterone levels determined &
corrected.
 Olfaction (smell) – focus on olfactory
experiences.
 Sight - Keep eyeglass prescriptions up-
to-date.
 Taste – add variety!
Expand all sensory experiences. 17
*Bush. Ear Hear. 2015
©pspilman2015

18.  Use all of your cognitive abilities.
 Try something new.
 Be a teacher.
 Discuss ideas.
 Master a new skill.
 Focus intently on a new subject.
 Consider video* or brain training
software or games to follow
performance.
Why are we expected to learn less as
we age?
18
*Kuhn Mol. Psychiatry 2014
©pspilman2015

19.  Give yourself a sense of purpose
beyond career.
 Volunteer using your skill set.
 Interact with & contribute to your
community*.
 Maintain inter-generational
relationships.
 Pursue spirituality, whatever that
means to you.
 Help your friends to do this too!
19
*Paganini-Hill Alz. Dis & Assoc. Dis. 2015
©pspilman2015

20. X
X
X
 Share activities with friends & family.
 Be a “good” host providing healthy
choices.
 Suggest a walk after a meal.
 The holidays do not have to be
unhealthy!
 Friends & spouses share similar
“healthstyles”.*
 Share your knowledge.
20
*Christakis N Engl J Med. 2007
©pspilman2015

21. ?
Not
Accurate Diagnosis is Critical
Diagnostics include:
Computer-assisted tomography (CAT) for structural
abnormalities
Positron emission tomography (PET) for glucose use
& amyloid imaging
Function magnetic resonance (fMRI) for blood flow
Tests of cognitive function
Other causes of memory loss:
Depression, infection, multiple sclerosis, low B12,
hypothyroidism, medication interactions, tumor
Not all dementia is AD:
Vascular dementia, Parkinson’s/Lewy Body
disease, frontotemporal dementia
Memory & Aging Centers at UCSF/Stanford
©pspilman2015

22.  You can donate to the Buck Institute.
 You can donate to a specific laboratory.
 You can donate to the Drug Discovery lab as
an individual or as an action group.
 Meet with our team to discuss “Venture
Philantropy” – your contribution might be a
better investment than you can imagine!
 Get updated reports and presentations with
your support.
 www.theBuck.org
©pspilman2015

23. 23
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right hippocampus in taxi drivers. J Neurosci. 1997 Sep 15;17(18):7103-10.
2. Spilman P, Descamps O, Gorostiza O, Peters-Libeu C, Poksay KS, Matalis A, Campagna J,
Patent A, Rao R, John V, Bredesen DE. The multi-functional drug tropisetron binds APP and
normalizes cognition in a murine Alzheimer's model. Brain Res. 2014 Mar 10;1551:25-44.
3. Bredesen DE. Reversal of cognitive decline: a novel therapeutic program. Aging (Albany
NY). 2014 Sep;6(9):707-17.
4. Nascimento CM, Pereira JR, de Andrade LP, Garuffi M, Talib LL, Forlenza OV, Cancela
JM, Cominetti MR, Stella F. Physical exercise in MCI elderly promotes reduction of pro-
inflammatory cytokines and improvements on cognition and BDNF peripheral levels. Curr
Alzheimer Res. 2014;11(8):799-805.
5. Brown TI, Whiteman AS, Aselcioglu I, Stern CE. Structural differences in hippocampal and
prefrontal gray matter volume support flexible context-dependent navigation ability. J
Neurosci. 2014 Feb 5;34(6):2314-20.
6. Zhou R, Zhou H, Rui L, Xu J. Bone loss and osteoporosis are associated with conversion
from mild cognitive impairment to Alzheimer's disease. Curr Alzheimer Res. 2014;11(7):706
7. Kreutzmann J, Havekes R, Abel T, Meerlo P. Sleep deprivation and hippocampal
vulnerability: changes in neuronal plasticity, neurogenesis and cognitive function.
Neuroscience. 2015 Apr 29.
8. Levy HB. Non-benzodiazepine hypnotics and older adults: what are we learning about
zolpidem? Expert Rev Clin Pharmacol. 2014 Jan;7(1):5-8.
©pspilman2015

24. 24
9. Chen Z, Chen JQ, Kamei C. Effect of H1-antagonists on spatial memory deficit evaluated
by 8-arm radial maze in rats. Acta Pharmacol Sin. 2001 Jul;22(7):609-13.
10. Arli B, Bilen S, Titiz AP, Ulusoy EK, Mungan S, Gurkas E, Oztekin ZN, Ozcan M, Ak F.
Comparison of Cognitive Functions Between Obstructive Sleep Apnea Syndrome and
Simple Snoring Patients: OSAS May Be a Modifiable Risk Factor for Cognitive Decline. Appl
Neuropsychol Adult. 2014 Dec 12:1-5.
11. Wells RE, Yeh GY, Kerr CE, Wolkin J, Davis RB, Tan Y, Spaeth R, Wall RB, Walsh J,
Kaptchuk TJ, Press D, Phillips RS, Kong J. Meditation's impact on default mode network and
hippocampus in mild cognitive impairment: a pilot study. Neurosci Lett. 2013 Nov 27;556:15
12. Bush AL, Lister JJ, Lin FR, Betz J, Edwards JD. Peripheral Hearing and Cognition: Evidence
From the Staying Keen in Later Life (SKILL) Study. Ear Hear. 2015 Jan 13.
13. Cuddy LL, Sikka R, Vanstone A. Preservation of musical memory and engagement in
healthy aging and Alzheimer's disease. Ann N Y Acad Sci. 2015 Mar;1337:223-31.
14. Kühn S, Gleich T, Lorenz RC, Lindenberger U, Gallinat J. Playing Super Mario induces
structural brain plasticity: gray matter changes resulting from training with a commercial
video game. Mol Psychiatry. 2014 Feb;19(2):265-71.
15. Paganini-Hill A, Kawas CH, Corrada MM. Lifestyle Factors and Dementia in the Oldest-
old: The 90+ Study. Alzheimer Dis Assoc Disord. 2015 Mar 6.
16. Christakis NA, Fowler JH. The spread of obesity in a large social network over 32 years. N
Engl J Med. 2007 Jul 26;357(4):370-9.
©pspilman2015