healthy aging and dementia research update 2019 - du.edu · healthy vs. not so healthy aging goldie...
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Healthy Aging and dementia
Research Update 2019
Knoebel Institute for Healthy Aging
Quality in Life, Wellness and Community
Lotta Granholm
Knoebel Institute for Healthy Aging
University of Denver
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Outline❖ How to stay healthy
❖ The Aged Brain
❖ How can we study aging?
❖ Animal/cell studies
❖ Biomarkers
❖ Clinical outcome studies
❖ What is dementia?
❖ Different forms of dementia
❖ Down syndrome and AD
❖ Pathological changes
❖ Protein aggregation (amyloid/tau)
Neuronal loss
Inflammation
http://selfhealthguide.blogspot
.com/2012/10/the-blue-
zones.html
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Healthy vs.
not so healthy Aging
Goldie Hawn, 72 years oldKeith Richards 73
But appearance is only one aspect of aging:
It is who you are on the inside that
matters!
“You don't stop laughing when you grow
old, you grow old when you stop laughing.”
― George Bernard Shaw
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“10 Keys”™ to Healthy Aging
University of Pittsburgh
How do we age successfully?
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Blue zones Centenarian Lifestyle Geographic properties
Philosophical outlook – jovial -purpose
Eat until 80% full
Move naturally, no stress
Fish, vegetables, legumes, barley, goat milk
Red wine in moderation
A respectful life.com
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How can we study aging?
❖Animal/cell studies
❖Biomarkers
❖Clinical outcome studies
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Animal studies of aging
Human long lifespan makes aging studies
difficult
Yeast - days
Fruit flies (Drosophila) – 50-60 day
lifespan
Worms (C. Elegans) - 20 day lifespan
Rodents – 2 to 3 year lifespan
Non-Human primates – 30 year lifespan
https://www.deviantart.com/nu
nt/art/drosophila-160708584
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Human Aging studies
Cross sectional
Longitudinal
Cross-sequential
https://www.slideshare.net/g
uest1d8cad/research-3042787
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Example cross-sectional study
Ledreux et al 2019
> 100 older adults aged 65 and older
4 different interventions
Purpose: life style effects on brain health proteins (BDNF)
0 1 0 2 0 3 0 4 0 5 0
-2 0
-1 5
-1 0
-5
0
5
1 0
1 5
2 0
B D N F B a s e lin e
(n g /m L )
BD
NF
le
ve
ls c
ha
ng
e (
ng
/mL
) B o s to n S w e d e n
-4
-2
0
2
4
BD
NF
ch
an
ge
(n
g/m
L)
P h y s . C o g n . M in d . C o n t.
F e m a le
M a le
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The Aged Brain
1. Dementia:
risk double every 5 years;
> 40% in people over 85 years of age
2. Motor dysfunction:
Prevalence of extrapyramidal symptoms:
15% in 65-74 years of age
30% in 75-84 years of age
>50% in > 85 year olds
www.livestrong.com
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The many faces of dementia
Salvador Dali
Omar Sharif
Norman Rockwell
Rita Hayworth
Margaret Thatcher
Rosa Parks
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http://www.dfwsheridan.org/types-dementia
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Alzheimer’s
Disease Most common form of dementia
Incidence will double next 15 years
Pathology includes amyloid and tau accumulation
wwww.alz.org
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Down syndrome
From: Matt Janicki
•Most: extra copy of Chr 21 from mother
•In < 5% of cases extra copy of Chr 21 from
the father
•Remaining cases, the error occurs after
fertilization
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• Equal in all ethnic groups
• Increased risk and earlier onset
• 80% eventually develop dementia
• Medically underserved population
Hamlett et al., 2016
Down syndrome and Alzheimer’s
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Biological correlates of dementia
Protein aggregation - Amyloid and Tau
Nerve cell (neuronal) Loss
Inflammation
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Protein aggregation
▪ accumulation of both plaques and tangles
▪ Similar to Alzheimer pathology
▪ Oxidative stress, inflammation
Control 63 yrs DS+AD 61 yrs
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Tau grant: aims and prelim data
Tau levels and species in exosomes and
brain tissue in Down syndrome
Spread of tau pathology in mouse brain
Aggregation properties of tau in vitro
Mouse and cell models
University of Denver
Karolinska Institutet
Barrow Neurological Institute
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Biomarkers
MRI or PET imaging
Biomarkers in blood or CSF
Exosomes in blood containing markers
Studies of brain tissue post mortem
Pre mortem
Blood/CSF
Post mortem
Blood/CSF/Brain
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Towards improved imaging
biomarkers
Collaboration with Agneta Nordberg and Laetitia Lemoine
Karolinska Institutet, Stockholm
autoradiography
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Exosomes – a novel biomarker
method
• Released into the blood stream from all cells
• Contain RNA, proteins, lipids, surface markers
• Function as both signaling to other cells and “garbage
disposal”
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Neuron-derived exosomes
Aurelie Ledreux
Eric Hamlett
A. Brain cortex B. Liver
Neuron-derived: L1CAM
Photos:Human Protein Atlas licensed under the Creative
Commons Attribution-ShareAlike 3.0 International
License (thus not copyrighted). From (Uhlen et al.,
2015).
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Exosomal biomarkers in a population
with Down syndrome
Aβ1-42 levels by Age
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0 5 5 6 0 6 5 7 0 7 5 8 0
0
2
4
6
8
1 0
1 2
1 4
1 6
1 8
2 0
2 2
A G E
A
1-4
2 (
no
rm
ali
ze
d) p
g/m
l
C o n tro l
D S
P-(S396)-Tau levels by Age
0 5 1 0 1 5 2 0 2 5 3 0 3 5 4 0 4 5 5 0 5 5 6 0 6 5 7 0 7 5 8 0
0
5
1 0
1 5
2 0
2 5
3 0
3 5
4 0
A G E
P-(S
39
6)-T
au
(n
orm
ali
ze
d) p
g/m
l C o n tro l
D S
Down syndrome Controls
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AD biomarkers by diagnosis
➢Can exosomes be validated as “liquid biopsy”?
➢Predict onset decades prior to onset of dementia?
➢Used for longitudinal disease risk biomarkers
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CD65↑ drives
expulsion
Down syndrome and
dysfunction of autophagy pathway
Endosome
Endocytosis
MVB
Lysosome
ExosomesEnlarged
Increased release
Disrupted
autophagy
MVB = multivesicular body
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How does pathology spread
from region to region?
Is it via exosomes?
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Aggregation of Tau in
vitro and in vivo A B
C DCan Tau
pathology
spread between
species/individu
als?
P-Tau antibodies (S396)
Amplification of Tau
fibrils from exosomes
obtained from blood.
M = marker, C = control
exosomes, DS =Down
syndrome exosomes.
Margittai et al
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To examine connection
between human
pathology and behavior:
we need mice:
Study gene-gene interactions
Develop prevention strategies
Validate biological function of
drugs
Perform longitudinal intervention
studies
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Mouse models for DS
~ 100 genes common
to these models
http://www.dsrtf.org
Ts65Dn mouse
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Memory loss in Ts65Dn mice
www.BIOBSERVE.COM
Novel object recognition task
Water Radial arm maze
Spatial memory
Working memory
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Gradual loss of nerve cells
18 month
Ts65DnNormosomic
@Interstellate Twitter
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Loss of cholinergic cells
Control Trisomic
Control Trisomic
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Loss of locus coeruleus
noradrenergic neurons
Rostral LC degenerates in both AD and DS (German et al, 1992)
LC loss increases AD pathology and inflammation
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DREADDs are designer receptors exclusively activated by designer
drugs. By replacing endogenous receptors with artificial receptors that
respond to an inert compound clozapine-N-oxide (CNO), one can
either increase or decrease firing rate in specific neurons. hM3 =
increase, hM4 = decrease firing rates of LC neurons
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Designer receptors
TH mCherry Double label
Hyperactivity
By giving CNO
in drinking
water, one can
turn ON and
OFF the cells
Working memory
OFF
OFF
ON
ON
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Clinical treatment with LC
enhancing drugs Adrenergic agonists or Droxidopa in clinical trials for ADHD and DS
These adrenergic-enhancing drugs increase attention and working
memory and hold hope for Alzheimer’s disease also in the general
population
Clinical trials networks:
Trial Match® Alz Association
Down Syndrome Clinical Trials Network
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Neuroinflammation
CD45
GFAP
COX-2
Normosomic Trisomic
Rela
tive C
OX
-2 d
en
s
0
.25
.5
.75
11.25
1.51.75
2
2.25
Ts65
NS
12 months
Cox-2 staining
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Inflammation resolution
Resolvins metabolic byproducts of omega-3 fatty acids
that help establish homeostasis after an infection
Patients with Alzheimer’s disease: lower resolvins and
increased receptors
Wang et al., 2015
Alzheimer Control Are people with
Alzheimer’s less able
to handle
inflammation?
Inflamed Resolution
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UKY
CU
DU
Arizona Barcelona
MUSC
Sites involved in the DS Biobank Consortium
UC
Irvine
DS Biobank Consortium
Train graduate students and physicians
Provide tissues and biofluids to other researchers
Generate standard neuropathology staging
Advocate for brain donation
Harvard
Stockholm
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Effects of concussions on
dementia later in life
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Concussion and AD biomarkers
High impact sports:
football/Lacrosse/soccer/hockey players
Veterans with blast injuries
Increased risk for psychiatric and
neurological conditions
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Concussion program at DU
Interdisciplinary DU group
Human dynamics lab
Cognitive performance
Biomarkers – longitudinal study
Human Dynamics lab DU – Brad Davidson, Kevin Shelburne
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Cohort demographics DU ConcussionTable 1: Cohort demographics by sport played
Total
particpants
recruited
Male/FemalePercent
Male/Female
Total 317 170/147 54/46
Lacrosse 94 52/42 55/45
Soccer 42 21/21 50/50
Hockey 40 40/0 100/0
Swimming 29 18/11 62/38
Basketball 29 15/14 52/48
Skiing 22 8/14 36/64
Tennis 20 10/10 50/50
Golf 11 4/7 36/64
Gymnastics 14 0/14 0/100
Volleyball 11 0/11 0/100
Diving 5 2/3 40/60
Sport:
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Demographic data
35.6%
29
2 13
23 3
4
11
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Exosome biomarkers concussion
0
1
2
3
Pla
sm
a T
au
(p
g/m
L)
B a s e lin e A c u te 1 w e e k 1 m o n th 6 m o n th s
A .
Recent mTBI <12 months
> than 12 months
0
2 0
4 0
6 0
8 0
ND
E B
iom
ark
er (
pg
/mL
)
T o ta l T a u A 42 N F -lig h t
P A S T -m T B IR e c e n t-m T B I
Plasma Tau
At baseline and after mTBI
Exosomal cargo
Goetzl et al FASEB J. 2019
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Future goals
New technology diagnosis/treatment/prevention
Include DU athletes 10, 20, 30 years after sports
career
Validate exosome biomarker technology
Psychology
Athletics
Basic
Sciences
Engineering
KIHA
Craig Hospital CU/UCCS
Porter Hospital
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Lifestyle
GeneticsInjury
The perfect storm
Memory loss
Protein aggregation
Nerve cell (neuronal) Loss
Inflammation
dementia
What can we do? Early detection
Exercise/diet
Reduce stress
Battle inflammation
Reduce systemic conditions
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Thank you!! Brad Davidson
Kevin Shelburne
Dan Linseman
Aurelie Ledreux
Anah Gilmore
Daniel Paredes
Eric Hamlett
Elliott Mufson
Liz Head
Angela LaRosa
Julie Campbell
Moira Pryhoda
Juan Fortea
Kim Gorgens
Mary Cullen
Linda Newman
Martin Margittai
Sara Thomas
Marianne Schultzberg
Agneta Nordberg
Erik Hjorth
Laetitia Lemoine
Funding: Alzheimer's Association, National
Institutes on Aging, LeJeune Foundation,
Global Down syndrome Foundation, University
of Denver, Bright Focus Foundation
Join the Alzheimer's Walk Pioneer Team!
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Together we can stop Alzheimer’s
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