Internalized Racism and it’s effect on Cortisol Levels
Lott
1. Oxidative Stress in DownOxidative Stress in Down
SyndromeSyndrome
Ira T. Lott, MDIra T. Lott, MD
ProfessorProfessor
UCI School of MedicineUCI School of Medicine
2. Oxidative stress in canine model ofOxidative stress in canine model of
aging (Head et al)aging (Head et al)
Aging canine model of AD shows similarAging canine model of AD shows similar
evolution of oxidized Abeta to that seen inevolution of oxidized Abeta to that seen in
individuals with Down syndromeindividuals with Down syndrome
Canine model shows a robust andCanine model shows a robust and
sustained improvement to antioxidantsustained improvement to antioxidant
supplementationsupplementation
4. Mitochondria and Oxidative StressMitochondria and Oxidative Stress
in Down syndrome (Coskun et al)in Down syndrome (Coskun et al)
Control region mutations seen in brain andControl region mutations seen in brain and
peripheral tissues from individuals withperipheral tissues from individuals with
DS, DS+AD, and AD in the generalDS, DS+AD, and AD in the general
populationpopulation
5. mtDNA RCR mutation analysis in brain. A. shows the control mutation frequency withmtDNA RCR mutation analysis in brain. A. shows the control mutation frequency with
age. B. shows mtDNA mutation frequency in DS, DSAD, AD brains C. shows theage. B. shows mtDNA mutation frequency in DS, DSAD, AD brains C. shows the
mutation analysis by surveyor nuclease assay in same group tested in B.(Coskun et al)mutation analysis by surveyor nuclease assay in same group tested in B.(Coskun et al)
40-64 65-68 80-95
0
1.0×10-4
2.0×10-4
3.0×10-4
4.0×10-4
5.0×10-4
6.0×10-4
7.0×10-4
8.0×10-4
Age
frequency/bp
#ofvisiblecutsite
A.
C.
B.
p<0.05 ANOVA
p<0.05 ANOVA
p<0.05 ANOVA
6. mtDNA RCR mutation analysis in Peripheral tissues. A. shows cell free mtDNA mutationmtDNA RCR mutation analysis in Peripheral tissues. A. shows cell free mtDNA mutation
frequency in cell free mtDNA in serum and Brain in very old control and ADs. B. showsfrequency in cell free mtDNA in serum and Brain in very old control and ADs. B. shows
only contol versus AD cell free mtDNA mutation frequency, C. Shows LCL mtDNAonly contol versus AD cell free mtDNA mutation frequency, C. Shows LCL mtDNA
mutation frequency in control, DS, DSAD and AD groups.mutation frequency in control, DS, DSAD and AD groups.
p=0.001 ANOVA
A. B. p=0.056
p<0.05 ANOVA
C.
Frequency/bp
7. High potency antioxidantsHigh potency antioxidants
supplements to treat DS+dementiasupplements to treat DS+dementia
(Lott et al, in press)(Lott et al, in press)
Vitamin E, vitamin C and alpha-lipoic acidVitamin E, vitamin C and alpha-lipoic acid
supplementationsupplementation
Randomized 2 year double blind-placeboRandomized 2 year double blind-placebo
controlled repeated measures analysis ofcontrolled repeated measures analysis of
variance studyvariance study
8. Did not attend screening
n=2
Enrolled/Screened
n=71 Ineligible
n=12
Reasons:
Non-AD n=11
Non-DS n=1Eligible
n=59
Randomized
n=58
Refused to participate
n=1
Allocated to antioxidant
n=29
Evaluated - Year 1
n=23
Evaluated - Year 2
n=16
Discontinued
n=7
Reasons:
Death n=1
Refused to participate n=6
Discontinued
n=4
Reasons:
Death n=1
Refused to participate n=3
Initiated allocated
intervention
n=27
Did not initiate allocated
intervention
n=2
Allocated to placebo
n=29
Evaluated - Year 1
n=22
Evaluated - Year 2
n=15
Discontinued
n=7
Reasons:
Death n=1
Refused to participate n=3
Disallowed medication n=3
Discontinued
n=4
Reasons:
Death n=1
Refused to participate n=3
Initiated allocated
intervention
n=26
Did not initiate allocated
intervention
n=3
Invited for screening
n=73
AOX pilot trial – NIA (Lott et al, in press)
9. Alpha-tocopherol Level in Plasma showsAlpha-tocopherol Level in Plasma shows
compliance with regimencompliance with regimen
10. No therapeutic effect noted over 2 years ofNo therapeutic effect noted over 2 years of
studystudy
Factor analysis shows high inter-Factor analysis shows high inter-
correlation of measurescorrelation of measures
12. ConclusionsConclusions
Oxidative stress is a feature of Down syndromeOxidative stress is a feature of Down syndrome
Animal models show cognitive improvement withAnimal models show cognitive improvement with
antioxidant dietantioxidant diet
However, human trial of demented individualsHowever, human trial of demented individuals
with DS show no benefit from high potencywith DS show no benefit from high potency
antioxidants.antioxidants.
Future trials should target pre-demented state inFuture trials should target pre-demented state in
DSDS
13. Current FocusCurrent Focus
Identification of imaging and biomarkerIdentification of imaging and biomarker
factors that predict cognitive decline infactors that predict cognitive decline in
adults with DS (HD 65160)adults with DS (HD 65160)
14. Co-Investigators and SupportCo-Investigators and Support
Elizabeth Head, PhDElizabeth Head, PhD
Pinar Coskun, PhDPinar Coskun, PhD
Doug Wallace, PhDDoug Wallace, PhD
NIH: AG 25912, AG 16573, MO1-RR-NIH: AG 25912, AG 16573, MO1-RR-
0082700827
Editor's Notes
Here, we analyzed the mtDNA regulatory control region somatic mutation frequency by cloning and direct sequencing method in DS, DSAD, AD and control brains. Panel A shows how mtDNA somatic mutations are accumulated over time in normal aging. Panel B demonstrates mutation frequencies in 4 different groups. Panel C shows the same idea that is represented in B, using another independent approach ( Surveyor nucleases assay –enzyme recognizes any base mismatches so I counted the number of cuts) to see if it is reproducible.
Here, we have looked at peripheral tissues for mtDNA somatic mutation accumulations. Panel A shows the cell free mtDNA in serum samples obtained from very old AD and Controls and compared to the same samples’ brain mtDNA mutations. Panel B only shows the AD and control cell free mtDNA mutations ( I took out the brain samples from panel A to show the changes only in cell free mtDNA ). Panel C is the lymphoblastoid cell lines from 4 groups. This is the catch of all these presentation: You can detect the mtDNA changes even in peripheral blood from the demented patients.
