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The Worldwide Epidemic of Senile Dementias- Challenges of Pre-Clinical Treatment Evolving Diagnostic...
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![Page 1: The Worldwide Epidemic of Senile Dementias- Challenges of Pre-Clinical Treatment Evolving Diagnostic Approaches Dimitrios Kapogiannis AAAS 2015 Annual.](https://reader035.fdocuments.in/reader035/viewer/2022062518/56649ebe5503460f94bc821d/html5/thumbnails/1.jpg)
The Worldwide Epidemic of Senile Dementias-Challenges of Pre-Clinical Treatment
Evolving Diagnostic Approaches
Dimitrios Kapogiannis
AAAS 2015 Annual Meeting
![Page 2: The Worldwide Epidemic of Senile Dementias- Challenges of Pre-Clinical Treatment Evolving Diagnostic Approaches Dimitrios Kapogiannis AAAS 2015 Annual.](https://reader035.fdocuments.in/reader035/viewer/2022062518/56649ebe5503460f94bc821d/html5/thumbnails/2.jpg)
Biomarkers in Alzheimer’s disease
AD
Age
Successful aging
MCI
Modified disease
Primary prevention interventions
Preclinical predictors
Disease modifying interventions
Cognition & function
Diagnostic biomarkersPredictors of MCI conversion
Biomarker outcomes
![Page 3: The Worldwide Epidemic of Senile Dementias- Challenges of Pre-Clinical Treatment Evolving Diagnostic Approaches Dimitrios Kapogiannis AAAS 2015 Annual.](https://reader035.fdocuments.in/reader035/viewer/2022062518/56649ebe5503460f94bc821d/html5/thumbnails/3.jpg)
Exosomes: a window into the cell
Bellingham et al. Frontiers Physiology. 2012
Pathogenic proteins for neurodegenerative diseases
![Page 4: The Worldwide Epidemic of Senile Dementias- Challenges of Pre-Clinical Treatment Evolving Diagnostic Approaches Dimitrios Kapogiannis AAAS 2015 Annual.](https://reader035.fdocuments.in/reader035/viewer/2022062518/56649ebe5503460f94bc821d/html5/thumbnails/4.jpg)
Plasma
Exosome isolation
Selection of neuronal exosomes with antibodies
A novel methodology for exosome isolation and neuronal enrichment
Exosome expressing neuronal markers
Ab for neuronal markers
“Breaking”of exosomesProtein quantification
Capture of sub-population of exosomes
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Nelson PT, et al. Neuropathology and Cognitive Impairment in Alzheimer Disease: a complex but coherent relationship. J Neuropathol Exp Neurol. 2009; 68: 1-14.
Aβ42 (+) plaques
Tau (+) tangles
Alzheimer’s disease pathogenic proteins
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Exos
omal
p-1
81-t
au (p
g/m
l)
Exos
omal
Aβ 42
(pg/
ml)
57 AD patients vs. 57 ControlsAll differences: p < 0.001
Fiandaca M, Kapogiannis D, et al. Alzheimer’s & Dementia, 2014
Controls AD patients Controls AD patients
Exosomes: a source for near-perfect diagnostic biomarkers?
![Page 7: The Worldwide Epidemic of Senile Dementias- Challenges of Pre-Clinical Treatment Evolving Diagnostic Approaches Dimitrios Kapogiannis AAAS 2015 Annual.](https://reader035.fdocuments.in/reader035/viewer/2022062518/56649ebe5503460f94bc821d/html5/thumbnails/7.jpg)
Distinguishing AD patients from cognitively intact elderly
Fiandaca M, Kapogiannis D, et al. Alzheimer’s & Dementia, 2014
Near-perfect discrimination!
![Page 8: The Worldwide Epidemic of Senile Dementias- Challenges of Pre-Clinical Treatment Evolving Diagnostic Approaches Dimitrios Kapogiannis AAAS 2015 Annual.](https://reader035.fdocuments.in/reader035/viewer/2022062518/56649ebe5503460f94bc821d/html5/thumbnails/8.jpg)
Willette and Kapogiannis; Psychiatry Research Neuroimaging, 2014
…better than MRI and CSF combined
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Exosomal biomarkers predict AD diagnosis
AP, AD vs. AC: p < 0.001AP vs. AD: N.S. AP, AD vs. AC: p < 0.001
AP vs. AD: P < 0.001
Fiandaca M, Kapogiannis D, et al. Alzheimer’s & Dementia, 2014
Diagnosis √Prognosis √Biomarker outcomes for clinical trials?
Controls Preclinical AD Clinical AD Controls Preclinical AD Clinical AD
![Page 10: The Worldwide Epidemic of Senile Dementias- Challenges of Pre-Clinical Treatment Evolving Diagnostic Approaches Dimitrios Kapogiannis AAAS 2015 Annual.](https://reader035.fdocuments.in/reader035/viewer/2022062518/56649ebe5503460f94bc821d/html5/thumbnails/10.jpg)
Exosome biomarkers
• Besides the obvious targets…• Helping us understand everything that
goes wrong with the disease…
![Page 11: The Worldwide Epidemic of Senile Dementias- Challenges of Pre-Clinical Treatment Evolving Diagnostic Approaches Dimitrios Kapogiannis AAAS 2015 Annual.](https://reader035.fdocuments.in/reader035/viewer/2022062518/56649ebe5503460f94bc821d/html5/thumbnails/11.jpg)
• Insulin resistance (IR): reduced cellular responsiveness to insulin type 2 diabetes.
• Patients with Diabetes show:o impaired cognitive performance (slightly, but
measurably…)o greater age-related decline
• Type 2 diabetes and IR are independent risk factors for AD (Ott et al., 1999; Luchsinger et al., 2001; Arvanitakis et al., 2004; Luchsinger et al., 2007; Toro et al., 2009)
Diabetes/IR and AD
![Page 12: The Worldwide Epidemic of Senile Dementias- Challenges of Pre-Clinical Treatment Evolving Diagnostic Approaches Dimitrios Kapogiannis AAAS 2015 Annual.](https://reader035.fdocuments.in/reader035/viewer/2022062518/56649ebe5503460f94bc821d/html5/thumbnails/12.jpg)
Bomfim et al., JCI, 2012
Brain Insulin Resistance in AD
Talbot et al., JCI, 2012Saline
Control MCI AD
p-Ser-IRS-1
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CN, DM vs. AD: p < 0.001 CN vs. DM: P < 0.001
Kapogiannis D, et al. FASEB J, 2014To
tal I
RS-1
(pg/
ml)
P-Se
r-IR
S-1
(pg/
ml)
P-Ty
r-IR
S-1
(pg/
ml)
P-Se
r/P-
Tyr-
IRS-
1 (p
g/m
l)
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Brain IR markers also distinguish AD patients from cognitively intact elderly …
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Bomfim et al., JCI, 2012
Moving forward: targeting brain IR in clinical trials (Exendin-4)
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Abnormal lysosomes in AD
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Lysosomal proteins in exosomes
Goetzl et al., Neurology, 2015
Controls AD patients
The hallmark of a good biomarker: little to no overlap!
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Exosomal biomarkers for AD prognosis diagnosis, therapeutics!
AD
Age
MCI
Preclinical predictors Exosomal p-Tau, p-IRS-1, lysosomal proteins
Cognition & function
Biomarker outcomesExosomal Aβ42, p-Tau, p-IRS-1, lysosomal proteins
MCI conversion predictors
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Thank you!