the worldwide epidemic of senile dementias- challenges of pre-clinical treatment evolving diagnostic...
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The Worldwide Epidemic of Senile Dementias-Challenges of Pre-Clinical Treatment
Evolving Diagnostic Approaches
Dimitrios Kapogiannis
AAAS 2015 Annual Meeting
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
Exosomes: a window into the cell
Bellingham et al. Frontiers Physiology. 2012
Pathogenic proteins for neurodegenerative diseases
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
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
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?
Distinguishing AD patients from cognitively intact elderly
Fiandaca M, Kapogiannis D, et al. Alzheimer’s & Dementia, 2014
Near-perfect discrimination!
Willette and Kapogiannis; Psychiatry Research Neuroimaging, 2014
…better than MRI and CSF combined
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
Exosome biomarkers
• Besides the obvious targets…• Helping us understand everything that
goes wrong with the disease…
• 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
Bomfim et al., JCI, 2012
Brain Insulin Resistance in AD
Talbot et al., JCI, 2012Saline
Control MCI AD
p-Ser-IRS-1
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)
Brain IR markers also distinguish AD patients from cognitively intact elderly …
Bomfim et al., JCI, 2012
Moving forward: targeting brain IR in clinical trials (Exendin-4)
Abnormal lysosomes in AD
Lysosomal proteins in exosomes
Goetzl et al., Neurology, 2015
Controls AD patients
The hallmark of a good biomarker: little to no overlap!
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
Thank you!