the worldwide epidemic of senile dementias- challenges of pre-clinical treatment evolving diagnostic...

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!