1. A Long Shadow over the Soul:
Molecular and Quantum Approaches to Psychopathology
An Interdisciplinary Dialog with Psychiatrists
Fano, Italy 29, 30, 31 March 2012
How much is the matter far away from the soul?
Andrea Peracino, MD, PhD
Vice President of the Giovanni Lorenzini Medical Science Foundation,
MilanĀ-I, HoustonĀ-TX
andrea.peracino@lorenzinifoundation.org
1
2. Summary
ā¢ Burden of chronic non communicable diseases
ā¢ Alliances for NCD
ā¢ A pathological approach
ā¢ NCD Common Soils
ā¢ Models
ā¢ Questions
2
3. Leading causes of attributable global mortality and
burden of disease, 2004 (Lancet 2009; 374:973-4)
Attributable Mortality Attributable DALYs
% %
2. High blood pressure 12.8 ā¢ Childhood underweight 5.9
3. Tobacco use 8.7 ā¢ Unsafe sex 4.6
4. High blood glucose 5.8 ā¢ Alcohol use 4.5
5. Physical inactivity 5.5 ā¢ Unsafe water, sanit. hygiene 4.2
6. Overweight and obesity 4.8 ā¢ High blood pressure 3.7
7. High cholesterol 4.5 ā¢ Tobacco use 3.7
8. Unsafe sex 4.0 ā¢ Suboptimal breastfeeding 2.9
9. Alcohol use 3.8 ā¢ High blood glucose 2.7
10. Childhood underweight 3.8 ā¢ Indoor smoke from solid fuels 2.7
11. Indoor smoke from solid fuels 3.3 ā¢ Overweight and obesity 2.3
59 million total global deaths 1.5 billion total global DALYs
3
4. The burden of chronic Non Communicable Disease - NCD
Major chronic non-communicable diseases (NCDs)āprimarily cardiovascular
disease (CVD), cancer, chronic obstructive pulmonary disease (COPD),
and diabetesāare responsible for 85% of the deaths and 70% of the burden
of disease in Europe.
Atherosclerosis Supplements 2009; 10: 1-30
The Disorders of the Brain -BD in Europe are responsible for around 15,8
million DALYs (26,6% of global DALYs) aged > 15 age: 7,3 million for men
(23,4%), 8,5 million for women (30,1%).
H.U. Witchen, F. Jacobi et alii European Neuropsychopharmacology 2011; 21: 655ā679.
4
5. European prevalence of Neurological Disorders-ND :
(in millions) H.U. Witchen, F. Jacobi et alii European Neuropsychopharmacology 2011; 21: 655ā679
Diagnosis Mio individuals
Headache 152,8
Sleep apnoea 12,5
Stroke 8,24
Dementias 6,34
Traumatic brain injury 3,75
Epilepsy 2,64
Parkinsonās disease 1,25
Multiple slcerosis 0,54
Neuromuscolar disorders 0,26
Brain dsorders 0,24
5
6. European prevalence rates of Mental Disorders ā MD
(H.U. Witchen, F. Jacobi et alii European Neuropsychopharmacology 2011; 21, 655ā679)
Diagnosis Yearly prevalence Mio individuals/year
Alcohol dependance %
3,4 14,6
Cannabis dependence 1,0 1,5
Psychotic disorders 1,2 5,0
Panic disorders 1,8 7,9
Personality disorder 1.3 4,3
Major depression 6,9 30.3
Insomnia 3,5 14,6
Anxiety disorders 14.0 61,5
ADHD/Hypercin disorders 5,0 6,3
Dementias 5,4 6,3
Somatoform disorder 4,9 20,4
Eating disorders 0,9 1,5
Any mental disorder 38.2 164.8
6
7. The size and burden of Mental Disorders and other
Disorders of the Brain in Europe 2010
(H.U. Witchen, F. Jacobi et alii European Neuropsychopharmacology 2011; 21: 655ā679)
7
8. Numbers in comparison
H.U. Witchen, F. Jacobi et alii European Neuropsychopharmacology 2011; 21, 655ā679
2010 report by Alzheimer's Disease International
http://www.europarl.europa.eu/sides/getDoc.do?type=TA&language=EN&reference=P7-TA-2011-0016
European CVD diseases Feb 2008
EU EU EU EU
Deaths /y suffering DALYs Costs
BD 164.9 mio 16.0 mio (26%) ā¬ 300 bio
53% w
Dementia 6.3 - 9.9 mio 5 (8%)
Stroke 0.5 mio 3,7 (6%)
57% w
CVD 2.0 mio 12.0 mio (19 %) ā¬ 200 bio
54% w
People worldwide worldwide worldwide
suffering 2010 2030 2050
Dementia 35.6 mio 65.7 mio 115.4 mio
8
9. Summary
ā¢ Burden of chronic non communicable diseases
ā¢ Alliances for NCD
ā¢ A pathological approach
ā¢ NCD Common Soils
ā¢ Models
ā¢ Questions
9
10. UN High-Level
Meeting on NCDs
19 -20 September 2011
ā¦36 million deaths every year
for NCD are demanding a
global commitment among
the decision makes world
wideā¦
10
11. UN High-Level Meeting on NCDs:
Politic al Declarations
16 September and 15 September 2011
Political Declaration of the High-level
Meeting of the General Assembly on the
Prevention and Control of Non-
communicable Diseases (http://www.who.int/
nmh/events/un_ncd_summit2011/en/index.html)
EU position and commitment in
advance of the UN high-level meeting
on the prevention and control of non-
communicable diseases.
http://www.europarl.europa.eu/sides/getDoc.do?
pubRef=//EP//NONSGML+PV+20110915+SIT+
DOC+PDF+V0//EN&language=EN.
11
12. Question
how much in the mentioned alliances there was a participation
of the experts on psychopathology?
how much of the probable, but not clearly defined and decided
in term of budget, will be allocated to support studies on how
to combine matter and soul in approaching the huge amount
of subjects suffering by NDDs ?
http://whqlibdoc.who.int/publications/2009/9789241597418_eng.pdf
12
13. Summary
ā¢ Burden of chronic non communicable diseases
ā¢ Alliances for NCD
ā¢ A pathological approach
ā¢ NCD Common Soils
ā¢ Models
ā¢ Questions
13
14. INTERHEART Study
Large case control study to
examine the importance of 9 IHD
risk factors : > 29.000 people
in 52 countries.
Worldwide, the 9 factors
collectively predicted
> 90% of the risk of MI.
The presence of all 9 risk
factors was associated with
an OR >256 .
Yusuf S et al. Effect of potentially modifiable risk factors with myocardial infarction in 52 countries (the INTERHEART study).
Lancet 2004;364: 937-52.
14
15. Figure 1
INTERSTROKE Study
Martin J O'Donnell et alii , Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the)
INTERSTROKE study : a case-control study. Lancet 2010;376:112-23
15
16. Figure 2
INTERSTROKE Study
Martin J O'Donnell et alii , Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the)
INTERSTROKE study : a case-control study. Lancet 2010;376:112-23
Source 16
18. Integrated Biomarkers: atherosclerosis
Infarction of the brain : by arterial thrombosis or embolism.
Intermediate infarct of the frontal lobe.
magnetic resonance imaging scan Microscopic aspect
revealing marked edema (the pale
areas)
18
19. Integrated Biomarkers: atherosclerosis
Infarction of the brain
The neurons are the most sensitive cells
to anoxic injury. Seen here are red
neurons which are dying as a result of
hypoxia.
Cerebral infarction demonstrates the presence of
many macrophages at the right which are
cleaning up the lipid debris from the
liquefactive necrosis
19
21. Integrated Biomarkers: atherosclerosis
Magnetic Resonance Imaging
MRI provides non-invasive, in vivo
characterization of human IC
atherosclerosis A
ECA
ā Histologically validated
ā Reproducible
MRI findings predictive of more rapid
progression and increased likelihood
of future ischemic events Plaque
by Thomas Hatsukami - Seattle 2008 CCA
CCA = common carotid artery ; ICA = internal carotid artery;
ECA = external carotid artery
21
26. Summary
ā¢ Burden of chronic non communicable diseases
ā¢ Alliances for NCD
ā¢ A pathological approach
ā¢ NCD Common Soils
ā¢ Models
ā¢ Questions
26
27. Scenarios
Non communicable diseases: diabetes, obesity, cardiovascular disease,
COPD
Crossroads or a common soil ? : mithocondria, metabolic
fuel, insulin resistance, inflammation, endothelial
dysfunction, neurohormonesā¦.
ā¦and what about NDs ?
astrocytes activation, BBB damage, apoptosis deregulation,
neurodegeneration, and metabolic disorders
27
28. Integrated Biomarkers: atherosclerosis
Coronary artery with thrombosis: occlusion of the lumen and consequently
acute coronary syndrome with ischemia and/or infarction of the
myocardium.
28
34. The mitochondrial respiratory chain
is the main source of ROS that increase damage to deoxyribonucleic acid
(DNA), proteins, or lipids accumulates with age progression, and impair cellular
function. ā¢Mitochondrial dysfunction,
mitochondrial loss
ā¢ROS
ā¢ insulin resistance
ā¢aging.
Telomere length is a sensitive
indicator of oxidative stress and is
implicated in senescence and
apoptotic signaling.
Telomere length was reduced up to
30% in cardiomyocytes of old
(normal-weight and obese) and young
obese subjects.
34
35. Categories of SIRT1
Targets for Deacetylation and Their Associated Diseases.
The protein targets of SIRT1, that
has been shown to regulate
metabolism and stress
response, include transcription
factors and cofactors, histones and
other chromatin proteins, and
components of DNA repair
machinery.
Guarente L. N Engl J Med 2011;364:2235-2244.
35
36. Potential mechanisms of action of SIRT6 on longevity
Lombard DB, Miller RA: Ageing Soting out the the sirtuins. Nature 2012 483: 166-67.
36
37. ...NCDs no longer by a silos approach, but rather
with a common effort of allied stakeholders...
NCD have many patho-mechanisms in common, and have
common genetic and environmental antecedents they would
spring from a ācommon soilā.
37
39. Summary
ā¢ Burden of chronic non communicable diseases
ā¢ Alliances for NCD
ā¢ A pathological approach
ā¢ NCD Common Soils
ā¢ Models
ā¢ Questions
39
40. Models
How much is it known on metabolic dysfunctions in NDs such as, e.g.,
Alzheimer's Disease-AD and Vascular Dementia-VD, or Depression?
40
41. legenda
Mitochondrial metabolic constellation: some pathways for medical exploration
interplay of major mitochondrial functions with cell and tissue pathological changes
AĆ: Ć amyloid OLGs: oligodendrocytes
ATP: adenosine-5'-triphosphate OPCs: oligodendrocyte precursor cells
BP: Blood pressure PAMPs: pathogen-associated molecular patterns
CHI: closed head injury PPARĪ± : peroxisome proliferator-activated receptors Ī±
CRH: corticotropin-releasing hormone PPARs: peroxisome proliferator-activated receptors
DAMPs: danger-associated molecular patterns PGC1Ī±: peroxisome proliferator-activated receptor Ī³
IL-6: Interleukin-6 co-activator 1Ī±
LCFA: long chain fatty acides RC: respiratory chain
mtDNA: mitochondrial deoxyribo-nucleic āacid ROS: reactive oxygen species
MMP-9: matrix metalloproteinase-9 TNFĪ±: Tumor necrosis factor alpha
NLRP3: NLR family, pyrin domain-containing 3 UCP: Uncoupling proteins
NO: nitric oxide VEGF-A: Vascular endothelial growth factor
OXPHOS: oxidative phosphorylation WMLs: White matter lesions
41
42. Summary
ā¢ Burden of chronic non communicable diseases
ā¢ Alliances for NCD
ā¢ A pathological approach
ā¢ NCD Common Soils
ā¢ Models
ā¢ Questions
42
43. Questions
How much can the combination of the studies on the matter and on the
soul, help to better manage the NCD patients?
How much can the psychopathologists help the physicians of the matter
to reduce the affliction of the soul?
43
44. Ī£Ļ Ī¼ĻĪ¬ĻĻĪµĪ¹ Ī· ĻĻ ĻĪ® ĻĻ ĻĻĪ¼Ī±ĻĪ¹ Ī½ĪæĻĪæĻĪ½ĻĪ¹ ĪŗĪ±Ī¹ ĻĪµĪ¼Ī½ĪæĪ¼ĪĪ½Ļ, ĻĪæ Ī“Īµ
ĻĻĪ¼Ī± ĻĪ· ĻĻ ĻĪ®
The soul suffers when the body is diseased or traumatized, while
the body suffers when the soul is ailing
Aristotle
44
45. āWe will now observe a moment of silence
to check our BlackBerrys.ā
45
Editor's Notes
Risk of stroke associated with number of cigarettes smoked for all stroke, ischaemic stroke, and intracerebral haemorrhagic stroke Data are adjusted for age, sex, and region.
Risk of all stroke associated with body-mass index and waist-to-hip ratio T=tertile.
.
A growing body of evidence, indicates that inflammatory mechanisms contribute to (secondary) neuronal injury after acute cerebral ischemia. This inflammatory response is characterized by the local expression of cytokines such as IL-1, TNF-a and IL-6, resulting in chemotactic cytokine release and adhesion molecules upregulation. This cytokines work in concert to activate leukocyte migration to the ischemic region. This white cells are leukocytes, almost plugging the microvessels, where they cause tissue injury by generation of oxygen free radicals, or Matrix Metalloproteinases release, both of which may disrupt the BBB, contributing to infarct growing.
Figure 2. Categories of SIRT1 Targets for Deacetylation and Their Associated Diseases.Ā The protein targets of SIRT1, a sirtuin that has been shown to regulate metabolism and stress response, include transcription factors and cofactors, histones and other chromatin proteins, and components of DNA repair machinery. The depictions of the associations between SIRT1 targets and the diseases that are affected are graphical, since the exact mechanisms of most of these associations are not known.
Figure 2. Categories of SIRT1 Targets for Deacetylation and Their Associated Diseases.Ā The protein targets of SIRT1, a sirtuin that has been shown to regulate metabolism and stress response, include transcription factors and cofactors, histones and other chromatin proteins, and components of DNA repair machinery. The depictions of the associations between SIRT1 targets and the diseases that are affected are graphical, since the exact mechanisms of most of these associations are not known.
