Progetto CNR Invecchiamento: innovazioni tecnologiche per un miglioramento
della salute dell'anziano
Neurophysiological and behavioural variables in cognitive impairment: towards a personalised monitoring system
M. Giovanna Trivella
Istituto di Fisiologia Clinica, Pisa, IT
Catania, 2-5 Settembre 2014
Outlines of presentation
Why monitoring, how, when Aging and homeostasis Sleep
Changes with age Sleep slow waves Synaptic weight
Social isolation Sleep disturbances and mortality Insomnia and neurodegeneration
Familial Fatal insomnia
Exercise and sleep relationship sEMG study and remote monitoring Olfactory tests The FP7 SensorART experience Pharmacological perspective Enrollment protocol
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Cognitive Impairment
a long way to understand a long work to treat
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Why increase of older people How holistic manner When to reduce and/or to prevent COGNITIVE IMPAIRMENT
AGING effects normal or abnormal functional reduction Fragility state
Aging & Homeostatic oscillations
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Healthy Older Adults
Frail Older Adults ( vulnerability to stressors!!!)
Dependent Older Adults
Healthy Adults
Older people: different conditions
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Quantitative Sleep parameters
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Synapses and homeostasis
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Sleep as “therapeutic” “preventive” mechanism
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Sleep slow waves aging
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How and Why social isolation is a risk factor for health
• Social isolation is a stressful condition
• Social isolation triggers mental disorders such as depression
• Social isolation predict mortality in general population and in somatic disease (i.e. CHD)
• Social isolation is considered a risk factor comparable to the major biomedical and psychosocial risk factors
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Berkman, 1995; Berkman and Glass, 2000
Sleep disturbances a risk factor
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Insomnia and neurodegeneration
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FFI as extreme clinical model
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Evidence that exercise promotes sleep
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Surface ElectroMyoGraphy (sEMG) Tartarisco et al. Neuromuscolar Disorders 2012
sEMG technology allows information regarding the overall muscle function and condition to be collected from the surface of the skin. This process is non-invasive and non-painful to the subject.
The sEMG signal detected on the skin surface includes information from a greater proportion of the muscle of interest than conventional clinical EMG, acquired using needle electrodes.
sEMG is widely used to evaluate muscle activity and can determine which muscles are active, their degree of activity, and how active; it can also used to estimate muscle force.
sEMG recordings provide
useful information about several
underlying mechanisms of fatigue
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Experimental setup
Participants Task
Subjects: 50 elderly (mean age=66±10)
Non-invasive hardware: BTS FREEEMG Setup: sitting Activity: quadriceps contraction Duration: 15 min
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sEMG as part of the remote monitoring system
• A pervasive activity system for the non-invasive evaluation of muscular fatigue in elderly
• The system can be integrate in a mobile platform to gain a continuous evaluation of the subject, an unobtrusive monitoring of physical activities and their related muscular fatigue
• Such platform can enable an early detection of excessive fatigue and activity abnormalities minimizing the risk and maximizing the benefits for the user
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Olfactometry
Wang S. et al., Diffusion Tensor Imaging in Amyotrophic Lateral Sclerosis: Volumetric Analysis of the Corticospinal Tract American Journal of Neuroradiology 27:1234-1238,2006
Functional Magnetic
Resonance Imaging (fMRI)
Diffusion Tensor Imaging (DTI)
Electroencephalography (EEG)
Neurodegeneration
Abrahams et al.,Word retrieval in amyotrophic lateral sclerosis: a functional magnetic resonance imaging study Brain, Vol. 127, No. 7, 1507-1517, 2004
Neurodegeneration Evaluation techniques
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Olfactory evaluation
Bibliography Neurophysiology: olfaction is a biomarker of future
neurodegeneration [Hawkes, 2003; Iijima et al., 2010;
Ozdener et al., 2004; Doty, 2009; Doty, 2003] and damage caused by ionizing radiation exposure [Dileo et al., 2008, Barnes, 2001]
Threshold, discrimination and identification olfactory test by commercial tools
(Sniffin’ Sticks Extended Test, Burghart MT [Hummel, 2007])
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Olfaction and Neurodegeneration
Movement Disorders, 2003; 18: 364 – 372 Hawkes C
Hawkes C, Olfaction in neurodegenerative disorder; Movement Disorders,
2003; 18: 364 – 372
Iijima M. et al.,. Cardiac Sympathetic Degeneration Correlates with Olfactory
Function in Parkinson’s Disease, Movement Disorders, 2010
Özdener M.H., Rawson N.E., Olfactory dysfunction in neurodegenerative
diseases, Eur J Gen Med1(3): 1-11, 2004.
Doty R.L., Do Environmental Agents Enter the Brain via the Olfactory
Mucosa to Induce Neurodegenerative Diseases?, International Symposium
on Olfaction and Taste: Ann. N.Y. Acad. Sci. 1170: 610–614, 2009
Doty R.L.. Odor perception in neurodegenerative diseases, In Handbook of
Olfaction and Gustation, 2nd ed. R.L. Doty, Ed.: 479–502. Marcel Dekker.
New York, NY, 2003
Dileo J. F. et al, Olfactory identification dysfunction, aggression and
impulsivity in war veterans with post-traumatic stress disorder, Psychological
Medicine 38, 523–531, 2008
Barnes J.G., `Sensitivity syndromes' related to radiation exposures, Medical
Hypotheses (2001) 57(4), 453±458
Hummel T. et al, Normative data for the “Sniffin’ Sticks” including tests of
odor identification, odor discrimination, and olfactory thresholds: an upgrade
based on a group of more than 3,000 subjects. Eur Arch Otorhinolaryngol
(2007) 264:237–243.
Olfactometry
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Test Pros Cons
UPSIT FDA Approved High cost, only identification test
STT FDA Approved High cost, only threshold test
Smell Diskettes Low cost, Made in Europe
Only identification test, no FDA Approved
Osmic RL, ID, D Automatic tests No FDA Approved, little used, high costs
Sniffin’Sticks Low cost, complete, easy to order and administer, often used in literature, Made in Europe
No FDA Approved
SDOIT Easy to use Little used, hard to order and purchase
Commercial olfactory kits
Sniffin’ Sticks Extended Test (Burghart MT, GmbH) N-butanol Threshold test Discrimination test Identification test TDI Score (sum of the three sub-scores)
Manual olfactory tests
Olfact RL (Osmic Ent., Inc.) N-butanol threshold test 20’ - 45’ PC-User Interface
Olfact ID (Osmic Ent., Inc.) 40-item Identification test 30’ overall PC-User Interface
Automated olfactory tests
Rx exposure and neurogenesis
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Society for Neuroscience, June 2007
Adult neurogenesis occurs in several areas, among which some are involved in olfactory processing (e.g.: olfactory bulb)
X Rays
Ionizing radiation
exposure
inhibits neurogenesis.
This could be monitored
by non-invasive
measurement
of olfactory function
Picano E, Vano E, Domenici L, Bottai M, Thierry-Chef I
BMC Neuroscience, 2012
FP7 SensorART experience (www.sensorart.eu)
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Data from Wearable Systems
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Data from Wearable Systems in VAD implanted patient
Brain important role in Glucose Homeostasis
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Reproduced from Dunstan Cooke & Steve Bloom Nature Reviews Drug Discovery 2006, 5, 919-931
GLP-1 has beneficial effects on both peripheral (Holst, 2007) and cerebral glucose homeostasis (Lerche et al., 2008; Gejl et al., 2012a)
Adapted from Baggio L. and Drucker DJ
Gastroenterology; 2007 132:2131-2157
GLP-1 a complex, intriguing story
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British Journal of Pharmacology (2012) 166 1586–1599
GLP-1 receptors (GLP-1R) have been found in the brain and it has been hypothesized that GLP-1R agonists could improve brain glucose metabolism.
Peripheral GLP-1 can access the central nervous system and modulate neuronal activity in humans (Alvarez, Journal of Neurochemistry 2005) Central GLP-1 signaling is linked to the control of blood glucose concentrations (D'Alessio et al., 2005), and studies reveal extrapancreatic effects of GLP-1 (Vella and Rizza, 2004; Bak et al., 2011; Gejl et al., 2012).
Binding of 125I-GLP-1(7-36) amide in
different regions in the human brain
Reproduced from Alvarez et al.
Journal of Neurochemistry, 2005, 92, 798–806
Exenatide study Dr. Eng. Amalia Gastaldelli IFC – San Antonio University
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Methods
We studied 15 male subjects
with impaired glucose tolerance (n=12)
or newly diagnosed with type 2 diabetes (n=3)
Age=56±8 y,
BMI=29±1 kg/m2,
HbA1c=5.7±0.1%
Each subject underwent 2 oral glucose tests
(OGTT 75 g) with double blind injection
of Exenatide (EX 5 mcg)
or placebo (PLC) 30min before OGTT
(in random order) with FDG-PET
and stable istotope tracer infusion
Exetanide study Conclusions
Catania, 2-5 Settembre 2014
These data show that Exenatide can modulates acutely cerebral glucose metabolism measured by PET, by increasing glucose uptake in multiple areas of the brain in subjects with impaired glucose tolerance or new diagnosed type 2 diabetes. These results, together with previous published data, support the use of this class of drugs also to improve cerebral glucose metabolism and/or to prevent neurodegeneration.
0.5 9.9
KBq
EXENATIDE PLACEBO
A B
C D E F C D E F
Effect of Exenatide on Brain Glucose Uptake
Data presented at the annual meetings ADA and EASD 2014
Future protocol in IFC
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Subjects > 65 yrs with or without mild cognitive impairment Clinical characterization
Cardiovascular and muscular Holter ECG 24 hours WinPack (ECG, SO2, respiration, posture, physical activity,Tp) Flow Mediated Dilation Carotid stiffness
Fatigue (sEMG) Sleep and psychometric characterization Olfactometry tests Metabolism Subcutaneous Fat (*) Protocol steps:
Time 0 after 3 months after 6 months
Personalized protocol with life style therapeutical indications (diet), daily physical activity, recovery of physiologic sleep (* Time 0 and after 6 months)
Pisa Group:
• Lucia Billeci
• Enrico Capobianco
• Amalia Gastaldelli
• Angelo Gemignani
• Vincenzo Gemignani
• Alessandro Tonacci
• M. Giovanna Trivella
Thank you
for the attention
Catania, 2-5 Settembre 2014