Progetto CNR Invecchiamento: innovazioni tecnologiche per un … · Progetto CNR Invecchiamento:...

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


Cognitive Impairment

a long way to understand a long work to treat


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


Healthy Older Adults

Frail Older Adults ( vulnerability to stressors!!!)

Dependent Older Adults

Healthy Adults

Older people: different conditions


Quantitative Sleep parameters


Synapses and homeostasis


Sleep as “therapeutic” “preventive” mechanism


Sleep slow waves aging


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


Berkman, 1995; Berkman and Glass, 2000

Sleep disturbances a risk factor


Insomnia and neurodegeneration


FFI as extreme clinical model


Evidence that exercise promotes sleep


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


Experimental setup

Participants Task

Subjects: 50 elderly (mean age=66±10)

Non-invasive hardware: BTS FREEEMG Setup: sitting Activity: quadriceps contraction Duration: 15 min


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


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


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])


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


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


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)


Data from Wearable Systems



Data from Wearable Systems in VAD implanted patient

Brain important role in Glucose Homeostasis


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


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


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


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


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


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