Day 1 :
National Institute of Neurological Disorders and Stroke – NIH, USA
Keynote: Aberrantally activated Cdk5 as a target for therapeutic approaches to neurodegenerative disorders like Parkinsion’s and Alzheimer’s Diseases
Time : 09:30-10:10
Pant received his M.A. and Ph.D. degrees in Physics from Agra University, Agra, India. His postdoctoral studies were conducted on the mechanisms of electron and ion transport in model membrane systems at the Department of Biophysics at Michigan State University. He joined the Laboratory of Neurobiology in the NIMH as a senior staff fellow in 1974 with Dr. Ichiji Tasaki where he studied the function of the axonal cytoskeleton in the squid giant axon. In 1979 he moved to the NIAAA extending his studies on the neuronal cytoskeleton and the effects of alcohol on its regulation. Pant moved to the NINDS, Laboratory of Neurochemistry in 1987 where he is presently chief of the section on Cytoskeleton Regulation. His laboratory is studying the mechanisms of topographic regulation of neuronal cytoskeleton proteins by post-translational modification, including the role of kinase cascades in normal brain and during neurodegeneration.
Our previous studies have shown that neuro-filaments & Tau the major neuronal cytoskeletal proteins are selectively phosphorylated in axons.The phosphorylation activity is tightly regulated under physiological conditions. Under neuropathological conditions, however, phosphorylation is deregulated, occurs abnormally in perikarya and induces pathology resembling that seen in many neurodegenerative diseases e.g. AD, ALS, PD). We identified cyclin dependent kinase 5 (Cdk5) together with its activator p35, as a major kinase regulating the topographic neuronal cytoskeleton phosphorylation.It is found that Cdk5, when deregulated by neuronal insults (A-beta, glutamate, oxidative stress, mutations and other), is hyper-activated as a stable complex with p25 (a truncated fragment of p35) and induces perikaryal hyper-phosphorylated tau, synuclein and NFPs as seen in AD, PD and ALS. At autopsy, AD, PD and ALS brain display hyperactive Cdk5 (Cdk5/p25) and have confirmed that Cdk5/p25 induces neuro-inflammation, tau and NF hyperphorylation along with cell death. A p25-overexpressing (P25Tg) AD model mouse displays the typical AD phenotypes. Accordingly, hyperactive Cdk5/p25 has been identified as a possible therapeutic target for neurodegeneration. All the therapeutic approaches inhibiting activities of kinases have been by interfering with ATP binding domains of the kinases that turned out to be non-specific and highly toxic. To modulate the Cdk5 activity instead of using the analogs of ATP we decided to study the effect of different truncated fragments of p35 on the regulation of Cdk5 activity. We identified a 126 amino acid (aa) truncated peptide of p35, (CIP) and smaller peptide p5 (24 aa) bind with Cdk5 with higher affinity than p25 and selectively inhibited Cdk5/p25 hyperactivity in culture, reduced tau, NFP hyper-phosphorylation and cell death without toxicity and affecting endogenous Cdk5/p35 activity. The question arose; will CIP and p5 be non toxic in vivo, in animals as in cell cultures and may prevent the phenotypes of an AD, PD and ALS transgenic mice models? Consistent with the model, we succeeded in showing that pathological and behavioral phenotypes in AD, PD and ALS model mice (over-expressing p25 transgenic) and the 5XFAD double transgenic can be alleviated after co-expression with CIP in p25 Tg and treatment with modified p5 (TFP5). We propose that CIP and TFP5 is novel therapeutic candidate to prevent Alzheimer’s disease phenotypes and pathologies.
Geneva University School of Medicine, Switzerland
Panteleimon Giannakopoulos obtained his MD degree in the University of Athens in 1989 before completing a full training on psychiatry and psychotherapy in
London (Maudsley Hospital and Geneva) as well as postdoc training in Paris (La Pitié-Sâlpetrière Hospital, Federation of Neurology). In 1998, aged 33 years,
he has been appointed as associate professor and medical head of the Division of Geriatric Psychiatry of the University Hospitals of Geneva. Later on (2004) he
obtained the position of full tenured professor of Psychiatry in the University of Geneva. From 2003 to 2011, he also assumed a parallel position of full professor
of Old Age Psychiatry in the University of Lausanne in order to promote the academic careers of junior staff locally. He has been Chairman of the Department of
Mental Health and Psychiatry in Geneva for ten years (2005-2015) and vice dean of the Faculty of Medicine in the University of Geneva in charge of postgraduate
and continuous education (2003-2011). From December 1st 2015, he is the medical head of the forensic psychiatry development in Geneva county. Specialist of
Alzheimer disase research, he published more than 220 peer reviewed articles in the fi eld of neurobiology of aging with particular focus on predictive biomarkers
of cognitive decline.
The presence of cerebral microbleeds has been associated with dementia and cognitive decline, although studies report confl icting
results. Our aim was to determine the potential role of the presence and location of cerebral microbleeds in early stages of
cognitive decline. Baseline 3T MR imaging examinations including SWI sequences of 328 cognitively intact community-dwelling
controls and 72 subjects with mild cognitive impairment were analyzed with respect to the presence and distribution of cerebral
microbleeds. A neuropsychological follow-up of controls was performed at 18 months post inclusion and identifi ed cases with subtle
cognitive defi cits were referred to as controls with a deteriorating condition. Group diff erences in radiologic parameters were studied
by using nonparametric tests, 1-way analysis of variance, and Spearman correlation coeffi cients. Cerebral microbleed prevalence was
similar in subjects with mild cognitive impairment and controls with stable and cognitively deteriorating conditions (25%-31.9%).
In all diagnostic groups, lobar cerebral microbleeds were more common. Th ey occurred in 20.1% of all cases compared with 6.5% of
cases with deep cerebral microbleeds. None of the investigated variables (age, sex, microbleed number, location and depth, baseline
Mini-Mental State Examination score, and the Fazekas score) were signifi cantly associated with cognitive deterioration with the
exception of education of >12 years showing a slight but signifi cant protective eff ect (OR, 0.44; 95% CI, 0.22-0.92; P = .028). Th e
Mini-Mental State Examination and the Buschke total score were correlated with neither the total number nor lobar-versus-deep
location of cerebral micro
University of Wisconsin, USA
Keynote: New approach to Neurorehabilitation: Cranial nerve noninvasive neuromodulation (CN-NINM technology)
Time : 10:00-10:40
Yuri P. Danilov, PhD, Senior Scientist and Neuroscience Director in Tactile Communication and Neuromudulation Laboratory (TCNL), Biomedical Engineering Department,
UW-Madison, is a system neuroscientist with over 35 years’ experience in research on brain functions and the special senses, including vision, taste, hearing and balance.
He is the lead discoverer of the balance retention effect, lead development of the specifi c training regimens, and continues to identify potential clinical and non-clinical
application of neuromodulation and sensory substitution technology. He received the M.S. degree in biophysics, in 1978, from St. Petersburg University in Russia and the
Ph.D. degree in neuroscience, in 1984, from the Pavlov Institute of Physiology, USSR Academy of Science. He was Senior Scientist (11/00 – 12/04) and Director of Clinical
Research at Wicab, Inc., where as co-inventor oversaw both conceptual development for the BrainPort vision and balance systems. He is a co-inventor the CN-NINM
technology and his interest areas are neuroplasticity, neurorehabilitation, enhancement of human performance.
Cranial-Nerve Non-Invasive NeuroModulation (CN-NINM) is a primary and complementary multi-targeted rehabilitation
therapy that initiates the recovery of multiple damaged or suppressed brain functions that are aff ected by neurological disorders.
CN-NINM was originally developed in our lab to facilitate and enhance the brain's innate ability to reorganize and “normalize”
its functional activity during targeted physical and occupational therapy, and thus improve movement control and cognition. It is
deployable as a simple, home-based device (portable tongue neurostimulator, PoNSTM) and training regimen following initial patient
training in an outpatient clinic. It may be easily combined with all existing rehabilitation therapies, and may reduce or eliminate need
for more aggressive invasive procedures or decrease the total medication intake.
CN-NINM uses sequenced patterns of electrical stimulation on the tongue. Our hypothesis is that CN-NINM induces
neuroplasticity by noninvasive stimulation of two major cranial nerves: trigeminal, CN-V, and facial, CN-VII. Th is stimulation excites
a natural fl ow of neural impulses to the brainstem (pons varolli and medulla), and cerebellum via the lingual branch of the cranial
nerve (CN-Vc), and chorda tympani branch of CN-VII, to eff ect changes in the function of these targeted brain structures, extending
to corresponding nuclei of the brainstem – at least in the sensory and spinal nuclei of trigeminal nuclei complex and the caudal part
of the nucleus tractus solitarius. We postulate that the intensive activation of these structures initiates a sequential cascade of changes
in neighboring and/or connected nuclei by direct collateral connections, brainstem interneuron circuitry and/or passive transmission
of biochemical compounds in the intercellular space. Combining neurostimulation with a specifi c set of physical, cognitive and/or
mental exercises we can further focus brain rehabilitation and target our eff ort on recovery of selected functional damage. Th e result is
essentially brain plasticity on demand – a priming or up-regulating of targeted neural structures to develop new functional pathways,
which is the goal of neuro-rehabilitation and a primary means of functional normalization and recovery.
CN-NINM represents a synthesis of a new non-invasive brain stimulation technique with applications in physical medicine,
cognitive, and aff ective neurosciences. Our new stimulation method appears promising for treatment of a full spectrum of movement
disorders, and for both attention and memory dysfunction associated with traumatic brain injury. Th e integrated CN-NINM therapy
proposed here aims to restore function beyond traditionally expected limits by employing both newly-developed therapeutic
mechanisms for progressive physical and cognitive training - while simultaneously applying brain stimulation through a portable
neurostimulation device. Based on our previous research and recent pilot data, we believe a rigorous in-clinic CN-NINM training
program, followed by regular at-home exercises that will also be performed with CN-NINM, will simultaneously enhance, accelerate,
and extend recovery from multiple impairments (e.g. movement, vision, speech, memory, attention, and mood), based on divergent,
but deeply interconnected neurophysiological mechanisms.