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Scandmodis - Scandinavian Movement Disorder Society Meeting, notes for @pdmovement link: by Mind Map: Scandmodis - Scandinavian
Movement Disorder Society
Meeting, notes for
@pdmovement link:
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Scandmodis - Scandinavian Movement Disorder Society Meeting, notes for @pdmovement link:

Genetic Aspects in Parkinson's Disease

Speaker

Thomas Gasser

Genetic Parkinsonism

Case presentation

genetic/non-genetic parkinsonisms, are not categorical distinguishable (not helpfull)

Many genes are involved

Some monogenetic ones

Early onset recessive PD

Feasibility of identifying genetic variants by risk-allele frequency and strength of genetic effect - 2009, Nature

Park 1/4

Alpha synuclein mutations

Some people think it's the central gene in pathophysiology

alfa-syn pathology in LRRK2 - mutations

Large variations in prevalence across world

Monogenic - risk factor genetic

This border begins to blur

Two pathways to PD

Mitophagy pathway

Alfa synuclein

Relation between these pathways not clear

Promising new technology

whole exome sequencing

Zimprich et al AJHG 2011

VPS 35 gene in PD

is it pathogenic?

what does this mutation mean?

Sharma et al, submitted

A multi-centered clinico-genetic analysis of the VPS35 gene in PD

Gaucher disease and PD

Gaucher disease, non-neuropathic type I, acute neuropathic type II, subacute neuropathic type, Multicenter analysis of glucocerebrosidase mutations in PD

GBA-associated PD presents with nonmotor characteristics, specific treatment?

Monogenic PD

tip of iceberg

Population stratifications

Genome wide association studies

Simon=sanchez et al, nat genet 2009

Satake et al - nat genetic 2009

pittman et al hum. mol. genet. 2004

Tau gene, haplotypes and gene expression implicate the MAPT region in PD, Different regions in brain and Tau metabolism - John Hardy

Are there more genes

simon sanchez et al PlosOne 2012

protein homeostasis pathway

energy homeostasis in mytochondria

There may be a few interlinked pathways rather than one common pathway

e.g. stratification of patients with certain degrees of various pathways involved could be a way forward

In sporadic cases

We need to move away from single gene, single therapy idea toward systems approach

Christopher Dunninger

Prion-like disease mechanism in PD?

Neuronal survival unit

Lab of Patrik Brundin

Neuropathology

mid brain dopaminergic neurons die

lewy bodies indicate protein misfolding

braak hypothesis- describes progression of lewy pathology

Alfa synuclein

proposed rol in vesicle transport

..

a-synuclein increases in age, correlated w dopamine neuron loss, 12 year old grafted neurons, 40% lewy bodies, 16 year old grafted neurons, 80% has lewy bodies

Braak staging of Lewy related pathology in PD

lewy bodies progress in time and place

clinical correlates

Grafting

lewy bodies in grafts

oxidative stress?

Excitotoxicity?

Coming from host brain?, most controversial.../interesting, alfa syn cell to cell transfer

does transmitted alfa synuclein recruit endogenous protein?

does the fluorescent substance "cause" the transfer?

Can transmitted alfa syn. seed aggregation?

bimoleculare fluorescence complementation (BiFC), this happens, no proof of aggregation, proof of interaction

Animal modelling, alfa synuclein seeding in vivo?

Exosomes

Alfa syn has been seen in exosomes

100 nanometers, 50 microliters of CSF needed for assay

cell culture model is replicating work of 2 other groups

Exosomes containing alfa synuclein affect kinetics of alfa synuclein aggregation

Exosomes are interesting why?, can probably spread pathology, can be of use in therapy

We know alfa syn spreads from cell to cell, but how we dont know

Alpha Synuclein ligomers as potential therapeutic target and biomarker

Martin Ingelsson, MD, PhD

Uppsala

Lewy bodies/neurites consist of alfa synuclein

Alfa syn aggergation pathway, tetramer -> monomer, -->misfolded protein, ->small oligomer, ->large oligomer, ->fibril, ->lewy body /neurite, not soluble, our focus, soluble, toxic, controversy on this step

Oxidative stress and formation of reactive aldehydes

to induce oligomers

to stabilise oligomers

Nasström et al.

alfa synuclein oligomers cause mitochondrial toxicity

Checking oligomers to various systems to check toxicity

Alfa synuclein oligomers decrease long term potentiation (LTP) in rat hippocampal neurons, oligomers have impact on this

Generation of monoclonal alfa synuclein antibodies, hybridoma production, made in mice, characterization of alfa syn oligomer selective antibodies, fagerqvist et al

Oligomer selective antibodies are internalized in H4 neuroglioma cells, Nässtrom et al Plos One 2011

The 49G antibody can interfere with early steps of alfa synuclein aggregation, bifluorescence complimentation assay

missed some notes here..

Notes taken for

www.parkinsonsmovement.com

Disclaimer: notes are personal notes, no substitute for peer reviewed work, please verify scientific papers if anything written here is interesting to you!

notes author:

Paul de Roos

www.paulderoos.com

http://www.twitter.com/paulderoos

Tremor and differential diagnosis - Jan Raethjen

Essential tremor

ET vs PD tremor, 10% of ET patients have some degree of resting tremor -- makes diagnostic process harder, postural tremor vs rest tremor, DAT scan - ET vs PD tremor, transcranial sonography, Accelerometric tremoranalysis, muthuraman 2011

dystonic

cerebellar

ET vs cerebellar, ataxia in both, ET + alcohol = tremor decreases, finger-nose exercise, Gait disorders in ET, with/without alcohol

parkinsonian

functional

Moving toward 'laboratory supported" criteria for psychogenic tremor, mov dis 2011, Schwingenschuh et al

ET vs Dystonic tremor, Some controversial aspects

Efficacy of treatments

elble et al 2007

Treatment of PD tremor

table w various steps, step 1, step 2, step 3, DBS for tremor

Why does thalamic stimulation selectively abolish termor leaving voluntary motor control in tact?

thalamocortical loop

Early phase PD - Richard Dodel

Centennial of the description of Lewy bodies 1912

Guidelines

S1, Expert

S3, Highest level of evidence

Main targets

pathophysiology

Meissner et al. Nat Rev Drug Discov 2011

LSVT BIG

ebersbach et al Mov Disord 2010

CBT in PD

Psychiatric complications: Depression

more focus on non drug treatment

notes missed

Conclusion

no evidence for neuroprotective therapies

no evidence for disease modifying therapies

gaps in evidence based therapy of early pd

considerable preliminary evidence for effect of CBT and physiotherapy

one missed

Advanced Phase PD - Angelo Antonini

Patient diary of a patient w advanced PD

based on effectiveness of levodopa

notes not taken

Kailash Bhatia - is there a connection between ET and PD?

What is ET?

e.g. Hereditary myoclonic Dystonia, Hereditary Torsion Dystonia and Hereditary Essential Myoclonus - an area of confusion --> terms disappeared from literature now...

Paper: Tremor - Some controversial aspects

MDS consensus criteria for ET

exclusion criteria include...dystonia etc.

Deuschl et al, Muslce Nerve 2001

controversy

ET and dystonia

ET and PD

how common is ET, epidemiology studies a 2750 fold difference among 20 studies

Tremor in unselected "normal" elderly, 98,7% has it, aged people w tremor usually dont visit clinics for this, but for other causes

"Benign" Essential Tremor (ET) the most common movement disorder, why in sporadic disorder PD a number of genes known, why in ET no genes found while most prevalent movement disorder and dominant inherited?, groups not homogeneous, garbage in = garbage out in genetics

The bimodal peak, early in life, later in life, which disease do you know w a bimodal peak?, actual different conditions?

Louis group, tremor of the head, more likely in women, more likely in late onset

Isolated ET of jaw

hypertrofic jaw muscle.. dystonia?

Is ET pathologically one disease?

Louis 2007, Shill 2008

no consistent pathology in ET

What other conditions are commonly mistaken for ET and vice versa?

enhanced physiological tremor

tremulous dystonia or dystonic tremor

pd

paper: Prevalence of movement disorders in men and women aged 50-89 age

Consensus statement of MDS on tremor

dystonic tremor: tremor in a body part that is affected by dystonia

Tremor associated w dystonia: tremor in a body part not affected by dystonia, but the patient has dystonia elsewhere

Dystonia gene-associated tremor: isolated tremor in patients with a dystonic pedigree

Deuschl. et al

Is ET associated w PD or PD w ET?

ET pts may only come to doctor when something else happens (e.g. development of PD)

PD may be tremor dominant (eg parkin disease can present w just tremor for many years)

Further misdiagnosis between familial dystonic tremor, PD and ET

various clinical cases presented

Message: be very careful w calling something ET

ET-no-nos, unilateral/very asymmetric arm tremor, etc..

lack of gold standard

Gesine Paul-Visse - Intracerebroventricular administration of PDGF-BB in moderate PD

Rationale

PDGF-BB, well known in angiogenesis, Recombinant human PDGF-BB = drug substance becaplermin, Regraneux, diabetic ulcers, GEM 21S, osteodental defects

PDGF in vitro neuroprotective for fetal DA neurons exposed to 6-OHDA

In vivo model: restorative effect PDGF-BB, increases periventricular cell proliferation, Zachrisson et al 2011, PDGF-BB increases nr of TH positive cells - effect is proliferation dependent, a mitosis inhibitor stops the effect, AraC, PDGF-BB increases striatal DAT binding-effect is proliferation dependent, Affects behavior!, suggested mechanism of action, missed notes

PDGF-BB for PD - a potentially disease modifying treatment

snn0031

Treatment paradigm, repeated injection will lead to disease modifaction

substance does not cross blood-brain barrier, delivered by pump, pump by medtronic

inclusion criteria, missed

outcome measures, primary objective, to assess safety and tolerability of drug, device and procedure, adverse events, vital signs, ecg, safety lab, cranial mri, fundoscopy, MMSE, MADRS, secondary, UPDRS, EQ-5D, DAT-PET

Jeff Kordower - Nurturing Gene therapy for PD

Ongoing clinical trials

symptomatic therapy, AAV2-AADC (genzyme/Avigen), AAV2-GAD ( ), needs to make things better...better than what?, better than DBS

protection(trofic factors)

GDNF, does not work in Alfa synuclein models(!) - Lo Bianco, Prevention of fine-motor deficits in mptp-treated monkeys by lentiviral gene delivery of GDNF, does give good results

Neurturin, GDNF --> in clinics stopped../intellectual property, signals through GDNF pathway, Neurturin is expressed in the caudate and putament following AAV-NTN (CERE-120) administration, symptomatic benefit MUST be demonstrated, in order to power studies, ADAGIO study --> showed that much is needed to show neuroprotective effect, Able to increase level of dopamine w the delivery, response = dose dependent, Monkey study, MPTP, MPTP + neurturin, recovery during 10 months, Phase 1, open label, Phase 2, inject vector in putamen, trial failed, Marks Olanow, Lancet, Change from Baseline in UPDRS (Part II) motor score "off", not significant in 12 months... some got significant after 18 months, three challenges, human brain does not express neurturin as well as non-human brain, only 15% of putamen expressed nurturin, miniscule trofic response, how much dopamine is really in the striatum when we do the surgery?, no dopamine fibers left after 5 years disease duration, =inclusion criterium, 1-3 years...=dopamine neurons available, where next?, inject in striatum, inject in SNc, increase dose, hope: enhanced clinical benefit, Early patients, biomarker, Synuclein staining?, in colon, loaded w alfa syn in PD patients, some cases: biopsies of sigmoid of patients years before PD diagnosis revealed high levels of Alfa synuclein, intestinal permeability in PD, Conclusions, more complicated than thought: use of trofic factors, go big or go home.., etc..

ARTN

PSPN

Eduardo Tolosa - Barcelona, Spain - Neuropharmacological treatment: pipeline and future perspectives

new therapies in clinical development

motor problems, dopaminergic agents, IPX066, a new extended-release oral formulation of levodopa - carbidopa, APEX-PD trial, Advanced OD and motor fluctuations: ADVANCE PD trial, 2 hours off time reduction, soon ready to marketed, what is optimal conversion rate CD-LD to IPX066, apomorphin inhalation, Apomorphine systemic delivery via the lung, Phase II Proof Of Concept pilot study inhaled APO, non invasive user-friendly, Safinamide, MAO-B inhibition, complemented by an effect on the glutamate pathway, promising effects on cognition, Motion study 666 pts randomized phase III, Settle study, phase III double-blind, placebo controlled, Open label, Randomized, Long Term Simple Study, PD-MED study, pardoprunox, etc, non-dopaminergic agents, Normal, Dyskinetic, :lancet Neurol 2008;7:927-38, New node, Preladenant, hauser et al, Adenosine A2A antagonists:, Modulation of GABAergic transmission in the striatopallidal system, Mori and Shindou, Preladenant in patients w PD and motor fluctuations: a phase 2, double blind RCT, Lancet Neurol 2011, AFQ056 - novartis, Stocchi et al, Reduced dyskinesisas in PD patients in 2 Phase II PBO controlled RCT, The first metabotropic glutamate receptor 5 to enter Phase III for the treatment of dyskinesia, how does this compare to amantadine?, Perampanel, eggert et al, Fipamezole, Selective Alpha 2 antagonist, tested in non-human primates, dimitrova et al 2007, FJORD study, LeWitt et al, no ffect in the intention to treat population in advanced PD

non-motor problems, Pathological gambling in PD is reduced by Amantadine, Amantadine use associated w impulse control disorders in PD..., dominion study, contradictory results, Falling, Reduce frequency of falls w Central cholinesterase inhibitor, donezepil, Postural hypotension, L-DOPS, Norepinephrine Precursor Therapy in Neurogenic Orthostatic Hypotension - 2003, L-DOPS Study 301, New node

other type of therapies

Physical exercise, LSVT BIG study, Self-management Rehabilitation and Health-Related Quality of Life in PD: a RCT, Tai Chi and Postural Stability in PD patients, NEJM

Tony Schapira - modifying PD

What

Schapira & Tolosa, Nat Rev. Neurol, New node

Mitochondrial function

Aging, lysosomal function decrease, autophagy function decreases

Oxidative forforylation and free radical creation

LRRK-2, many targets which cause fosforylation, alfa syn fosforylation, kinase inhibitors

Process of Autophagy, alfa synuclein degradation, destruction of organelles, mitochondria

Transport of mitochondria

Turn over of mitochondria, Repair?, Destroy?

Gegg et al 2010 HMG, Rakovic et al PLOS One

PGC-1 Alfa, increase mitochonrdial mass in physiological terms

Potential Therapeutic targets, Many!, Ca channel modulators, protein disaggregation

Who?

Genetic causes of PD, PARK genes, g2190s mutation, LRRK2 is common

environment, insignificant compated to genetic causes

should we develop personalised medicine for individuals w particular biochemical markers?, Cohorts of individuals w certain risk factors may benefit of some approaches, while others will not, DATATOP: Vit E/urate, LRRK2 inhibitors, GBA carriers, Ashkenazi jews

General application?, mitochondrial enhancers, ?, ?

When to treat?

logic: as soon as possible

prodromal stage, molecular, clinical

whom are the right patients?

How

how to treat

how to test

neuroprotection trial characteristics

Anders Björklund - Nurr1

why is it interesting in PD?

papers on a possible link

no notes made