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

1. Tremor and differential diagnosis - Jan Raethjen

1.1. Essential tremor

1.1.1. ET vs PD tremor

1.1.1.1. 10% of ET patients have some degree of resting tremor -- makes diagnostic process harder

1.1.1.2. postural tremor vs rest tremor

1.1.1.3. DAT scan - ET vs PD tremor

1.1.1.4. transcranial sonography

1.1.1.5. Accelerometric tremoranalysis

1.1.1.5.1. muthuraman 2011

1.2. dystonic

1.3. cerebellar

1.3.1. ET vs cerebellar

1.3.1.1. ataxia in both

1.3.1.2. ET + alcohol = tremor decreases

1.3.1.3. finger-nose exercise

1.3.1.4. Gait disorders in ET

1.3.1.4.1. with/without alcohol

1.4. parkinsonian

1.5. functional

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

1.5.2. ET vs Dystonic tremor

1.5.2.1. Some controversial aspects

1.6. Efficacy of treatments

1.6.1. elble et al 2007

1.7. Treatment of PD tremor

1.7.1. table w various steps

1.7.1.1. step 1

1.7.1.2. step 2

1.7.1.3. step 3

1.7.1.3.1. DBS for tremor

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

1.8.1. thalamocortical loop

2. Early phase PD - Richard Dodel

2.1. Centennial of the description of Lewy bodies 1912

2.2. Guidelines

2.2.1. S1

2.2.1.1. Expert

2.2.2. S3

2.2.2.1. Highest level of evidence

2.3. Main targets

2.3.1. pathophysiology

2.3.2. Meissner et al. Nat Rev Drug Discov 2011

2.4. LSVT BIG

2.4.1. ebersbach et al Mov Disord 2010

2.5. CBT in PD

2.5.1. Psychiatric complications: Depression

2.5.2. more focus on non drug treatment

2.6. notes missed

2.7. Conclusion

2.7.1. no evidence for neuroprotective therapies

2.7.2. no evidence for disease modifying therapies

2.7.3. gaps in evidence based therapy of early pd

2.7.4. considerable preliminary evidence for effect of CBT and physiotherapy

2.7.5. one missed

3. Advanced Phase PD - Angelo Antonini

3.1. Patient diary of a patient w advanced PD

3.2. based on effectiveness of levodopa

3.3. notes not taken

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

4.1. What is ET?

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

4.2. Paper: Tremor - Some controversial aspects

4.3. MDS consensus criteria for ET

4.3.1. exclusion criteria include...dystonia etc.

4.4. Deuschl et al, Muslce Nerve 2001

4.5. controversy

4.5.1. ET and dystonia

4.5.2. ET and PD

4.5.3. how common is ET

4.5.3.1. epidemiology studies a 2750 fold difference among 20 studies

4.5.4. Tremor in unselected "normal" elderly

4.5.4.1. 98,7% has it

4.5.4.2. aged people w tremor usually dont visit clinics for this, but for other causes

4.5.5. "Benign" Essential Tremor (ET) the most common movement disorder

4.5.5.1. why in sporadic disorder PD a number of genes known

4.5.5.2. why in ET no genes found while most prevalent movement disorder and dominant inherited?

4.5.5.2.1. groups not homogeneous

4.5.6. The bimodal peak

4.5.6.1. early in life

4.5.6.2. later in life

4.5.6.3. which disease do you know w a bimodal peak?

4.5.6.3.1. actual different conditions?

4.5.7. Louis group

4.5.7.1. tremor of the head

4.5.7.1.1. more likely in women

4.5.7.1.2. more likely in late onset

4.6. Isolated ET of jaw

4.6.1. hypertrofic jaw muscle.. dystonia?

4.7. Is ET pathologically one disease?

4.7.1. Louis 2007, Shill 2008

4.7.2. no consistent pathology in ET

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

4.8.1. enhanced physiological tremor

4.8.2. tremulous dystonia or dystonic tremor

4.8.3. pd

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

4.10. Consensus statement of MDS on tremor

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

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

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

4.10.4. Deuschl. et al

4.11. Is ET associated w PD or PD w ET?

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

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

4.11.3. Further misdiagnosis between familial dystonic tremor, PD and ET

4.12. various clinical cases presented

4.13. Message: be very careful w calling something ET

4.13.1. ET-no-nos

4.13.1.1. unilateral/very asymmetric arm tremor

4.13.1.2. etc..

4.13.2. lack of gold standard

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

5.1. Rationale

5.1.1. PDGF-BB

5.1.1.1. well known in angiogenesis

5.1.1.2. Recombinant human PDGF-BB = drug substance becaplermin

5.1.1.2.1. Regraneux

5.1.1.2.2. GEM 21S

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

5.1.3. In vivo model: restorative effect PDGF-BB

5.1.3.1. increases periventricular cell proliferation

5.1.3.1.1. Zachrisson et al 2011

5.1.3.2. PDGF-BB increases nr of TH positive cells - effect is proliferation dependent

5.1.3.2.1. a mitosis inhibitor stops the effect

5.1.3.3. PDGF-BB increases striatal DAT binding-effect is proliferation dependent

5.1.3.4. Affects behavior!

5.1.3.5. suggested mechanism of action

5.1.3.5.1. missed notes

5.2. PDGF-BB for PD - a potentially disease modifying treatment

5.2.1. snn0031

5.2.2. Treatment paradigm

5.2.2.1. repeated injection will lead to disease modifaction

5.2.3. substance does not cross blood-brain barrier

5.2.3.1. delivered by pump

5.2.3.1.1. pump by medtronic

5.2.4. inclusion criteria

5.2.4.1. missed

5.2.5. outcome measures

5.2.5.1. primary objective

5.2.5.1.1. to assess safety and tolerability of drug, device and procedure

5.2.5.1.2. adverse events

5.2.5.1.3. vital signs

5.2.5.1.4. ecg

5.2.5.1.5. safety lab

5.2.5.1.6. cranial mri

5.2.5.1.7. fundoscopy

5.2.5.1.8. MMSE

5.2.5.1.9. MADRS

5.2.5.2. secondary

5.2.5.2.1. UPDRS

5.2.5.2.2. EQ-5D

5.2.5.2.3. DAT-PET

6. Jeff Kordower - Nurturing Gene therapy for PD

6.1. Ongoing clinical trials

6.1.1. symptomatic therapy

6.1.1.1. AAV2-AADC (genzyme/Avigen)

6.1.1.2. AAV2-GAD ( )

6.1.1.3. needs to make things better...better than what?

6.1.1.3.1. better than DBS

6.2. protection(trofic factors)

6.2.1. GDNF

6.2.1.1. does not work in Alfa synuclein models(!) - Lo Bianco

6.2.1.2. Prevention of fine-motor deficits in mptp-treated monkeys by lentiviral gene delivery of GDNF

6.2.1.2.1. does give good results

6.2.2. Neurturin

6.2.2.1. GDNF --> in clinics stopped../intellectual property

6.2.2.2. signals through GDNF pathway

6.2.2.3. Neurturin is expressed in the caudate and putament following AAV-NTN (CERE-120) administration

6.2.2.4. symptomatic benefit MUST be demonstrated, in order to power studies

6.2.2.4.1. ADAGIO study --> showed that much is needed to show neuroprotective effect

6.2.2.5. Able to increase level of dopamine w the delivery

6.2.2.5.1. response = dose dependent

6.2.2.6. Monkey study

6.2.2.6.1. MPTP

6.2.2.6.2. MPTP + neurturin

6.2.2.7. Phase 1

6.2.2.7.1. open label

6.2.2.8. Phase 2

6.2.2.8.1. inject vector in putamen

6.2.2.8.2. trial failed

6.2.2.8.3. Marks Olanow, Lancet

6.2.2.8.4. Change from Baseline in UPDRS (Part II) motor score "off"

6.2.2.8.5. not significant in 12 months... some got significant after 18 months

6.2.2.8.6. three challenges

6.2.2.9. where next?

6.2.2.9.1. inject in striatum

6.2.2.9.2. inject in SNc

6.2.2.9.3. increase dose

6.2.2.9.4. hope: enhanced clinical benefit

6.2.2.10. Early patients

6.2.2.10.1. biomarker

6.2.2.11. Conclusions

6.2.2.11.1. more complicated than thought: use of trofic factors

6.2.2.11.2. go big or go home..

6.2.2.11.3. etc..

6.2.3. ARTN

6.2.4. PSPN

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

7.1. new therapies in clinical development

7.1.1. motor problems

7.1.1.1. dopaminergic agents

7.1.1.1.1. IPX066

7.1.1.1.2. apomorphin inhalation

7.1.1.1.3. Safinamide

7.1.1.1.4. pardoprunox

7.1.1.1.5. etc

7.1.1.2. non-dopaminergic agents

7.1.1.2.1. Normal

7.1.1.2.2. Dyskinetic

7.1.1.2.3. :lancet Neurol 2008;7:927-38

7.1.1.2.4. Preladenant

7.1.1.2.5. AFQ056 - novartis

7.1.1.2.6. Perampanel

7.1.1.2.7. Fipamezole

7.1.2. non-motor problems

7.1.2.1. Pathological gambling in PD is reduced by Amantadine

7.1.2.2. Amantadine use associated w impulse control disorders in PD...

7.1.2.2.1. dominion study, contradictory results

7.1.2.3. Falling

7.1.2.3.1. Reduce frequency of falls w Central cholinesterase inhibitor

7.1.2.4. Postural hypotension

7.1.2.4.1. L-DOPS

7.1.2.4.2. New node

7.2. other type of therapies

7.2.1. Physical exercise

7.2.1.1. LSVT BIG study

7.2.1.2. Self-management Rehabilitation and Health-Related Quality of Life in PD: a RCT

7.2.1.3. Tai Chi and Postural Stability in PD patients, NEJM

8. Tony Schapira - modifying PD

8.1. What

8.1.1. Schapira & Tolosa, Nat Rev. Neurol

8.1.1.1. New node

8.1.2. Mitochondrial function

8.1.3. Aging

8.1.3.1. lysosomal function decrease

8.1.3.2. autophagy function decreases

8.1.4. Oxidative forforylation and free radical creation

8.1.5. LRRK-2, many targets which cause fosforylation

8.1.5.1. alfa syn fosforylation

8.1.5.2. kinase inhibitors

8.1.6. Process of Autophagy

8.1.6.1. alfa synuclein degradation

8.1.6.2. destruction of organelles

8.1.6.2.1. mitochondria

8.1.7. Transport of mitochondria

8.1.8. Turn over of mitochondria

8.1.8.1. Repair?

8.1.8.2. Destroy?

8.1.9. Gegg et al 2010 HMG, Rakovic et al PLOS One

8.1.10. PGC-1 Alfa

8.1.10.1. increase mitochonrdial mass in physiological terms

8.1.11. Potential Therapeutic targets

8.1.11.1. Many!

8.1.11.2. Ca channel modulators

8.1.11.3. protein disaggregation

8.2. Who?

8.2.1. Genetic causes of PD

8.2.1.1. PARK genes

8.2.1.1.1. g2190s mutation

8.2.1.1.2. LRRK2 is common

8.2.2. environment

8.2.2.1. insignificant compated to genetic causes

8.2.3. should we develop personalised medicine for individuals w particular biochemical markers?

8.2.3.1. Cohorts of individuals w certain risk factors may benefit of some approaches, while others will not

8.2.3.2. DATATOP: Vit E/urate

8.2.3.3. LRRK2 inhibitors

8.2.3.4. GBA carriers

8.2.3.5. Ashkenazi jews

8.2.4. General application?

8.2.4.1. mitochondrial enhancers

8.2.4.2. ?

8.2.4.3. ?

8.3. When to treat?

8.3.1. logic: as soon as possible

8.3.2. prodromal stage

8.3.2.1. molecular

8.3.2.2. clinical

8.3.3. whom are the right patients?

8.4. How

8.4.1. how to treat

8.4.2. how to test

8.4.3. neuroprotection trial characteristics

9. Anders Björklund - Nurr1

9.1. why is it interesting in PD?

9.1.1. papers on a possible link

9.2. no notes made

10. Genetic Aspects in Parkinson's Disease

10.1. Speaker

10.1.1. Thomas Gasser

10.2. Genetic Parkinsonism

10.2.1. Case presentation

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

10.2.3. Many genes are involved

10.2.4. Some monogenetic ones

10.2.5. Early onset recessive PD

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

10.4. Park 1/4

10.4.1. Alpha synuclein mutations

10.4.2. Some people think it's the central gene in pathophysiology

10.5. alfa-syn pathology in LRRK2 - mutations

10.5.1. Large variations in prevalence across world

10.6. Monogenic - risk factor genetic

10.6.1. This border begins to blur

10.7. Two pathways to PD

10.7.1. Mitophagy pathway

10.7.2. Alfa synuclein

10.7.3. Relation between these pathways not clear

10.8. Promising new technology

10.8.1. whole exome sequencing

10.8.2. Zimprich et al AJHG 2011

10.9. VPS 35 gene in PD

10.9.1. is it pathogenic?

10.9.2. what does this mutation mean?

10.9.3. Sharma et al, submitted

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

10.10. Gaucher disease and PD

10.10.1. Gaucher disease

10.10.1.1. non-neuropathic type I

10.10.1.2. acute neuropathic type II

10.10.1.3. subacute neuropathic type

10.10.1.4. Multicenter analysis of glucocerebrosidase mutations in PD

10.10.2. GBA-associated PD presents with nonmotor characteristics

10.10.2.1. specific treatment?

10.11. Monogenic PD

10.11.1. tip of iceberg

10.11.2. Population stratifications

10.12. Genome wide association studies

10.12.1. Simon=sanchez et al, nat genet 2009

10.12.2. Satake et al - nat genetic 2009

10.12.3. pittman et al hum. mol. genet. 2004

10.12.4. Tau gene

10.12.4.1. haplotypes and gene expression implicate the MAPT region in PD

10.12.4.2. Different regions in brain and Tau metabolism - John Hardy

10.13. Are there more genes

10.13.1. simon sanchez et al PlosOne 2012

10.13.2. protein homeostasis pathway

10.13.3. energy homeostasis in mytochondria

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

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

10.14. In sporadic cases

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

11. Christopher Dunninger

11.1. Prion-like disease mechanism in PD?

11.2. Neuronal survival unit

11.2.1. Lab of Patrik Brundin

11.3. Neuropathology

11.3.1. mid brain dopaminergic neurons die

11.3.2. lewy bodies indicate protein misfolding

11.3.3. braak hypothesis- describes progression of lewy pathology

11.4. Alfa synuclein

11.4.1. proposed rol in vesicle transport

11.4.2. ..

11.4.3. a-synuclein increases in age

11.4.3.1. correlated w dopamine neuron loss

11.4.3.2. 12 year old grafted neurons

11.4.3.2.1. 40% lewy bodies

11.4.3.3. 16 year old grafted neurons

11.4.3.3.1. 80% has lewy bodies

11.5. Braak staging of Lewy related pathology in PD

11.5.1. lewy bodies progress in time and place

11.5.2. clinical correlates

11.6. Grafting

11.6.1. lewy bodies in grafts

11.6.2. oxidative stress?

11.6.3. Excitotoxicity?

11.6.4. Coming from host brain?

11.6.4.1. most controversial.../interesting

11.6.4.2. alfa syn cell to cell transfer

11.6.5. does transmitted alfa synuclein recruit endogenous protein?

11.6.6. does the fluorescent substance "cause" the transfer?

11.7. Can transmitted alfa syn. seed aggregation?

11.7.1. bimoleculare fluorescence complementation (BiFC)

11.7.1.1. this happens

11.7.1.2. no proof of aggregation

11.7.1.3. proof of interaction

11.7.2. Animal modelling

11.7.2.1. alfa synuclein seeding in vivo?

11.8. Exosomes

11.8.1. Alfa syn has been seen in exosomes

11.8.2. 100 nanometers

11.8.2.1. 50 microliters of CSF needed for assay

11.8.3. cell culture model is replicating work of 2 other groups

11.8.4. Exosomes containing alfa synuclein affect kinetics of alfa synuclein aggregation

11.8.5. Exosomes are interesting why?

11.8.5.1. can probably spread pathology

11.8.5.2. can be of use in therapy

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

12. Alpha Synuclein ligomers as potential therapeutic target and biomarker

12.1. Martin Ingelsson, MD, PhD

12.1.1. Uppsala

12.2. Lewy bodies/neurites consist of alfa synuclein

12.2.1. Alfa syn aggergation pathway

12.2.1.1. tetramer -> monomer

12.2.1.1.1. -->misfolded protein

12.2.1.1.2. controversy on this step

12.3. Oxidative stress and formation of reactive aldehydes

12.3.1. to induce oligomers

12.3.2. to stabilise oligomers

12.3.3. Nasström et al.

12.3.4. alfa synuclein oligomers cause mitochondrial toxicity

12.3.5. Checking oligomers to various systems to check toxicity

12.3.6. Alfa synuclein oligomers decrease long term potentiation (LTP) in rat hippocampal neurons

12.3.6.1. oligomers have impact on this

12.3.7. Generation of monoclonal alfa synuclein antibodies

12.3.7.1. hybridoma production

12.3.7.2. made in mice

12.3.7.3. characterization of alfa syn oligomer selective antibodies

12.3.7.3.1. fagerqvist et al

12.3.8. Oligomer selective antibodies are internalized in H4 neuroglioma cells

12.3.8.1. Nässtrom et al Plos One 2011

12.3.9. The 49G antibody can interfere with early steps of alfa synuclein aggregation

12.3.9.1. bifluorescence complimentation assay

12.3.10. missed some notes here..

13. Notes taken for

13.1. www.parkinsonsmovement.com

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

13.3. notes author:

13.3.1. Paul de Roos

13.3.2. www.paulderoos.com

13.3.3. http://www.twitter.com/paulderoos