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

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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:

1. Genetic Aspects in Parkinson's Disease

1.1. Speaker

1.1.1. Thomas Gasser

1.2. Genetic Parkinsonism

1.2.1. Case presentation

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

1.2.3. Many genes are involved

1.2.4. Some monogenetic ones

1.2.5. Early onset recessive PD

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

1.4. Park 1/4

1.4.1. Alpha synuclein mutations

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

1.5. alfa-syn pathology in LRRK2 - mutations

1.5.1. Large variations in prevalence across world

1.6. Monogenic - risk factor genetic

1.6.1. This border begins to blur

1.7. Two pathways to PD

1.7.1. Mitophagy pathway

1.7.2. Alfa synuclein

1.7.3. Relation between these pathways not clear

1.8. Promising new technology

1.8.1. whole exome sequencing

1.8.2. Zimprich et al AJHG 2011

1.9. VPS 35 gene in PD

1.9.1. is it pathogenic?

1.9.2. what does this mutation mean?

1.9.3. Sharma et al, submitted

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

1.10. Gaucher disease and PD

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

1.10.2. GBA-associated PD presents with nonmotor characteristics specific treatment?

1.11. Monogenic PD

1.11.1. tip of iceberg

1.11.2. Population stratifications

1.12. Genome wide association studies

1.12.1. Simon=sanchez et al, nat genet 2009

1.12.2. Satake et al - nat genetic 2009

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

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

1.13. Are there more genes

1.13.1. simon sanchez et al PlosOne 2012

1.13.2. protein homeostasis pathway

1.13.3. energy homeostasis in mytochondria

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

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

1.14. In sporadic cases

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

2. Christopher Dunninger

2.1. Prion-like disease mechanism in PD?

2.2. Neuronal survival unit

2.2.1. Lab of Patrik Brundin

2.3. Neuropathology

2.3.1. mid brain dopaminergic neurons die

2.3.2. lewy bodies indicate protein misfolding

2.3.3. braak hypothesis- describes progression of lewy pathology

2.4. Alfa synuclein

2.4.1. proposed rol in vesicle transport

2.4.2. ..

2.4.3. 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

2.5. Braak staging of Lewy related pathology in PD

2.5.1. lewy bodies progress in time and place

2.5.2. clinical correlates

2.6. Grafting

2.6.1. lewy bodies in grafts

2.6.2. oxidative stress?

2.6.3. Excitotoxicity?

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

2.6.5. does transmitted alfa synuclein recruit endogenous protein?

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

2.7. Can transmitted alfa syn. seed aggregation?

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

2.7.2. Animal modelling alfa synuclein seeding in vivo?

2.8. Exosomes

2.8.1. Alfa syn has been seen in exosomes

2.8.2. 100 nanometers 50 microliters of CSF needed for assay

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

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

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

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

3. Alpha Synuclein ligomers as potential therapeutic target and biomarker

3.1. Martin Ingelsson, MD, PhD

3.1.1. Uppsala

3.2. Lewy bodies/neurites consist of alfa synuclein

3.2.1. Alfa syn aggergation pathway tetramer -> monomer -->misfolded protein controversy on this step

3.3. Oxidative stress and formation of reactive aldehydes

3.3.1. to induce oligomers

3.3.2. to stabilise oligomers

3.3.3. Nasström et al.

3.3.4. alfa synuclein oligomers cause mitochondrial toxicity

3.3.5. Checking oligomers to various systems to check toxicity

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

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

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

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

3.3.10. missed some notes here..

4. Notes taken for


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

4.3. notes author:

4.3.1. Paul de Roos



5. Tremor and differential diagnosis - Jan Raethjen

5.1. Essential tremor

5.1.1. 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

5.2. dystonic

5.3. cerebellar

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

5.4. parkinsonian

5.5. functional

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

5.5.2. ET vs Dystonic tremor Some controversial aspects

5.6. Efficacy of treatments

5.6.1. elble et al 2007

5.7. Treatment of PD tremor

5.7.1. table w various steps step 1 step 2 step 3 DBS for tremor

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

5.8.1. thalamocortical loop

6. Early phase PD - Richard Dodel

6.1. Centennial of the description of Lewy bodies 1912

6.2. Guidelines

6.2.1. S1 Expert

6.2.2. S3 Highest level of evidence

6.3. Main targets

6.3.1. pathophysiology

6.3.2. Meissner et al. Nat Rev Drug Discov 2011


6.4.1. ebersbach et al Mov Disord 2010

6.5. CBT in PD

6.5.1. Psychiatric complications: Depression

6.5.2. more focus on non drug treatment

6.6. notes missed

6.7. Conclusion

6.7.1. no evidence for neuroprotective therapies

6.7.2. no evidence for disease modifying therapies

6.7.3. gaps in evidence based therapy of early pd

6.7.4. considerable preliminary evidence for effect of CBT and physiotherapy

6.7.5. one missed

7. Advanced Phase PD - Angelo Antonini

7.1. Patient diary of a patient w advanced PD

7.2. based on effectiveness of levodopa

7.3. notes not taken

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

8.1. What is ET?

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

8.2. Paper: Tremor - Some controversial aspects

8.3. MDS consensus criteria for ET

8.3.1. exclusion criteria include...dystonia etc.

8.4. Deuschl et al, Muslce Nerve 2001

8.5. controversy

8.5.1. ET and dystonia

8.5.2. ET and PD

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

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

8.5.5. "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

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

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

8.6. Isolated ET of jaw

8.6.1. hypertrofic jaw muscle.. dystonia?

8.7. Is ET pathologically one disease?

8.7.1. Louis 2007, Shill 2008

8.7.2. no consistent pathology in ET

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

8.8.1. enhanced physiological tremor

8.8.2. tremulous dystonia or dystonic tremor

8.8.3. pd

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

8.10. Consensus statement of MDS on tremor

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

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

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

8.10.4. Deuschl. et al

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

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

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

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

8.12. various clinical cases presented

8.13. Message: be very careful w calling something ET

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

8.13.2. lack of gold standard

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

9.1. Rationale

9.1.1. PDGF-BB well known in angiogenesis Recombinant human PDGF-BB = drug substance becaplermin Regraneux GEM 21S

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

9.1.3. 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 PDGF-BB increases striatal DAT binding-effect is proliferation dependent Affects behavior! suggested mechanism of action missed notes

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

9.2.1. snn0031

9.2.2. Treatment paradigm repeated injection will lead to disease modifaction

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

9.2.4. inclusion criteria missed

9.2.5. 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

10. Jeff Kordower - Nurturing Gene therapy for PD

10.1. Ongoing clinical trials

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

10.2. protection(trofic factors)

10.2.1. 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

10.2.2. 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 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 where next? inject in striatum inject in SNc increase dose hope: enhanced clinical benefit Early patients biomarker Conclusions more complicated than thought: use of trofic factors go big or go home.. etc..

10.2.3. ARTN

10.2.4. PSPN

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

11.1. new therapies in clinical development

11.1.1. motor problems dopaminergic agents IPX066 apomorphin inhalation Safinamide pardoprunox etc non-dopaminergic agents Normal Dyskinetic :lancet Neurol 2008;7:927-38 Preladenant AFQ056 - novartis Perampanel Fipamezole

11.1.2. 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 Postural hypotension L-DOPS New node

11.2. other type of therapies

11.2.1. 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

12. Tony Schapira - modifying PD

12.1. What

12.1.1. Schapira & Tolosa, Nat Rev. Neurol New node

12.1.2. Mitochondrial function

12.1.3. Aging lysosomal function decrease autophagy function decreases

12.1.4. Oxidative forforylation and free radical creation

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

12.1.6. Process of Autophagy alfa synuclein degradation destruction of organelles mitochondria

12.1.7. Transport of mitochondria

12.1.8. Turn over of mitochondria Repair? Destroy?

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

12.1.10. PGC-1 Alfa increase mitochonrdial mass in physiological terms

12.1.11. Potential Therapeutic targets Many! Ca channel modulators protein disaggregation

12.2. Who?

12.2.1. Genetic causes of PD PARK genes g2190s mutation LRRK2 is common

12.2.2. environment insignificant compated to genetic causes

12.2.3. 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

12.2.4. General application? mitochondrial enhancers ? ?

12.3. When to treat?

12.3.1. logic: as soon as possible

12.3.2. prodromal stage molecular clinical

12.3.3. whom are the right patients?

12.4. How

12.4.1. how to treat

12.4.2. how to test

12.4.3. neuroprotection trial characteristics

13. Anders Björklund - Nurr1

13.1. why is it interesting in PD?

13.1.1. papers on a possible link

13.2. no notes made