genetic/non-genetic parkinsonisms, are not categorical distinguishable (not helpfull)
Many genes are involved
Some monogenetic ones
Early onset recessive PD
Alpha synuclein mutations
Some people think it's the central gene in pathophysiology
Large variations in prevalence across world
This border begins to blur
Relation between these pathways not clear
whole exome sequencing
Zimprich et al AJHG 2011
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, 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?
tip of iceberg
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
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
We need to move away from single gene, single therapy idea toward systems approach
Lab of Patrik Brundin
mid brain dopaminergic neurons die
lewy bodies indicate protein misfolding
braak hypothesis- describes progression of lewy pathology
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
lewy bodies progress in time and place
lewy bodies in grafts
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?
bimoleculare fluorescence complementation (BiFC), this happens, no proof of aggregation, proof of interaction
Animal modelling, alfa synuclein seeding in vivo?
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
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
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..
Paul de Roos
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
ET vs cerebellar, ataxia in both, ET + alcohol = tremor decreases, finger-nose exercise, Gait disorders in ET, with/without alcohol
Moving toward 'laboratory supported" criteria for psychogenic tremor, mov dis 2011, Schwingenschuh et al
ET vs Dystonic tremor, Some controversial aspects
elble et al 2007
table w various steps, step 1, step 2, step 3, DBS for tremor
S3, Highest level of evidence
Meissner et al. Nat Rev Drug Discov 2011
ebersbach et al Mov Disord 2010
Psychiatric complications: Depression
more focus on non drug treatment
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
e.g. Hereditary myoclonic Dystonia, Hereditary Torsion Dystonia and Hereditary Essential Myoclonus - an area of confusion --> terms disappeared from literature now...
exclusion criteria include...dystonia etc.
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
hypertrofic jaw muscle.. dystonia?
Louis 2007, Shill 2008
no consistent pathology in ET
enhanced physiological tremor
tremulous dystonia or dystonic 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
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
ET-no-nos, unilateral/very asymmetric arm tremor, etc..
lack of gold standard
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
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
symptomatic therapy, AAV2-AADC (genzyme/Avigen), AAV2-GAD ( ), needs to make things better...better than what?, better than DBS
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..
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
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
Schapira & Tolosa, Nat Rev. Neurol, New node
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
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, ?, ?
logic: as soon as possible
prodromal stage, molecular, clinical
whom are the right patients?
how to treat
how to test
neuroprotection trial characteristics
papers on a possible link