Parkinson’s Disease.

1. Parkinson’s Disease. Complex of disease processes affecting movement control mediated by damage to dopamine pathways in the CNS

2. What is the role of dopamine? • Dopamine is a neurotransmitter • Originates in neurones of the SubstantiaNigra • Dopaminergic fibres radiate to the striatum • The nigrostriatal pathway-the main pathway damaged in Parkinson’s Disease due to loss of neurones in the SN • There is also a tuberohyperphyseal pathway serving thalamic functions associated with hormonal control • The action of dopamine can be excitatory or inhibitory depending on what receptors are activated

4. Parkinson’s Disease-clinical features James Parkinson 1755 – 1823 1817 : “An essay on the shaking palsy” Described the disease in the following terms: “an involuntary, tremulous motion, with lessened muscular power, in parts not in action and even when supported, with a propensity to bend the trunk forwards and to pass from a walking to a running pace: the senses and intellect being unimpaired”

5. Epidemiologyof Parkinson’s disease PREVALENCE Approximately 250/100,000 in UK (PD and PD syndromes) AGE Most commonly diagnosed after the age of 50 but some syndromes appear earlier at 30+ High prevalence in the population aged over 80 years GENDER Slightly higher incidence in men than women GENETICS Familial but not directly inherited

6. Susceptibility to PD Genetic evidence-complex and a “work in progress” Familial not inherited a-synuclein (A-S) identified as gene PARK1 Examples. Variants of PARK1 may correlate with disease severity and type. “Typical Parkinsonism” in wild type PARK1 gene and Ala53Thr variant genome Dementia is more commonly associated with a Ala30Pro variant. PARK2 associated with younger onset Parkinsoniansyndromes characterised by muscle stiffness and dystonia

7. Parkinsonian Syndromes Degenerative Non degenerative Neurofibrillar Tangle type Parkinsonian dementia Idiopathic parkinsonism Lewy body dementia Neuroleptics induced Multiple System Atrophy Manganese Viral encephalitis Tumour Striato-nigralDegeneration Olivopontine Cerebellar atrophy

8. Classification of the various forms of Parkinsonism based on differential aetiology Parkinson’s Disease Idiopathic Parkinson’s Disease (defined by DA cell loss + presence of Lewy bodies) Parkinsonian syndromes Steele-Richardson-Olsewiski disease Striatonigral degeneration Corticobasal degeneration Hallervorden-Spatz disease Wilson’s disease (Cu induced dystonia) Shy-Drager syndrome Olivopontocerebellar atrophy Symptomatic parkinsonism Toxin-induced (e.g. *MPTP, CO, Mn, rotenone etc.) Drug-induced (e.g. reserpine, calcium antagonists, neuroleptics etc.) Infectious (e.g. encephalitis lethargica) Vascular trauma Brain carcinoma Brain trauma-e.g in boxers? MPTP = N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine Neurotoxin specific for dopaminergic cells of SubstantiaNigra

10. Parkinson’s DiseaseClinical symptoms “The most common disorder of the basal ganglia” Early symptoms characterised by: Rigidity. Resistance to passive movement of the joints due to increased muscle tone leads to “cog-wheeling” or “clasp knife” responses Tremor at rest (3 to 5Hz) especially noticed in the hands-early symptom In later stages tremor occurs in lips, tongue and feet and persists during voluntary movement (action tremor 4 – 8 Hz) Postural tremor may be present (8-10Hz)

11. Parkinson’s Disease Clinical symptoms Akinesia occurs in the final stages of the disease Bradykinesia – slow movements. Affected person requires much concentration to perform a movement Postural difficulties – push to the shoulders causes overbalance, failure to throw limbs out to protect body during a fall Shuffling gait Face has a mask-like appearance Arms do not swing while walking Can sit or stand motionless-may “freeze” Micrographia Difficulty swallowing food or drink - marked weight loss Dementia may occur in later stages

12. Basal Ganglia Group of 5 nuclei lateral to the thalamus Caudate, putamen, globuspallidus, subthalamic nucleus and substantianigra (SN) SN main source of dopaminergic fibres in CNS Controls and modulates movement Main links are input from (motor) cerebral cortex and output via the thalamus to the same cortical areas Pathways are functionally arranged so that limb, trunk, head and oculomotor tracts are separate

15. Causes of Parkinson’s symptoms Widespread progressive degeneration of Dopamine (DA) producing neurones in the nigrostriataltract Concomitant fall in DA levels in the striatum When DA levels fall below 80% symptoms appear ACh releasing neurones still active in striatum but their excitatory signals are no longer checked by DA

17. Striatal dopamine concentrations in Parkinson’s Disease, Parkinsonian Syndromes and other neurodegenerative disorders Disease % normal control values caudate nucleus putamen Parkinson’s Disease 18- 31% 6 – 22% Postencephalitic Parkinsonism 6 6 Parkinsonian syndromes Striatonigral degeneration <0.4 <0.4 Steele-Richardson syndrome 20 27 Hallervorden-Spatz disease 1.4 0.9 Olivopontocerebellar atrophy 0.3 0.01 AIDS 43 not measured Huntington’s disease 86* 99* Alzheimer’ disease 61* 50* Alzheimer’s + Lewy body pathology 16 5 (*) = not a significant change

18. Causes of Parkinson’s symptoms Two symptom patterns: “positive” = increased nervous activity “negative”= decreased nervous activity e.g. Loss of inhibitory influence of DA in basal ganglia leads to increased activity of the cerebral cortex-basal ganglia feedback loop leading to oscillation and tremor. Tremor at rest caused by excess excitatory signals in the corticospinal tract leading to excess stimulation of a/gmotor neurones Negative symptoms like akinesia and bradykinesia due to inhibitory activity

19. Causes of symptoms Positive symptoms (tremor and rigidity) are produced secondarily by other areas of the brain released from the influence of the affected inhibitory DA producing cells. Tremor and rigidity are secondary symptoms caused by loss of basal ganglia control on other structures Negative symptoms –failure to move or slow poor quality movement

20. Understanding the Causes of PD Symptoms associated with different types and stages may differ. Evidence for development of symptoms from N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine neurotoxin MPTP cases and experimental studies. Causes specific damage to dopaminergic cells of SubstantiaNigra Evidence for course and origins of PD from genetic studies

21. MPTP Model MPTP is toxic to dopaminergic cells in the substantianigra MPTP is converted to 1-methyl-4-phenylpyridinium (MPP+) which is produced by metabolism of MPTP by MAO-B MPP+inhibits the mitochondrial respiratory chain via inhibition of Complex 1 leading to DA cell death Inhibition of Complex 1 causes reduction of ATP synthesis, increased amounts of superoxide leading the increased lipid peroxidation Reduced Complex1 has been shown in the SN of PD patients Evidence from MPP+ suggests that cell death in the SN is caused by oxidative stress Possible that excess Fe in SN of PD patients is matched with reduced levels in the iron-binding protein ferratin High levels of Fe, in a form suitable for free radical production could lead to oxidative stress and cell death

24. PD and L-DOPA L-DOPA revolutionised PD treatment by displacing anticholinergic drugs (especially when combined with a peripheral decarboxylase inhibitor such as carbidopa) L-DOPA shown to induce apoptosis-and – effect of L-DOPA inhibited by anti-oxidants L-DOPA-induced apoptosis not inhibited by drugs that prevent the conversion of L-DOPA to DA which suggests that production of DA is not the cause of apoptosis L-DOPA prolongs patient survival by around 5 years but it may also trigger the onset of dementia L-DOPA therapy also causes hyperkinesia, dyskinesia, hallucinations, appalling dreams L-DOPA “honeymoon” period 3 -5 years in 60% of patients followed by progressive loss of efficacy and later on/off fluctuations in efficacy leading to unpredictable “freezing”. Schizophrenic symptoms occur in about 50% of patients

25. L-Deprenyl (Selegiline) a protectant therapy? Deprenyl inhibits MAO-B and will protect against the effects of MPTP Believed originally (erroneously) to delay onset of L-DOPA-induced dementia. Deprenyl used as an adjunctive therapy with L-DOPA in an attempt to reduce adverse effects of L-DOPA BUT one study suggested that deprenyl plus L-DOPA actually leads to a higher mortality rate that L-DOPA alone

26. DA agonists DA agonists are prescribed as adjuncts to L-DOPA to improve response and reduce “off” time and motor fluctuations and thereby reduce the dose of L-DOPA and/or delay the onset of L-DOPA use Bromocriptine: less effective than L-DOPA with high non-response rates – hallucinogenic and causes dyskinesias Lisuride: more potent than bromocriptine but less effective than L-DOPA in early onset PD - hallucinogenic and causes dyskinesias Ropinerole: a non-ergoline DA agonist with a high affinity for D2-Rs and in MPTP-dose-related reversal of motor deficits. Pramipexole: also a non-ergoline DA agonist which causes dose –related reversal of locomotor deficits in MPTP-lesioned rhesus monkeys as well as inhibiting dyskinesias caused by chronic dosing of MPTP-treated monkeys with haloperidol Cabergole: an ergot derivative which will overcome PD-like symptoms as well as dyskinesia caused by L-DOPA

27. Alternative approaches Peripherally active inhibitor of catechol-O-methyl- transferase (COMT) increases the duration of L-DOPA response Brain penetrant COMT inhibitor tolcapone allows reduced L-DOPA usage in non-fluctuating patients – used in conjunction with carbidopa Foetal cell/stem cell transplantation GDNF

30. Glial cell line-derived neurotrophic factor (GDNF) GDNF is a potent and relatively selective trophic factor for DA neurones Lentiviruses used to provide transgene expression and infect non-dividing cells including neurones Lenti-GDNF treatment of young rhesus macaques with stable hemiparkinsonian state (induced by unilateral MPTP) improved functional capabilities by 75% (compared to control injected with lenti-b-galactosidase Markers of DA function (e.g.TH) also increased in treated monkeys and was associated with the functional recovery TH-immunoreactive neurones increased following lenti-GDNF therapy regardless of the degree of functional recovery Suggests that lenti-GDNF therapy can promote survival and regeneration of DA containing neurones Human studies show that lenti-GDNF also leads to an increase in TH-I and sustained functional recovery – some patients show classical degeneration after 9 – 36 months

31. Deep Brain Stimulation What is deep Brain Stimulation DBS? A surgically implanted, battery-operated neurostimulator (similar to a heart pacemaker) and approximately the size of a stopwatch Delivers electrical stimulation to targeted areas in the brain that control movement Blocks the abnormal nerve signals that cause tremor and PD symptoms.  Electrodes are positioned under local anaesthetic to determine position where tremor is most reduced is used.

33. The most famous PD patient? “ Physically he presented a dreadful sight, he dragged himself about painfully and clumsily – throwing his torso forward and dragging his legs after him from his living room to the conference room of the Bunker” He had lost his sense of balance – if he was detained on the brief journey (75 – 100 feet), he had to sit down on one of the benches that had been placed along either wall for this purpose, or else cling to the person he was talking to. His eyes were bloodshot and although all the documents intended for him were typed about 3X ordinary size on special “Führer typewriters” he could only read them with the aid of a magnifying glass. Saliva frequently dripped from the corner of his mouth. Whenever Hitler took his glasses into his left hand during the daily report, they clinked against the desk top as his hand shook. His lips were dry and covered in crumbs, his clothing stained with food”