6/23/2016 Review of Parkinsons Disease: Outline PD demographics - PowerPoint PPT Presentation

6/23/2016 Review of Parkinson’s Disease: Outline � PD demographics Parkinson’s Disease for the Primary Care Provider � PD diagnostic criteria � Main PD motor symptoms � Non-motor PD symptoms � Cognition and PD � Clinical course of PD � Pathology of PD Maya Katz, M.D. � Pathophysiology of PD Assistant Professor of Neurology Movement Disorder and Neuromodulation Center � Etiology of PD UCSF Medical Center � Review treatments for PD Parkinson’s disease: Demographics Parkinson’s disease Diagnostic Criteria : UK Brain Bank MOTOR SYMPTOMS Step 1 Bradykinesia and either rest tremor (4-6 Hz tremor), rigidity 1-2% of people 60 years of age or older (~130-140 per or postural instability 100,000) EXCLUSION CRITERIA Step 2 2 nd most common neurodegenerative disorder e.g. history of repeated strokes or TBI, h/o neuroleptic treatment at symptom onset, cerebellar signs, or non- Average age of onset: 60 years old (range 20-95) responsiveness to levodopa, early severe autonomic involvement, early and severe dementia Men are more likely to develop Parkinson’s disease compared to women SUPPORTIVE CRITERIA (at least 3) Step 3 Typical life expectancy: 12-20 years (range: 12-40) e.g, history of unilateral onset and persistent asymmetry of symptoms, 70-100% responsiveness to levodopa, presence of dyskinesias, clinical course for > 10 years, 1 Wickremaracthi et al. 2009. J Neurol Neurosurg Psych; levodopa response for 5 years or more Walker et al. 2010. Parkinsonism and Related Disorders 2 Lees et al. 2009. The Lancet Hughes et al. 2001, Neurology 1

6/23/2016 Group A: Parkinson’s disease: characteristic of PD NINDS Diagnostic Criteria Cardinal motor symptoms: Tremor Resting tremor (4-6 Hz) Bradykinesia Possible Parkinson’s disease Rigidity At least 2 features in Group A, with one of them being either tremor or Asymmetric onset bradykinesia, no features in group B Group B: present, and sustained response to suggestive of alternative diagnosis dopaminergic therapy Onset of the following symptoms < 3 Probable Parkinson’s disease years after PD onset: postural instability At least 3 of 4 features in group A freezing present, no features in group B hallucinations for > 3 years, and sustained response to dementia dopaminergic therapy Supranuclear gaze palsy (other than restriction of upgaze or slowed Definite Parkinson’s disease saccades) All criteria met for Possible PD, plus Severe dysautonomia histopathologic confirmation of Other condition known to cause diagnosis at autopsy parkinsonism Gelb et al. 1999, Archives Neurol Cardinal motor symptoms: Bradykinesia Cardinal motor symptoms: Gait Impairment 2

6/23/2016 PD non-motor symptoms: Categories Motor symptoms are Just the tip of the iceberg… � Autonomic � Psychiatric � Fatigue � Orthostasis � Constipation � Depression � Anxiety � Urinary urgency � Apathy � ED � Psychosis � Sleep � Cognitive � RBD � Executive dysfunction � Poor sleep � Impaired attention maintenance � Impaired visuo-spatial � Sensory function � Loss of smell � Relative preservation of anterograde memory � Loss of taste � Mild cognitive impairment � Pain � Dementia Barrone et al. 2009, Mov Disord Langston, 2006, Ann Neurol PD non-motor symptoms: Prevalence Cognitive deficits: Prevalence and clinical course • Normal PD-MCI: � Most PD patients report an primarily nonamnestic single average of 8 non-motor symptoms domain impairment ↓ • ~30% meet criteria for � Non-motor symptoms are often: PD-MCI PD-MCI within 3 years after � more difficult to treat diagnosis � impair quality of life more than motor symptoms ↓ • ~50% meet criteria for PD-MCI after 5 years PD Dementia (PDD) Barrone et al. 2009, Mov Disord Litvan et al., 2011, Mov Disord; Litvan et al., 2012, Mov Disord; Marras et al. 2013, Mov Disord 3

6/23/2016 PD pathology: Parkinson’s disease: Clinical course substantia nigra pars compacta degeneration Stage 1: ~2 years Stage 3: ~2 years Unilateral involvement Mild to moderate bilateral involvement, Postural instability, Stage 2: ~7 years Still independent Mild bilateral involvement Stage 4: ~2 years Severe disability, Stage 5: ~2 years Needs an assistive Wheelchair bound or bedridden device to walk or stand Can only ambulate with another person assisting Zhao et al. 2010, Mov Disord Scarr et al., 2013, Front. Cell. Neurosci.; Jenner 2002, Neurology PD pathology: Lewy body PD pathology: prion like disease 4

6/23/2016 PD pathology: Peripheral Lewy Bodies PD pathology: Braak Staging Braak et al., 2004, Cell Tissue Research Tolosa and Vilas, 2015, Brain PD imaging: DaTSCAN PD imaging: DaTSCAN � DAT can be used as an imaging biomarker for PD DaTSCANs detect presnaptic dopaminergic � Predictable change in Specific Binding Ratio (SBR) � neuronal loss using SPECT imaging annually, an average 7% SBR reduction annually, Measures Ioflupane ( 123 I), which is a DAT greater than 20 times the rate of signal loss seen in � ligand that binds to presynaptic dopamine normal aging transporters in the striatum de la Feunte-Fernandez 2012. Neurology Pigott 1998; Seibyl et al. 2016, presented at PPMI Investigator Conference Piggott 1998; Fang and Martin, 2015, Parkinsonism and Related Disorders 5

6/23/2016 PD pathophysiology: Rate Model PD pathophysiology: Rate Model Basal Ganglia Direct and Indirect Pathways The basal ganglia has two major intrinsic pathways: Direct and Indirect The direct pathway facilitates movement. • The indirect pathway inhibits movement • Striatal dopamine excites the direct pathway • (increasing movement), and suppresses the indirect pathway (increasing movement) PD pathophysiology: Brain Arrhythmia PD etiology: Multifactorial • Complex interplay between Phase amplitude coupling genetics (ingredients) • � Increased bursting of environment (recipe) • neuronal activity � Increased synchronization in neuronal activity � Increased oscillatory activity Tanner et al. 2011, Envi Health Perspectives Abbott et al. 2015, Neurology de Hemptinne et al. 2013, PNAS 6

6/23/2016 PD Treatments: Role of exercise PD Treatments: Role of cognitive training Oguh et al. 2014, Parkinsonism and Related Disorders Shu et al. 2014, PLOS Yang et al. 2014, PLOS Sharp and Hewitt, 2014, Neurosci Biobehav Rev Paris et al. 2011, Movement Disorders PD Treatment: Medications PD Treatment: Medications Carbidopa/Levodopa: Carbidopa/Levodopa: Mechanism of Action Effects � The most effective and generally well-tolerated medicine for PD � Short half-life (~90 minutes), may need to be taken frequently as PD progresses � Should be taken 30-60 minutes before or after a protein-rich meal � Main side effects: nausea, lightheadedness, hallucinations, and dyskinesias Cenci 2015, Frontiers in Neurology Cannas et al. 2010, Neuropsychiatr Dis Treat; Jenner, 2002, Neurology 7

6/23/2016 PD Treatment: Medications PD Treatment: Medications Carbidopa/Levodopa Extenders: Carbidopa/Levodopa: Mechanism of Action Formulations Sinemet IR • Rasagaline (Azilect) • Selegiline (Eldepryl) Parcopa • Entacapone (Comtan) Sinemet CR • Tolcapone (Tasmar) Rytary Najib 2001, Clinical Therapeutics, Youdim 2006, Nature Rev PD Treatment: Medications PD Treatment: Medications Dopamine Agonist: Carbidopa/Levodopa Extenders: Mechanism of Action Effects Rasagaline (Azilect) 1 HOUR INCREASED ON-TIME Side effects: drug interactions • Pramipexole (Mirapex) 1 HOUR INCREASED ON-TIME Selegiline (Eldepryl) Side effects: drug interactions, HTN, insomnia, delirium • Ropinirole (Requip) Entacapone (Comtan) 1 HOUR INCREASED ON-TIME • Rotigotine (Neupro) Side effects: diarrhea, orange urine Tolcapone (Tasmar) 2-3 HOURS INCREASED ON-TIME Side effects: Liver failure Najib 2001, Clinical Therapeutics Jenner, 2002, Neurology 8

6/23/2016 PD Treatment: Medications PD Treatment: Motor Fluctuations & Dyskinesias Dopamine Agonist: Effects � Compared to carbidopa/levodopa � Lasts longer, half-life: ~6 hours � Lower risk of causing dyskinesias � More mild benefit � Main side effects: sleep attacks, ICDs, sedation, confusion, hallucinations, cognitive deficits, dry mouth, lightheadedness � Usually not prescribed to people over 70 years of age Jenner, 2002, Neurology Cenci, 2014, Frontiers Neurology PD Treatment: Motor Fluctuations PD Treatments: Dyskinesias OFF MEDICATIONS ON MEDICATIONS 9