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PARKINSON’S DISEASE Non-Motor Features • • • • • Cognitive Dysfunction Depression Hallucinations (late) Autonomic dysfunction Personality change • restricted vs. compulsive behavior PARKINSON’S DISEASE Associated Features • • • • • Nigro-Striatal Pathway Meso-limbic & Meso-cortical Pathways Hypomimia (masked facies) • Dementia Shuffling or festinating gait • Depression (stooped posture, • Personality imbalance, short steps) Postural instability (easily Extra-CNS Structures pulled off balance) • Dermatitis Hypophonia (soft voice) • Constipation Dystonia (painful muscle • Sensory deficits contractions) Adjusted for age, gender, education and psychomotor speed Elgh et al., 2009 Symptomatic Treatment for PD • Replacement (Levodopa/Carbidopa) – • provide exogenous DA • most effective in relieving symptoms • use is typically delayed • may hasten emergence of diurnal fluctuations (‘off-on’, ‘wearing off’ periods) and dyskinesias • typically not prescribed until gait/postural problems arise or job is threatened • visual hallucinations, vivid dreams or nightmares occur in 20% of older patients Motor fluctuations • Duration of levodopa benefit for motor symptoms decreases with disease progression “Bad” ON with dyskinesia “Good” ON without dyskinesia OFF Treatmentinduced impairment Early PD C/L IR 25/100 Rasagiline 1mg AM midday evening 1 1 1 1 Mid-stage with moderate motor fluctuations C/L IR 25/100 C/L CR 50/200 Comtan 200mg Pramipexole 0.5mg 7AM 10AM 1PM 4PM 7PM 1.5 1 1 1 1 1 1 1 1 1 1 1 1 bedtime 1 1 Advanced with severe motor fluctuations C/L IR 25/100 C/L CR 50/200 Comtan 200mg Selegiline 5mg Amantadine 100mg 7AM 2 1 1 9AM 1 1 1 11AM 1 0.5 1PM 1.5 1 1 1 3PM 1 0.5 5PM 1 0.5 7PM 1.5 1 9PM 1 11PM 2 1 1 Pahwa 2006 Neurology 66:983 ∙ changes the brain firing pattern but does not slow the progression of the neurodegeneration ∙ associated with reduction of sxs, so may enable reduction of medication ∙ can lead to a significant improvement in dyskinesias ∙ does not improve cognitive symptoms in PD and indeed may worsen them, so it is not generally used if there are signs of dementia. DBS clinical trial endpoint: Patient diaries Huntington’s Disease • • • • • • Case presentation Clinical features Neuropsychological profile Pathology Epidemiology Treatment Susan • 55 yo female, unaware why at evaluation • Language: tongue tied, mispronouncing words, forgetting names • Memory: forgetting ingredients, leaving pot on stove, misplacing objects • By brother: progressive cognitive difficulties • poor decisions at work, unsafe • Not driving 2 yrs • Living with brother ~ 1.5 yrs • Brother manages IADLs Susan • Neurological exam • progressive gait disturbance, imbalance, dysarthria • Irritability • Cognitive decline • Dx: Huntington’s disease Huntington’s Disease • Named for Long Island, NY physician who described disorder in 1872 • Progressive loss of functional ability and death within 10-30 yrs from onset (ave = 15) Huntington’s Disease • Key clinical features: • Hyperkinetic movement disorder • Psychiatric manifestations • Cognitive impairment/Dementia Clinical Features: Movement Disorder • Chorea - brief, abrupt, irregular movements Athetosis – writhing, twisting • Motor impersistence • Postural instability • Early in disorder - eye movement abnormalities, dystonia • Later in disorder - bradykinesia • Less common but seen – tics, tremor, myoclonus (rapid jerks) Choreic movements Huntington’s Disease Clinical Features • Other motor features: • Impaired dexterity and fine-motor coordination • Dysarthria • Dysphagia and aspiration • Progressive gait disturbance • balance/incoordination • increased risk of falls/injury Behavioral and Psychiatric Features • Can be initial presenting symptom in HD • Prevalence of psychiatric symptoms ranges from 35% - 75% • Most common psychiatric disorder is depression (30% - 50% prevalence) • Increased suicide ideation and attempts post-diagnosis • No increased risk in presymptomatic individuals who test gene positive Behavioral and Psychiatric Features • Psychosis • Paranoid ideation and persecutory delusions most common • Personality Changes • irritability, apathy, social withdrawal, intermittent explosive, anxiety, impulsiveness, mania • Restlessness/Agitation • Hypo/Hypersexuality • Apathy Huntington’s Disease Neuropsychological Profile • Deficits seen in at-risk patients prior to motor symptom onset • Frontal-subcortical dysfunction due to striatal degeneration • Mechanism of cortical involvement presumably reflects effect of gene defect on neocortical cell death Huntington’s Disease Clinical Features • Cognitive impairment • loss of recent memory • poor judgment • impaired concentration • Occurs in nearly all patients • May precede onset of motor symptoms • Progresses to global dementia in later stages Huntington’s Disease Neuropsychological Profile Frontal - Subcortical Deficits • Motor speed/dexterity • Dysarthria • Executive • • • • • Attention/concentration Verbal fluency Programming Abstraction Perseveration • Verbal retrieval (vs. preserved recognition) Cortical Deficits • Language • Dysprosodia (poor modulation of tone) • Reduced syntactic complexity • Visuo-spatial • Object misidentification (BNT) • Visual construction • Mental rotation HUNTINGTON’S DISEASE • Autosomal dominant neurodegenerative disorder • Determined by genetic mutation on short arm of chromosome 4 – • Mutation is an expanded and unstable trinucleotide repeat of cytosine-adenosine-guanine (CAG); • < 35 No symptoms • 35–39 Variable expression • > 39 Essentially all become symptomatic HUNTINGTON’S DISEASE • Mutated gene codes for IT15 protein (now known as HTT or ‘huntingtin’) • Function of huntingtin protein unknown, but • critical for development • highly expressed in brain • involved in signalling, transport and protecting against cell death • Higher number of repeats in mutant gene associated with earlier symptom onset Higher number of CAG repeats associated with earlier symptom onset Age at Onset Basal Ganglia Pathology in HD • Neuronal loss throughout cortex • Most prominent in striatum Epidemiology • United States • Prevalence: 5-10/100,000 • 30,000 Americans with HD • ~150,000 - 200,000 at-risk • Prevalence is geographically heterogeneous • Europe: 1.6-9/100,000 • Finland and Japan: <1/100,000 • 560 per 100,000 (Moray Firth, Scotland) • 700 per 100,000 (Lake Maracaibo, Venezuela) Epidemiology • Onset is usually between ages 30-45 • Mean 37, range 2-80 • Mean aoo differs by cohort • Venezuelan kindreds 34.4y • US: 37.5 y • Canada: 40.4 y • Modifying genes and environmental factors influence age of onset • CAG repeat length correlates inversely with aoo • Correlation stronger when onset of sxs occurs earlier Juvenile HD • onset of HD in patients younger than 20 y • ~5-10% of all affected patients • Most inherit the disease from their father • onset after age 20 y are more likely to have inherited gene from mother • Inheritance through the father can lead to anticipation HD Treatment • Currently no pharmacological treatment available • Can treat psychiatric manifestations (i.e., depression, anxiety, psychosis) • No cognitive agents available yet • Use of DA blocking agents will chorea • Research directions • Reduce huntingtin production • Improve cell survival • neuronal replacement Susan’s Results MMSE WAIS-III SS Digit Span Letter-Num Seq WMS-III 21/30 Imm. Memory Delayed Memory RBANS 7 Immediate Memory < 0.1 Delayed Memory < 0.1 DC SS 1 Trail Making A 2 DC Trail Making B DC %ile Phonemic Fluency Attention < 0.1 Language 5 Visuospatial %ile 0.1 2