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PARKINSON’S DISEASE “Involuntary with lessened muscle power in parts, not in action even when supported; with the propensity to bend the trunk forwards and to pass from a walking to running pace; the senses and intellect being uninjured” Dr. James Parkinson, 1817 PARKINSON’S DISEASE SYMPTOMS Bradykinesia Tremor Rigidity Postural instability Gait disturbance Other features: Dementia Psychiatric disturbance Autonomic dysfunction Dystonia Eye movement abnormalities PD EPIDEMIOLOGY ~ 1,000,000 patients in the United States Annual incidence of about 50,000 – 60,000 Net prevalence increase of 15,000 patients annually Average age of onset: 50 – 65 years old 85% of patients over age 65 COGNITIVE CHANGES IN PARKINSON’S DISEASE Estimates range from 30% - 90% Important to distinguish “dementia” from specific cognitive changes: Dementia: global deterioration of intellect – occurs in about 10% - 20% of PD patients Specific pattern of cognitive impairment seen in a majority of PD patients COGNITIVE CHANGES IN PD General findings: Slowed information processing Difficulty starting or stopping mental activity Delayed response times Memory impairment: – Reduced attention span – Impaired spontaneous recall of information – Relatively preserved recognition memory Impairment of “working memory” – Capacity to hold information in brief, short-term storage in order to perform a mental manipulation COGNITIVE CHANGES IN PD Other Cognitive Findings: Mental Inflexibility – Tendency to get “stuck” on a thought or action – Inability to shift attention or thought process – Decreased planning/organizational ability – Tendency to repeat things over and over Visuospatial impairment – Independent of motor component – Deficits in visual analysis and integration – Difficulty with visual discrimination and matching – Intact abilities: perceptual orientation, mental rotation DEPRESSION IN PD Can occur in 20% to 40% of PD patients Major reactive depression (initial diagnosis) Adjustment disorder (physical/cognitive limitations) May be part of the clinical spectrum of PD ANXIETY IN PD ANXIETY: A state characterized by a vague and unpleasant sense of apprehension, often accompanied by physical symptoms such as sweating and dry mouth IN PD: Anxiety is often caused by lack of effectiveness of PD medications, dyskinesias, motor fluctuations, fear of freezing/falling. Panic attacks are common ANXIETY DISORDERS IN PD 1. Generalized anxiety disorder 2. Panic Attacks/Disorder – tend to occur when PD medications become less effective or patients experience various motor fluctuations 3. Social Phobias – fear of an inability to function in social settings 4. Obsessive-Compulsive Disorder (fear of disabling physical capacity, excessive worry about taking medication, fear of freezing or falling, repetitive checking (e.g., pill box, clock) PSYCHOSIS IN PD Relatively uncommon in PD Occurs in about 20% of patients with advanced PD and on chronic anti-PD medications Almost always drug-induced (e.g., Sinemet) Often characterized by visual hallucinations, vivid dreams or nightmares Usually accompanied by a clear sensorium (e.g., the patient is alert and not delirious) Older patients with cognitive impairment at higher risk Most common reason for nursing home placement PUTATIVE CAUSES OF PD Environmental risk factors: Pesticides Living in a rural environment Consumption of well water Exposure to herbicides, pesticides Proximity to industrial plants or quarries Drug addicts who developed parkinsonism after injection of 1methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) Patients developed bradykinesia, rigidity, and tremor, which progressed over several weeks and improved modestly with dopamine replacement therapy A chemical resemblance between MPTP and some herbicides and pesticides suggest an MPTP-like environmental toxin, but no specific agent has been identified Neuronal Loss in Parkinson's Disease Loss of substantia nigra pars compacta cells cause reduced nigral-striatal dopamine input to the putamen: 1. Loss of striatal excitatory dopamine input (D1-mediated direct pathway): • Loss of dopamine-mediated excitation of an inhibitory GABA pathway causes GPi hyperactivity which leads to excessive thalamic inhibition (GPi output is inhibitory - GABA) Neuronal Loss in Parkinson's Disease Loss of substantia nigra pars compacta cells cause reduced nigral-striatal dopamine input to the putamen: 2. loss of an striatal inhibitory dopamine input (D2mediated, indirect pathway) • loss of dopamine-mediated inhibition of a GABA inhibitory pathway; more GABA release and GPe hypoactivity • GPe hypoactivity decreases GABA (inhibitory) output to subthalamic nuclei. • Increased subthalamic nuclei excitatory output (glutamate-mediated) further increases GPi hyperactivity leading to further thalamic inhibition. Neuronal Loss in Parkinson's Disease 3. Decreased activity of direct pathway (less GPi inhibition) increased GPi activity increased thalamic inhibition • increased activity of the indirect pathway (more GPe inhibition) less subthalamic nuclei inhibition increased GPi activity increased thalamic inhibition OXIDATIVE HYPOTHESIS OF PD The oxidative metabolism of dopamine by MAO leads to the formation of hydrogen peroxide. Hydrogen peroxide normally is cleared rapidly by glutathione. If hydrogen peroxide is not cleared adequately, it may lead to the formation of highly reactive hydroxyl radicals that can react with cell membrane lipids to cause lipid peroxidation and cell damage. In PD, levels of reduced glutathione are decreased, suggesting a loss of protection against formation of free radicals. Iron is increased in the substantia nigra and may serve as a source of donor electrons, thereby promoting the formation of free radicals. Indices of lipid peroxidation are increased in PD. Thus, PD is associated with increased dopamine turnover, decreased protective mechanisms (glutathione), increased iron (a pro-oxidation molecule), and evidence of increased lipid peroxidation. This hypothesis raises concern that increased dopamine turnover due to levodopa administration could increase oxidative damage and accelerate loss of dopamine neurons. GENETIC FACTORS IN PD Twin Studies • In a study of 193 twins, overall concordance for MZ and DZ pairs was similar. • In 16 pairs of twins in whom PD was diagnosed at or before age 50 years, all 4 MZ pairs, but only 2 of 12 DZ pairs, were concordant. Family Studies • One large family with highly penetrant, autosomal-dominant, autopsy-proven PD originated in the town of Contursi in southern Italy. Of 592 family members, 50 were affected by PD. • Linkage analysis incriminated a region in chromosome 4 and sequencing revealed an A-for-G substitution at the alpha-synuclein gene. HUNTINGTON’S DISEASE Named for Long Island, NY physician who described disorder in 1872 Autosomal dominant neurodegenerative disorder Determined by genetic mutation on short arm of chromosome 4 Mutation is an expanded and unstable trinucleotide repeat of cytosine-adenosineguanine (CAG); 34 Normal Range 39 Positive Inheritance 35–38 Indeterminate Age of Onset and CAG Repeat Length CAG repeat length on normal and HD chromosomes and age at onset in HD. The CAG repeat length distribution of alleles found on normal (blue line) and HD (red line) The mean age at onset associated with each CAG repeat length is plotted as a red square (against the left axis). The pink area surrounding the mean age at onset denotes the range of ages at onset associated with any given repeat length, with deviations presumably being due to the effects of genetic or environmental modifiers. HUNTINGTON’S DISEASE Estimated 30,000 Americans with HD 200,000 individuals at-risk Onset is usually between ages 30-45 although there is a juvenile variant Progressive loss of functional ability and death within 10-30 yrs from onset Key clinical features: Motor impairment Cognitive impairment Psychiatric manifestations Decline in ADL’s HUNTINGTON’S DISEASE Cognitive Changes 100% of patients experience progressive cognitive decline Pattern of cognitive decline: “Subcortical” - slowed information processing, encoding and retrieval deficits (intact recognition memory) Anterior cortical – mental inflexibility, impaired planning, organization, sequencing and decreased judgement, reasoning and problem-solving Late Stage HD – global dementia HUNTINGTON’S DISEASE 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) Modestly increased suicide rate in HD No increased risk in presymptomatic individuals who test gene positive HUNTINGTON’S DISEASE Behavioral and Psychiatric Features Psychosis Paranoid ideation and persecutory delusions most common Auditory and visual hallucinations commonly reported in patients with psychosis Anxiety and OCD Shared pathophysiology between HD and OCD Anxiety symptoms typically secondary to worry and concern about financial difficulty, guilt about passing gene to offspring HUNTINGTON’S DISEASE Behavioral and Psychiatric Features Other Psychiatric/Behavioral Problems Changes in personality (irritability, apathy, antisocial, intermittent explosive) Change in sexual behavior (hypo- and hypersexuality) Restlessness and agitation Apathy (? link to frontal dysfunction) Increased risk for alcohol and drug dependency Bipolar disorder and/or manic episodes reported but less common Effect of the HD Mutation on Huntingtin • • • • • Huntingtin is a large protein of more than 3,100 amino acids that bears no close similarity to any other protein Normal and mutant huntingtin proteins are both expressed widely, inside and outside the nervous system CAG in HD gene is translated into an uninterrupted stretch of glutamine residues – leads to alteration of structural and biochemical properties of neurons Polyglutamine tracts result in insoluble and toxic precipitates creating “cellular” aggregates similar to amyloid deposits seen in senile plaques Similar aggregates have been found in HD brains, brains of transgenic mice (with 115-156 CAG repeats), and in cultured cells HUNTINGTON’S DISEASE Pathophysiology Excitotoxicity NMDA receptor mediated glutamatergic neurotransmission Neuronal loss confined to GABA striatal neurons “Energetic” Mitochondrial energy defects lead to production of free-radicals, lactate levels Results in DNA, RNA and protein damage, and ultimately, neuronal death HD Treatment Currently no pharmacological treatment available Can treat psychiatric manifestations Use of DA blocking agents will chorea NMDA receptor antagonists (data disappointing thus far) Free Radical Scavengers Coenzyme Q10 Creatine Caspase Inhibition – Minocycline Inhibition of acetyltransferases – HDAC inhibitors reverse neuronal degeneration in drosophila model of HD Ongoing investigation of huntingtin Agents that prevent nuclear aggregation Agents that “cleave” protein rendering non-toxic