Parkinsonism

• Parkinson's Disease Overview:

  • As noted below, Parkinson's disease, a relatively common group of progressive neurodegenerative pathologies, exhibits four primary features.¹⁰⁸

  • In addition to those features, Parkinson's disease manifests non-motor symptomatologies relating to psychiatric, cognitive, autonomic, sensory, and sleep abnormalities.¹⁰⁸

    • Later in this section the pharmacological consequence of understanding dopamine's role in Parkinson's disease will be addressed in terms of specific drugs.

    • This disease affects about 1 million individuals in the United States, including about 1% of people over 55 years of age. ¹⁰⁸

      • The peak onset occurs in the early 60s; however, the range of age-onset is fairly broad, 35-85 years.

      • The progressive character of the disease is reflected in the range of illness duration-from between 10 and 25 years.

    • There some familial forms of Parkinson's disease, including known autosomal dominant and recessive variations (maybe about 5% of cases).¹⁰⁸

      • These genetically defined forms typically exhibit earlier ages of onset, often before the age of 45 and usually exhibit a longer course.

      • Overall however, most Parkinson's disease patients do not exhibit a strong genetic determinant and at least epidemiological analysis suggests that the disease may be caused by interactions between genetic predispositions or vulnerabilities and environmental factors.

      • The risk factors for Parkinson's disease include a positive family history; however, other factors such as male gender, head injury, consumption of well water, rural living, and pesticide exposure may also play a role.

• Four principal motor features describe Parkinsonism¹⁰¹

   

  • (1) Reduced movement or slow movement, known as bradykinesia

    • Bradykinesia represents the most disabling motor pathology associated with Parkinson's disease.¹⁰⁸

      • This conclusion stems from its effects on all aspects of daily living,  ranging from getting up out of a chair, to walking, turning over in bed, as well as dressing.

  • (2) Muscular rigidity

  • (3) Resting tremor (this type of tremor decreases upon initiation of voluntary movement)

    • Rest tremor (4-6 Hz (events per second) typically presents on one side and distally typically associated with digits and wrist. The character of finger movement resembles "pill-rolling."

  • (4) Balance difficulties that predispose to falling and gait abnormalities.

    • Clinical presentation of gait abnormalities has a basis both in neurological deficit and functional adaptations. Sometimes the adaptive response makes the particular features of the underlying gait abnormalities difficult to describe.¹⁰⁶

    • Gait abnormalities include cautious gait, stiff-legged gait, parkinsonism and freezing gait, frontal gait disorder, cerebellar gait ataxia, sensory ataxia, neuromuscular disease, toxic and metabolic disorders, and psychogenic gait disorder.¹⁰⁶

  • Other motor features:¹⁰⁸ 

    • Impairment of fine motor control reduces manual dexterity and promotes "micrographia", which describes abnormally small and cramped handwriting with a tendency to progress even smaller handwriting.

    • Additional presentations include hypophonia or soft speech and sialorrhea.

    • Stooped posture and shuffling gait are prominent features of Parkinson's disease.¹⁰⁶

      • Parkinson's Disease Sketch¹⁰⁷

        • Patients may accelerate while walking or display "retropulsion" (a tendency to walk backward). ¹⁰⁶

        • Difficulties in gait initiation a.k.a. freezing may also be prominent.¹⁰⁶

        • Parkinsonian Gait Demonstration^106a

          Attribution: Bilal M Parkinsonian Gait Demonstration  https://www.youtube.com/watch?v=j86omOwx0Hk Mhd Bilal Youtube Channel https://www.youtube.com/channel/UCCFtqtdz-RiGiY00IPbCGOQ

        • Parkinson's disease progression may be accompanied by imbalance and falls. Freezing gait itself may be associated with other neurodegenerative pathologies including multiple system atrophy, supranuclear palsy, primary pallidal degeneration and corticobasal degeneration; moreover, presentations may include axial stiffness, shuffling gait and postural instability. However, "pill-rolling" Parkinson's disease tremor is often not exhibited in these other syndromes.¹⁰⁶

  • Non-Motor Presentations in Parkinson's Disease¹⁰⁸

    • As suggested earlier, non-motor presentations in Parkinson's disease are numerous.¹⁰⁸

      • These other presentations include:

        • Abnormalities in autonomic function

        • Cognitive impairment

        • Sleep disturbances

        • Pain

        • Depression

        • Anxiety and

        • Loss of smell (anosmia).

  • Non-motor presentations may be present before overt motor abnormalities are noted.¹⁰⁸

    • Some sensory symptoms have been described as an "inner restlessness", which may be a type of akathisia.

    • Another important presenting symptom is extremity discomfort, including pain. The symptom can occur either before medication is initiated or when antiparkinsonian drug effects are wearing off.

    • Even in the absence of underlying cardiovascular pathology, some patients report feeling shortness of breath.

    • Patients with Parkinson's disease also exhibit abnormalities in sleep, along with reduced daytime alertness.

      • Motor factors that impair sleep include bradykinesia and rigidity, tremor, involuntary movements such as myoclonic jerks and difficulty in turning in bed.

      • Restless leg along with rapid eye movement disorder can occur prior to Parkinson's disease motor presentations.  

      • Some drugs used to manage Parkinson's disease are "dopaminomimetic" (producing dopamine-like effects).

      • Dopaminomimetic agents are associated with hallucinations and vivid dreams, both of which may disrupt sleep.

      • Sleep apnea has also been reported.

    • Improvement in these sleep disorders may lead to betterment in daytime functioning, although daytime alertness is likely to remain attenuated.

  • Autonomic dysfunctions are associated with a variety of presentations including constipation, urinary urgency and frequency, orthostatic hypotension, sweating and seborrhea.¹⁰⁸

    • The orthostatic hypotension may occur as a result of diminished vasomotor reflexes, cardiac sympathetic denervation or dopaminomimetic drug treatment.

  • Parkinson's disease is also associated with neuropsychiatric symptoms.¹⁰⁸ 

    • Among these include behavioral changes, altered mood, and altered cognition.

    • These psychiatric changes may be associated with Parkinson's disease or with other diseases that may occur along with Parkinson's disease, such as Alzheimer's disease or cortical dementia with Lewy bodies.

      • Another possibility is that these neuropsychiatric presentations are due to medication side effects.

    • Depression:¹⁰⁸ 

      • About 50% of Parkinson's disease patients exhibit depressive syndromes and depression may be present at any disease phase.

      • The diagnosis of depression may be more complex,  given the need to discriminate between endogenous depression and vegetative and somatic presentations seen in Parkinson's disease.

      • Because of this difficulty, depression may not be appropriately recognized and treated.

      • If depression is inherent in Parkinson's disease as opposed to a response to the disabling effects of the disease, early recognition of depression is especially important, as it may explain changes in Parkinsonian motor symptoms, presentation of new somatic symptoms or changes in sleep patterns. Depression, as an intrinsic aspect of Parkinson's disease itself, is considered likely.

        • Another possibility  is that depression could be associated with medications to treat Parkinson's disease or by other psychoactive drugs used to treat other symptoms.

        • A differential diagnostic approach for depression in patients with Parkinson's disease is appropriate, given that hypothyroidism, vitamin B 12 deficiency or hypogonadism, for example, could be present and account for the depressive state.

    • Anxiety:¹⁰⁸

      • Patients with Parkinson disease may exhibit anxiety, either as a singular presentation or as part of a depressive syndrome or associated with cognitive impairment.

        • Anxiety disorders may also be associated with inadequate management of motor symptoms.

        • Drug-induced fluctuations of this type may result in anxiety, during the drug's "off periods" and that this anxiety may present as panic attack.

    • Cognitive Dysfunction: ¹⁰⁸  

      • "Mild to moderate" cognitive deficits are common with Parkinson's disease.

      • Frontal lobe dysfunction is especially likely in later disease stages.

      • Cognitive dysfunctions may include:

        • Working memory

        • Attention

        • Mental flexibility

        • Executive function

        • Visuospatial function, and

        • Word fluency.

      • Parkinson's disease cognitive effects typically do not degrade language and "simple" mathematical skills to the same extent observed in Alzheimer's disease patients.

      • Cognitive deficits or decline may be associated with drugs used in management of Parkinson's disease or other syndromes; these drugs include:

        • Anticholinergics

        • Dopaminomimetics

        • Psychotropics, and

        • Amantadine.

      • Reversible causes of acute cognitive function change in Parkinson's disease must also include depression and other concurrent medical illness, such as urinary tract infection, infection elsewhere, or dehydration.

    • Dementia:¹⁰⁸  

      • Significant dementia in Parkinson's disease patients may occur with an incidence perhaps six times greater than observed in age-matched control individuals.

        • Possibly 70% of patients, or even a higher percentage, may exhibit significant dementia with long-term observation, defined as greater than eight years.

        • Substantial cognitive deficit appearing late in Parkinson's disease progression affects therapeutic opportunities and may be more important than Parkinson's disease motor symptoms with respect overall disability impact.

      • There are predictors of Parkinson's disease dementia.

        • These predictors include:

          • Akinetic-rigid phenotype

          • Late age onset

          • Presence of severe depression

          • Frequent hallucinations and advanced disease stage.

      • α-synuclein and amyloid related pathologies in the basal forebrain, frontal lobes, hippocampus, and amygdala may be responsible for symptom progression.

        • Alpha-synuclein¹⁰⁹

          "Alpha-synuclein also known as SNCA is a protein that, in humans, is encoded by the SNCA gene.109a,109b,109c An alpha-synuclein fragment, known as the non-Abeta component (NAC) of Alzheimer's disease amyloid,  originally found in an amyloid-enriched fraction, is shown to be a fragment of its precursor protein, NACP, by cloning of the full-length cDNA.109a It was later determined that NACP was the human homologue of Torpedo synuclein. Therefore, NACP is now referred to as human alpha-synuclein."109

           

        • Events in alpha-synculein toxicity¹¹⁰

          "Events in α-synuclein toxicity"110 "The central panel shows the major pathway for protein aggregation. Monomeric α-synuclein is natively unfolded in solution but can also bind to membranes in an α-helical form.  It seems likely that these two species exist in equilibrium within the cell, although this is unproven. From in vitro work, it is clear that unfolded monomer can aggregate first into small oligomeric species that can be stabilized by β-sheet-like interactions and then into higher molecular weight insoluble fibrils. In a cellular context, there is some evidence that the presence of lipids can promote oligomer formation: α-synuclein can also form annular, pore-like structures that interact with membranes. The deposition of α-synuclein into pathological structures such as Lewy bodies is probably a late event that occurs in some neurons. On the left hand side are some of the known modifiers of this process. Electrical activity in neurons changes the association of α-synuclein with vesicles and may also stimulate polo-like kinase 2 (PLK2), which has been shown to phosphorylate α-synuclein at Ser129. Other kinases have also been proposed to be involved. As well as phosphorylation, truncation through proteases such as calpains, and nitration, probably through nitric oxide (NO) or other reactive nitrogen species that are present during inflammation, all modify synuclein such that it has a higher tendency to aggregate. The addition of ubiquitin (shown as a black spot) to Lewy bodies is probably a secondary process to deposition. On the right are some of the proposed cellular targets for α-synuclein mediated toxicity, which include (from top to bottom) ER-golgi transport, synaptic vesicles, mitochondria and lysosomes and other proteolytic machinery. In each of these cases, it is proposed that α-synuclein has detrimental effects, listed below each arrow, although at this time it is not clear if any of these are either necessary or sufficient for toxicity in neurons." 110

    • Psychosis ¹⁰⁸

      • As many as 40% of patients with Parkinson's disease may exhibit psychotic presentations.

        • The likelihood of psychotic symptoms may be dependent on the age, Parkinson's disease duration, and the presence of dementia within the population evaluated.

          • Early psychotic symptoms in this setting include visual illusions and formed visual hallucinations.

        • The most important risk factors for psychotic presentations in Parkinson's disease appear to be depression and dementia.

        • Psychotic symptoms are most likely, however, associated with drug therapy.

          • Pharmacological agents most likely to induce psychotic symptoms include dopaminomimetics e.g. dopamine agonists, anticholinergics, amantadine and psychotropic agents.

      • Behavioral disturbances associated with some Parkinson's disease patients have been a focus of more recent recognition and emphasis and have been classified as "impulse control disorders".

        • Presentations include pathologic gambling, compulsive shopping, hypersexuality, and compulsive eating. These conditions appear correlated with the use of dopaminergic drugs.

         

    • Genetics and Parkinson's Disease¹⁰⁸

      • Genetic predispositions is likely important in some forms of Parkinson's disease.

        • Heredity may be especially important in early-onset disease defined as Parkinson's disease in individuals less than 45 years of age.

      • Familial Parkinson's disease is likely associated with eight genes  (loci PARK1-PARK8).

        • These genes include SNCA (PARK1) coding for α-synuclein (see above) .

          • α-synuclein may be involved in regulation of vesicular transport.

        • In addition to PARK1, PARK4 and PARK5 are associated with an an autosomal dominant form of the disease characterized by, in part, both early onset and rapid progression.

      • Another gene (locus PARK2)  is PRKN which codes for the protein parkin.^108,111,112

        • Parkin mutations may cause a form of autosomal recessive juvenile Parkinson's disease.^111,112

          • The protein itself, parkin, is an element of a multiprotein E3 ubiquitin protein ligase complex.

          • This complex is part of a larger system, the ubiquitin-proteasome system which is involved in regulation of protein degradation.^111,112

        • Patients with an autosomal recessive history of Parkinson's disease are substantially more likely to have parkin mutations if onset age is less than 20 years.¹¹⁴  

        • Protein PARK2¹¹³

          Structure of the PARK2 protein. Based on PyMOL rendering of PDB113

      • PARK7 mutations also result in an autosomal recessive disorder with varied presentations, including juvenile onset.¹¹⁵

        • The PARK7 gene codes for the DJ-1 protein which may be involved in cellular protection from oxidative stress due to free radicals.¹¹⁵

          • The DJ-1 protein may also be involved in facilitating protein-folding, as a "chaperone molecule".

          • Lastly, the DJ-1 protein has also been implicated in cellular functions associated with production and processing of RNA.

        • There are greater than 10 PARK7 mutations associated with early-onset Parkinson's disease. In some circumstances much of the PARK7 gene is deleted,  resulting in a lack of functional DJ-1 protein.¹¹⁵

          • Other PARK7 mutations result in abnormally small DJ-1 proteins; whereas, other mutations associated with amino acid substitutions result in loss of protein stability.

          • The cytogenetic location of PARK7 has been determined to be 1p36.23 [short (p) arm of chromosome 1 at position 36.23] with the molecular location described as chromosome 1: base pairs 8,021,713 to 8,045,341.

        • PARK7 gene location¹¹⁵

          Cytogenetic location 1p36.23 (short arm (p) of chromosome 1 at position 36.23.115 Molecular location:  from base pair 8,021,713 to base pair 8,045,341 on chromosome 1.115

      • The PARK5 gene, also known as the UCHL1 gene, codes for ubiquitin carboxy-terminal hydroxylase  L1.¹⁰⁸

        • Ubiquitin carboxy-terminal hydroxylase  L1 seems to exhibit two enzymatic activities.¹¹⁶

          • One activity,  hydrolase activity, both removes and recycles ubiquitin from degraded proteins.

          • Also present is a ligase activity involved in linking ubiquitin molecules, a process which facilitates protein identification for disposal.

        • A normal variation in the PARK5 (UCHL1) gene decreases risk of Parkinson's disease in young adults especially.¹¹⁶

          • This polymorphic variation involves a substitution of the amino acid tyrosine for serine at position 18.

            • This variation is especially common in Chinese and Japanese populations but is observed less often in European populations.

            • A consequence of this polymorphism is a decrease in ligase activity of the enzyme with a little affect on hydrolase activity.

        • Another mutation in the PARK5 (UCHL1) may increase the risk of Parkinson's disease development.¹¹⁶

          • In this case the amino acid isoleucine is replaced by methionine at position 93. This change decreases hydrolase activity which reduces cellular ability to degrade proteins.

            • This observation has been limited to a single family, making conclusions concerning the association of this polymorphic change with Parkinson's disease quite preliminary and tentative.

        • Both PARK5 and PARK2 code for proteins associated with ubiquination, a process which identifies proteins for degradation in the proteome system.

          • As a consequence of this observation, abnormal proteasomal processing may be involved in some forms of Parkinson's disease pathologies.¹⁰⁸

        • PARK5 (UCHL1) gene location¹¹⁶

          Cytogenetic location 4p14 (short (p) arm of chromosome 4 at position 14).116 Molecular location:  from base pair 41,258,897 to 41,270,445 on chomosome 4.116

      • PARK8 is associated with the LRRK2 gene (Leucine-rich repeat kinase 2, LRRK2) and the protein product dardarin, a cytosolic kinase.^108,117

        • Parkinson's disease associated with LRRK2 tends to be late onset and slowly progressive.

        • Abnormal kinase activity due to PARK8 mutations might be responsible for dopamine cell death.

        • More than 20 LRRK2 mutations have been identified in families with late-onset Parkinson's disease.¹¹⁷ 

          • These mutations involve replacement of one amino acid with a different one in the protein product, dardarin. Parkinson's disease in the Basque region between Spain and France is commonly caused by a mutation in LRRK2 which involves replacement of the amino acid arginine with lysine.

            • The protein name, dardarin, is derived from a Basque word "dardara"  which means tremor.

          • In addition, a common LRRK2 mutation noted in 3%-7% of familial Parkinson's disease cases involves replacement of L-glycine with serine at protein position 2019.

          • Chinese and Japanese populations exhibit on LRRK2 mutation more likely to occur in patients with Parkinson's disease than in individuals without disease. This mutation involves replacement of lysine with arginine at position 2385.¹¹⁷

        • PARK8 (LRRK2) gene location¹¹⁷

          Cytogenetic location:  12q12--long (q) arm of chromosome 12 at position 12.117 Molecular location:  from base pair 40,618,812 to base pair 40,763,086. 117

  • Differential Diagnosis¹¹⁸

    • Challenges in the diagnosis of Parkinson's disease are especially prominent in mild presentations.

      • Minimal or absent tremors contribute to difficulty in the differential. Sometimes depression if it presents with "expressionless face, poorly modulated voice and reduction in voluntary activity" may be hard to distinguish from Parkinson's disease.

        • As noted earlier, depression may coexist with Parkinson's disorder.

      • Discrimination of essential tremor from Parkinson's disease symptoms may be facilitated by:

        • Analysis of family history

        • Consideration of the details of tremor and

        • Lack of other neurological signs.

      • With respect to Wilson's disease, its relatively early age of onset, expression of other abnormal motor presentations, Kayser-Fleischer rings along with chronic hepatitis and increased tissue copper are indicative of Wilson's.

        •  Kayser-Fleischer Rings ^119,120

        • Kayser-Fleischer rings are described as copper deposits localized where the cornea meets the sclera.119 These rings first appear as a crescent at the cornea's top; however, a second crescent appears below at 6 o'clock. Eventually these deposits encircle the cornea forming rings.120

           

      • Huntington's disease, which may present with rigidity and bradykinesia, may be diagnosed as Parkinson's disease; however, family history and accompanying dementia may be helpful in the differential.¹¹⁸

        • Huntington's disease is a progressive neurodegenerative disorder that affects not only muscle coordination but also cognition. Cognitive decline and dementia are characteristics of the disorder.  Abnormalities in the Huntingtin gene  which codes for protein, Huntingtin is likely causative of Huntington's disease.

        • Neuron with mHtt Inclusion¹²¹

          "A montage of three images of single striatal neurons transfected with a disease-associated version of huntingtin, the protein that causes Huntington's disease.121 Nuclei of untransfected neurons are seen in the background (blue). The neuron in the center (yellow) contains an abnormal intracellular accumulation of huntingtin called an inclusion body (orange). Studies using an automated microscope and survival analysis demonstrated that neurons with disease-associated huntingtin that form inclusion bodies survive longer than those that do not ..."

      • Multisystem atrophy a.k.a. Shy-Drager syndrome presents with Parkinson's disease symptoms along with autonomic insufficiency.¹¹⁸

      • In progressive supranuclear palsy, rigidity and bradykinesia are also associated with a supranuclear eye-movement disorder, pseudobulbar palsy, pseudo-emotional lability as well as axial dystonia.¹¹⁸

      • Creutzfeldt-Jakob disease combines parkinsonism with dimentia along with myoclonic jerking. Moreover, ataxia and paramidal signs may present and EEG findings are also helpful in the differential.¹¹⁸

      • Finally, in corticobasal degeneration (asymmetric degeneration) Parkinson's disease symptoms are associated with clear signs of cortical dysfunction including sensory inattention, dementia, aphasia (impairment of language including difficulty in comprehending spoken or written language), and apraxia (inability to execute learned, purposeful movements, a disorder of motor planning).¹¹⁸

  • The principal cellular pathologic manifestation in Parkinson's disease is a decrease in the pigmented, dopamine neurons localized in the substantia nigra pars compacta (29 in figure below).

   

  • Human brain frontal (coronal) section description:  note location of the substantia nigra (tag 29 in the figure) ¹⁰⁵

   

  • Along with dopamine neuronal loss is the appearance of intracellular inclusions a.k.a. Lewy bodies.

     

    • "Immunohistochemistry for alpha-synuclein showing positive staining (brown of an intraneural Lewy-body in the Substantia nigra in Parkinson disease"¹⁰⁴

  • Substantial dopamine-containing neuronal loss is required for clinical manifestation of Parkinson's disease; the loss required may be about 70%-80%.¹⁰¹

  • Parkinson's disease, without clinical intervention, tends to progress over a 5-10 year period leading to a "rigid, akinetic state".¹⁰¹

    • In this condition patients require significant assisted care.

    • Death occurs often from sequelae of immobility including pulmonary embolism or aspiration pneumonia.

    • Improvement in mobility and extended life expectancy are obtainable through pharmacological and sometimes surgical intervention.

  • Parkinsonism, as a collection of symptoms, may be induced by other circumstances such as stroke, dopamine-receptor blockers, and other neurodegenerative diseases.

    • Specifically, some antipsychotic medications, such as thorazine (Chlorpromazine) and haloperidol (Haldol) on one hand and drugs categorized as anti-emetics, e.g., metoclopramide (Reglan) and prochloperazine (Compazine) on the other can induce parkinsonism.

    • The pharmacological basis for management of Parkinson's disease was derived from three considerations: ^101,102,103

      • (1) Loss of dopaminergic cells in the substantia nigra pars compacta meant that there was reduced dopaminergic innervation to the caudate and putamen (striatum).

      • (2) A reduction in striatal dopamine content of >80% was observed and

      • (3) The reduction in striatal dopamine paralleled loss of substantia nigral neurons.

        • These observations suggest that dopamine replacement might be helpful in reversal of parkinsonism.

 

References

Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.199-242 Stoelting, R.K., "Sympathomimetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, p. 260 Carotic Baroreceptors:  CRRx:  Mediine ReEnvisioned  http://www.cvrx.com/patients/index.php?id=41 Westfall, TC and Westfall DP Adrenergic Agonists and Antagonists in Goodman and Gilman's The Pharmacological Basis of Therapeutics, eleventh editions, (Brunton LL, Lazo JS and Parker KL, eds), McGraw-Hill Medical Publishing Division, New York, 237-295, 2006. Catecholamine Biosynthesis:  The Interactive Library; Edinformatics.com:  http://www.edinformatics.com/interactive_molecules/info/adrenaline.htm . Standaert DG and Young AB Treatment of Central Nervous System Degenerative Disorders In Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp536-537. Adrenergic Neuronal Diagram adapted from http://www.drugabuse.gov/pubs/teaching/Teaching4/Teaching.html Guanetidine (Ismelin™, brand name not available in the U.S.) pharmacology:  Clinical Pharmacology, RxList:  The Internet Drug Index, http://www.rxlist.com/ismelin-drug.htm . Williams FM and Turner TJ Adrenergic Pharmacology in Principles of Pharmacology:  The Pathophysiologic Basis of Drug Therapy, 2nd Edition (Golan DE, Tashijan Jr AH, Armstrong EJ and Armstrong AW, eds) Wolters Kluwer-Lippincott Williams & Wilkins, Philadelphia, 129-144, 2008. Moss J and Glick D Autonomic Function in Anesthetic Pharmacology:  Physiological Principles and Clinical Practice: A Companion to Miller's Anesthesia (Evers AS and Maze M, eds) Churchill Livingstone, Philadelphia, Chapter 14, 209-226, 2004. Presynaptic Proteins, Synaptic Vesicle Docking and Membrane Fusion, http://neuromuscular.wustl.edu/pathol/snare.htm#cachan, Neuromuscular Disease Center, Washington University, St. Louis, MO USA (http://neuromuscular.wustl.edu/index.html) Sudhof TC The Synaptic Vesicle Cycle, Annual Review of Neuroscience, July 200, Vol. 27, pp 509-547. Phenochomocytoma picture (http://health-pictures.com/pheochromocytoma.htm); Geneva Foundation of Medical Education and Research, Pheochromocytoma, http://www.gfmer.ch/selected_images_v2/detail_list.php?cat1=1&cat2=113&cat3=22&cat4=2&stype=n . Brown H, Goldberg PA, Selter JG, Cabin HS, Marieb NJ, Udelsman R and Setaro JF Hemorrhagic Pheochromocytoma Associated with Systemic Corticosteroid Therapy and Presenting as Myocardial Infarction with Severe Hypertension. Clinical Case Seminar, J Clin Endocrinol Metab 2005 90: 563-569. (http://jcem.endojournals.org/cgi/content/full/90/1/563). "Clevidine (Cleviprex) for IV Treatment of Severe Hypertension", Table 1.  Some Parenteral Drugs for Hypertensive Emergencies.  The Medical Letter® on Drugs and Therapeutics, Volume 50 (Issue 1295) September 22, 2008. Katzung, BG Introduction to Autonomic Pharmacology (Section II: Autonomic Drugs) in: Basic and Clinical Pharmacology (10th edition), (Katzung BG, ed) McGraw-Hill Medical , New York, pp. 75-92, 2007. Sympathetic Nerve Pathway:  Neuroeffector Junction ("Simplified diagram of a sympathetic neuroeffector junction displaying genes which may be involved"); PharmGKb modified slightly to highlight uptake1, uptake-2, uptake 1 block, and location of intravesicular norephinephrine synthesis. (Pharmacogenomics Knowledge Base). http://www.pharmgkb.org/search/pathway/neurotransmitter/neuroeffector.jsp . T.E. Klein, J.T. Chang, M.K. Cho, K.L. Easton, R. Fergerson, M. Hewett, Z. Lin, Y. Liu, S. Liu, D.E. Oliver, D.L. Rubin, F. Shafa, J.M. Stuart and R.B. Altman, "Integrating Genotype and Phenotype Information: An Overview of the PharmGKB Project" (220k PDF), The Pharmacogenomics Journal (2001) 1, 167-170. Tellioglu T, Robertson D (November 2001). "Genetic or acquired deficits in the norepinephrine transporter: current understanding of clinical implications". Expert Rev Mol Med 2001: 1–10. Kekuda R, Prasad PD, Wu X, Wang H, Fei YJ, Leibach FH, Ganapathy V (Aug 1998). "Cloning and functional characterization of a potential-sensitive, polyspecific organic cation transporter (OCT3) most abundantly expressed in placenta". J Biol Chem 273 (26): 15971–9. Amphoux A, Vialou V, Drescher E, Brüss M, Mannoury La Cour C, Rochat C, Millan MJ, Giros B, Bönisch H, Gautron S. (Jun 2006). "Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain.". Neuropharmacology 50 (8): 941–952. Bourne HR and von Zastrow M "Drug Receptors and Pharmacodyamics" Chapter 2 in Basic and Clinical Pharmacology (10th edition), (Katzung BG, ed) McGraw-Hill Medical , New York, pp. 17-27, 2007. Muller M Lecture Material Online:  Lecture 6: "Cellular Communication" http://www.uic.edu/classes/bios/bios100/summer2003/lect06.htm. Bowman T and Jove R STAT Proteins and Cancer:  From the Molecular Oncology Program at the H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida http://www.moffitt.org/moffittapps/ccj/v6n6/dept6h.htm . Tong L, Warren TC, King J, Betageri R, Rose J, Jakes S (March 1996). "Crystal structures of the human p56lck SH2 domain in complex with two short phosphotyrosyl peptides at 1.0 A and 1.8 A resolution". J. Mol. Biol. 256 (3): 601–10. Sadowski I, Stone JC, Pawson T (December 1986). "A noncatalytic domain conserved among cytoplasmic protein-tyrosine kinases modifies the kinase function and transforming activity of Fujinami sarcoma virus P130gag-fps". Mol. Cell. Biol. 6 (12): 4396–4408. Russell RB, Breed J, Barton GJ (June 1992). "Conservation analysis and structure prediction of the SH2 family of phosphotyrosine binding domains". FEBS Lett. 304 (1): 15–20. von Zastrow M and  Bourne HR "Drug Receptors and Pharmacodynamics" Chapter 2 in Basic and Clinical Pharmacology (11th edition), (Katzung BG, Masters, SB and Trevor AJ,  eds) McGraw-Hill Medical , New York, on-line version (Access Medicine) 2009. Powledge TM (2004) Nicotine as Therapy. PLoS Biol 2(11): e404. doi:10.1371/journal.pbio.0020404 (http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.0020404) Green T, Heinemann SF and Gusella JF Molecular Neurobiology and Genetics:  Investigation of Neuron Function and Dysfunction (Review) Neuron, Vol. 20, 427-444, March, 1998 (Cell Press (c), 1998). Unwin N Nicotinic acetylcholine receptor at 9 Å resolution. J. Mol. Biol. 229, 1101-1124. Eyford, T Adenylyl cyclase http://proteopedia.org/wiki/index.php/Adenylyl_cyclase . 31 a. Hurley JH. Structure, mechanism, and regulation of mammalian adenylyl cyclase. J Biol Chem. 1999 Mar 19;274(12):7599-602. 31 b, Zhang G, Liu Y, Ruoho AE, Hurley JH. Structure of the adenylyl cyclase catalytic core. Nature. 1997 Mar 20;386(6622):247-53. Goodsell DS illustrator, The Scrips Research Institute, public domain work, http://en.wikipedia.org/wiki/Adenylate_cyclase . Ranganathan R, Ross E (1997). "PDZ domain proteins: scaffolds for signaling complexes.". Curr Biol 7 (12): R770–3 PDZ domain  http://en.wikipedia.org/wiki/PDZ_domain Biaggioni I and Robertson D Adrenoceptor Agonists & Sympathomimetic Drugs (Chapter 9) in  in Basic and Clinical Pharmacology (11th edition), (Katzung BG, Masters, SB and Trevor AJ, eds) McGraw-Hill Medical , New York, on-line version (Access Medicine) 2009. Korte E "PIP2 cleavage by PLC to release IP3 and DAG", public domain, http://en.wikipedia.org/wiki/File:PIP2_cleavage_to_IP3_and_DAG.jpg . McVary KT A review of combination therapy in patients with benign prostatic hyperplasia, Clinical Therapeutics 2007 29 (3):  387-398. Caine M The present role of alpha-adrenergic blockers in the treatment of benign prostatic hypertrophy. J Urol. 1986; 136:  1-4. Shapiro E Hartanto V and Lepor H. The response to alpha blockade in benign prostatic hyperplasia is related to the percent area density of prostate smooth muscle. Prostate. 1992; 21:  297-307. Brittsan AG and Kranias EG Review:  Phosphlakmban and Cardiac Contractile Function. J. Mol Cell Cardiol 32. 2131-2139. Lomize A Phospholamban Pentamer, protein image from OPM database, public domain media (http://en.wikipedia.org/wiki/File:1zll_opm.gif) Foex P and Highan H. Myocardial Performance:  Physiological Principles and Clinical Practice: A Companion to Miller's Anesthesia (Evers AS and Maze M, eds) Churchill Livingstone, Philadelphia, Chapter 14, 284-2285, 2004. 42(a)  Weiss HR Effect of coronary artery occlusion on regional arterial and venous O2 saturation, O2 extraction, blood flow and O2 consumption in the dog heart. Circulation Research 47(3) 400-407, September 1980. Khouri EM Gregg DE and Rayford CR Effect of exercise on cardiac output, left coronary flow and myocardial metabolism in the unanesthetized dog. Circulation Research 17(5) 327-437, November 1965. Epicardial Vessels:  Gray's Anatomy, 20th U.S. edition of Gray's Anatomy of the Human Body, originally publishedin 1918, public domain. Beta-2 Adrenergic Receptor, figure public domain (http://en.wikipedia.org/wiki/File:2RH1.png); original crystallographic citations: 45 (a) Cherezov V, Rosenbaum DM, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Kuhn P, Weis WI, Kobilka BK, Stevens RC (2007). "High-resolution crystal structure of an engineered human β2-adrenergic G protein-coupled receptor". Science 318 (5854): 1258–65. 45 (b) Rosenbaum DM, Cherezov V, Hanson MA, Rasmussen SG, Thian FS, Kobilka TS, Choi HJ, Yao XJ, Weis WI, Stevens RC, Kobilka BK (2007). "GPCR engineering yields high-resolution structural insights into β2-adrenergic receptor function". Science 318 (5854): 1266–73. Westfall, TC and Westfall DP Neurotransmission:  The Autonomic and Somatic Motor Nervous System in Goodman and Gilman's The Pharmacological Basis of Therapeutics, eleventh editions, (Brunton LL, Lazo JS and Parker KL, eds), McGraw-Hill Medical Publishing Division, New York, 137-181, 2006. Emorine LJ Marullo S Briend-Sutren MM Patey G Tate K Delavier-Klutchko C Strosberg AD Molecular characterization of the human β3-adrenergic receptor. Science, Vol. 245, No. 4922, Sep. 8, 1989, pp. 1118-1121. Walston J Silver K Bogardus C Knowler W Celi FS Austin S Manning B Strosberg AD Stern MP Raben N Sorkin JD Roth J Shuldiner AR Time of onset of non-insulin-dependent diabetes mellitus and genetic variation in the β3-adrenergic receptor gene.  New England J. of Medicine, Vol. 333 No. 6, August 10, 1995, pp. 343-347. Hoffman BB Adrenoceptor-Activating & Other Sympathomimetic Drugs in: Basic and Clinical Pharmacology (10th edition), (Katzung BG, ed) McGraw-Hill Medical , New York, pp. 121-140, 2007. Goodsell, DS, Tyrosine Hydroxylase, The Scripps Research Institute, public domain image, http://en.wikipedia.org/wiki/File:Tyrosine_Hydroxylase.png . Chemical Synapse, http://schools-wikipedia.org/wp/c/Chemical_synapse.htm . Frang H Cockcroft V Karskela T Scheinin M Marjamaki A Phenoxybenzamine binding reveals the helical orientation of the third transmembrane domain of adrenergic receptors JBC, 276, 31279-31284, June 6, 2001. http://www.jbc.org/content/276/33/31279.full Barrett KE Barman SM Boitano S Brooks H "The Adrenal Medulla & Adrenal Cortex" in:  Ganong's Review of Medical Physiology, 23e, Chapter 22, on-line version, 2010. Achermann JC and Jameson JL "Disorders of Sex Development" in Harrison's Principles of Internal Medicine (eds, Fauci AS Braunwald E Kasper DL Hauser SL Longo DL Jameson JL Loscalzo J), 17th edition, pp 2345-2346, 2008, McGraw-Hill Medical, New York. Goldenberg M Aranow H Jr Smith AA Faber M Pheochromocytoma and essential hypertensive vascular disease. Arch. Intern. Med. 86: 823-826, 1950. Carrim YO "The Cardiovascular system, heart muscle; The heart as a pump." http://samedical.blogspot.com/2010/08/heart-muscle-heart-as-pump.html . "Madhero88" "A graphical representation of the electrical conduction system of the heart showing the sinoatrial node, atrioventricular none, bundle of His, Purkinje fibers and Bachmann's bundle, http://en.wikipedia.org/wiki/File:ConductionsystemoftheheartwithouttheHeart.png . Ewy GA Cardiopulmonary and Cardiocerebral Resuscitation, Chapter 50,  in Hurst's The Heart, 12th edition (eds, Fuster V O'Rourke RA Wash RA Poole-Wilson P; associate eds: King II SB Roberts R Nash IS Prystowsky EN; Editors of the online edition:  senior editors:  Walsh RA and Simon DI; associate Editors;  Hoit BD Fang JC Costa M), 2008, on-line edition. 58a. American Heart Association.  2005 American Heart Association guidelines for cardiopulmonary resuscitation and emergency cardiovascular care.  Circulation, 2005; 112 (Suppl IV): IV-1-IV-211. Mohrman DE and Heller LJ "Vascular Control" Chapter 7, in Cardiovascular Physiology, 6th edition, The McGraw-Hill Companies, Inc, 2006, on-line edition. Stoelting, RK and Dierdorf, SF, "Asthma" in Anesthesia and Co-Existing Disease, 4th edition, Chapter 14, pp 194-204, Churchill-Livingstone, Philadelphia, 2002 60a. Kingston, HGG, Hirshman, CA Perioperative management of the patient with asthma. Anesth Analg 1984; 63: 844-55. (second sourced from reference 1) Roisen, MF, "Anesthetic Implications of Concurrent Diseases" in Anesthesia, 5th edition, (Miller, R.D, editor), Chapter 25, pp 996-997, Churchill-Livingstone, Philadephia 2000. Barrett KE Barman SM Boitano S Brooks H "Endocrine Functions of the Pancreas & Regulation of Carbohydrate Metabolism" in:  Ganong's Review of Medical Physiology, 23e, Chapter 21, on-line version, 2010. Narayanese and YassineMrabet, Citric acid cycle (Tricarboxylic acid cycle), public domain, GNUU Free Documentation License, http://en.wikipedia.org/wiki/Citric_acid_cycle . Elayat AA, el-Naggar MM, Tahir M (1995). "An immunocytochemical and morphometric study of the rat pancreatic islets". Journal of Anatomy 186 (Pt 3): 629–37. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1167020/pdf/janat00134-0170.pdf) 64a.  Islets of Langerhans;  http://en.wikipedia.org/wiki/Islets_of_Langerhans Süß C Sukale J Solima M "light microscopy of a paraffin embedded mouse islet; labels: insulin green, glucagon red, nuclei blue" Solimena Lab, Med. Fac., University of Technology, Dresden, Germany.  http://en.wikipedia.org/wiki/File:Mouse_islet_LM_SolimenaLab.jpg . http://en.wikipedia.org/wiki/File:PDB_3tgl_EBI.jpg courtesy:  http://www.ebi.ac.uk/ Chapus C, Rovery M, Sarda L, Verger R (1988). "Minireview on pancreatic lipase and colipase". Biochimie 70 (9): 1223–1234. Barrett KE Barman SM Boitano S Brooks H "General Principles & Energy Production in Medical Physiology in:  Ganong's Review of Medical Physiology, 23e, Chapter 1, on-line version, 2010. Austgen L and Bowen R "Brown Adipose Tissue" http://www.vivo.colostate.edu/hbooks/pathphys/misc_topics/brownfat.html . Ropper AH and Samuels MA "Ion Channel Disorders:  The periodic paralyses and hereditary nondystrophic mytonias (Channelopathies) in Adams & Victor's Principles of Neurology, 9e, 2009, online edition. Estelle F Simons R Gu X and Simons KJ Epinephrine absorption in adults:  Intramuscular versus subcutaneous injection J Allergy Clin Immunol 2001; 108:  871-873. Flavine Adenine Dinucleotide (FAD) public domain images http://en.wikipedia.org/wiki/Flavin_adenine_dinucleotide . Axelrod J (August 1957). "O-Methylation of Epinephrine and Other Catechols in vitro and in vivo". Science 126 (3270): 400–1. Entacapone PubMed Health http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000168 . Dopamine Degradation by "Neurotiker", public domain image, http://en.wikipedia.org/wiki/File:Dopamine_degradation.svg . Haggstrom M Breakdown of norepinephrine, public domain inkscape http://en.wikipedia.org/wiki/File:Noradrenaline_breakdown.svg . Fvasconcellos "Cartoon diagram of human catechol-O-methyl transferase (COMT) in complex with S-adenosyl methionine and 3,5-dinitrocatechol; public domain drawing. 77a. Rutherford K, Le Trong I, Stenkamp RE, Parson WW (June 2008). "Crystal structures of human 108V and 108M catechol O-methyltransferase". J Mol Biol 380 (1): 120–30, http://www.rcsb.org/pdb/explore/explore.do?structureId=3BWM . Stoelting, R.K., "Local Anesthetics", in Pharmacology and Physiology in Anesthetic Practice, Lippincott-Raven Publishers, 1999, pp 158-181. Parrmann C Decision Making and Local Anesthesia Dimensions of Dental Hygiene, October 2008; 6(10): 24. http://www.dimensionsofdentalhygiene.com/ddhright.aspx?id=2384 . Allwood MJ Cobbold AF and Ginsberg J. Peripheral vascular effects of noradrenaline, isopropylnoradrenaline, and dopamine.  Br. Med. Bull., 1963, 19:  132-136. Bloom FE Neurotransmission and the Central Nervous System in Goodman and Gilman's The Pharmacological Basis of Therapeutics, eleventh editions, (Brunton LL, Lazo JS and Parker KL,eds)McGraw-Hill Medical Publishing Division, New York, 317-340  2006. The dopamine pathways in the brain, Lundbeck Institute, CNSforum, Educational Resources, Image Bank, http://www.cnsforum.com/imagebank/item/Neuro_path_DA/default.aspx . Diseases associated with abnormalities in the basal ganglia, Lundbeck Institute, CNSforum, Educational Resources, Image Bank, http://www.cnsforum.com/imagebank/item/brain_struc_bagang_ALZ/default.aspx . Factor SA and Weiner WJ Molecular Characterization of Dopamine Receptors in Parkinson's Disease:  Diagnosis and Management http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=parkinsons&part=A2249 . Dopamine receptors-7- transmembrane spanning, G-protein coupled receptors, Lundbeck Institute, CNSforum, Educational Resources, Image Bank, http://www.cnsforum.com/imagebank/item/D_struc_level2/default.aspx . Standaert DG and Galanter JM Pharmacology of Dopaminergic Neurotransmission  in Principles of Pharmacology:  The Pathophysiologic Basis of Drug Therapy, 2nd Edition (Golan DE, Tashijan Jr AH, Armstrong EJ and Armstrong AW, eds) Wolters Kluwer-Lippincott Williams & Wilkins, Philadelphia, 185-206, 2008. Dopamine receptor subtypes, Lundbeck Institute, CNSforum, Educational Resources, Image Bank, http://www.cnsforum.com/imagebank/item/DA_rcpt_subtypes/default.aspx . D2 receptor antagonist,  Lundbeck Institute, CNSforum, Educational Resources, Image Bank, http://www.cnsforum.com/imagebank/item/hrl_rcpt_sys_DA2_antag/default.aspx . Henkel J Structure of the basal ganglia, including thalamus, globus paladus, substantia nigra and cerebellum, http://en.wikipedia.org/wiki/File:Basal_Ganglia_and_Related_Structures.svg . Dopamine and Serotonin pathways, http://en.wikipedia.org/wiki/File:Dopamineseratonin.png . Valeryns G-protein receptor http://en.wikipedia.org/wiki/File:7TM4_(GPCR).png Bensaccount G-protein coupled receptor http://en.wikipedia.org/wiki/File:7TM4_(GPCR).png . Jahnichen S Activation cycle of G-proteins by G-protein-coupled receptors, http://en.wikipedia.org/wiki/File:GPCR-Zyklus.png . Raashid AS So CH Kong MMC Furtak T El-Ghundi M Cheng R O'Dowd BF George SR D1-D2 dopamine receptor heterooligomers with unique pharmacology are couple to rapid activation of Gq/11 in the striatum. PNAM, January 9, 2007, 104(2): 654-659. Dopamine Pathways, NIDA Research Report Series--Methamphetamine Abuse and Adiction, http://en.wikipedia.org/wiki/File:Dopamine_Pathways.png . Davie CA (2008). "A review of Parkinson's disease". Br. Med. Bull. 86: 109–27. 96a."Madhero88" Midbrain Section http://commons.wikimedia.org/wiki/File:Midbrainsection.svg . 96b Hauser RA Parkinson's Disease:  Early Diagnosis and Treatment http://www.youtube.com/watch?v=T8lXjNUMaWA . Haggstrom M (images by Gillies A, (Araru) and Lynch PJ Basal Ganglia Circuits, http://en.wikipedia.org/wiki/File:Basal_ganglia_circuits.svg  . Gillies A Classic connectivity diagram of the basal ganglia, showing glutamatergic pathways  as red, dopaminergic as magenta and GABA pathways as blue. http://en.wikipedia.org/wiki/File:Basal-ganglia-classic.png . Gillies A (Araru) basal-ganglia-coronal-sections, http://commons.wikimedia.org/wiki/File:Basal-ganglia-coronal-sections-large.png . 99a Fisch A Basal Ganglia- Drawit to Know it- Neuroantomy Tutorial,  http://www.youtube.com/watch?v=-5PXAUdWDgU . Draw it to know it site:   http://www.drawittoknowit.com/  . Burns JM Wilkinson S Kieltyka J Overman J Lundsgaarde T Tollefson T Koller WC Pahwa R Troster AI Lyons KE Batnitzky S Wetzel L and Gordon MA Analysis of pallidotomy lesion positions using three-dimensional reconstruction of pallidal lesions, the basal ganglia, and the optic tract.  Neurosurgery 41(6), December 1997, pp 1303-1318. 100a.  Thomas BG, Insertion of an electrode during deep brain stimulation for Parkinson's disease. http://en.wikipedia.org/wiki/File:Parkinson_surgery.jpg . 100b. Deep brain simulation for Parkinson's Disease, http://www.youtube.com/watch?v=IOHtUzW02cg . Standaert DG and Young AB Treatment of Central Nervous System Degenerative Disorders:  In Goodman and Gillman's The Pharmacological Basis of Therapeutics, (Brunton LL, Lazo JS and Parker KL,eds) The McGraw-Hill Companies, Inc., 2006, pp.527-538. Cotzias GC Papavasilious PS Gellene R Modification of Parkinsonism:  Chornic treatment with L-DOPA. New Engl. J. Med., 19769, 280:  337-345. (cited by primary reference 101) Hornykiewicz O. Dopamine in the basal ganglia:  Its role and therapeutic indictions (including the clinical use of L-DOPA).  Br. Med. Bull., 1973, 29:  172-178. (cited by primary reference 101) "Marvin 101" Immunohistochemistry for alpha-synuclein showing positive staining (brown of an intraneural Lewy-body in the Substantia nigra in Parkinson disease. August 2009, http://en.wikipedia.org/wiki/File:Lewy_Body_alphaSynuclein.jpg . Beal JA Frontal (Coronal) section of the brain http://en.wikipedia.org/wiki/File:Human_brain_frontal_(coronal)_section_description_2.JPG . Sudarsky Lewis, "Chapter 24. Gait and Balance Disorders" (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine, 17e, 2008, on-line edition. 106a. Parkinsonian Gait Demonstration http://www.youtube.com/watch?v=j86omOwx0Hk . Sir William Richard Gowers, neurologist, researcher and artist, drew this illustration in 1886 as part of his documentation of Parkinson's Disease. The image appeared in his book, A Manual of Diseases of the Nervous System, still used today by medical professionals as a primary reference for this disease. (public domain due to copyright expiration). http://commons.wikimedia.org/wiki/File:Sir_William_Richard_Gowers_Parkinson_Disease_sketch_1886.svg . DeLong Mahlon R, Juncos Jorge L, "Chapter 366. Parkinson’s Disease and Other Extrapyramidal Movement Disorders" (Chapter). Fauci AS, Braunwald E, Kasper DL, Hauser SL, Longo DL, Jameson JL, Loscalzo J: Harrison's Principles of Internal Medicine, 17e,2008, on-line edition. 108a Silver D Parkinson's Disease Dementia MDTV http://www.youtube.com/watch?v=ZPnpmVWU0Hk . UCtelevision, January 31, 2008. Alpha-synuclein http://en.wikipedia.org/wiki/Alpha-synuclein . 109a. Uéda K, Fukushima H, Masliah E, Xia Y, Iwai A, Yoshimoto M, Otero DA, Kondo J, Ihara Y, Saitoh T (December 1993). "Molecular cloning of cDNA encoding an unrecognized component of amyloid in Alzheimer disease". Proc. Natl. Acad. Sci. U.S.A. 90 (23): 11282–6. 109b. Xia Y, Saitoh T, Uéda K, Tanaka S, Chen X, Hashimoto M, Hsu L, Conrad C, Sundsmo M, Yoshimoto M, Thal L, Katzman R, Masliah E (October 2001). "Characterization of the human alpha-synuclein gene: Genomic structure, transcription start site, promoter region and polymorphisms". J. Alzheimers Dis. 3 (5): 485–494. 109c. Xia Y, Saitoh T, Uéda K, Tanaka S, Chen X, Hashimoto M, Hsu L, Conrad C, Sundsmo M, Yoshimoto M, Thal L, Katzman R, Masliah E (2002). "Characterization of the human alpha-synuclein gene: Genomic structure, transcription start site, promoter region and polymorphisms: Erratum p489 Fig 3". J. Alzheimers Dis. 4 (4): 337. Cookson MR Events in alpha synuclein toxicty http://en.wikipedia.org/wiki/File:Events_in_alpha_synuclein_toxicity.jpg . (Cookson Molecular Neurodegeneration 2009 4:9) . Kitada T, Asakawa S, Hattori N, Matsumine H, Yamamura Y, Minoshima S, Yokochi M, Mizuno Y, Shimizu N (April 1998). "Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism". Nature 392 (6676): 605–8. Matsumine H, Yamamura Y, Hattori N, Kobayashi T, Kitada T, Yoritaka A, Mizuno Y (April 1998). "A microdeletion of D6S305 in a family of autosomal recessive juvenile parkinsonism (PARK2)". Genomics 49 (1): 143–6 ENW Structure of the PARK2 protein http://en.wikipedia.org/wiki/File:Protein_PARK2_PDB_1iyf.png . 113a. Parkin (ligase) http://en.wikipedia.org/wiki/Parkin_(ligase) . Lohmann E, Periquet M, Bonifati V, Wood NW, De Michele G, Bonnet AM, Fraix V, Broussolle E, Horstink MW, Vidailhet M, Verpillat P, Gasser T, Nicholl D, Teive H, Raskin S, Rascol O, Destée A, Ruberg M, Gasparini F, Meco G, Agid Y, Durr A, Brice A (2003). "How much phenotypic variation can be attributed to parkin genotype?". Ann. Neurol. 54 (2): 176–85. PARK7 Gene, NIH Genetic home reference:  http://ghr.nlm.nih.gov/gene/PARK7 . UCHL1 gene (PARK5), NIH Genetic home reference:  http://ghr.nlm.nih.gov/gene/UCHL1 . LRRK2 gene (PARK8), NIH Genetic home reference:  http://ghr.nlm.nih.gov/gene/LRRK2 . Aminoff MJ and Kerchner GA Nervous System Disorders, Chapter 24 in Current Medical Diagnosis & Treatment 2011 (McPhee SJ, Papadakis MA, eds. Rabow MW, Associate Ed) McGraw-Hill, Fiftieth edition, 2011, on-line edition. Kayser-Fleischer Ring http://en.wikipedia.org/wiki/Kayser%E2%80%93Fleischer_ring . Mattheis E  Kayser-Fleicher Ring http://www.gourmandizer.com/wilsons/kf2.html . Finkbeiner S Gladstone Institute of Neurological Disease, The Taube-Koret Center for Huntington's Disease Research, and the University of California San Francisco, http://en.wikipedia.org/wiki/File:Neuron_with_mHtt_inclusion.jpg and http://www.ninds.nih.gov/news_and_events/news_articles/pressrelease_huntington's_inclusion_bodies_101304.htm . Collinge J, UCL Insitute of Neurology, Department of Neurodegenerative Disease, National Hospital for Neurology & Neurosurgery, London (http://www.ion.ucl.ac.uk/departments/neurodegeneration) Creutzfeldt-Jakob disease (CJD) http://www.youtube.com/watch?v=vKGXnwXrPCQ .

This Web-based pharmacology and disease-based integrated teaching site is based on reference materials, that are believed reliable and consistent with standards accepted at the time of development. Possibility of human error and on-going research and development in medical sciences do not allow assurance that the information contained herein is in every respect accurate or complete. Users should confirm the information contained herein with other sources. This site should only be considered as a teaching aid for undergraduate and graduate biomedical education and is intended only as a teaching site. Information contained here should not be used for patient management and should not be used as a substitute for consultation with practicing medical professionals. Users of this website should check the product information sheet included in the package of any drug they plan to administer to be certain that the information contained in this site is accurate and that changes have not been made in the recommended dose or in the contraindications for administration.  Advertisements that appear on this site are not reviewed for content accuracy and it is the responsibility of users of this website to make individual assessments concerning this information.  Medical or other information  thus obtained should not be used as a substitute for consultation with practicing medical or scientific or other professionals.