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  1. 1. INTRODUCTION Neurodegenerative disorders are characterized by progressive and irreversible loss of neurons from specific regions of the brain. Prototypical neurodegenerative disorders. 1. Parkinson's disease (PD) 2. Huntington's disease (HD) -In both there is loss of neurons from structures of the basal ganglia results in abnormalities in the control of movement. 3. Alzheimer's disease (AD) -Where the loss of hippocampal and cortical neurons leads to impairment of memory and cognitive ability. 4. Amyotrophic lateral sclerosis (ALS)
  2. 2. -Where muscular weakness results from the degeneration of spinal, bulbar, and cortical motor neurons. Rang and Dale’s Pharmacology, 6th ed.
  3. 3. Mechanisms of selective neuronal vulnerability in neurodegenerative diseases. Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
  4. 4.  Organization of the extrapyramidal motor system and the defects that occur in Parkinson's disease (PD) and Huntington's disease. • Normally, activity in nigrostriatal dopamine neurons causes excitation of striatonigral neurons and inhibition of striatal neurons that project to the globus pallidus. • In either case, because of the different pathways involved, the activity of GABAergic neurons in the substantia nigra is suppressed, releasing the restraint on the thalamus and cortex, causing motor stimulation. • In PD, the dopaminergic pathway from the substantia nigra (pars compacta) to the striatum is impaired.
  5. 5. • In Huntington's disease, the GABAergic striatopallidal pathway is impaired, producing effects opposite to the changes in PD.
  6. 6. Rang and Dale’s Pharmacology, 6th ed.
  7. 7. Parkinson’s disease is neurodegenerative disorder characterized by a preferential loss of the dopaminergic neurons of the substantia nigra pars compacta (SNpc). images
  8. 8. HISTORY JAMES PARKINSON • Parkinson's disease was first formally described in modern times in "An Essay on the Shaking Palsy,"published in 1817 by a London physician named James Parkinson (1755-1824). • James Parkinson systematically described the medical history of six individuals who had symptoms of the disease that eventually bore his name. • Unusually for such a description, he did not actually examine all these patients himself but observed them on daily walks. VIARTIS, AMEZON. COM, PD HEALTH
  9. 9. • The purpose of his essay was to document the symptoms of the disorder, which he described as "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 uninjured." • It was not until 1861 and 1862 that Jean-Martin Charcot (1825- 1893) with Alfred Vulpian (1826-1887) added more symptoms to James Parkinson's clinical description (Charcot and Vulpian, 1861, 1862) and then subsequently confirmed James Parkinson's place in medical history by attaching the name Parkinson's Disease to the syndrome.
  11. 11. EPIDEMIOLOGY  Onset of PD variable in age, usually between 50 and 80 yrs.  Prevalence of PD is about 100 cases/100,000 population and insidence is estimated at 20cases/100,000 people annually.  An estimated 100,000 Americance of the population age more than 65 yrs have PD. Applied Therapeutics by Mary Anne Koda Kimble et. Al., Ninth ed.
  12. 12. Etiology CAUSES OF IDIOPATHIC PARKINSON'S DISEASE • There are a variety of causes of Parkinson's Disease including toxic, genetic, head trauma, drug induced, plus a number of medical disorders that can cause the same symptoms. • However, these causes of Parkinson's Disease represent only a minority of cases. • The majority of people with Parkinson's Disease suffer from idiopathic Parkinson's Disease, which is effectively no obvious initiating cause.
  13. 13. TOXIC CAUSES • There are a number of toxins that may cause Parkinson's disease or cause symptoms mimicking Parkinson's disease. These include : Paraquat (herbicide), Rotenone (pesticide), Maneb (fungicide), Manganese, MPTP (drug by product), Toluene (solvent), N-hexane (solvent), Carbon disulfide (usually in solvents or pesticides), Carbon monoxide, Mercury, Cyanide, and Copper. GENETIC CAUSES • There are also genetic causes of Parkinson's Disease, that can be inherited or acquired. These include genetic mutations named PARK1, PARK2, PARK3, PARK5, PARK6, PARK7, PARK8, and PARK12. Rather than inevitably cause Parkinson's Disease, these genetic mutations normally make somebody more prone to developing Parkinson's Disease. HEAD TRAUMA • A prior head injury with amnesia or loss of consciousness was associated with an increased risk of developing Parkinson's Disease. The risk was increased further after subsequent head injuries and with head injuries
  14. 14. requiring hospitalisation. People who experienced a mild head trauma with only amnesia had no increased risk of developing Parkinson's Disease. DRUG INDUCED • Some of the Anti-psychotics - drugs that are used to treat schizophrenia and psychosis - can induce the symptoms of Parkinson's disease by lowering dopaminergic activity, as can Trimetazidine. Due to feedback inhibition, L-dopa can eventually cause the symptoms of Parkinson's Disease that it initially relieves. Dopamine receptors can also eventually contribute to Parkinson's disease symptoms by decreasing the sensitivity of dopamine receptors.
  15. 15. Tremor : Tremor can occur in the fingers, hands, arms, legs, chin, tongue, lips, eyelids, and the head. It is most commonly in the hand and fingers because of the large size of the colony of pyramidal tract cells concerned with hand and finger movement. It often ceases during sleep only to return again on waking. Rigidity : Rigidity and stiffness occurs in the muscles as a primary symptom, because of their constant muscle contraction. This can lead to pain in rigid areas. Hypokinesia: Hypokinesia, which is a poverty of movement of muscles goes through three stages. Firstly, there is hypokinesia, which is impaired movement without any obvious disturbance of power or of coordination. Movement tends to be interrupted by pauses. There can also be difficulty with small movements. Secondly, there is bradykinesia, which is when voluntary movements can be performed, but slowly. Thirdly, there is akinesia, which is a loss of physical movement, which can begin with brief periods of complete immobility called akinetic attacks. VIARTIS, AMEZON. COM, PD HEALTH
  16. 16.  Changes in facial expression ("mask" appearance, may be unable to close mouth)  Voice/speech changes (slow speech, low-volume voice, difficulty speaking)  Loss of fine motor skills (difficulty writing, eating or any activity that requires small movements)  Memory loss decline in intellectual function  gastrointestinal symptoms (mainly constipation)  Drooling  Loss of smell, vision or color perception. VIARTIS, AMEZON. COM, PD HEALTH
  17. 17. PATHOPHYSIOLOGY  In PD, nigral dopamine neurons and other cells die from a combination of factors, including: (1) Genetic vulnerability (e.g., abnormal processing or folding of α-synuclein) (2) Oxidative stress (3) Proteosomal dysfunction (4) Abnormal kinase activity (5) Environmental factors, most of which have yet to be identified. Rang and Dale’s Pharmacology, 6th ed.
  18. 18. Pathogenesis of dopamine cell death in Parkinson's disease (PD) and possible sites for therapeutic intervention in PD Harrison's PRINCIPLES OF INTERNAL MEDICINE, 17th Edition
  19. 19.  Eight genes have been clearly linked to familial forms of PD and a number of other candidate genes or genetic loci have been identified as possibly causative of PD.  PARK1, PARK4, and PARK5 lead to an autosomal dominant form of PD with atypical features such as early age of onset and rapid progression of symptoms.  PARK1 is due to a mutation in the gene for α-synuclein leading to abnormal aggregation of this protein.  PARK2 and PARK7 lead to autosomal recessive disorders also with atypical features, including juvenile forms of parkinsonism.  PARK2 encodes parkin, an E3 ubiquitin protein ligase. Mutations in parkin appear to be the major cause of autosomal recessive PD. 1. Genetic vulnerability
  20. 20.  PARK5 codes for the ubiquitin carboxy-terminal hydroxylase L1 (UCH-L1), another component of the ubiquitin proteasomal system. Because ubiquitination of proteins targets them for degradation in the proteasome system, these findings suggest that abnormal proteasomal processing is important in the pathogenesis of at least some forms of PD. Harrison's PRINCIPLES OF INTERNAL MEDICINE, 17th Edition Genetically Based Parkinson's Disease
  21. 21. AD, autosomal dominant; AR, autosomal recessive,UCH-L1:ubiquitin carboxyl-terminal hydrolase L1, PINK1: PTEN-induced putative kinase 1, Harrison's PRINCIPLES OF INTERNAL MEDICINE, 17th Edition
  22. 22. α-Synuclein • α-synuclein is a 140-amino-acid protein belonging to a family of related synucleins that include β- and γ –synuclein. • Structurally, human α-synuclein consists of an N-terminal amphipathic region containing six imperfect repeats, a hydrophobic central region [containing the non-amyloid-β component ) (NAC domain], and an acidic C-terminal region
  23. 23. Molecular Pathophysiology of Parkinson’s Disease by Darren J. Moore et. al.
  24. 24. Molecular Pathophysiology of Parkinson’s Disease by Darren J. Moore et. al. • Play an important role in regulating synaptic vesicle size. • Both the A30P and A53T mutant proteins display an increased propensity to self-aggregate to form oligomeric species and LB-like fibrils in vitro compared with wild-type α-synuclein • protofibrils might cause inappropriate permeabilization of cellular membranes. Schematic of α-synuclein fibrillogenesis.
  25. 25. Parkin • The parkin gene encodes a 465-amino-acid protein. • That contains an N-terminal ubiquitin-like ) (UBL domain, a central linker region, and a C-terminal RING domain comprising two RING finger motifs separated by an in- between-RING (IBR) domain.
  26. 26. Molecular Pathophysiology of Parkinson’s Disease by Darren J. Moore et. al.
  27. 27.  The ubiquitin proteasome system. • Ubiquitin (Ub) monomers are activated by the Ub- activating enzyme (E1) and are then transferred to a Ub-conjugating enzyme (E2). • Normal or abnormal target proteins are recognized by a Ub protein ligase (E3), such as parkin, which mediates the transfer of Ub from the E2 enzyme to the target protein. Molecular Pathophysiology of Parkinson’s Disease by Darren J. Moore et. al.
  28. 28. • The resulting poly-Ub chains are recycled to free Ub monomers by deubiquitinating (DUB) enzymes, such as UCH- L1, for subsequent rounds of ubiquitination. • Parkin mutations are thought to result, in general, in the improper targeting of its substrates for proteasomal degradation leading to their potentially neurotoxic accumulation. DJ-1 • The DJ-1 gene encodes a highly conserved protein of 189 amino acids. Molecular Pathophysiology of Parkinson’s Disease by Darren J. Moore et. al.
  29. 29. • The physiological function of DJ-1 is unclear although many lines of evidence suggest that DJ-1 may function as an anti- oxidant protein or as a sensor of oxidative stress. • Missense mutations may similarly reduce the ability of DJ-1 to protect against selective forms of oxidative stress Molecular Pathophysiology of Parkinson’s Disease by Darren J. Moore et. al.
  30. 30. 2. TOXINS AND PD • Consideration of a role for environmental factors in the cause of PD was given major impetus with the discovery in 1983 that exposure to MPTP is capable of inducing parkinsonism in humans. MPTP • MPTP (1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine) is a chemical that may be produced accidentally during illicit manufacture of the recreational drug MPPP, which is a synthetic heroin substitute. • MPTP inhibits tyrosine hydroxylation, which is essential for the formation of dopamine. So MPTP causes acute Parkinson's disease by lowering dopamine levels.
  31. 31. VIARTIS, AMEZON. COM, PD HEALTH How MPTP shows neurodegeneration?
  32. 32. VIARTIS, AMEZON. COM, PD HEALTH ROTENONE • Rotenone is an insecticide that has the potential to cause Parkinson's disease. Insecticides are also known to affect well water. • Rotenone is commonly used in powdered form to treat parasitic mites on chickens and other fowl, and so can be found in poultry. • Rotenone inhibits tyrosine hydroxylation, which is essential for the formation of dopamine. So rotenone could cause Parkinson's disease by lowering dopamine levels. • Rotenone toxicity is also caused by complex I inhibition, depletion of cellular and oxidative damage. • These processes cause loss of midbrain dopaminergic neurons, leading to depletion of dopamine in the brain.
  33. 33. MANEB • Maneb is a fungicide that contains manganese. It causes Parkinson's Disease symptoms via the same means as manganese, which is by inhibiting tyrosine hydroxylation, which is essential for the formation of dopamine. VIARTIS, AMEZON. COM, PD HEALTH
  34. 34. CARBON MONOXIDE • Carbon monoxide causes hemoglobin to turn in to carboxyhemoglobin. Oxygen is required for the formation of L-dopa. So carbon monoxide may cause Parkinson's disease symptoms by interfering with the availability of oxygen to the brain. VIARTIS, AMEZON. COM, PD HEALTH
  35. 35. DIAGNOSIS
  36. 36. Diagnosis of PD, CME, Elseware Radiology/Laboratory Tests not as useful in diagnosis: • Results of computed tomography (CT), magnetic resonance imaging (MRI), cerebrospinal fluid analysis, and electroencephalography (EEG) are usually normal and of little diagnostic asistance. • Positron-emission tomography (PET scan) using radio-labeled dopa may be helpful in confirming a diagnosis. Radiology/Laboratory Tests helpful in diagnosis of other conditions: • CT, MRI useful to eliminating other disease processes such as tumors, strokes, hydrocephalus, etc. Laboratory investigation should be performed when atypical symptoms exist, there is a strong family history or early age of onset.
  37. 37. Diagnosis of PD, CME, Elseware Imaging Biomarkers for Parkinson's Disease Method Tracer Assessment Expected results with PD fMRI1 NA Indirect marker of neuronal activity ↓ activation in specific brain areas SPECT1,2 [123I]b-CIT DA transporter levels ↓ levels [99mTc]TRODAT [11C]MP PET1,2 [18F]DOPA Estimate number of DA terminals and ↓ levels nigral neurons PET1,2 [11C]DTBZVMAT2 as estimate of number of DA ↓ levels terminals and nigral neurons PET1,3 [11C]RAC • Striatal DA receptor availability • Early PD: ↑ in putamen • Estimate synaptic DA concentration • Advanced PD or after chronic DRT: ↓ in caudate PET1,2,4 FDG Metabolic activity of basal ganglia network ↑PDRP and PDCP 11C = carbon 11; 18F = fluoride 18; 99mTc = technetium 99 metastable nuclear isomer; 123I = iodine 123; β-CIT = 2β-carbomethoxy-3-β (4-iodophenyl) tropane; DA = dopamine; DTBZ = dihydrotetrabenazine; FDG = fluorodeoxyglucose; fMRI = functional magnetic resonance imaging; MP = d- threomethylphenidate; NA = not applicable; PDCP = PD-related cognitive pattern; PDRP = PD-related motor pattern; PET = positron emission tomography; RAC = raclopride; SPECT = single-photon emission computerized tomography; VMAT2 = vesicular monoamine transporter type 2.
  38. 38. Diagnosis of PD, CME, Elseware
  39. 39. TREATMENT • The goal in the management of IPD • To improve motor and nonmotor symptoms so that patients are able to maintain the best possible quality of life. • Specific objectives to consider when selecting an intervention include preservation of function and ability to perform activities of daily living; improvement of mobility; minimization of adverse effects and treatment complications; and improvement of nonmotor features such as cognitive impairment, depression, fatigue, and sleep disorders.
  41. 41. ALZHEIMER’S DISEASE Alzheimer’s is an irreversible, progressive neurodegenerative disease that slowly destroys memory and thinking skills, eventually even the ability to carry out the simplest tasks. • It is the most common cause of dementia. • Dementia is the loss of intellectual abilities, such as thinking, remembering, and reasoning, that is severe enough to interfere with daily functioning. Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)
  42. 42. HISTORY  In 1906, a German physician, Dr. Alois Alzheimer, specifically identified a collection of brain cell abnormalities as a disease.  One of Dr. Alzheimer’s patients died after years of severe memory problems, confusion and difficulty understanding questions. Upon her death, while performing a brain autopsy, the doctor noted dense deposits surrounding the nerve cells (neuritic plaques).  Inside the nerve cells he observed twisted bands of fibers (neurofibrillary tangles).  Today, this degenerative brain disorder bears his name, and when found during an autopsy, these plaques and tangles mean a definite diagnosis of Alzheimer's disease (AD).
  43. 43. EPIDEMIOLOGY • Although Alzheimer’s disease is diagnosed in adults of any age, it is much more common among people age 75 and older. Some 77 percent of the elderly population with Alzheimer’s disease is age 75 and older. • Because Alzheimer’s disease is highly associated with aging, and women have a longer life expectancy than men, women account for over two- thirds of the elderly population with this disease.
  44. 44. Alzheimer’s Disease and Dementia, A growing challenge, NATIONAL ACADEMY ON AN AGING SOCIETY
  45. 45. Alzheimer’s Disease and Dementia, A growing challenge, NATIONAL ACADEMY ON AN AGING SOCIETY
  46. 46. SYMPTOMS The onset and symptoms of Alzheimer's disease are usually very slow and gradual, seldom occurring before the age of 65. It occurs in the following three stages: Stage 1: forgetfulness, poor insight, mild difficulties with word-finding, personality changes, difficulties with calculations, losing or misplacing things, repetition of questions or statements and a minor degree of disorientation Stage 2: memory worsens, words are used more and more inappropriately, basic self-care skills are lost, personality changes, agitation develops, can't recognize distant family or friends, has difficulty communicating, wanders off, becomes deluded and may experience hallucinations Stage 3: bedridden, incontinent, uncomprehending and mute
  47. 47. PATHOPHYSIOLOGY • The loss of cholinergic neurons in the hippocampus and frontal cortex is a feature of the disease, and is thought to underlie the cognitive deficit and loss of short-term memory that occur in AD. • Alzheimer's disease is associated with brain shrinkage and localised loss of neurons, mainly in the hippocampus and basal forebrain. The loss of cholinergic neurons in the hippocampus and frontal cortex is a feature of the disease, and is thought to underlie the cognitive deficit and loss of short-term memory that occur in AD. • Two microscopic features are characteristic of the disease, namely extracellular amyloid plaques, consisting of amorphous extracellular deposits of β-amyloid protein (known as Aβ), and intraneuronal neurofibrillary tangles, comprising filaments of a phosphorylated form of a microtubule-associated protein (Tau).
  48. 48. ALZHEIMER’S DISEASE Unravelingt he Mystery, National Institute on Aging
  49. 49. Proposed mechanisms underlying Alzheimer's disease Nature revieves, april 2007, vol-6, no-4
  50. 50. AD MECHANISMS 1. Aβ hypothesis • It has been shown that increased production of , aggregation and accumulation of Aβ fiber leads to senile plaques, neurotoxicity and the clinical manifestation of AD. • Thus most of the drug in development for AD target Aβ amyloidosis by inhibiting or reducing the production of amyloidogenic Aβ peptide , or by promoting the clearance of Aβ oligomers and other Aβ aggregates. Nature revieves, april 2007, vol-6, no-4
  51. 51.  Amyloid precursor protein (APP) is the precursor to amyloid plaque. 1. APP sticks through the neuron membrane. 2. Enzymes cut the APP into fragments of protein, including beta-amyloid. 3. Beta-amyloid fragments come together in clumps to form plaques. • In AD, many of these clumps form, disrupting the work of neurons. This affects the hippocampus and other areas of the cerebral cortex. Nature revives, april 2007, vol-6, no-4
  52. 52. 2. Tau HYPOTHESIS Neurofibrillary Tangles • Healthy neurons have an internal support structure partly made up of structures called microtubules. • These microtubules act like tracks, guiding nutrients and molecules from the body of the cell down to the ends of the axon and back. • A special kind of protein, tau, makes the microtubules stable. • In AD, tau is changed chemically. It begins to pair with other threads of tau and they become tangled up together. • When this happens, the microtubules disintegrate, collapsing the neuron’s transport system. • This may result first in malfunctions in communication between neurons and later in the death of the cells Nature revieves, april 2007, vol-6, no-4
  53. 53. ALZHEIMER’S DISEASE Unraveling the Mystery, National Institute on Aging
  54. 54. ALZHEIMER’S DISEASE Unraveling the Mystery, National Institute on Aging
  55. 55. The Changing Brain in Alzheimer’s Disease Mild AD • As the disease begins to affect the cerebral cortex, memory loss continues and changes in other cognitive abilities emerge. • The clinical diagnosis of AD is usually made during this stage. • Signs of mild AD can include: o Memory loss , Confusion about the location of familiar places (getting lost begins to occur) o Takinglonger to accomplish normal daily tasks o Troublehandling money and paying bills o Poor judgment leading to bad decisions o Loss of spontaneity and sense of initiative o Mood and personality changes, o increased anxiety
  56. 56. ALZHEIMER’S DISEASE Unraveling the Mystery, National Institute on Aging
  57. 57. Moderate AD
  58. 58. • AD damage has spread further to the areas of the cerebral cortex that control language, reasoning, sensory processing, and conscious thought. • The symptoms of this stage can include: o Increasing memory loss and confusion o Shortened attention span o Problems recognizing friends and o family members o Difficulty with language; problems with o reading, writing, working with numbers o Difficulty organizing thoughts and o Restlessness, agitation,anxiety, tearfulness, o Hallucinations, delusions, suspiciousness o or paranoia, irritability ALZHEIMER’S DISEASE Unraveling the Mystery, National Institute on Aging
  59. 59. Severe AD • In the last stage of AD, plaques and tangles are widespread throughout the brain, and areas of the brain have atrophied further. • symptoms : o Weight loss o Seizures, skin infections, difficulty o swallowing o Groaning, moaning or grunting o Increased sleeping o Lack of bladder and bowel control
  60. 60. ALZHEIMER’S DISEASE Unraveling the Mystery, National Institute on Aging
  61. 61. DIaGNOSIS • There is no singular test that can definitively diagnose Alzheimer's disease, although imaging technology designed to detect Alzheimer's plaques and tangles is rapidly becoming more powerful and precise. • Medical history This should include questions about past illnesses, prior injuries and surgeries, and current chronic conditions in order to identify other possible causes for Alzheimer's-like symptoms. • Medication history This should include allergies, experienced side effects from past medications, and a list of current medications and dosages.
  62. 62. • Complete physical exam To assess hearing, vision, blood pressure, pulse, and other basic indicators of health and disease. A current physical exam can detect acute medical conditions such as an infection that might be causing Alzheimer's-like symptoms. • Imaging procedures Detailed pictures of the brain, such as a CT scan (computed tomography), an MRI (magnetic resonance imaging), or a PET scan (positron emission tomography) to identify changes in brain structure or size indicative of Alzheimer's, or to look for brain tumors, blood clots, strokes, normal pressure hydrocephalus (NPH), or other abnormalities that might account for Alzheimer's-like symptoms.
  63. 63. Treatments for AD
  64. 64. REFERENCES 1. Nature revieves, april 2007, vol-6, no-4, page no- 295-299. 2. Neurophychopharmacology by Kenneth L. Davis, Dennis Charney, Joseph T. Coyle, Charles Nemeroff., 5 th ed, Page no- 1189-1339 and 1761-1795. 3. 4. H. P. Rang, M. M. Dale, J. M. Ritter, R. J. Flower,. Rang and Dales Pharmacology., 6th 2009;655-660. 5. The Pharmacological basis of Therapeutics by Goodman and Gilman’s, 11 ed. (2006)