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.
-Where muscular weakness results from the degeneration of
spinal, bulbar, and cortical motor neurons.
Rang and Dale’s Pharmacology, 6th
ed.

3.
Mechanisms of selective neuronal vulnerability in
neurodegenerative diseases.
Goodman & Gilman's The Pharmacologic Basis of Therapeutics - 11th Ed. (2006)

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.
• In Huntington's disease, the GABAergic
striatopallidal pathway is impaired,
producing effects opposite to the changes
in PD.

6.
Rang and Dale’s Pharmacology, 6th ed.

7.
Parkinson’s disease is neurodegenerative disorder
characterized by a preferential loss of the dopaminergic neurons
of the substantia nigra pars compacta (SNpc).
www.google.com images

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.
• 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.

10.
VIARTIS, AMEZON. COM, PD HEALTH

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.
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.
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.
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.
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

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 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.
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.
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.
 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

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 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.
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.
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.
Molecular Pathophysiology of Parkinson’s Disease by Darren J. Moore et. al.

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.
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.
Molecular Pathophysiology of Parkinson’s Disease by Darren J. Moore et. al.

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.
• 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.
• 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.
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.
VIARTIS, AMEZON. COM, PD HEALTH
How MPTP shows neurodegeneration?

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.
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.
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.
DIAGNOSIS

36.
Diagnosis of PD, CME, Elseware www.google.com
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.
Diagnosis of PD, CME, Elseware www.google.com
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.
Diagnosis of PD, CME, Elseware www.google.com

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.

40.
MANAGEMENT OF PARKINSONISM
www.google.com images

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.
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).
www.google.com

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.
Alzheimer’s Disease and Dementia, A growing challenge, NATIONAL ACADEMY ON AN AGING SOCIETY

45.
Alzheimer’s Disease and Dementia, A growing challenge, NATIONAL ACADEMY ON AN AGING SOCIETY

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
www.google.com

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.
ALZHEIMER’S DISEASE Unravelingt he Mystery, National Institute on Aging

49.
Proposed mechanisms underlying Alzheimer's
disease
Nature revieves, april 2007, vol-6, no-4

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.
 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.
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.
ALZHEIMER’S DISEASE Unraveling the Mystery, National Institute on Aging

54.
ALZHEIMER’S DISEASE Unraveling the Mystery, National Institute on Aging

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.
ALZHEIMER’S DISEASE Unraveling the Mystery, National Institute on
Aging

57.
Moderate AD

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.
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.
ALZHEIMER’S DISEASE Unraveling the Mystery, National Institute on Aging

61.
www.google.com
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.
www.google.com
• 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.
www.google.com
Treatments for AD

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. www.google.com
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)