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Drug Treatment for Drug Treatment for
Neurodegenerative Disorders Neurodegenerative Disorders
Edwin Santini Rios, Ph.D. Edwin Santini Rios, Ph.D.
Assistant Professor Assistant Professor
Nova Southeastern University Nova Southeastern University
College of Pharmacy College of Pharmacy
Ponce, Puerto Rico Site Ponce, Puerto Rico Site
Introduction Introduction
Neurodegenerative diseases are incurable Neurodegenerative diseases are incurable
and debilitating conditions that result in and debilitating conditions that result in
progressive degeneration and/or death of progressive degeneration and/or death of
nerve cells. This causes problems with nerve cells. This causes problems with
Neurodegenerative disease Neurodegenerative disease
pp
movement, or mental functioning. movement, or mental functioning.
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Examples of neurodegenerative diseases Examples of neurodegenerative diseases
include Alzheimers, Parkinsons, and include Alzheimers, Parkinsons, and
Huntingtons disease. Huntingtons disease.
Cont. Cont.
Alzheimers
Disease
Early onset
Normal onset
Vascular
Dementia
Lewy
Body
Dementia
DEMENTIA
Other Dementias
Metabolic
Drugs/toxic
White matter disease
Mass effects
Depression
Infections
Parkinsons
Fronto-
Temporal
Lobe
Dementias
Cont. Cont.
Neurodegenerative diseases include: Neurodegenerative diseases include:
Alzheimers disease (AD) Alzheimers disease (AD)
Parkinsons disease Parkinsons disease
F t t l F t t l d ti d ti Frontotemporal Frontotemporal dementia dementia
Huntingtons disease Huntingtons disease
Spinocerebellar Spinocerebellar ataxia ataxia
Amyotrophic Lateral Sclerosis (ALS) Amyotrophic Lateral Sclerosis (ALS)
Neurodegenerative Disorders Neurodegenerative Disorders
Etiology Etiology
Genetic predisposition Genetic predisposition
Environmental toxins Environmental toxins
Oxidative stress Oxidative stress Oxidative stress Oxidative stress
Aging Aging
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Neurodegenerative Disorders Neurodegenerative Disorders
General clinical features General clinical features
Gradual onset Gradual onset
Progressive Progressive
No No apparent evoking apparent evoking factor factor
Selective involvement of neuronal systems Selective involvement of neuronal systems Selective involvement of neuronal systems, Selective involvement of neuronal systems,
that are anatomically or physiologically that are anatomically or physiologically
related. related.
The damage is caused The damage is caused by: by:
Excitotoxicity Excitotoxicity
Oxidative Stress Oxidative Stress
Neurodegenerative Neurodegenerative Disorders ( Disorders (NDDs NDDs))
Oxidative Stress Oxidative Stress
Apoptosis/Degeneration of Neurons Apoptosis/Degeneration of Neurons
Neurodegenerative Disorders Neurodegenerative Disorders
Basic Basic pathogenetic pathogenetic mechanisms mechanisms
Apoptosis vs. Degeneration: Apoptosis vs. Degeneration:
Apoptosis: Apoptosis:
Gradual Gradual neuron loss, not preceded by neuron loss, not preceded by
accumulation of accumulation of degenerative products degenerative products and is and is
i t d ith i t d ith di d di d li i li i associated with associated with dispersed dispersed gliosis gliosis. .
Degeneration: Degeneration:
More rapid neuronal breakdown/loss, associated More rapid neuronal breakdown/loss, associated
with deposition of with deposition of degenerative products degenerative products and and
evokes vigorous evokes vigorous phagocytosis phagocytosis and and gliosis gliosis. .
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Neurodegenerative Disorders Neurodegenerative Disorders
Degenerative products Degenerative products
NDDs NDDs appear to have common cellular and appear to have common cellular and
molecular mechanisms including molecular mechanisms including degenerative degenerative
products: products:
protein protein aggregation and inclusion body aggregation and inclusion body formation formation protein protein aggregation and inclusion body aggregation and inclusion body formation formation
Most Most likely represent a later stage of a molecular likely represent a later stage of a molecular
cascade leading to cell death. cascade leading to cell death.
Tau Tau Protein Protein
Tau Tau is a neuronal Microtubule stabilizing protein, is a neuronal Microtubule stabilizing protein,
It contribute to axonal transport, growth & It contribute to axonal transport, growth &
morphology. morphology.
Tau Tau misregulation misregulation and deposition correlates with and deposition correlates with
neuronal cell death in: neuronal cell death in:
Frontotemporal Frontotemporal dementia dementia
Alzheimers Disease Alzheimers Disease
aa- -Synuclein Synuclein Protein Protein
aa- -Synuclein Synuclein. .
misfolded misfolded aa- -synuclein synuclein is part of the abnormal is part of the abnormal
protein aggregate found in protein aggregate found in Lewy Lewy bodies. bodies.
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NDDs NDDs characterized by intracellular characterized by intracellular
aggregation of aggregation of a a- -synuclein synuclein: :
Parkinsons Disease Parkinsons Disease
Dementia with Dementia with Lewy Lewy Bodies Bodies
aa- -Synuclein Synuclein Protein Protein
Lewy Lewy Body Variant of Body Variant of AD AD
Neurodegenerative Disorders Neurodegenerative Disorders
Degenerative products deposition Degenerative products deposition
Abnormal protein tends to aggregates Abnormal protein tends to aggregates
and accumulate as a consequence of and accumulate as a consequence of::
Proteasome Proteasome--Ubiquitin Ubiquitin System System
Proteasome Proteasome is a barrel is a barrel--shaped enzyme shaped enzyme, , labelled labelled the the
master controller of the cell: master controller of the cell:
It breaks down protein molecules and abnormal It breaks down protein molecules and abnormal
misfolded misfolded proteins, and recycles regulatory proteins. proteins, and recycles regulatory proteins.
Ubiquitin Ubiquitin is a tiny molecule that is a tiny molecule that attaches onto attaches onto the the
d d i d i i h d d i d i i h damaged protein and carries it to the damaged protein and carries it to the proteasome proteasome, ,
where the protein is sliced and diced. where the protein is sliced and diced.
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Neurodegenerative Disorders Neurodegenerative Disorders
Proteasome Proteasome--Ubiquitin Ubiquitin system system
Defective proteins clump together into Defective proteins clump together into
aggregates aggregates aggregates build up aggregates build up
(defective protein may clog (defective protein may clog proteasome proteasome))
interfere with interfere with proteasome proteasome function function
accumulation accumulation of more aggregates that of more aggregates that
further impair the further impair the proteasome proteasome. .
A A viscious viscious circle! circle!
Proteasome Proteasome--Ubiquitin Ubiquitin system system
Onset of the disease occurs when aggregates Onset of the disease occurs when aggregates
build up build up reaches reaches significant level. significant level.
In Huntington diseases, the In Huntington diseases, the ubiquitin ubiquitin--
proteasome proteasome system breaks down. system breaks down. Huntingtin Huntingtin
aggregates are noted to contain thousands of aggregates are noted to contain thousands of aggregates are noted to contain thousands of aggregates are noted to contain thousands of
misfolded misfolded proteins with proteins with ubiquitin ubiquitin flags flags
attached to them. attached to them.
Alzheimers Disease (AD) Alzheimers Disease (AD) Alzheimer s Disease (AD) Alzheimer s Disease (AD)
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What What is Alzheimers Disease ? is Alzheimers Disease ?
It is a degenerative disease in which nerve It is a degenerative disease in which nerve
cells die in areas that are important for cells die in areas that are important for
memory and simple tasks that need to be memory and simple tasks that need to be
performed. performed.
The The levels of the chemicals which carry the levels of the chemicals which carry the
messages across the synapses from neurons messages across the synapses from neurons
decrease. decrease.
Overview Overview
Alzheimers Alzheimers Disease is Disease is associated with the associated with the
selective damage of selective damage of brain regions brain regions and neural and neural
circuits critical for memory and circuits critical for memory and cognition. cognition.
Th Th th i f thi di i l th i f thi di i l The The pathogenesis of this disease is complex, pathogenesis of this disease is complex,
and involves many molecular, cellular, and and involves many molecular, cellular, and
physiological physiological pathologies. pathologies.
Alzheimers Disease Alzheimers Disease
Progression of AD is characterized by a Progression of AD is characterized by a
deterioration in: deterioration in:
Cognition Cognition
Functional abilities Functional abilities
Behavioral mood Behavioral mood
On average, AD progresses from diagnosis to On average, AD progresses from diagnosis to
death in 8 death in 8- -10 years. 10 years.
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The History and Background The History and Background
It was discovered by Dr. It was discovered by Dr. Alois Alois
Alzheimer, a German doctor, in Alzheimer, a German doctor, in
1906. 1906.
It It is believed is believed 4 4- -5 5 million older million older
Americans have AD. Americans have AD.
The The average age that people get average age that people get
Alzheimers is after the age of 60 Alzheimers is after the age of 60..
The Case Auguste The Case Auguste Deter Deter
This patient This patient was was under under the the
care of Dr. Alzheimer care of Dr. Alzheimer until until
her her death death. . He He did did an an
autopsy autopsy examined examined her her autopsy autopsy, , examined examined her her
brain brain & & described described the the
typical typical abnormalities abnormalities of of
what what would would be be called called later later
Alzheimers Alzheimers Disease Disease. .
What Causes What Causes Alzheimers Disease? Alzheimers Disease?
Age is the number one risk factor. Age is the number one risk factor.
A A family history of having AD is another risk factor. family history of having AD is another risk factor.
It has been strongly suggested that It has been strongly suggested that the main cause the main cause
f b i ll d h i l i f h i f b i ll d h i l i f h i of brain cell death is an accumulation of the protein of brain cell death is an accumulation of the protein
Amiloyd Amiloyd--Beta (A). Beta (A).
Once Once a brain cell dies it doesnt come back, so AD a brain cell dies it doesnt come back, so AD
causes a gradual loss of brain function. causes a gradual loss of brain function.
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Initial Symptoms Initial Symptoms
The initial symptoms include mild The initial symptoms include mild
forgetfulness forgetfulness- -
The AD patient might not be able to solve The AD patient might not be able to solve
simple math problems. simple math problems.
Th t t b h t Th t t b h t These symptoms may not be enough to cause These symptoms may not be enough to cause
alarm. alarm.
Advanced Symptoms Advanced Symptoms
As the disease progresses the symptoms are more As the disease progresses the symptoms are more
easily noticed. easily noticed.
The AD patient may The AD patient may not be able to think clearly and not be able to think clearly and
may fail to recognize familiar people or places. may fail to recognize familiar people or places.
People with AD can become anxious or aggressive People with AD can become anxious or aggressive People with AD can become anxious or aggressive People with AD can become anxious or aggressive
or or go away go away from home. from home.
Mild, Moderate & Severe stages Mild, Moderate & Severe stages
Mi ld Moderate Severe Mi ld Moderate Severe
Dementia/Alzheimers Dementia/Alzheimers
Stage Stage
Memor y Memor y
loss loss
Language Language
pr oblems pr oblems
Mood Mood
swi ngs swi ngs
Personali ty Personali ty
changes changes
Di mi ni shed Di mi ni shed
j udgment j udgment
Behavi oral, Behavi oral,
personali ty personali ty
changes changes
Unable to lear n/ r ecall Unable to lear n/ r ecall
new i nformati on new i nformati on
Long Long- -ter m memory term memory
affected affected
agi tati on, agi tati on,
aggr essi on, aggr essi on,
confusi on confusi on
Requi r e Requi r e assi stance assi stance
i nconti nence i nconti nence, ,
motor motor
di stur bances di stur bances
Placement Placement i n i n
long long--ter m car e ter m car e
needed needed
Symptoms Symptoms
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Clinical Diagnosis of Clinical Diagnosis of Dementia: Dementia:
The The Mini Mini--Mental Mental S Status Exam (MMSE) tatus Exam (MMSE)
1. 1. Orientation to time, place & persons Orientation to time, place & persons
2. 2. Registration of 3 items (immediate memory) Registration of 3 items (immediate memory)
3. 3. Calculation Calculation
4. 4. Recall of the 3 items (recent memory) Recall of the 3 items (recent memory) 4. 4. Recall of the 3 items (recent memory) Recall of the 3 items (recent memory)
5. 5. Naming objects Naming objects
6. 6. Repetition Repetition
Diagnosing AD Diagnosing AD
Definite AD Definite AD -- Histopathological Histopathological evidence (requires autopsy) evidence (requires autopsy)
-- Course and examination characteristic of AD Course and examination characteristic of AD
Probable AD Probable AD - - Deficits in > Deficits in > 2 2 areas of cognition areas of cognition
-- Onset Onset usually > usually > 65 65; ; progressive course progressive course
Possible Possible AD AD - - Deficit in only 1 area of cognition Deficit in only 1 area of cognition
-- Atypical course Atypical course
-- Other Other types of dementia might be present types of dementia might be present
Unlikely AD Unlikely AD -- Sudden onset Sudden onset
-- Focal signs Focal signs
-- Seizures Seizures
Positron Emission Tomography (PET)
Alzheimers Disease Progression vs. Normal Brains
Normal
Early
Alzheimers
Late
Alzheimers
G. Small, UCLA School of Medicine. G. Small, UCLA School of Medicine.
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How is Alzheimers Disease managed How is Alzheimers Disease managed
at at present? present?
Ideally, management should involve an Ideally, management should involve an
interdisciplinary approach for assessment, interdisciplinary approach for assessment,
treatment & treatment & education. education.
The The roles of roles of physicians, nutritionists physicians, nutritionists, caregivers, , caregivers,
nurses, social workers and patients associations nurses, social workers and patients associations
can be vital for the can be vital for the long long- -term care. term care.
Pharmacotherapy. Pharmacotherapy.
Alzheimer's Alzheimer's Pathophysiology Pathophysiology
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The two most significant physical The two most significant physical
findings in Alzheimer's disease are: findings in Alzheimer's disease are:
Amyloid Plaques Amyloid Plaques Neurofibrillary Neurofibrillary
Alzheimers pathology Alzheimers pathology
Amyloid Plaques Amyloid Plaques Neurofibrillary Neurofibrillary
Tangles Tangles
Alzheimers pathology Alzheimers pathology
Amyloid Amyloid Plaques Plaques also called Senile, also called Senile,
Dendritic Dendritic, or , or Neuritic Neuritic Plaques Plaques
Neurofibrillary Neurofibrillary Tangles Tangles
Cholinergic projection system Cholinergic projection system
Neuronal Neuronal death and brain death and brain atrophy atrophy
Amyloid Amyloid Precursor Proteins ( Precursor Proteins (APPs APPs) )
Alzheimers patients show numerous Alzheimers patients show numerous plaques plaques which which
are composed of 4 are composed of 4 kD kD Amyloid Amyloid--beta ( beta (A) A) peptides peptides, ,
which are derived from which are derived fromAmyloid Amyloid PPrecursor recursor PProteins roteins
((APPs APPs). ).
APP APP is a membrane associated glycoprotein of 110 is a membrane associated glycoprotein of 110--
135 135 kDa kDa that is proposed to normally behave in the that is proposed to normally behave in the
brain as a cell surface signaling brain as a cell surface signaling molecule. molecule.
A peptides are A peptides are cleavaged cleavaged from the APP by from the APP by Beta, Beta,
alpha, and gamma alpha, and gamma secretases secretases. .
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Beta Beta A Amyloid myloid
Presenilins Presenilins
Presenilin Presenilin 1 (PS1) and 1 (PS1) and presenilin presenilin 2 (PS2) are highly 2 (PS2) are highly
homologous 43 homologous 43- -50 50 kD kD proteins with proteins with 8 8
transmembrane transmembrane domains. domains.
Presenilins Presenilins are thought to contributes to the are thought to contributes to the
neurodegeneration neurodegeneration in in AD. AD.
Presenilins Presenilins are crucial components of the enzymes are crucial components of the enzymes
that work to cleave APP, and mutations in that work to cleave APP, and mutations in
presenilins presenilins cause the production of cause the production of A A- -beta42 beta42 and A and A- -
beta43 peptides beta43 peptides (insoluble forms of A (insoluble forms of A- -beta beta). ).
PS1 and PS2 ( PS1 and PS2 (Presenilin Presenilin 1 and 2) 1 and 2)
5% of Alzheimers caused by mutation in these 5% of Alzheimers caused by mutation in these
two or two or APP. APP.
Can be inherited in dominant fashion. Can be inherited in dominant fashion.
Leads Leads to early onset (<65) to early onset (<65) y ( 5) y ( 5)
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Apolipoprotein Apolipoprotein EE
In the CNS, In the CNS, ApoE ApoE is mainly produced by is mainly produced by
astrocytes astrocytes, and transports cholesterol to , and transports cholesterol to
neurons. neurons.
3 3 common common forms: forms:
22, , 33, , 44 22, , 33, , 44
Apo Apo 4 4 most linked to leading to most linked to leading to Alzheimers Alzheimers
Apo Apo 2 2 may have protective may have protective effect effect
ApoE ApoE4 4 is a protein found with beta is a protein found with beta amyloid amyloid
in in neuritic neuritic plaques. plaques.
ApoE ApoE genotype is the most important genetic genotype is the most important genetic
risk factor for AD. risk factor for AD.
Amyloid Amyloid Plaque formation Plaque formation
AA- -Beta40 Beta40
AA- -Beta42 Beta42 and A and A- -Beta43 Beta43
AA--beta42 and A beta42 and A- -beta43 are highly beta43 are highly fibrillogenic fibrillogenic, ,
readily aggregated, and readily aggregated, and neurotoxic neurotoxic. .
AA- -beta42 and A beta42 and A- -beta43 preferentially form beta43 preferentially form
networks of salt linkages and strong hydrogen networks of salt linkages and strong hydrogen
bonds between which thus form the plaques. bonds between which thus form the plaques.
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APP Protein:
(1) -secretase cuts APP protein, giving:
-secretase Pathway:
(not drawn to scale)
(2) -secretase cuts this residue, giving:
or
A40 Fragment
Soluble
A42 Fragment
Unsoluble,
aggregates into
plaques
Most cases of early onset AD are familial Most cases of early onset AD are familial
autosomal autosomal dominant disorders caused by dominant disorders caused by
mutations in APP, PS1, and mutations in APP, PS1, and PS2. PS2.
Various Various studies have studies have found various mutations found various mutations
Early Onset Early Onset Alzheimers Alzheimers
that cause the individuals to secrete a higher that cause the individuals to secrete a higher
fraction of A fraction of A- -beta42 and/or A beta42 and/or A- -beta43 beta43
peptides. peptides.
Late Onset Alzheimers Late Onset Alzheimers
In late onset In late onset AAlzheimers lzheimers, there are no specific , there are no specific
gene mutations that are associated with the gene mutations that are associated with the
inheritance of the inheritance of the disease. disease.
However, specific alleles of However, specific alleles of A Apoliprotein poliprotein E4 E4
(ApoE4) are (ApoE4) are associated with increased risk of associated with increased risk of
AD. AD.
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Amyloid Amyloid Plaques Plaques
Amyloid Amyloid Plaque Plaque
Bacskai Bacskai et al. (2003) PNAS et al. (2003) PNAS
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Neurofibrillary Neurofibrillary pathology pathology
Affected Affected neurons accumulate neurons accumulate tau tau proteins proteins
within within neurofibrillary neurofibrillary tangles, in cell bodies tangles, in cell bodies
and and dendrites. dendrites.
Every neuron has a cytoskeleton, an internal support Every neuron has a cytoskeleton, an internal support
structure partly made up of structures called structure partly made up of structures called
microtubules microtubules.. The The tau tau protein stabilizes protein stabilizes the the
microtubules when microtubules when phosphorylated phosphorylated..
I I AD AD d h i l h b i d h i l h b i
Neurofibrillary tangles Neurofibrillary tangles
In In AD, AD, tau tau undergoes chemical changes, becoming undergoes chemical changes, becoming
hyperphosphorylated hyperphosphorylated; it then begins to pair with ; it then begins to pair with
other threads, creating other threads, creating neurofibrillary neurofibrillary tangles and tangles and
disintegrating the neuron's transport system. disintegrating the neuron's transport system.
Amyloid Amyloid Plaques Plaques Neurofibrillary Neurofibrillary Tangles Tangles
Alzheimer's Pathophysiology Alzheimer's Pathophysiology
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AD AD related Hypotheses related Hypotheses AD AD--related Hypotheses related Hypotheses
Amyloid Amyloid Hypothesis Hypothesis
The trigger for The trigger for AD AD is the A is the A- -beta peptide, and the beta peptide, and the
accumulation of this peptide in the form of plaques accumulation of this peptide in the form of plaques
is the initiating molecular is the initiating molecular event. event.
The The plaques trigger an inflammatory response, plaques trigger an inflammatory response,
neuronal cell death and gradual cognitive neuronal cell death and gradual cognitive decline decline neuronal cell death, and gradual cognitive neuronal cell death, and gradual cognitive decline. decline.
The The rest of the disease process, including formation rest of the disease process, including formation
of of neurofibrillary neurofibrillary tangles containing tangles containing tau tau protein, is protein, is
caused by an imbalance between A caused by an imbalance between A- -beta beta production production
and A and A- -beta beta clearance clearance. .
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Support for the Support for the Amyloid Amyloid Hypothesis Hypothesis
The A The A- -beta peptide is the primary component beta peptide is the primary component
of the necrotic brain of the necrotic brain tissue. tissue.
Mutations in the gene encoding the Mutations in the gene encoding the tau tau
proteins cause proteins cause frontotemporal frontotemporal dementia with dementia with
parkinsonism. parkinsonism.
However, parkinsonism is characterized by However, parkinsonism is characterized by
severe deposition of severe deposition of tau tau in in neurofibril neurofibril tangles tangles
in the brain, but there is no deposition of in the brain, but there is no deposition of
amyloid amyloid. .
Support for the Support for the Amyloid Amyloid Hypothesis Hypothesis
Growing evidence indicates that genetic Growing evidence indicates that genetic
variability in A variability in A--beta catabolism and beta catabolism and
clearance may contribute to the risk of late clearance may contribute to the risk of late
onset of onset of AD. AD.
Plasmin Plasmin
In the brain, In the brain, plasminogen plasminogen and its and its proteolytic proteolytic
fragment are abundant in the fragment are abundant in the hippocampus. hippocampus.
Plasmin Plasmin is the key is the key active protease active protease and is capable of and is capable of
cleaving A. cleaving A.
It has been hypothesized that brains of patients with It has been hypothesized that brains of patients with It has been hypothesized that brains of patients with It has been hypothesized that brains of patients with
AD may have lower levels of AD may have lower levels of plasmin plasmin..
The higher production of The higher production of amyloid amyloid peptide together peptide together
with with less efficient degradation would less efficient degradation would contribute to contribute to
the the A A- -beta accumulation and beta accumulation and aggregation aggregation. .
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Calcium Hypothesis Calcium Hypothesis
Calcium modulates many neural processes, Calcium modulates many neural processes,
including synaptic plasticity and including synaptic plasticity and apoptosis. apoptosis.
Dysregulation Dysregulation of intracellular calcium of intracellular calcium
signaling has been implicated in the signaling has been implicated in the
pathogenesis of pathogenesis of AD AD pathogenesis of pathogenesis of AD. AD.
Increased intracellular calcium elicits the Increased intracellular calcium elicits the
characteristic lesions of this disorder, characteristic lesions of this disorder,
including the accumulation of including the accumulation of amyloid amyloid--beta, beta,
the the hyperphosphorylation hyperphosphorylation of of tau tau protein and protein and
neuronal neuronal death. death.
Calcium Hypothesis Calcium Hypothesis
The disruption of calcium homeostasis might The disruption of calcium homeostasis might
be one of the principal mechanisms by which be one of the principal mechanisms by which
AA- -beta manifests its beta manifests its neurotoxicity. neurotoxicity.
AA- -beta has been shown to destabilize beta has been shown to destabilize
neuronal calcium homeostasis, generally neuronal calcium homeostasis, generally
leading to an increase in leading to an increase in cytosolic cytosolic calcium calcium
which can then trigger neuronal which can then trigger neuronal apoptosis. apoptosis.
Pharmacotherapy Pharmacotherapy
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Research Directions Research Directions
As of 2010, the safety and efficacy of more As of 2010, the safety and efficacy of more
than 400 pharmaceutical treatments are than 400 pharmaceutical treatments are
being investigated in clinical trials being investigated in clinical trials
worldwide. worldwide.
Research Research Treatments Treatments
One area of clinical research is focused on reduction One area of clinical research is focused on reduction
of of amyloid amyloid beta levels, and numerous compounds beta levels, and numerous compounds
are under investigation. are under investigation.
Immunotherapy Immunotherapy or or vaccination vaccination for the for the amyloid amyloid
protein is one treatment modality under protein is one treatment modality under study* study* protein is one treatment modality under protein is one treatment modality under study . study .
Other Other approaches are approaches are neuroprotective neuroprotective agents. agents.
In In 2008, a clinical trial showed positive results with 2008, a clinical trial showed positive results with
methylthioninium methylthioninium chloride chloride ((Rember Rember), ), a drug that a drug that
inhibits inhibits tau tau aggregation. aggregation.
Cholinergic Hypothesis of Cortical Dysfunction Cholinergic Hypothesis of Cortical Dysfunction
Centrally acting muscarinic blocking agents Centrally acting muscarinic blocking agents
induces loss of recent induces loss of recent memory. memory.
80 80- -90% loss of Ach in cerebral cortex and 90% loss of Ach in cerebral cortex and
hippocamus hippocamus of AD of AD patients. patients.
In AD patients, loss of neurons in nucleus In AD patients, loss of neurons in nucleus
basalis basalis of of Meynert Meynert. .
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Ach central pathways Ach central pathways
Acetylcholinesterase Acetylcholinesterase ( (AChE AChE) )
A globular enzyme embedded in the neuronal cell A globular enzyme embedded in the neuronal cell
membrane, post membrane, post- -synaptic to cholinergic synaptic to cholinergic
terminals. terminals.
Rapidly hydrolyzes Rapidly hydrolyzes ACh ACh to to choline choline and acetate and acetate Rapidly hydrolyzes Rapidly hydrolyzes ACh ACh to to choline choline and acetate and acetate
which are inactive. which are inactive.
The The choline choline produced by metabolism of produced by metabolism of ACh ACh can can
be taken up be taken up presynaptically presynaptically and combined with and combined with
Acetyl Acetyl- -CoA CoA provided by the provided by the mitocondria mitocondria to to
reform Acetylcholine. reform Acetylcholine.
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Acetylcholinesterase Acetylcholinesterase ( (AChE AChE) )
AChE AChE is found in two forms: globular G4 and G1. is found in two forms: globular G4 and G1.
Highest concentration of G4 form can be found in Highest concentration of G4 form can be found in
the hippocampus and cortex two regions known the hippocampus and cortex two regions known the hippocampus and cortex, two regions known the hippocampus and cortex, two regions known
to be highly affected in AD. to be highly affected in AD.
Treatment Treatment
Acetylcholinesterase Acetylcholinesterase I Inhibitors nhibitors
Donepezil Donepezil ( (Aricept Aricept) )
Galantamine Galantamine ((Reminyl Reminyl) )
Rivastigmine Rivastigmine (Exelon) (Exelon)
Drugs used to treat Drugs used to treat mild to moderate mild to moderate AD AD
symptoms include: symptoms include:
Donepezil Donepezil ( (Aricept Aricept) )
Galantamine Galantamine ((Reminyl Reminyl) )
Rivastigmine Rivastigmine (Exelon) (Exelon)
Treatment Treatment
An An additional drug, additional drug, Memantine Memantine ( (Namenda Namenda)), , has has
been approved to treat symptoms of been approved to treat symptoms of moderate to moderate to
severe severe AD. These drugs can help improve some AD. These drugs can help improve some
patients abilities to carry out activities up to a patients abilities to carry out activities up to a
year or so, but they do not stop or reverse AD. year or so, but they do not stop or reverse AD.
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The 3 targets of The 3 targets of Anticholinesterase Anticholinesterase
Inhibitors and Inhibitors and Memantine Memantine
Cognitive Cognitive decline decline
Behavioral Behavioral abnormalities abnormalities
Activities of Daily Activities of Daily Living Living Activities of Daily Activities of Daily Living Living
Acetylcholinesterase Acetylcholinesterase Inhibitors in the Inhibitors in the
Therapy of AD Therapy of AD
Currently recommended only for patients with Currently recommended only for patients with
mild to moderate dementia, although some mild to moderate dementia, although some
studies suggest benefits in later stages of AD. studies suggest benefits in later stages of AD.
Simple enhancement of synaptic Simple enhancement of synaptic ACh ACh levels can levels can
only partially compensate for the loss of neurons only partially compensate for the loss of neurons
and receptors that occurs during the course of and receptors that occurs during the course of
AD. AD.
Acetylcholinesterase Acetylcholinesterase Inhibitors in the Inhibitors in the
Therapy of AD Therapy of AD
These agents only provide symptomatic control These agents only provide symptomatic control
and slowing the rate of cognitive decline; they do and slowing the rate of cognitive decline; they do
not cure AD. not cure AD.
Keep in mind that cholinergic pathways are only Keep in mind that cholinergic pathways are only
one of many neuronal pathways destroyed in AD. one of many neuronal pathways destroyed in AD.
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Donepezil Donepezil ( (Aricept Aricept) )
Mechanism of Action: It is a competitive, Mechanism of Action: It is a competitive,
reversible reversible AChE AChE inhibitor. inhibitor.
High degree of selectivity for High degree of selectivity for AChE AChE in the CNS in the CNS High degree of selectivity for High degree of selectivity for AChE AChE in the CNS in the CNS
and little affinity for peripheral and little affinity for peripheral AChE AChE (a property (a property
common to all common to all AChE AChE inhibitors used to treat AD). inhibitors used to treat AD).
Long T Long T
1/2 1/2
: 70 hrs. : 70 hrs.
Donepezil Donepezil ( (Aricept Aricept) )
Peak plasma concentration 3 to 4 hours Peak plasma concentration 3 to 4 hours
Metabolized in the liver by CYP2D6 and CYP3A4 Metabolized in the liver by CYP2D6 and CYP3A4
Donepezil Donepezil and metabolites are excreted mainly in and metabolites are excreted mainly in
the urine, partially in the feces. the urine, partially in the feces.
Donepezil Donepezil ( (Aricept Aricept) )
Donezepils Donezepils adverse effects are common to all adverse effects are common to all
AChE AChE inhibitors used in AD (these effects are inhibitors used in AD (these effects are
predictable from an increased cholinergic predictable from an increased cholinergic
activity): activity): v y) v y)
Nausea, vomiting, diarrhea, abdominal pain, anorexia, Nausea, vomiting, diarrhea, abdominal pain, anorexia,
weight loss weight loss
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Donepezil Donepezil ( (Aricept Aricept) )
Rivastigmine Rivastigmine (Exelon) (Exelon)
A non A non- -competitive, competitive, AChE AChE inhibitor. inhibitor.
TT
1/2 1/2
: 1.5 hrs : 1.5 hrs
Peak plasma concentration in 1 hr. Peak plasma concentration in 1 hr.
b li b li i i i i i i i h d l d b i h d l d b Metabolism: Metabolism: Rivastigmine Rivastigmine is hydrolyzed by is hydrolyzed by
esterases esterases to a metabolite which is excreted in the to a metabolite which is excreted in the
urine. urine.
Rivastigmine Rivastigmine (Exelon) (Exelon)
Rivastigmine Rivastigmine produces the greatest incidence of produces the greatest incidence of
nausea, vomiting, diarrhea, GI effects amongst nausea, vomiting, diarrhea, GI effects amongst
the the AChE AChE inhibitors used in AD. inhibitors used in AD.
To minimize nausea, vomiting and other effects: To minimize nausea, vomiting and other effects:
3/6/2013
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e

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r
o
m

b
a
s
e
l
i
n
e
,

o
g

p
o
i
n
t
s
Improvement -2
-1.5
-1
-0.5
0
Exelon tablets versus placebo: Exelon tablets versus placebo:
improve improve cognition cognition

2
4
-
w
e
e
k

c
h
a
n
g
e
A
D
A
S
-
c
o
Worsening
Exelon
12 mg/day
capsules
n =253
Placebo
n =281
0
0.5
1
1.5
*p <0.05 versus placebo
IDEAL study
ITT-LOCF population
Winbladet al Int J Geriatr Psychiatry 2007
Exelon patch: a new approach to Exelon patch: a new approach to
dementia therapy dementia therapy
Potential benefits of a skin patch Potential benefits of a skin patch
Bypasses the gastrointestinal tract & not Bypasses the gastrointestinal tract & not
influenced by food influenced by food intake. intake.
Smooth, continuous drug delivery (for Smooth, continuous drug delivery (for , g y (f , g y (f
continuous efficacy continuous efficacy). ).
Potentially reduced side Potentially reduced side effects. effects.
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Galantamine Galantamine ( (Razadyne Razadyne) )
Mechanism of Action: reversible, competitive Mechanism of Action: reversible, competitive
AChE AChE inhibitor. inhibitor.
Unique feature is that it also Unique feature is that it also allosterically allosterically
enhances the binding of Ach to nicotinic receptors. enhances the binding of Ach to nicotinic receptors.
Thi lt i i d l f A h f Thi lt i i d l f A h f This results in increased release of Ach from This results in increased release of Ach from
presynaptic terminals. presynaptic terminals.
Galantamine Galantamine ( (Razadyne Razadyne) )
Peak plasma concentration in 1 hr. Peak plasma concentration in 1 hr.
TT
1/2 1/2
: 7 hrs : 7 hrs
Adverse effects: Adverse effects:
Galantamine Galantamine ( (Razadyne Razadyne) )
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Tacrine Tacrine ( (Cognex Cognex) )
The first of the The first of the AChE AChE inhibitors approved for the inhibitors approved for the
treatment of AD. treatment of AD.
Competitive and reversibly inhibits both Competitive and reversibly inhibits both AChE AChE
and and BChE BChE. .
Severe Severe hepatotoxicity hepatotoxicity has made this agent the has made this agent the
drug of last resort when considering therapy for drug of last resort when considering therapy for
AD. Liver function monitoring is required. AD. Liver function monitoring is required.
Some better ones..? Some better ones..?
Donezepil Donezepil: not : not hepatotoxic hepatotoxic..
Rivastigmine Rivastigmine: longer lasting; CNS selective; : longer lasting; CNS selective;
fewer peripheral side fewer peripheral side effects. effects.
Galanthamine Galanthamine: plant : plant alkaloid; alkaloid; two two effects: effects:
Cholinesterase inhibitor Cholinesterase inhibitor
Activation of brain nicotinic Ach receptors Activation of brain nicotinic Ach receptors
Memantine Memantine ( (Nemenda Nemenda) )
FDA approved in Oct 2003 for the treatment of FDA approved in Oct 2003 for the treatment of
moderate to severe moderate to severe AD. AD.
Memantine Memantine blocks the pathological effects of blocks the pathological effects of
elevated glutamate levels. elevated glutamate levels.
In animals, In animals, Memantine Memantine is observed to protect is observed to protect
neurons against glutamate neurons against glutamate- -induced induced excitotoxicity excitotoxicity
while preserving fundamental synaptic plasticity while preserving fundamental synaptic plasticity
mechanisms that underlie learning and memory. mechanisms that underlie learning and memory.
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Memantine Memantine ( (Nemenda Nemenda) )
Mechanism of Action: Mechanism of Action:
Similar to other NMDA blockers, Similar to other NMDA blockers, Memantine Memantine at at
high concentrations can inhibit mechanisms of high concentrations can inhibit mechanisms of
synaptic plasticity thus disrupting learning and synaptic plasticity thus disrupting learning and
memory processes. memory processes.
Memantine Memantine ( (Nemenda Nemenda) )
Memantine Memantine enters the NMDA receptor once the enters the NMDA receptor once the
channel has been opened by glutamate and channel has been opened by glutamate and
glycine glycine. .
When glutamate and When glutamate and glycine glycine dissociate from the dissociate from the
t d th h l b i t l t d th h l b i t l receptor and the channel begins to close some receptor and the channel begins to close some
memantine memantine becomes trapped in the vestibule of becomes trapped in the vestibule of
the channel. the channel.
Memantine Memantine dissociates from only a portion of the dissociates from only a portion of the
channels, while the rest of the channels remain channels, while the rest of the channels remain
persistently blocked. persistently blocked.
glutamate glutamate
Memantine Memantine: : blocking blocking excitotoxicity excitotoxicity
Memantine Memantine
(Namenda) (Namenda)
NMDA NMDA
receptors receptors
Ca Ca
2+ 2+
/Na /Na
++
Budd and Budd and Rao Rao, 2000 , 2000
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Memantine Memantine ( (Nemenda Nemenda) )
By persistently blocking a significant portion of By persistently blocking a significant portion of
NMDA receptors, low doses of NMDA receptors, low doses of Memantine Memantine can can
prevent prevent excitotoxic excitotoxic destruction of neurons when destruction of neurons when
synaptic release of glutamate are in excess synaptic release of glutamate are in excess
(seizure trauma hypoxia in the presence of A) (seizure trauma hypoxia in the presence of A) (seizure, trauma, hypoxia, in the presence of A). (seizure, trauma, hypoxia, in the presence of A).
In vitro, In vitro, memantine memantine is also able to protect against is also able to protect against
the heightened the heightened excitotoxic excitotoxic sensitivity to glutamate sensitivity to glutamate
that is displayed by neurons in the presence of A. that is displayed by neurons in the presence of A.
Memantine Memantine ( (Nemenda Nemenda) )
Since some of the NMDA receptors remain Since some of the NMDA receptors remain
unblocked by unblocked by Memantine Memantine, ongoing NMDA , ongoing NMDA
receptor receptor- -mediated synaptic transmission mediated synaptic transmission
continues to a degree that is sufficient to avoid continues to a degree that is sufficient to avoid
disrupting the function of circuits that require the disrupting the function of circuits that require the disrupting the function of circuits that require the disrupting the function of circuits that require the
integrity of NMDA receptors. integrity of NMDA receptors.
In animal In animal hippocampal hippocampal slices, slices, Memantine Memantine confers confers
neuroprotection neuroprotection at concentrations 5 fold lower at concentrations 5 fold lower
than those that significantly block LTP. than those that significantly block LTP.
Memantine Memantine ( (Nemenda Nemenda) )
Dosing: Initial dose Dosing: Initial dose 55mg daily, increased weekly mg daily, increased weekly
by by 5 5mg increments to a max of mg increments to a max of 10 10mg. mg.
TT1 1/ /2 2: : 60 60- -80 80 hrs, elimination: Kidney. hrs, elimination: Kidney.
Adverse effects: Adverse effects:
Combination of Combination of memantine memantine and and donezepil donezepil is well is well
l d d ff h h l l d d ff h h l tolerated and is more effective than either alone. tolerated and is more effective than either alone.
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Aricept Aricept + + Namenda Namenda
Tariot Tariot et al., JAMA 2004; mod et al., JAMA 2004; mod- -severe AD severe AD
Already on Already on donepezil donepezil; ; memantine memantine 5/20 mg/ 5/20 mg/dd 24 wks 24 wks
0-100
Ampakines Ampakines
Ampakines Ampakines are agents that indirectly are agents that indirectly
((allosterically allosterically) enhance the actions of AMPA ) enhance the actions of AMPA
glutamate receptors by decreasing its dissociation glutamate receptors by decreasing its dissociation
from the receptor. from the receptor.
O i f th AMPA t O i f th AMPA t i t d N i t d N Opening of the AMPA receptor Opening of the AMPA receptor--associated Na associated Na
channel is thus prolonged, leading to enhance channel is thus prolonged, leading to enhance
neuronal depolarization. This action promotes neuronal depolarization. This action promotes
LTP induction and also effectively boots LTP induction and also effectively boots
neurotransmission in complex neuronal neurotransmission in complex neuronal
networks. networks.
Phosphodiesterase Phosphodiesterase IV Inhibitors IV Inhibitors
The transcription factor CREB is critical in The transcription factor CREB is critical in
turning on the genes that restructure the synapses turning on the genes that restructure the synapses
to form long to form long- -term memories. term memories.
However CREB must first be However CREB must first be phosphorylated phosphorylated in in However, CREB must first be However, CREB must first be phosphorylated phosphorylated in in
order for it to modulate the expression of those order for it to modulate the expression of those
genes. genes.
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Phosphodiesterase Phosphodiesterase IV Inhibitors IV Inhibitors
PKA is one kinase that can PKA is one kinase that can
phosphorylate phosphorylate and activate and activate
CREB but first PKA requires CREB but first PKA requires
activation by activation by cAMP cAMP. .
Ph h di t Ph h di t IV i IV i Phosphodiesterase Phosphodiesterase IV is an IV is an
enzyme found in high enzyme found in high
abundance in the hippocampus, abundance in the hippocampus,
it normally degrades it normally degrades cAMP cAMP, ,
rendering it unable to activate rendering it unable to activate
PKA. PKA.
Phosphodiesterase Phosphodiesterase IV Inhibitors IV Inhibitors
Selective inhibition of Selective inhibition of phosphodiestrase phosphodiestrase IV will IV will
increase cellular increase cellular cAMP cAMP levels by inhibiting its levels by inhibiting its
degradation. degradation.
Increased levels of Increased levels of cAMP cAMP will lead to increased will lead to increased Increased levels of Increased levels of cAMP cAMP will lead to increased will lead to increased
activation of PKA, increased phosphorylation of activation of PKA, increased phosphorylation of
CREB, and ultimately increased gene expression. CREB, and ultimately increased gene expression.
MEM 1414 is a selective MEM 1414 is a selective phosphodiesterase phosphodiesterase IV IV
inhibitor currently in Phase II clinical trials. inhibitor currently in Phase II clinical trials.
Immunization Immunization
One promising approach to the prevention and One promising approach to the prevention and
treatment of AD is based on stimulating the treatment of AD is based on stimulating the
immune system to remove the A from the brain. immune system to remove the A from the brain.
Mice immunized with human A or directly Mice immunized with human A or directly Mice immunized with human A or directly Mice immunized with human A or directly
administered A antibodies, showed remarkable administered A antibodies, showed remarkable
clearance of A plaques from their brains, and clearance of A plaques from their brains, and
improvements of memory deficits. improvements of memory deficits.
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Immunization Immunization with A with A
42 42
Schenk D, Barbour R, Dunn W, et al. (1999) Immunization with amyloid Schenk D, Barbour R, Dunn W, et al. (1999) Immunization with amyloid-- attenuates attenuates
Alzheimer Alzheimer- -disease disease--like pathology in the PDAPP mouse. Nature, 400: 173 like pathology in the PDAPP mouse. Nature, 400: 173- -177. 177.
Vaccinated Vaccinated Unvaccinated Unvaccinated
Immunization Immunization
300 patients were immunized with a synthetic 300 patients were immunized with a synthetic
form of A known as AN form of A known as AN--1792. 1792.
There was evidence of an increased cognition and There was evidence of an increased cognition and
activities of daily living in some patients that were activities of daily living in some patients that were
immunized immunized immunized. immunized.
However, there was no difference in the rate of However, there was no difference in the rate of
cognitive decline in responders cognitive decline in responders vs vs those who did those who did
not receive the vaccine. not receive the vaccine.
Immunotherapy Immunotherapy
Autopsy findings from 2 patients from the Autopsy findings from 2 patients from the
AN AN--1792 1792 study: study:
Kokjohn Kokjohn et al 2006 found that active et al 2006 found that active
immunotherapy disrupted immunotherapy disrupted amyloid amyloid plaques but plaques but
lead to an increase in lead to an increase in soluble soluble amyloid amyloid that was that was lead to an increase in lead to an increase in soluble soluble amyloid amyloid that was that was
not adequately not adequately cleared. cleared.
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Human Vaccination with A Human Vaccination with A
42 42
Major problems! Major problems!
Nicoll Nicoll et al. Neuropathology of human Alzheimers disease after immunization with et al. Neuropathology of human Alzheimers disease after immunization with
amyloid amyloid-- peptide: a case report. peptide: a case report. Nature Medicine 9(4):448 Nature Medicine 9(4):448- -452, 2003 452, 2003
Meningoencephalitis Meningoencephalitis developed in 18 of 298 (6%) of developed in 18 of 298 (6%) of
patients treated with A patients treated with A
42 42
Immunization Immunization
The development of The development of meningoencephalitis meningoencephalitis in in 18 18
patients who were administered the AN patients who were administered the AN- -1972 1972 lead lead
to the discontinuation of the trials. to the discontinuation of the trials.
Autopsy of the brain of one of the Autopsy of the brain of one of the 18 18 patients who patients who Autopsy of the brain of one of the Autopsy of the brain of one of the 18 18 patients who patients who
developed developed meningoencephalitis meningoencephalitis after after 5 5
immunizations uncovered astonishing evidence of immunizations uncovered astonishing evidence of
an effective immune response against A. an effective immune response against A.
Statins Statins
Statins appear to show efficacy against AD in part Statins appear to show efficacy against AD in part
by influencing APP cleavage. by influencing APP cleavage.
Molecules known as Molecules known as isoprenoids isoprenoids normally activate normally activate
a small G a small G--protein know as protein know as rho rho. .
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Statins Statins
Activated Activated rho rho, in turn, activated kinase known as , in turn, activated kinase known as
ROCK 1 which ROCK 1 which phosphorylates phosphorylates an accessory an accessory
molecule. molecule.
The The phosphorylated phosphorylated form of the accessory form of the accessory
molecule interferes with the action of the molecule interferes with the action of the -- molecule interferes with the action of the molecule interferes with the action of the
secretase secretase. As a result, bad cleavage of APP by . As a result, bad cleavage of APP by --
and and --secretase secretase occurs more frequently, leading to occurs more frequently, leading to
increased production of increased production of A. A.
Statins Statins
Statin Statin--mediated inhibition of the enzyme HMG mediated inhibition of the enzyme HMG--
CoA CoA reductase reductase, inhibits not only the synthesis of , inhibits not only the synthesis of
cholesterol but also decreases the synthesis of cholesterol but also decreases the synthesis of
other intermediates that precede cholesterol in the other intermediates that precede cholesterol in the
synthetic pathway. These intermediates include synthetic pathway. These intermediates include y p y y p y
the the isoprenoids isoprenoids which are needed to activate which are needed to activate rho rho. .
Statins Statins
Statin Statin--mediated decreases in mediated decreases in isoprenoid isoprenoid synthesis synthesis
leads to decreased leads to decreased rho rho activation, which restores activation, which restores
cleavage of APP by the cleavage of APP by the --secretase secretase. .
ROCK1
Accessory proteins
-secretase
+
-
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Statins Statins
Statin Statin--mediated decreases in mediated decreases in isoprenoid isoprenoid synthesis synthesis
leads to decreased leads to decreased rho rho activation, which restores activation, which restores
cleavage of APP by the cleavage of APP by the --secretase secretase. .
ROCK1
Accessory proteins
-secretase
+
-
Researchers also are looking at other Researchers also are looking at other
treatments, including: treatments, including:
cholesterol cholesterol- -lowering drugs lowering drugs
called called statins statins. .
anti anti--oxidants (vitamins) and oxidants (vitamins) and
folic folic acid acid folic folic acid. acid.
substances substances that prevent that prevent
formation of beta formation of beta- -amyloid amyloid
plaques. plaques.
nerve growth factor to keep nerve growth factor to keep
neurons neurons healthy. healthy.
Parkinsons disease Parkinsons disease Parkinson s disease Parkinson s disease
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Overview Overview
Second most common human Second most common human
neurodegenerative disorder. neurodegenerative disorder.
Prevalence of 1 out 272 in U.S. Prevalence of 1 out 272 in U.S.
Increases to 4 to 5% for ages 85 and over Increases to 4 to 5% for ages 85 and over. .
Degeneration. Degeneration.
Cont. Cont.
Symptoms caused by insufficient dopamine. Symptoms caused by insufficient dopamine.
3 main symptoms: 3 main symptoms:
Tremors Tremors
Rigidity Rigidity Rigidity Rigidity
Slowed Slowed motion* motion*
Other symptoms include: Other symptoms include:
Dementia, sleep disturbances, depression, etc. Dementia, sleep disturbances, depression, etc.
Cont. Cont.
Common cause of chronic progressive Common cause of chronic progressive
parkinsonism. parkinsonism.
Exact causes still yet unknown. Exact causes still yet unknown.
Gene mutation Gene mutation
Toxins Toxins
Trauma Trauma
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Parkinsons Disease Parkinsons Disease
Mainly affects > 60 years Mainly affects > 60 years
Tremors Tremors
Rigidity Rigidity
Bradykinesia Bradykinesia
H ki i H ki i Hypokinesis Hypokinesis
Postural disturbances Postural disturbances
Cognitive dysfunction Cognitive dysfunction
Dementia Dementia
Severe impairment of memory, abstract thinking Severe impairment of memory, abstract thinking
and language and language
Parkinsons Disease Parkinsons Disease
Etiology Etiology
In sporadic Parkinson's disease In sporadic Parkinson's disease
Several Several genes are identified in hereditary genes are identified in hereditary g f y g f y
cases cases! !
Diagnosis Diagnosis
No definitive tests for PD. PET scans can aid No definitive tests for PD. PET scans can aid
to determine levels of dopamine. to determine levels of dopamine.
Difficult to diagnose, many symptoms shared Difficult to diagnose, many symptoms shared
with other disorders. with other disorders.
Medical history and neurological tests are Medical history and neurological tests are
conducted to diagnose conducted to diagnose..
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Parkinsons Parkinsons pathology pathology Parkinson s Parkinson s pathology pathology
Parkinsons pathology: Parkinsons pathology:
Lewy Lewy bodies bodies
Intraneuronal Intraneuronal inclusions comprised of inclusions comprised of alpha alpha
synuclein synuclein and other and other proteins. proteins.
Initially thought to be confined to Initially thought to be confined to substantia substantia nigra nigra
and other projection systems that deteriorate in and other projection systems that deteriorate in PD. PD.
Subsequently identified throughout the nervous Subsequently identified throughout the nervous
system, from brainstem to system, from brainstem to cortex. cortex.
Incidental Incidental Lewy Lewy bodies bodies seen in as many as seen in as many as 77- -10 10% of % of
asymptomatic individuals over age asymptomatic individuals over age 60 60. .
Parkinsons pathology: Parkinsons pathology:
Lewy Lewy bodies bodies
Lewy Lewy body body
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Parkinsons Parkinsons pathogenesis: a pathogenesis: a progressive progressive
synuclein synuclein- -opathy opathy: :
Lewy Lewy bodies spread caudal bodies spread caudal-- -->>rostral rostral
Stage 1 Stage 1--2: 2: Lewy Lewy bodies in medulla and bodies in medulla and
olfactory bulb (asymptomatic olfactory bulb (asymptomatic). ).
Stage 3 Stage 3--4: 4: Lewy Lewy bodies in bodies in substantia substantia nigra nigra Stage 3 Stage 3--4: 4: Lewy Lewy bodies in bodies in substantia substantia nigra nigra, ,
locus locus coeruleus coeruleus, cholinergic basal forebrain , cholinergic basal forebrain
((parkinsons parkinsons symptoms appear when >80% symptoms appear when >80%
of of nigral nigral neurons gone neurons gone). ).
Stage 5 Stage 5--6: 6: Lewy Lewy bodies in forebrain bodies in forebrain
(dementia (dementia). ).
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Parkinson Disease Parkinson Disease
Pathology Pathology
Protein Protein inclusion bodies: inclusion bodies:
Lewy Lewy bodies & bodies & Lewy Lewy neurits neurits
Lewy Lewy bodies: alpha bodies: alpha synuclein synuclein
11- -Methyl Methyl- -44--phenyl phenyl- -44--propionoxypiperidine propionoxypiperidine
((MPPP) MPPP)
Barry Barry Kidson Kidson: student and recreational drug user : student and recreational drug user
(1976) (1976)
Made MPPP (similar to opioid analgesic; Made MPPP (similar to opioid analgesic;
idi idi D l) D l) meperidine meperidine or Demerol) or Demerol)
Injected: Injected:
Diagnosed Diagnosed as catatonic schizophrenic as catatonic schizophrenic
Antipsychotic drugs Antipsychotic drugs
Contaminant Contaminant MPTP MPTP
11- -methyl methyl- -44--phenyl phenyl- -1,2,3,6 1,2,3,6- -tetrahydropyridine tetrahydropyridine
Neurotoxin Neurotoxin destroys DA neurons in destroys DA neurons in
b i b i ii d l d l i l i l DA DA
11- -Methyl Methyl- -44--phenyl phenyl- -44--propionoxypiperidine propionoxypiperidine
((MPPP) MPPP)
substantia substantia nigra nigra: depletes : depletes striatal striatal DA DA
66- -hydroxydopamine ( hydroxydopamine (66- -OHDA) OHDA)
Behavioural syndrome similar to PD Behavioural syndrome similar to PD
Responds to treatment with L Responds to treatment with L- -DOPA DOPA
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Parkinsons Parkinsons pathogenesis pathogenesis
other models: other models:
MPTP model MPTP model
Gives rise to selective neuronal death and Gives rise to selective neuronal death and
parkinsonism, but no parkinsonism, but no Lewy Lewy bodies bodies
Parkinsons treatments: Parkinsons treatments:
Dopaminergic Dopaminergic therapy has dramatic therapy has dramatic
symptomatic symptomatic effect. effect.
Surgical therapies Surgical therapies- ---
Gene therapy Gene therapy is is under under investigation. investigation.
No proven No proven neuroprotective neuroprotective therapy to therapy to date. date.
Substantia Substantia Nigra Nigra: : Dopamine (DA) Dopamine (DA) main transmitter main transmitter
Immunohistochemical Immunohistochemical stain for tyrosine stain for tyrosine hydroxylase hydroxylase
show loss of DA cells in Parkinsons Disease (PD): > show loss of DA cells in Parkinsons Disease (PD): >
80% 80%
Also, in PD, severe decline of DA content in Also, in PD, severe decline of DA content in the the
Striatum Striatum (caudate nucleus and (caudate nucleus and putamen putamen) ) Striatum Striatum (caudate nucleus and (caudate nucleus and putamen putamen) )
termination of termination of s.nigral s.nigral axons. axons.
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Substantia Nigra: Dopamine (DA) main transmitter
Progressive damage to ascending DA system Progressive damage to ascending DA system
Parkinsons Parkinsons
Symptoms appear once Symptoms appear once striatal striatal DA levels DA levels 70 70- -
80% of 80% of normal. normal.
Correlation Correlation between degree of damage to DA between degree of damage to DA
d d i f h i f h system and system and severity of the symptoms. severity of the symptoms.
Pharmacotherapies Pharmacotherapies aimed at increasing DA aimed at increasing DA
availability, or stimulating DA receptors, reduce availability, or stimulating DA receptors, reduce
symptoms. symptoms.
Destruction of Destruction of nigrostriatal nigrostriatal DA pathway produces DA pathway produces
motor deficits as in motor deficits as in PD. PD.
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Other neurotransmitter systems Other neurotransmitter systems
Hypokinesia Hypokinesia most clearly related to DA most clearly related to DA loss. loss.
Rigidity/tremor relate to complex disturbances Rigidity/tremor relate to complex disturbances
of of ACh ACh, NE, 5 , NE, 5- -HT, HT, GABA. GABA.
Cholinergic neurones in Striatum contain highest Cholinergic neurones in Striatum contain highest Cholinergic neurones in Striatum contain highest Cholinergic neurones in Striatum contain highest
concentration of concentration of Ach in brain. Ach in brain.
Dopamine/ Dopamine/ACh ACh imbalance imbalance PD symptoms PD symptoms
Extrapyramidal System: Extrapyramidal System: Nigrostriatal Pathway Nigrostriatal Pathway
Striatum
Thalamus
Motor Cortex
Putamen
Caudate
Nucleus Motor Cortex
Many Cortical Areas
+
Substantia
nigra
Globus
Pallidus
Thalamus
Striatum
-
-
Extrapyramidal Extrapyramidal Symptoms (EPS) Symptoms (EPS)
Dopamine Dopamine Vs Vs Acetylcholine Acetylcholine
Dopamine and Acetylcholine have a reciprocal Dopamine and Acetylcholine have a reciprocal
relationship in the relationship in the Nigrostriatal Nigrostriatal pathway. pathway.
A delicate balance allows for normal movement. A delicate balance allows for normal movement.
Dopamine Dopamine blockade: a blockade: a relative increase in cholinergic relative increase in cholinergic
activity activity activity activity
causing EPS causing EPS
When high potency antipsychotics are chosen, it is When high potency antipsychotics are chosen, it is
often prescribe anti often prescribe anti- -ACh ACh medication like: medication like:
Cogentin Cogentin, , diphenhydramine diphenhydramine
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Striatal Circuitry Striatal Circuitry
+
ACh
GABA
-
DA-
SN
Striatum
How does a loss of How does a loss of striatal striatal DA produce profound DA produce profound
behavioural disturbances? behavioural disturbances?
Basal ganglia Basal ganglia subcortical subcortical system forms a loop system forms a loop
with the cerebral with the cerebral cortex. cortex.
Basal ganglia gate movement commands Basal ganglia gate movement commands
originating in motor originating in motor cortex. cortex. o iginating in moto o iginating in moto co tex. co tex.
DA projections to striatum DA projections to striatumnormal movement. normal movement.
Loss of DA activity impairs Loss of DA activity impairs the initiation the initiation and and
control voluntary control voluntary movements. movements.
Dopamine Blockers for Dopamine Blockers for Schizophrenia Schizophrenia
Antipsychotic Antipsychotic agents agents (to (to treat schizophrenia) treat schizophrenia)
produce produce EPS. EPS.
Result Result from blockade of dopamine from blockade of dopamine--2 2
receptors ( receptors (hypodopaminergic hypodopaminergic state). state).
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Pharmacotherapy Pharmacotherapy Pharmacotherapy Pharmacotherapy
Drug therapy Drug therapy
Does not slow or prevent disease progression Does not slow or prevent disease progression
Improves quality of Improves quality of life. life.
55--10% respond poorly to all 10% respond poorly to all medications. medications.
Trying to stimulate the Trying to stimulate the dopaminergic dopaminergic system system Trying to stimulate the Trying to stimulate the dopaminergic dopaminergic system system
and control the resulting excitation in and control the resulting excitation in
cholinergic cholinergic pathways. pathways.
Treatment Treatment Parkinsons Disease Parkinsons Disease
No cure for PD. No cure for PD.
Treatment can be divided into two stages. Treatment can be divided into two stages.
Early and Later stages Early and Later stages
Early stage Early stage
Onset of symptoms treated with physical therapy and Onset of symptoms treated with physical therapy and Onset of symptoms, treated with physical therapy and Onset of symptoms, treated with physical therapy and
medications ( medications (Levodopa Levodopa, dopamine agonists, etc) , dopamine agonists, etc)
Later stage Later stage
Usually after having received 5+ years of Usually after having received 5+ years of levodopa levodopa
treatment. treatment.
Wearing Wearing- -off and On/Off effect develops, other off and On/Off effect develops, other
medication in conjunction medication in conjunction levodopa levodopa is commenced. is commenced.
MAO MAO--B and COMT inhibitors. B and COMT inhibitors.
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How to treat deficit of dopamine? How to treat deficit of dopamine?
Levodopa (L Levodopa (L- -DOPA) DOPA) the first the first--line line drug drug
Levodopa Levodopa Dopamine Dopamine
Dopa Dopa
decarboxylase decarboxylase
About 80% of parkinsonian patients show initial About 80% of parkinsonian patients show initial
improvement with levodopa, particularly of improvement with levodopa, particularly of
rigidity and hypokinesia, and about 20% are rigidity and hypokinesia, and about 20% are
restored virtually to normal motor function. Some restored virtually to normal motor function. Some
symptoms (cognitive decline dysphagia) are not symptoms (cognitive decline dysphagia) are not
Levodopa Levodopa (L (L- -DOPA) DOPA)
symptoms (cognitive decline, dysphagia) are not symptoms (cognitive decline, dysphagia) are not
improved improved..
W i t W i t h h t i m e t i m e the the effectiveness of levodopa effectiveness of levodopa
gradually gradually declines, it declines, it reflects reflects: :
the natural progress of the natural progress of
disease disease
++
receptor down receptor down--regulation regulation
Levodopa Levodopa (L (L- -DOPA DOPA))
Oral: rapidly absorbed; 95% converted to Oral: rapidly absorbed; 95% converted to
dopamine in dopamine in plasma. plasma.
Crosses the BBB Crosses the BBB barrier to CNS (DA cannot barrier to CNS (DA cannot
cross barrier cross barrier). ).
LL- -DOPA DOPA converted to DA mainly within converted to DA mainly within
presynaptic terminals of DA neurones in presynaptic terminals of DA neurones in
basal basal ganglia. ganglia.
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LL- -DOPA destroyed by GI and Liver DOPA destroyed by GI and Liver
enzyme enzyme
..and converted to DA in peripheral ..and converted to DA in peripheral
circulation circulation eg eg nausea nausea
Levodopa Levodopa (L (L- -DOPA DOPA))
Need to reduce high levels of systemic DA Need to reduce high levels of systemic DA
while maintaining sufficient levels in while maintaining sufficient levels in brain. brain.
Dopa Dopa decarboxylase decarboxylase converts DOPA to DA converts DOPA to DA
Selectively inhibit enzyme in systemic Selectively inhibit enzyme in systemic
circulation but circulation but not in not in brain brain- -Carbidopa Carbidopa. .
Side effects include Side effects include
Psychiatric symptoms; linked to depression Psychiatric symptoms; linked to depression
Nausea and vomiting Nausea and vomiting
Prolonged use can cause wearing Prolonged use can cause wearing- -off effect. off effect.
Levodopa Levodopa (L (L- -DOPA DOPA))
Leads to other motor complications, such as Leads to other motor complications, such as
dyskinesia dyskinesia..
Still the preferred treatment for symptoms. Still the preferred treatment for symptoms.
Sinemet Sinemet
Carbidopa Carbidopa ((Sinemet Sinemet))
Active in body, but does not cross BBB: Active in body, but does not cross BBB:
metabolic conversion occurs in CNS only metabolic conversion occurs in CNS only
Used in combination with L Used in combination with L- -DOPA DOPA
Reduced Reduced side effects side effects
No loss of CNS effects No loss of CNS effects
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Catechol Catechol O O--Methyl Methyl Transferase Transferase (COMT) (COMT)
Inhibitors Inhibitors
Inactivates Inactivates and degrades neurotransmitters, such as and degrades neurotransmitters, such as
dopamine. dopamine.
Mainly used in combination with L Mainly used in combination with L- -DOPA, it DOPA, it
increases the half increases the half--life of L life of L- -DOPA. DOPA. ff f f f f
Delays wearing Delays wearing- -off effect of L off effect of L- -DOPA and other DOPA and other
motor complications such as motor complications such as dyskinesia dyskinesia. .
COMT ( COMT (catechol catechol- -o o--methyltransferase methyltransferase) inhibitors ) inhibitors
COMT active in liver and GI COMT active in liver and GI tract. tract.
Half life of Half life of Sinemet Sinemet increased by increased by
adding COMT adding COMT inhibitor. inhibitor.
Tolcapone Tolcapone ( (Tasmar Tasmar) 1998 ) 1998
Blocks COMT enzyme, increased half Blocks COMT enzyme, increased half
life life of of LL DOPA DOPA life life of of LL--DOPA. DOPA.
Liver toxicity: Liver toxicity: withdrawn ( withdrawn (black black- -box box
warning). warning).
Entacapone Entacapone 2001 ( 2001 (Comtan Comtan))
Inhibits Inhibits peripheral COMT, no effect on peripheral COMT, no effect on
CNS COMT; inhibition of peripheral L CNS COMT; inhibition of peripheral L--
DOPA breakdown increases central L DOPA breakdown increases central L--
DOPA (hence DA DOPA (hence DA). ). Stalevo Stalevo. .
Stalevo Stalevo (2004) (2004)
Combination product Combination product
Levodopa Levodopa
Carbidopa Carbidopa: increases DA in brain : increases DA in brain
Entacapone Entacapone: inhibits degradation of : inhibits degradation of Entacapone Entacapone: inhibits degradation of : inhibits degradation of
LL- -DOPA through inhibition of its DOPA through inhibition of its
degradative degradative enzyme enzyme COMT. COMT.
Combination provides more brain DA, for Combination provides more brain DA, for
longer time periods: less wearing off longer time periods: less wearing off. .
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Limitations of L Limitations of L- -DOPA DOPA
Each dose becomes less Each dose becomes less effective. effective.
Increasing dose leads to movement disorders Increasing dose leads to movement disorders
((dyskinesias dyskinesias). ).
rigidity, rigidity, akinesia akinesia of of PD PD rigidity, rigidity, akinesia akinesia of of PD PD
May accelerate the May accelerate the cause cause of PD of PD
ie ie ameliorating the ameliorating the symptoms symptoms may aggravate the disease may aggravate the disease
Dopamine receptor agonists Dopamine receptor agonists
Loss of response to L Loss of response to L- -DOPA. DOPA.
Progressive inability for Progressive inability for neurons neurons to to
synthesise and store synthesise and store DA DA synthesise and store synthesise and store DA. DA.
Receptor agonists Receptor agonists postsynaptic DA postsynaptic DA
receptors. receptors.
Acts Acts directly on the dopamine receptors. directly on the dopamine receptors.
Initially was used with L Initially was used with L- -DOPA. DOPA.
Today, sometimes prescribed before L Today, sometimes prescribed before L- -
DOPA to delay wearing DOPA to delay wearing--off effect and off effect and
Dopamine receptor agonists Dopamine receptor agonists
DOPA, to delay wearing DOPA, to delay wearing--off effect and off effect and
other motor complications brought on by other motor complications brought on by
prolonged use of L prolonged use of L--DOPA. DOPA.
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DA Agonists DA Agonists
Bromocryptine Bromocryptine
Pergolide Pergolide
Pramipexole Pramipexole
Ropinirole Ropinirole Ropinirole Ropinirole
Drowsiness Drowsiness, dizziness, nausea, , dizziness, nausea,
hallucinations, insomnia hallucinations, insomnia
Adverse side effects Adverse side effects
Nausea, dizziness, hallucinations Nausea, dizziness, hallucinations
Sleep attacks, hypotension Sleep attacks, hypotension
Permax Permax ( (pergolide pergolide) pulled after direct link to ) pulled after direct link to
Dopamine receptor agonists Dopamine receptor agonists
fibrosis of cardiac valves that can lead to death. fibrosis of cardiac valves that can lead to death.
MAO MAO--B Inhibitors B Inhibitors
MAO MAO- -B is an enzyme that metabolizes B is an enzyme that metabolizes
dopamine. dopamine.
From the breakdown of dopamine, From the breakdown of dopamine,
hydrogen peroxide is produced which hydrogen peroxide is produced which hydrogen peroxide is produced, which hydrogen peroxide is produced, which
the oxidative stress can damage the oxidative stress can damage
dopaminergic dopaminergic neurons in the neurons in the
substantia substantia nigra nigra. .
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Monoamine Monoamine Oxidase Oxidase B (MAO B (MAO
BB
) )
Inhibitors Inhibitors
Delays Delays or reduces breakdown of dopamine or reduces breakdown of dopamine
by by MAO MAO
BB
..
Used as Used as monotherapy monotherapy or in conjunction or in conjunction py py jj
with with LL- -DOPA, it can reduce the dosage of DOPA, it can reduce the dosage of
LL- -DOPA by 15%. DOPA by 15%.
MAO MAO--B Inhibitors B Inhibitors
Side effects of L Side effects of L- -DOPA may be enhanced by DOPA may be enhanced by
selegeline. selegeline.
Nausea and dizziness. Nausea and dizziness.
Selegiline Selegiline
Monoamine Monoamine oxidase oxidase MAO: 2 MAO: 2 isoenzymes isoenzymes
MAO MAO--A: NE and serotonin A: NE and serotonin
MAO MAO--B: DA (striatum) B: DA (striatum)
S l ili S l ili f i ll i hibi MAO f i ll i hibi MAO B (i B (i Selegiline Selegiline preferentially inhibits MAO preferentially inhibits MAO--B (in B (in
doses < 10mg doses < 10mg day). day).
Therefore preserves small amounts of DA Therefore preserves small amounts of DA
present. present.
Slows down progression of Slows down progression of disease disease..
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Other Drugs Other Drugs
Amantadine Amantadine
Antiviral agent. Antiviral agent.
Known to aid in reducing Known to aid in reducing dyskinesia dyskinesia. .
Anticholinergics Anticholinergics
Improve tremors and stiffness Improve tremors and stiffness
Cause impairment and constipation Cause impairment and constipation
Anticholinergic Anticholinergic Drugs Drugs
Muscarinic Receptors Muscarinic Receptors localized to localized to striatal striatal
neurons. neurons.
May May cause presynaptic inhibition of dopamine cause presynaptic inhibition of dopamine
release. release.
T ih h id l T ih h id l ((A t A t ) d ) d B t i B t i Trihexyphenidyl Trihexyphenidyl ((Artane Artane) and ) and Benztropine Benztropine
((Cogentin Cogentin). ).
Therapeutic Effectiveness Therapeutic Effectiveness
Useful in patients administered Useful in patients administered neuroleptics neuroleptics as anti as anti- -
dopaminergic dopaminergic properties of these drugs antagonize effects of properties of these drugs antagonize effects of
levodopa levodopa..
Improve muscle rigidity and tremor but have little effect on Improve muscle rigidity and tremor but have little effect on
bradykinesia bradykinesia. .
Adverse Effects Adverse Effects
Surgical Procedures Surgical Procedures
Deep Brain Stimulation Deep Brain Stimulation
Creating a lesion in the Creating a lesion in the
subthalamic subthalamic nucleus or nucleus or
Surgery Surgery
subthalamic subthalamic nucleus or nucleus or
globus globus pallidus pallidus
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Surgery Surgery
Before commerciality of Before commerciality of levodopa levodopa, surgical , surgical
treatment were preferred. treatment were preferred.
Early Early surgeries were successful with tremors, surgeries were successful with tremors, yy g f , g f ,
but failed to relieve other symptoms. but failed to relieve other symptoms.
Means of last resort due to high risk of Means of last resort due to high risk of
potential complications potential complications..
Surgery Surgery
Deep Brain Stimulation Deep Brain Stimulation
Brain pacemaker, sends electrical impulses Brain pacemaker, sends electrical impulses
to brain to stimulate the to brain to stimulate the subthalamic subthalamic
nucleus. nucleus.
Improves motor functions and reduce Improves motor functions and reduce
motor complications. motor complications.
Complications include Complications include:. :.
New New Research Research
Nicotine Nicotine
Intake of nicotine has shown to slow the Intake of nicotine has shown to slow the
degeneration of neurons. degeneration of neurons.
Acts similar to levodopa. Acts similar to levodopa.
Melatonin Melatonin
Serotonin derivative that helps insomnia. Serotonin derivative that helps insomnia.
Also shown to cause a reduction in production of Also shown to cause a reduction in production of
neurodegenerative radicals. neurodegenerative radicals.
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Treatment Treatment Physical Therapy Physical Therapy
Regular exercise Regular exercise
Recommended throughout the life of disorder. Recommended throughout the life of disorder.
Helps maintain and improve mobility and Helps maintain and improve mobility and
strength. strength.
Ph i l i id i i idit li f l Ph i l i id i i idit li f l Physical exercise aids in rigidity relief, muscle Physical exercise aids in rigidity relief, muscle
strength and flexibility, balance, etc. strength and flexibility, balance, etc.
Caution is advised to avoid sudden Caution is advised to avoid sudden
movements. movements.
To Recap: To Recap: Pathophysiology Pathophysiology AD and PD AD and PD
Frontotemporal Frontotemporal dementia dementia- -clinical clinical
Presents as personality change and Presents as personality change and
disinhibition disinhibition, in the absence of significant , in the absence of significant
memory memory loss. loss.
Also may present as a primary disorder of Also may present as a primary disorder of
language. language.
Progresses to a more generalized dementia Progresses to a more generalized dementia
over over time. time.
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Frontotemporal Frontotemporal dementia (Picks Disease) dementia (Picks Disease)
Clinical syndrome with a variety of Clinical syndrome with a variety of
underlying underlying pathologies pathologies (Picks bodies (Picks bodies- -tau tau
protein) protein)
Many have Many have neurofibrillary neurofibrillary tangles tangles
Frontotemporal Frontotemporal dementia dementia- -genetics genetics
Most cases of FTD are sporadic Most cases of FTD are sporadic
A mutation in the A mutation in the tau tau protein is a cause of protein is a cause of
FTD. FTD.
FTD FTD- -Treatment Treatment
Nothing available Nothing available
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Amyotrophic lateral Amyotrophic lateral sclerosis (ALS) sclerosis (ALS)
Also known as Also known as motor neuron disease motor neuron disease or or
Lou Gehrigs disease Lou Gehrigs disease
Presents as slowly progressive weakness and Presents as slowly progressive weakness and
muscle wasting. muscle wasting.
Death within 2 Death within 2- -5 years in most patients due 5 years in most patients due
to respiratory to respiratory failure. failure.
ALS ALS- -pathology pathology
ALS ALS- -treatment treatment
Riluzole Riluzole, , prevents stimulation of glutamate prevents stimulation of glutamate
receptors, receptors, prolongs survival by a few prolongs survival by a few months. months.
No No other symptomatic or other symptomatic or neuroprotectant neuroprotectant
therapy. therapy.
No No directed therapy. directed therapy.
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Spinocerebellar Spinocerebellar ataxia ataxia
Slowly progressive gait disorder, slurred Slowly progressive gait disorder, slurred
speech, and speech, and clumsiness. clumsiness.
Age of onset widely variable Age of onset widely variable-- --from early from early
childhood to late childhood to late life. life.
Patients look like they are intoxicated with Patients look like they are intoxicated with
alcohol. alcohol.
Spinocerebellar Spinocerebellar ataxia ataxia- -pathology pathology
Neurodegeneration Neurodegeneration- -Summary Summary
signs region histology protein
AD dementia HC, ctx Plq, NFT AB, tau
PD motor S. nigra Lewy b. alphasyn
FTD dementia ctx NFT tau
ALS weakness Motor n. MN loss SOD-1
SCA ataxia Cb, SC Cerebelr
atrophy
many
HD Chorea,
dementia
Caudate,
ctx
inclusion Hunting-
tin