Lecture 2 (chapter 4) Flashcards
AD & PD
Alzheimer’s Diagnostic Criteria (match performance on memory test to genetics to diagnose)
(1) A/B
(2) A/B
The major caveat in diagnosing AD?
Mild Alzheimer’s:
• Probable Alzheimer’s disease:
o Patients with mild neurocognitive disorder
(e.g., learning and memory, attention), a
family history or genetic mutation must be
present
• Possible Alzheimer’s disease:
o Steady and progressive decline in
cognition, memory, and learning in the
absence of other neurodegenerative
conditions, no need for genetic evidence.
Major Alzheimer’s:
• Probable Alzheimer’s disease:
o have evidence of genetic mutation or a
steady and progressive decline in cognition,
memory and learning.
• Possible Alzheimer’s disease:
o do not have a family history or genetic
mutation but display an insidious onset of
symptoms and progressive cognitive
impairment.
*The pathophysiologic process of
Alzheimer’s disease that manifests in later
adulthood begins years or decades before
detectable cognitive changes (diagnosis
comes late in the neurodegenerative
process: people start forgetting significant
things)
Prevalence
• New case of AD develops every 33
seconds
• ~13.8 million people worldwide have the
disease
• ~46 million people live with some form of
dementia worldwide
• By 2050, this number is projected to
increase to more than 131 million
• The disease rises sharply with increasing
age
• 7% of diagnosed cases affect those
between 65 and 74 years of age
• 53% of diagnosed cases involved
individuals between the ages of 74 and 84
years of age
• Alzhiemers rates are higher in nursing
homes worldwide.
• One in four Americans who survive to age
65 will likely be diagnosed with dementia
in their lifetime!
- Common 1 in 4
- late-onset more common than early-onset
Sex Differences
• Two-thirds of Americans with Alzheimer’s
disease are women (worldwide)
• Meta-analytic studies from across United
States, Europe, and Asia also indicate that
women are at significantly greater risk of
developing Alzheimer’s disease
• Alzheimer’s affects cognitive functioning in
women more severely than men.
- women > men
- effects cognition more severely in women
Race and Ethnicity (varies significantly with ethnicity)
• African Americans (26.6/1,000 person-
years)
• American Indian/Alaska Natives
(22.2/1,000 person-years)
• Latinos (19.6/1000 person-years)
• Pacific Islanders (19.6/1,000 person-years)
• Whites (19.3/1,000 person-years)
• Asian Americans (15.2/1,000 person-years
• Risk was 65% greater from african
americans than asian americans in both
men and women (but magnitude greater in
men).
Comorbidity (AD)
Link between AD and PD
- Apathy: 88% of the patients
- Aggression: 66%
- Sleep disturbances: 54%
- Irritability and appetite changes in 60%
- Depression: 56%
- Delusions: 55%
- Anxiety symptoms: 52%
• Early-stages: Depression and apathy
• Mid-stages: Agitation, aggression,
combativeness, irritability, wandering,
and psychotic symptoms (getting lost)
• Late stages: Incontinence, seizures,
muscle rigidity and spasms, and
disturbances in gait (can’t eat or
swallow)
• Siblings of individuals with parkinsons
and dementia were 3x more likely to
develop alzheimers relative to controls.
• Its common for people with parkinsons
to develop dementia & for people with
alzheimers to develop extrapyramidal
symptoms characteristic of parkinsons.
*Using medication to treat specific symptoms
the molecular changes will have a
cascading effect on other behaviours
*As the disease progresses symptoms get
more severe; peoples behaviour change to
the point where they are not able to look
after themselves and you are asked
whether to put a tube in their stomach or let
her starve (increases lifespan of a person
who has no idea who they are or where
they are; how do we not understand the
disease enough to provide better care?)
Etiology (what causes it? Understand it so we can fix it)
- Complex and not well understood!
- Most important risk factor is age
*Linked with age and gender but why? If we
can delay disease progression down to
postpone the disease to improve life
outcomes.
Overview of Genetics
how many chromosomes? where are they located? DNA consists of a sequence of ... DNA provides the coded instructions ... what are mutations? what are alleles?
• Humans have 23 pairs of chromosomes
(one of each is inherited from each parent)
• Chromosomes are located inside the
nucleus of a cell
•DNA consists of a sequence of molecules
[(A), cytosine (C), guanine (G), and thymine
(T)]
• DNA provides the coded instructions for
synthesis of messenger RNA which leaves
the nucleus, attaches to ribosomes where
it is translated into proteins, carries out the
genetic code, and leads to the expression
of characteristics that are inherited
• Gene (in DNA) has a code which tells cell
how much RNA messenger to synthesis
and the proteins it produces.
• Mutations: Accidental alterations in
individual genes (deletion, substitution,
inverted, inserted, duplication etc.;
evolutionary theory shows that mutations
allow natural selection to occur and aids he
survival of the species; can be bad if
mutation makes proteins being over or
under produced)
• Mutated versions of DNA are referred to as
alleles
• Mutations can contribute to inherited risk
for a disease or disorder depending on
whether the mutations are passed on by
one or both parents
Degree of Heritability
what is it?
what doesn’t it tell us?
• The degree of heritability of a construct
(intelligence) or disease/disorder can be
estimated and are referred to as heritability
estimates
• Important note – heritability refers to a
population not an individual.
• Heritability refers to the proportion of
phenotypic variation between individuals in
a population due to genetic variation
between individuals in that population.
• Heritability estimates are a numerical value
which ranges from 0-1 (0-100%) and
represent the fraction of phenotype
variability which can be attributed to
genetic variation. They do not provide any
information about an individual or about
specific genes that contribute to a disorder.
• Heritability estimates via twin, adoption and
family studies; the role of genetic factor
underlying the pathophysiology of these
disorders has been explored through –
linkage, genome-wide association,
candidate genes and molecular studies.
*Genes do not explain what will happen but
the variability of what will happen. The
interaction between the gene and the
environment tell us whether the gene will
produce the trait or not. Therefore, genes
cannot explain the cause of disease onset
but can tell us the variability of what will
happen in the future.
(3) Genetic Study Types
• Genetic linkage studies search for
chromosomal locations (“marker loci”)
where disease genes may be found. Aim to
determine whether specific chromosomal
regions in individuals with disease have
specific DNA markers relative to those
without the disorder.
• Candidate gene studies then explore how
specific genes and mutation(s) may be
involved in the etiology of Alzheimer’s
disease
• Genome-wide association studies (GWAS)
use a specific statistical approach to scan
complete sets of DNA (genomes) of
thousands of people across all
chromosomes simultaneously to find
genetic variations associated with
Alzheimer’s disease
Genetic Findings: Family and Twin Studies
AD
• Family studies indicate that Alzheimer’s
disease aggregates in families
o Lifetime risk for Alzheimer’s disease is
25.9% in relatives of individuals with the
disease compared to 19.1% in control
relatives (6% increased risk if someone in
the family has Alzheimer’s; evidence that
something genetic is happening)
• Twin Studies
o Concordance rate of 67-78% among
monozygotic twins (identical)
o Concordance rate of 22-39% for dizygotic
twin (fraternal)
o Significant increase in risk 30% for identical
twins (doesn’t guarantee you’ll get it but
supports genes are causing mutations in
protein production)
Genetic Findings: Early Onset (more devastating but less common)
• Early onset Alzheimer’s disease occurs
before age 65 and represents
approximately 10% of all people with
Alzheimer’s
• Relatives of individuals with very late onset
alzheimers (85+) had a substantially lower
risk of developing alzheimers than relatives
of early onset alzheimers.
• Early onset Alzheimer’s disease has a
prominent genetic basis (more linked to
genes than late onset)
• Typically, more aggressive and associated
with a shorter survival rate
• Three genes are associated with early
onset cases:
1. Presenilin 1 (PSEN1) - range 35–55 years
2. Presenilin 2 (PSEN2) - range 40–65 years
3. Amyloid precursor protein (APP) - range
40–70 years
Presenilin 1 (PSEN1)
• PSEN1 provides instructions for making a
protein called presenilin 1 that cuts apart
other proteins into smaller pieces (cleaving)
o This process is important in several
chemical signaling pathways that transmit
signals from outside the cell into the
nucleus
o One protein that presenilin 1 helps to cut is
the amyloid precursor protein (APP)
• Mutations of the presenilin-1 gene, located
on chromosome 14, are estimated to be
responsible for 70% to 80% of all cases of
early onset cases
• APP is cleaved (cut) into soluble amyloid
precursor protein (sAPP) and several
versions of amyloid-beta (β) peptide
• Mutations lead to increased production of
amyloid beta peptide (main component of
amyloid-beta plaques characteristic of
Alzheimer’s; only see this when people are
dead so is not a good way to help patients)
*Diagnosis of AD only emerged in 2000’s
otherwise people had to wait till they died
*Overproduction
Presenilin 2 (PSEN2) –produces different protein mutations
• Located on chromosome 1
• Provides instructions for the protein
presenilin 2 that plays an important role
in cutting amyloid beta peptides
• Mutations are associated with faulty
calcium signaling, aggregation of
amyloid beta plaques, and neuronal
death
• If we know what genes are present,
what proteins are being overproduced
and cognitive symptoms are present
then we can diagnose people (only
since 2000’s when we have techniques
to measure people’s genetics)
*Structure of the cell
Amyloid precursor protein gene (APP)
• Located on chromosome 21
• Over 32 mutations of the APP gene have
been linked to early onset of Alzheimer’s.
• Provides instructions for making amyloid
precursor protein which plays an
important role in neural growth and
repair, helps direct the migration of
neurons during early brain development
and mutations are hypothesized to lead
to overproduction of the amyloid protein.
Taken together, damage to cell structure and over/underproduction of proteins from gene mutations inhibits communication between cells, cell death and overtime, cognitive/behavioural changes.
Collectively, mutations of these three genes are estimated to account for approximately 50% of early onset cases but only 0.5% of all Alzheimer’s cases – indicating that late onset Alzheimer’s are caused by other factors
Scientific Breakthroughs (AD)
• Individuals with Down syndrome inevitably
develop neuropathological changes
characteristic of Alzheimer’s disease (all
people with down-syndrome develop AD;
Accumulation of amyloid plaques and
neurofibrillary tangles in the brain)
• Given that Down syndrome is due to
trisomy 21, scientists focused on
chromosome 21 and specifically the
amyloid precursor protein gene (APP) to
study Alzheimer’s disease
Late-Onset (AD genetics)
Late-Onset
• Onset of the disease after 65 years of age
• More prevalent than early-onset
• Most cases are sporadic with no family
history of the disease
• Progresses more slowly
*Less linked to genetics and affected by lifestyle and environmental factors as well!
Genetic Findings: Late Onset
• Most common gene associated with the
disease is apolipoprotein E (APOE)
• Located on chromosome 19, provides
instructions for making a protein called
apolipoprotein E (APOE)
• APOE is important in synaptogenesis and
neuronal plasticity, and is produced mainly
by glial cells but also by neurons
• packages and carries cholesterol and other
types of fat/lipids in the bloodstream
*Neuroplasticity of neural networks is compromised
APOE gene
• Gene effects the production of
apolipoprotein and binds with tau protein,
found in the neurofibrillary tangles of
individuals with Alzheimer’s disease
• Three common forms:
o APOE e2: Least common form, reduces the
risk of Alzheimer’s disease
o APOE e3: Most common and does not
affect the risk of the disease
o APOE e4: Increases the risk of Alzheimer’s
disease
*APOE gene linked to the structure of the axon
APOE e4
• Found more frequently than APOE e2 or
APOE e3 in late onset cases of Alzheimer’s
disease
• Risk of the disease is significantly increased
in individuals with one or two copies of the
e4 allele
• Presence of the APOE-E4 allele in
conjunction with impaired olfaction is
associated with a 4.9 times increased risk of
cognitive decline
• plaques and tangles are commonly found
throughout the olfactory pathways in
patients with Alzheimer’s disease (due to
gene mutations in production of proteins)
• The APOE e4 allele is neither necessary nor
sufficient for the development of
Alzheimer’s disease! People with them may
not develop alzheimers & people with
alzheimers do not have it. It doesn’t tell us
the cause of the disease but areas which
breakdown and are associated with some
cases of AD.
APOE-E4 and Ethnicity
• When the APOE-E4 allele is present: The
risks for Alzheimer’s disease is similar for
whites, African Americans, and Hispanics
• When the APOE-E4 allele is not present:
The risks for Alzheimer’s is four times
higher for African Americans and two times
higher for Hispanics compared to whites,
and two times higher for Hispanics
compared to Whites. Indicating the
presence of other genes which increases
risk for these groups.
• Among Koreans APOE e4 allele is more
prevalent in patients with Alzheimer’s
disease
• Prevalence of Alzheimer’s disease is
significantly lower in India, but the
association of the disease with the APOE
e4 allele in Indian is similar to that in the US
*Risk of APOE-E4 varies in ethnicity but we
do not know if it is genetic or cultural
diagnosis differences
Additional Genes
• Genome-wide association studies implicate
several chromosomes 1, 9, 10, 12 in the
development of late onset Alzheimer’s
disease
• The ABCA7 gene encodes a protein
involved in transportation of substances
across the cell membrane and is
hypothesized to play a role in amyloid
plaque deposits two variants of this gene
are associated with increased risk of late
onset in African Americans.
• Genes that encode proteins that play a role
in brain inflammation have also been linked
to late onset Alzheimer’s disease - the
clusterin gene (CLU), TREM2, CR1 gene.
• Active area of research!
Structural Findings
Beta-Amyloid
• APP provides instructions to produce
amyloid precursor protein (overproduction
of it)
• Amyloid precursor protein is processed by
the endoplasmic reticulum and then
transported to various parts of the cell
• Beta-amyloid is a protein fragment derived
(cleaved) from the amyloid precursor
protein
• The process involves two enzymes, β-
secretase and γ-secretase, that remove part
of the amyloid precursor protein into the
extracellular space (do not remove amyloid
properly so fragment accumulate to form
plaques)
• These plaques are found primarily in the
extracellular space but can also accumulate
inside the cell
• Accumulation of beta-amyloid accelerates:
• Neuronal death
• Glial cell degeneration and death
• Loss of synaptic connections
• Inflammatory reactions
• Development of cerebral vascular disease
• Whether beta-amyloid plaques are a cause
or consequence of Alzheimer’s disease
remains unclear
• Amyloid deposits can form on the walls of
blood vessels in the brain which promotes
cerebral vascular disease & is found in 90%
of alzheimers patients. Cerebral vascular
disease is believed to promote beta-
amyloid deposits by interfering with
production, cleavage and elimination of
beta-amyloid fragments (chicken or the egg)
• Amyloid plaques may serve as biomarkers
rather than causal agents (i.e., decreased
metabolic brain activity inturn increases
beta secretase linked to amyloid-beta
plaques & cognitive decline)
• Studies have reported evidence of plaque
formation in elderly subjects without
dementia!
• The explanation for the perseveration of
cognitive functions is unclear, although
some have hypothesized innate
intelligence, educational or occupational
attainments, and lifestyle may supply a
cognitive reserve (i.e., cognitive protective
factors for some people which complicates
diagnosis)
*presence of plaques doesn’t guarantee AD.
its associated with severity of AD symptoms
but is not present in all AD patients and
some HCs with plaques do not develop AD
(i.e., asymptomatic AD.
structural findings
tau protein
Tau Protein
• Encoded by the MAPT gene located on
chromosome 17
• Tau binds to tubulin, the main constituent of
microtubules, and provides stabilization
(structure support)
• If defective, it forms neurofibrillary tangles
that inhibit the normal functioning and
assembly of microtubules and neuron
communication
• Overexpression of tau is toxic to healthy
neurons
• Retards cell growth
• Changes the shape of cells
• Collapses microtubules
• The formation and pattern of these tangles
increase rapidly with increasing age and
severity of Alzheimer’s disease
• Neurons that are in the process of
neurofibrillary degeneration release the tau
protein, which can be detected in the
cerebral spinal fluid (CSF) and are elevated
in Ads
• Higher levels of tau proteins are found in
Alzheimer’s patient with a family history of
Alzheimer’s and carries APOE-e4, relative to
patients without a family history.
Gene mutation leads to the overproduction of tau proteins causes microtubules breakdown it prevents communication of information through the axon; collapses and dies.
Biomarkers (genes being used as biomarkers)
structural findings
• Neuroimaging (MRI, PET, SPECT) can be
used to examine brain structure and the
accumulation of beta-amyloid (β-amyloid) in
the brain
• In the early stages of the disease,
diagnosis can be challenging, particularly
with asymptomatic patients (do not want to
tell people the will develop AD and they
don’t)
• Three biomarkers, with an estimated 95%
sensitivity and 85% specificity, have been
established for Alzheimer’s
• Amyloid beta protein
• Tau protein
• Phospho-tau protein
• Require cerebral spinal fluid! Painful
procedure with need injected into spine.
structural findings
brain volume and structures
Brain Volume (can use scans to see)
• Accumulation of cortical tangles are
strongly associated with total brain volume
loss
• 2.8% mean yearly loss of brain volume
during the mild stage, figure that increased
by 0.32% each year thereafter
Specific Structures
• Severity of Alzheimer’s disease is
associated with a progressive deterioration
of frontal-temporal structures, evidenced by
psychiatric symptoms, such as
uncooperativeness, wandering, emotional
lability, and psychotic symptoms
• The hippocampus is significantly smaller in
people with Alzheimer’s disease compared
to controls and is associated with memory
loss
• Neuronal atrophy in the parahippocampal
gyrus and the cortex of the temporal lobe is
associated with severe dementia.
• Scans of structures of the medial temporal
lobe (entorihinal cortex, temporal sulcus,
anterior cingulate) could differentiate
between mild alzheimers patients and
controls with 100% accuracy.
• Atrophy of white matter (myelin) is effected
by age.
• Patterns of brain atrophy varies substantially
between individuals, and these patterns
effect the impact it has on patients with
alzheimers function overtime.
Functional Findings
Glucose Metabolism reduced because…. this leads to ___ and __
Inflammatory response causes ___
Regional Cerebral Blood Flow reduced in __-__ region
Acetylcholine inhibitors linked to increased ____
Glucose Metabolism
• Changes in glucose metabolism in brains of
patients with Alzheimer’s disease
o Due to changes in gray matter (i.e., right
frontal, temporal, and parietal regions),
particularly synaptic structure and cellular
function such as changes in mitochondria
function which results in cellular death
o Reductions in glucose metabolism persists
after controlling for brain atrophy
o Glucose metabolism was significantly
increased in white matter as a result of
neuroinflammatory activity of glial cells
responding to beta-amyloid plaques.
Regional Cerebral Blood Flow
• Alzheimers is characterized by functional
blood flow changes that progressively
worsen overtime and support a functional
disconnection between prefrotal regions
and subcortical structures important in
memory.
• Reduced blood flow in the temporal-parietal
regions of both hemispheres in patients with
alzheimers relative to controls.
• rCBF decline in participants with mild
cognitive impairments that later developed
alzheimers (i.e., posterior cingulate gyri, left
hippocampus, and parahippocampal gyrus).
• PET & rCBF measures can be used to
discriminate alzheimers patients who
respond well to treatment and non-
responders.
o E.g., lower rCBF in the lateral and medial
frontal lobes in non responders to donepezil
(a cholinergic inhibitor). Donepezil treatment
increased global as well as regional blood
flow to the frontal lobes in patients with
alzheimers disease who showed
symptomatic improvement after taking
medication
o E.g., acetylocholinesterase inhibitors
increased rCBF to the frontal lobe to help
maintain functional brain activity in patients
with alzheimers disease.
Pharmacology (AD)
What is the main drug treatment for AD?
Pharmacology
• Neurons that synthesize and release
acetylcholine (Ach) are of particular interest
given their major role learning and memory
• Alzheimer’s disease is characterized by
degeneration of acetylcholine-releasing
neurons, and this process is accompanied
by cognitive decline
• These drugs prevent the enzyme
acetylcholinesterase from breaking down
acetylcholine; thus, more of the
neurotransmitter is available at the level of
the synapse
• Cholinesterase inhibitors function to
decrease the breakdown of acetylcholine.
• Although cholinesterase inhibitors improve
memory and cognitive abilities in many, they
do not slow the progression of the disease
at a physiological level!
• The effectiveness of these medications
appears to wane as the disease progresses
(less effective overtime)
• Short term side effects of cholinesterase
inhibitors include nausea, diarrhea,
vomiting, suppression of appetite, weight
loss and indigestion.
• Memantime & namzaric side effects include
diarrhea, insomnia, dizziness, headaches,
and less commonly hallucinations.
• In addition, serotonin, glutamate, and
dopamine are implicated in Alzheimer’s
disease
• Cerebrovascular dysfunction precedes
cognitive decline and onset of
neurodegenerative changes in Alzheimer’s
disease
• Therefore, the effects of thrombin (enzyme
in the blood that causes clotting) inhibitors
have been investigated
• Elevated thrombin levels can be toxic and
cause an inflammatory effect in endothelial
cells, microglia and astrocytes.
• In mice models’ thrombin inhibitors reduce
neurotoxic and inflammatory effects of
thrombin to improve cognition
• Antipsychotic and anticonvulsant
medications are prescribed to improve
hallucinations, agitation, and violent
outbursts but Questions remain about the
concomitant use of these medications with
those specifically approved for the
treatment of Alzheimer’s (e.g., increased
confusion, dependency)
• Antioxidants/Vitamin E & Anti-inflammatory
medications have mixed findings on their
efficacy to treat AD.
Risk Factors and protective factor (AD)
Risk Factors
• Early childhood environment is associated
with risk of Alzheimer’s disease
• Growing up in a family of five or more
siblings increases the risk of developing
Alzheimer’s by 39%
o The risk increases by 8% with each
additional family member
• Growing up in an urban area (versus a
suburb) is associated with increased risk
(most reliable risk factor)
• Number of siblings and area of residence
are related to socioeconomic level and may
reflect a poorer quality of living environment
that interferes with normal brain
development and maturation, and therefore
increase the risk of Alzheimer’s disease
later in life.
• Several studies have reported that fewer
years of education are associated with
greater Alzheimer’s risk
Controversial Risk Factor findings (mixed findings)
• History of head injury
• Psychological distress
• History of migraines
• Smoke Cigarettes
• Exposed to industrial solvents and/or
electromagnetic fields
Dietary factors (2x increase production of APP and 1x protective factor)
AD
Dietary factors
• Free radicals (preservatives) are associated
with increased production of beta-amyloid,
and these free radicals alter cell membrane
structure and function, and ultimately result
in cellular death
• High caloric and fat intake at greater risk for
Alzheimer’s disease
• APOE-e4 allele (+) high caloric intake had
greater risk
• APOE-e4 allele transports cholesterol and
leads to increased production of
apolipoprotein and ultimately the plaques
and tangles
• Several studies have found a relationship
between cholesterol levels and Alzheimer’s
disease
• Antioxidants, such as those found in fresh
fruits and vegetables, improved learning
and memory performance in aged rats
Protective Factors (AD)
Protective Factors
• These findings offer promising implications
for diet as a modifiable risk factor for
Alzheimer’s disease
• Participation in leisure activities and
intellectually stimulating activities is
negatively correlated with risk of
Alzheimer’s disease
• Exercise also decreases the risk of
Alzheimer’s disease
• Commercial brain training programs that
claim to improve a broad range of mental
processes in healthy individuals have
produced mixed findings!
• Overall, this suggests that dementia is
preventable.
Brain Stimulation (under investigation)
• Repetitive transcranial magnetic stimulation
(rTMS)
o Preliminary finding supports that rTMS of
the precuneus induced improvement and
episodic memory but no other cognitions.
• DBS was well tolerated and associated with
less cognitive decline.
• Electroconvulsive therapy (ECT)
o found a meaningful response in 72% of
acute ECT cases and only adverse effects
on cognitive functioning and 7% of cases
• Not sure how this can temporarily improve
memory but not cure disease
What is Parkinson’s?
What is Parkinson’s?
• Parkinson’s disease is a progressive
neurological disorder characterized by
resting tremor (handshakes uncontrollably
in resting position), rigidity (tense posture),
postural instability, and slowed ability to
start and continue movements
(bradykinesia).
Prevalence
Prevalence
• Second most common neurodegenerative
disease after Alzheimer’s disease
• Age is the greatest risk factor for the
development of Parkinson’s disease
• There are two main types of Parkinson’s
disease:
o Familial early onset (< 50 years)
o Later onset (50+, sporadic)
• In the United States, it is estimated that
approximately 0.5% of the population
between 65 and 69 has the disease while
3% of those 85 and older have Parkinson’s
disease (3 out f 100 people get it; greater
age greater prevalence)
• 4% of cases are diagnosed before the age
of 50
• Higher rates found among males compared
to females
• Prodromal symptoms include impaired
olfaction (smells), depression, excessive
daytime sleepiness, rapid eye movement
sleep behavior disorder, and gastrointestinal
problems
• Impairments in executive functioning and
language processing
• Major or mild neurocognitive disorder
commonly occurs in 75% of individuals
Comorbidity (changes associated with PD)
• Awareness of bodies in space diminishes
• Individuals with Parkinson’s disease are at
high risk for psychiatric problems:
o Anxiety
o Depression
o Somatization
o Psychosis
o Obsessive compulsive symptoms
• Depression, occurrence of falls, and
patient’s negative perceptions of the
disease are associated with advancing
severity and disease deterioration
• Depression in patients with Parkinson’s
disease results from reduced levels of
serotonin as well as disruptions in
dopamine rich reward pathways extending
to and from the midbrain to the frontal
regions.
• Changes in dopamine pathways (in
substantian nigra) are also associated with
deficits in facial expressions
• Approximately 30% of Parkinson’s patients
develop psychotic symptoms, most
frequently visual hallucinations
• Later-stage Parkinson’s disease is
associated with loss of autonomy and self-
esteem, social isolation, vocal and speech
impairments, gait impairment, frequent
choking, and substantial deterioration in
both physical and mental health
• Patients with Parkinson’s disease are at
increased risk for weight loss and
malnutrition, which in turn impacts the
progression of the disease and
exacerbates dyskinesia symptoms and
further contributes to cognitive decline.
*People’s behaviour changes significantly
and don’t resemble who they once were
due to brain changes
Hoarding and Compulsive Behavior
• Pathological acquisition of and failure to
discard large numbers of possessions in
living areas
Patients with Parkinson’s disease who are
prescribed dopamine replacement therapy
(e.g., dopamine agonsists) develop
impulsive or compulsive behaviors,
including hypersexuality, compulsive
shopping and gambling excessive
grooming, and complex stereotyped
behaviors known as pruning.
• 28% of participants with Parkinson’s
disease had excessive hoarding tendencies
relative to 6% of healthy controls.
This is linked to the medication of
Parkinson’s disease, regions of the brain
involved in self-control and decision
making, and documenting pathways that
govern pleasure, addictive behaviors. and
for board behavior (venturalmedial
prefrontal cortex).
*PD linked to Hoarding and Compulsive
Behaviour stems from damaged dopamine
reward pathways
Genetics (early-onset PD)
___ accounts for 50% of all early onset PD cases
Linked to neuro__ and death of __
Inserted by __ parent
Genetics
• Over 23 locations on various chromosomes
and 19 genes have been implicated in
Parkinson’s disease
Early onset
• Mutations of three genes, PRKN, PINK1, and
PARK7
• Individuals with Parkinson disease have
two copies of the mutated gene—one from
each parent (autosomal recessive
inheritance)
• Each parent only carried one copy of the
altered gene, they most likely did not show
signs and symptoms of the disease, but
when both altered genes are inherited, the
individual has a high probability of
developing Parkinson’s disease
PRKN gene
o Located on chromosome 6, provides
instructions for making a protein called
parkin
o Parkin plays an important role in the
degradation of other proteins that are not
needed by the cell
§ 50% of early onset cases are due to PRKN
mutations
o Exactly how parkin leads to the
manifestation of Parkinson’s disease is
unknown, but it is believed to result in the
death of dopamine-releasing neurons in
the substantia nigra
PINK1 gene
• Located on chromosome 1, provides
instructions for making a protein called
PTEN
• This protein is located inside the
mitochondria of cells and is thought to help
protect mitochondria during periods of
cellular stress, such as unusually high-
energy demands
• The absence (or reduction) of this protein is
thought to cause neurons to die, thereby
weakening muscle movements
PARK7 gene • Located on chromosome 1 provides instructions for making the DJ-1 protein • DJ-1 functions are not well understood, but believed to: o Protect neurons o Fold newly produced proteins o Refold damaged proteins o Produce RNA
Genes (late-onset PD)
Two genes are __ and ___
Inherited from __ parent
Linked to alpha synulien __production which triggers ___ and leads to ____ death
Genes
• Parkinson’s disease is also associated with
two genes that can be inherited from only
one parent (autosomal dominance)
o LRRK2
o SNCA
LRRK2 gene
• Located on chromosome 12 provides
instructions for the protein dardarin
o Dardarin is important in enzymatic activities
that help turn on and off various cell
actions
• More than 100 different mutations of the
LRRK2 gene have been linked to late onset
Parkinson’s disease
• Dysfunction of LRRK2 gene results in the
accumulation of a protein known as alpha
synuclein, the protein found in Lewy body
deposits
• Alpha synuclein triggers inflammatory
responses by glial cells
SNCA gene
• Located on chromosome 4 and implicated
in late onset Parkinson’s disease
• Encodes the protein alpha synuclein
located in the presynaptic terminals to
maintains an adequate supply of synaptic
vesicles in presynaptic terminals and
regulate the release of dopamine
Genes
• Genetic mutations that result in Parkinson’s
disease exist in only a small number of
individuals: in the majority of cases, there is
no family history, and genetic causes have
not been identified
• The underlying cause of Parkinson’s
disease appears to be multifactorial
involving genetic factors, environmental
factors, gene-environment interactions, and
unknown influences
Structural Findings
Substantia Nigra Dopamine Basal ganglia Lewy Bodies Glial Cells Patterns of Atrophy Autophagy
Substantia Nigra
• Movement involves coordination among
numerous brain regions and motor
pathways
• Characterized by degeneration of
dopaminergic neurons in the substantia
nigra and the ventral tegmental area (have
the highest levels of dopamine which are
projected to different subregions linked to
motor control; PD have cells which no
longer produce dopamine; stimulated
dopamine neurons is needed for
coordinated action – i.e., shaky movement
in video when electrode was off)
• Substantian nigra in the middle of the brain
where most of the dopamine neurons are
located. Snake looking thing is not
pronounced in PD patients.
*Multiple brain regions coordinate action
Dopamine
• Degeneration and death of dopaminergic
neurons leads to dopamine reductions in
the striatum (putamen, caudate nucleus,
and nucleus accumbens) and projecting
pathways to the frontal lobes that form
parallel loops or circuits
• Approximately 70% - 75% dopamine
neurons have died by the time Parkinson’s
disease symptoms are typically diagnosed.
Basal ganglia
• Consists of the caudate nucleus, putamen,
and the globus pallidus
o The striatum receives input from the cortex
and other structures (thalamus and
amygdala) and projects information to
widespread regions, such as the brain
stem and the prefrontal cortex
§ The nigrostriatal system extends from the
substantia nigra to the striatum
• Loss of dopaminergic neurons is
hypothesized to result in decreased
excitatory activity of the nigrostriatal
pathway
Lewy Bodies (brain structural level)
• Parkinson’s disease is characterized by
Lewy bodies
o Aggregates of abnormally folded proteins
found primarily inside the cell and destroys
the cell body and communication between
cells
• Expression of alpha synuclein is thought to
lead to the formation of Lewy bodies and
caused by SNCA gene mutation
Glial Cells (protects the brain; loss of myeline and communication)
• The presence of excessive levels of alpha
synuclein and Lewy body deposits induces
astrocytes (glial cells) to release pro-
inflammatory cytokines
Patterns of Atrophy
• Reduced gray matter volume in the frontal
lobe (PD without dementia)
• Atrophy in the occipital lobe (PD with
Dementia)
• Different patterns of atrophy based on
whether PD is accompanied by dementia
• Collectively, these findings suggest that
structural changes associated with
Parkinson’s disease are more specific to
subcortical structures, but as the disease
progresses and is accompanied by
dementia and increased motor and non-
motor symptoms, widespread brain atrophy
is observed (atrophy less specialized when
severity increases)
Autophagy
• Is the process whereby lysosomes degrade
misfolded proteins and debris.
• Deficits in this process can result in the
accumulation of protein aggregates such as
Lewy bodies
Functional Findings PD
Reduced activity
Reduced receptors density in ___
Compensatory response of increased blood flow and Increased Glucose Metabolism in brain regions because…
Three neurotransmitters linked to PD are..
Treatments are less effective if….
Functional Findings
• Decreased striatal activity in early stages of
the disease (not enough neuron firing)
• Increased blood flow in cortical regions as a
compensatory response to the degradation
of motor systems.
• Decreased density of dopamine
transporters
• authors found differential activation of brain
regions and subjects with and without
• During motor tasks they had impaired
activation of subcortical as well as prefrontal
and motor cortical.
• Tremor was negatively correlated with
activity in the putamen and cerebellum,
while rigidity was positively correlated with
activity in the putamen.
• Increased glucose metabolism and the
ventrolateral region of the thalamus of
patients with Parkinson’s: this finding was
positively correlated with the degree of
resting tremor.
• PET scans could be used as a biomarker for
identifying patients with Parkinson’s disease
who are at risk of developing dementia.
• Indicates that as the disease progresses
more brain regions are recruited to perform
cognitive and motor tasks compared to
those without disease.
Neurotransmitters associated with PD
Dopamine: Substantia nigra (dopamine
activity is regulated by serotonergic,
glutamatergic, and GABAergic neurons)
• Serotonin: Caudate, putamen, and striatum
(reduced serotonin receptor density, high
comorbidity with depression, reward related
behavior, and medication-induced
dyskinesia)
• Acetylcholine: Nucleus basalis of Meynert
(comorbidity with dementia and psychosis;
degradation of cholinergic neurons in the
nucleus basalis of meynert linked to
cognitive impairment)
*Given the heterogeneity of motor and non-
motor symptoms in PD, its neuropathology is
likely to be mediated by conflicts
interconnected neurotransmitter systems.
*Treatments that focus exclusively on the
dopamine system do not effectively treat
either motor or non-motor symptoms.
Pharmacological Interventions
Main treatments are dopamine ___ or __ inhibitors
Ldopa used to treat ___ stage PD
Pharmacological Interventions
*Empirically established disease altering
treatments with Parkinson’s does not exist
because the underlying cause of the
disease remains a mystery.
Treatment (no cure neurons will continue to die; regulate molecules)
• Increase dopamine production (levodopa;
more dopamine allows neurons which
require dopamine to fire and aid motor
movements)
• Mimic the effects of dopamine at the level
of the receptor (dopamine agonists)
• Target other neurotransmitter systems
L-Dopa
• During the 1950s it was demonstrated that
treatment with levodopa (L-Dopa) improved
Parkinson-like symptoms
• Prescribed to treat later stage PD
• 95% of patients show a moderate to very
good response to levodopa
• Tyrosine (rate-limiting enzyme) which
converts L-Dopa into Dopamine
• (Blood-brain barrier! The brain protects
itself from substances. L-Dopa can
penetrate the barrier and tyrosine is
converted into dopamine)
Dopamine agonists
• Attach to postsynaptic receptors are also
used to treat the symptoms of early stages
of the disease
• While L-Dopa is converted in the brain into
dopamine, dopamine agonists mimic the
effects of dopamine without having to be
converted
• These medications have been found to
reduce the degree of dyskinesia however
they are associated with increased
impulsive behavior, freezing, sleep
problems, hallucinations, headaches,
gastrointestinal problems, and
hypotension.
• Work better when used in combination
with medications that increase dopamine
production.
Other neurotransmitter systems
• Monoamine oxidase inhibitors (MAO
inhibitors) prevent the breakdown of
dopamine
• In cigarettes, prevents enzymes from
breaking down dopamine, longer effects of
dopamine.
Catechol-o-methyl transferase (COMT)
inhibiters entacapone or comtan) are also
used to treat Parkinson’s disease
symptoms.
Side effects of CONT inhibitors include
nausea, headaches, confusion,
gastrointestinal problems, and involuntary
muscle movements.
Surgical Interventions 2x
• Ablative procedures, a pallidotomy
involves destruction of part of the globus
pallidus and can be performed unilaterally
or bilaterally to improve unwanted
muscular contractions as well as rigidity.
• Thalamotomy (destruction of part of the
thalamus) has been found to improve
tremor, rigidity and unwanted excessive
motor movements
• Gamma knife radiosurgery has been used
to treat Parkinson’s and is similarly effective
and safer than thalamotomy methods
Deep brain stimulation (when medication does work, and symptoms are severe)
• Dominant surgical procedure for
Parkinson’s disease
• A small lead with an electrode is inserted
in specific target areas of the brain (globus
pallidus, subthalamic nucleus). The
frequencies at which the stimulation is
delivered can be adjusted
• Doesn’t destroy tissue
• Increases cerebral blood flow to various
brain regions.
• Long term follow-up studies of deep brain
stimulation have found sustained
improvement and motor functions up to
five years after stimulation.
ECT and TMS
Targets release of ___ neurons
ECT and TMS
• Improve motor and depression symptoms of
Parkinson’s disease (resets system to allow
more dopamine production to increase)
• Mixed findings concerning its effectiveness
Lifestyle Changes
Neurotrophins
Transplantation
Lifestyle Changes
• Exercise has been associated with a lower
risk of developing neurodegenerative
disease, including Parkinson’s disease
Neurotrophins
• Reduction of neurotrophic factors (BDNF,
NGF) in several brain regions (substantia
nigra, caudate, putamen, frontal cortex,
cerebellum) of individuals with Parkinson’s
disease
• Neurotrophins are substances released by
glial cells and neurons that promote the
survival of neurons in the brain and release
of dopamine
Transplantation
• Transplantation of human embryonic or
fetal dopamine cells into the brains
(putamen) of individuals suffering from
Parkinson’s disease
• Three years after the transplantation the
dopaminergic neurons continue to survive
and reduce clinical symptoms
• Other studies have failed to replicate
results! (i.e., found it worked on young but
not older patients; 56% patients developed
dyskinesia and saw no symptom
improvement).
Environmental Factors
Environmental Factors
• The rate for Parkinson’s disease is higher
in urban than rural areas of Japan
o The death rate was higher in the
southwest than the northeast regions of
Japan
• Meta-analytic studies in the United States
have also concluded that living in rural
areas increases the risk of Parkinson’s
disease
• Synthetic heroin MPTP well severely toxic
to brain cells and specifically destroyed
nerve cells in the substantia nigra produce
motor symptoms similar to PD.
Environmental Factors (higher risk)
• Lead
• Copper
• Insecticide
• Pesticide
• Herbicides
• Heavy metals
• Drinking well water
• Agent orange
• Repeated head injuries resulting in the
loss of consciousness
• Obesity and a sedentary lifestyle
*increases oxidative stress, neurotoxicity,
inflammation and cellular death.
Environmental Factors (lower risk)
• Moderate alcohol consumption
• Moderate and high caffeine
consumption
• Green and black teas (possibly
decrease inflammation & aggregation
of alpha-synuclein proteins in the brain)
• Cigarette smoking in people with a
family history of PD
• Pets
Most cases of AD and PD are…
Late onset - sporadic and no family history
