Lecture 2 (chapter 4)

Question 1

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?

Answer 1

 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)

Question 2

Prevalence

Answer 2

• 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

Question 3

Sex Differences

Answer 3

• 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

Question 4

Race and Ethnicity (varies significantly with ethnicity)

Answer 4

• 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).

Question 5

Comorbidity (AD)

Link between AD and PD

Answer 5

• 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?)

Question 6

Etiology (what causes it? Understand it so we can fix it)

Answer 6

• 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.

Question 7

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?

Answer 7

• 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

Question 8

Degree of Heritability

what is it?
what doesn’t it tell us?

Answer 8

• 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.

Question 9

(3) Genetic Study Types

Answer 9

• 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

Question 10

Genetic Findings: Family and Twin Studies

AD

Answer 10

• 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)

Question 11

Genetic Findings: Early Onset (more devastating but less common)

Answer 11

• 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

Question 12

Presenilin 1 (PSEN1)

Answer 12

• 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

Question 13

Presenilin 2 (PSEN2) –produces different protein mutations

Answer 13

• 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

Question 14

Amyloid precursor protein gene (APP)

Answer 14

• 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

Question 15

Scientific Breakthroughs (AD)

Answer 15

• 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

Question 16

Late-Onset (AD genetics)

Answer 16

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

Question 17

APOE gene

Answer 17

• 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

Question 18

APOE e4

Answer 18

• 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.

Question 19

APOE-E4 and Ethnicity

Answer 19

• 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

Question 20

Additional Genes

Answer 20

• 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!

Question 21

Structural Findings

Beta-Amyloid

Answer 21

• 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.

Question 22

structural findings

tau protein

Answer 22

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.

Question 23

Biomarkers (genes being used as biomarkers)

structural findings

Answer 23

• 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.

Question 24

structural findings

brain volume and structures

Answer 24

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.

Question 25

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 ____

Answer 25

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.

Question 26

Pharmacology (AD) What is the main drug treatment for AD?

Answer 26

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.

Question 27

Risk Factors and protective factor (AD)

Answer 27

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 ```

Question 28

Dietary factors (2x increase production of APP and 1x protective factor) AD

Answer 28

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

Question 29

Protective Factors (AD)

Answer 29

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.

Question 30

Brain Stimulation (under investigation)

Answer 30

• 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

Question 31

What is Parkinson’s?

Answer 31

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).

Question 32

Prevalence

Answer 32

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

Question 33

Comorbidity (changes associated with PD)

Answer 33

• 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

Question 34

Hoarding and Compulsive Behavior

Answer 34

• 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

Question 35

Genetics (early-onset PD) ___ accounts for 50% of all early onset PD cases Linked to neuro__ and death of __ Inserted by __ parent

Answer 35

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 ```

Question 36

Genes (late-onset PD) Two genes are __ and ___ Inherited from __ parent Linked to alpha synulien __production which triggers ___ and leads to ____ death

Answer 36

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

Question 37

Structural Findings ``` Substantia Nigra Dopamine Basal ganglia Lewy Bodies Glial Cells Patterns of Atrophy Autophagy ```

Answer 37

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

Question 38

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....

Answer 38

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.

Question 39

Pharmacological Interventions Main treatments are dopamine ___ or __ inhibitors Ldopa used to treat ___ stage PD

Answer 39

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.

Question 40

Surgical Interventions 2x

Answer 40

• 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.

Question 41

ECT and TMS Targets release of ___ neurons

Answer 41

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

Question 42

Lifestyle Changes Neurotrophins Transplantation

Answer 42

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).

Question 43

Environmental Factors

Answer 43

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 ```

Question 44

Most cases of AD and PD are...

Answer 44

Late onset - sporadic and no family history