Predisposition Testing for Neurodegenerative Disease II

Question 1

What are the cognitive domains that characterize Dementia?

Answer 1

must involve at least two:
memory
executive function
visuospatial abilities
language
personality/behavior

Question 2

What is Dementia?

Answer 2

progressive cognitive impairment interferes with activities of daily living in the home, at work, or in social activities
misfolded protein transmission as mechanism for neurodegeneration

Question 3

What are the causes of Dementia?

Answer 3

infections (neurosyphilis, Herpes encephalitis, HIV)
Metabolic disorders (hypothyroidism, B12 deficiency, Wilson's disease)
alcoholism, drugs
toxins
head trauma
hydrocephalus
brain tumor
pseudodementia/depression

Question 4

What neurodegeneraitve disorders causing dementia?

Answer 4

Alzheimer's disease (AD)
Vascular dementia, CADASIL (VD)
Dementia with Lewy Bodies (DLB)
Frontotemporal dementia (FTD, Pick's)
Corticobasal degeneration (CBD)
Prion diseases- Creutzfeld-Jakob disease (CJD)
Progressive supranuclear palsy (PSP)
Huntington Disease (HD)

Question 5

How is Dementia diagnosed?

Answer 5

symptoms due to the part of the brain that is affected NOT due to underlying pathology
diagnoses overlap with one another and is really the physician’s best guess using existing technology
diagnosis can change as disease progresses
knowing the correct diagnosis is key for genetic testing

Question 6

What are targeted questions to ask about neurodegenerative diseases?

Answer 6

What were the earliest symptoms?
Was the person forgetful? Did they repeat themselves a lot? Did they forget appointments?
Did they get lost?
Did they have any mood changes such as depression?
Did their behavior change? Did they do anything they wouldn’t have done before? Did they lose interest in things and people?
Did their speech change?
Did they fall?
Did they have any other neurological symptoms?

Question 7

How is Dementia diagnosed?

Answer 7

symptom history (onset, types and duration symptoms, other medical history, drug/alcohol use, environmental exposure)
family history (age of onset, number of affected family members, degree of relationship)
neurological exam
neuropsychological testing (Mini-mental state exam)
lumbar puncture
lab testing
genetic testing (only if appropriate)
definitive diagnosis is autopsy

Question 8

What is noticed on autopsy of patients with Dementias?

Answer 8

visualize hyperphosphorylated Tau (in neurons and helps to maintain their structure) neurofibrillary tangle
amyloid plaque

Question 9

Describe the different kinds of aggregations in neurodegenerative diseases.

Answer 9

amyloid plaques= AD
tangles (Tau) = AD and FTD
Lewy bodies (alpha-syn)= PD and DLB

Question 10

Describe risk factors for Alzheimer’s Disease?

Answer 10

having a first degree relative with AD increases lifetime risk 2-3 fold
heritability is 70% (only 30% explained by known genes)

Question 11

Describe the inheritance of Alzheimer’s disease.

Answer 11

AD: early onset familial (21q21.3 amyloid precursor protein), early onset familial (14q24.13 presenilin 1), early onset familial/ Volga (1q31.42 Presenilin 2)
Genetic Susceptibility Factor: late onset familial adn ~50% sporadic (19q13.2 APOE -epsilon4)

Question 12

What genes are associated with Alzheimer’s disease?

Answer 12

APP (32 variants; onset in 40s-50s; 100% penetrance)
PSEN1 (>220 variants; onset 30s-60s usually; 100% penetrance; MOST COMMON GENETIC CAUSE)
PSEN2 (19 variants; onset 40s-70s; less than 100%)

Question 13

What are the nuances of Next Gen sequencing for neurodegenerative diseases?

Answer 13

Pro: tests more genes for less money (more genes not necessarily better, order small panels when you can; databases are largely based on Western Caucasion populations; doesn’t test everything- will not detect triple repeat or expansion disorders or large deletions/duplications; some labs detect small del/dups but not others
cons: the more genes tested, the higher the chance for VUS

Question 14

What are the APOE testing guidelines?

Answer 14

insuficient sensitivity or specificity to be used for diagnostic testing
neither necessary nor sufficient for teh development of AD so NOT recommended for predictive testing

Question 15

What is Frontotemporal Degeneration (FTD)?

Answer 15

25-50% of presenile dementias (5-15% of all dementias reported on autopsy)
often misdiagnosed as Alzheimer disease or psychiatric disorder
age of onset: 40-75 (average 56)

Question 16

What are the FTD subclasses and related diseases?

Answer 16

behavioral variant frontotemporal dementia (bvFTD)/Pick's Disease
FTD/ALS
PPA: Language variant FTD (PNFA- progressive nonfluent aphasia, problems with expressing but able to understand language; SD- semantic dementia, naming and word finding, comprehension problems with preservation of spoken language; Logopenic- AD pathology) 
related tauopathies (PSP- progressive supranuclear palsy; CBD- corticobasal degeneration)

Question 17

What are the symptoms of bvFTD?

Answer 17

disinhibition
emotional blunting, apathy
decreased executive function (planning, problem solving, and judgement)
loss of personal awareness (hygeine and grooming)
ritualistic or perseverative behaviors and beliefs
loss of insight
utilization behavior (repeated use of objects within visual field)
hyperorality
changed speech (echolalia, perseveration, reduced output)
incontinence

Question 18

What genes are associated with Autosomal Dominant FTD?

Answer 18

Tau gene (17q21-22; MAPT)
Progranulin (17q21; PGRN)
C9orf72 (FTD/ALS)

Question 19

C9orf72…what?

Answer 19

hexanucleotide intronic repeat: GGGGCC
expansion >30 repeats
somatic mosaicism reported
possible anticipation

Question 20

What is Motor Neuron Disease (MND)?

Answer 20

group of progressive neurological disorders caused by degeneration of motor neurons
motor neurons are cells that control voluntary muscle activity (speaking, walking, breathing, swallowing, etc.)

Question 21

What are the disease classifications for motor neuron diseases?

Answer 21

Amyotrophic lateral sclerosis (ALS): both upper and lower motor neuron involvement
Primary lateral sclerosis (PLS): upper motor neuron involvement
Progressive Muscular Atrophy: affects only lower motor neurons in the spinal cord

Question 22

What are the symptoms of motor neuron diseases?

Answer 22

upper motor neurons (spasticity, hyper-reflexia, pseudobulbar affect)
lower motor neurons (fasciculations, muscle atrophy)
other neuronal populations (fronto-executive circuits, movement disorders)

Question 23

Describe the onset of symptoms for ALS.

Answer 23

commonly begin ~55-75 years of age
bulbar onset (speed changes, difficulty swallowing)
spinal onset (difficulty walking, increased falling, difficulty writing or using hands)
variability in disease progression

Question 24

What is Amylotrophic lateral sclerosis?

Answer 24

(meaning no muscle nourishment in the area of the spinal cord where neurons signal muscles with scaring due to neuronal deterioration)
progressive deterioration of the motor neurons resulting in the loss of ability of the brain to initiate and control muscle movements (voluntary muscles)

Question 25

Prion Protein… discuss.

Answer 25

PRNP gene
prion is a proteinaceous infectious particle that self propigates misfolded prion proteins
causes mammalian transmissible spongiform encephalopathies (TSEs) such as BSV (mad cow disease), Scrapie (sheep), CWD (chronic wasting disease in sheep), Kuru (Paupa New Guinea)

Question 26

What is Creutzfeld-Jakob disease (CJD)?

Answer 26

E200K most common pathogenic mutation

vCJD is mad cow disaese

Question 27

List the human prion diseases.

Answer 27

Creutzfeld-Jakob disease (CJD)
Gerstmann-Straussler-Scheinker (GSS)
Fatal Familial Insomnia (FFI)

Question 28

What is Fatal Familial Insomnia?

Answer 28

1 in 1,000,000
85% sporadic
10-15% hereditary
<1% iatrogenic (neurosurgical instrument contamination, corneal grafts, hGH injections, blood transfusions)